Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim

Abstract Introduction In this pre-clinical in vitro study conducted in estrogen receptor positive (ER+) breast cancer cells, we have characterized the effects of insulin-like growth factor I (IGF-1) on the cytostatic and cytotoxic action of antiestrogen treatment when used as a single agent or in combination with the antiprogestin mifepristone (MIF). Our goal was to identify new molecular targets to improve the efficacy of hormonal therapy in breast cancer patients that have a poor response to hormonal therapy, in part, due to high circulating levels of unbound insulinIGF-1. Methods IGF-1-mediated effects on cytostasis and apoptotic cell death were determined with cell counts conducted in the presence and absence of trypan blue; enzyme-linked immunosorbent assays to determine the intracellular levels of cleaved cytokeratin 18, a marker of epithelial cancer cell apoptosis; and immunoblot analysis to determine the levels of cleaved poly-ADP ribose polymerase (PARP) and lamin A that result from caspase-dependent apoptosis. Cytotoxicity was further characterized by determination of the levels of reactive oxygen species (ROS) and the percent of mitochondrial membrane depolarization in cell populations treated with the different hormones in the presence and absence of IGF-1. Small molecule inhibitors of the dual-specificity protein kinase MEK1, MEK1 siRNA, Bim siRNA, and vectors overexpressing MEK1 wild type and mutant, dominant negative cDNA were used to identify key IGF-1 downstream prosurvival effectors. Results IGF-1, at physiologically relevant levels, blocked the cytotoxic action(s) of the antiestrogens 4-hydroxytamoxifen (4-OHT) and tamoxifen (TAM) when used as single agents or in combination with the antiprogestin MIF. The antiapoptotic action of IGF-1 was mediated primarily through the action of MEK1. MEK1 expression reduced the levels of ROS and mitochondrial membrane depolarization induced by the hormonal treatments via a mechanism that involved the phosphorylation and proteasomal turnover of the proapoptotic BH3-only Bcl-2 family member Bim. Importantly, small-molecule inhibitors of MEK1 circumvented the prosurvival action of IGF-1 by restoring Bim to levels that more effectively mediated apoptosis in ER+ breast cancer cells. Conclusion his study provides strong support for the use of MEK1 inhibitors in combination with hormonal therapy to effectively affect cytostasis and activate a Bim-dependent apoptotic pathway in ER+ breast cancer cells. We discuss that MEK1 blockade may be a particularly effective treatment for women with high circulating levels of IGF-1, which have been correlated to a poor prognosis

Hepatoprotective effect of ethanolic extract of <it>Trichosanthes lobata</it> on paracetamol-induced liver toxicity in rats

<p>Abstract</p> <p>Background</p> <p><it>Trichosanthes lobata</it> (family cucurbitaceae) is used to treat malarial fever and liver disorders. This study aims to investigate possible hepatoprotective activities of ethanolic extract of <it>Trichosanthes lobata</it> against paracetamol-induced hepatotoxicity.</p> <p>Methods</p> <p>Hepatotoxicity was induced in Wistar male rats by oral administration, 2 g/kg body weight on 7th day after the administration of ethanolic extract of <it>Trichosanthes lobata</it> and silymarin (100 mg/kg). Ethanolic extract of <it>Trichosanthes lobata</it> was administered orally at doses of 200 mg/kg and 400 mg/kg body weight daily for 7 days. Several serum markers, aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin, total protein was measured to assess the effect of the extract on paracetamol (acetaminophen)-induced hepatic damage. The study included histopathological examination of liver sections.</p> <p>Results</p> <p>Blood samples from rats treated with ethanolic extract of <it>Trichosanthes lobata</it> (200 mg/kg body weight and 400 mg/kg body weight) had significant reductions in serum markers in paracetamol administered animals, indicating the effect of the extract in restoring the normal functional ability of hepatocytes. Silymarin (100 mg/kg, p.o.) was used as a reference drug.</p> <p>Conclusion</p> <p>The ethanolic extract of <it>Trichosanthes lobata</it> exhibits protective effects against paracetamol‒induced hepatotoxicity.</p

Neural network model applied to electromagnetic shielding effectiveness of ultra-light Ni/Cu coated polyester fibrous materials

Funding Information: This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic and the European Union—European Structural and Investment Funds in the frames of Operational Programme Research, Development and Education—project Hybrid Materials for Hierarchical Structures (HyHi, Reg. No. CZ.02.1.01/0.0/0.0/16_019/0000843). Publisher Copyright: © 2022, The Author(s).The purpose of effective electromagnetic interference (EMI) shielding is to prevent EMI from smartphone, wireless, and utilization of other electronic devices. The electrical conductivity of materials strongly influences on the EMI shielding properties. In this work, mainly focus to predict the EMI shielding effectiveness on the ultralight weight fibrous materials by artificial neural network (ANN). Prior to the ANN modelling, the ultra-lightweight fibrous materials were electroplated with different concentration of Ni/Cu and then coated with different silanes. This work utilizes the algorithm to provide accurate quantitative values of EMI shielding effectiveness (EM SE). To compare its performance, the experimental and the predicted EM SE values were validated by root-mean-square error (RMSE), mean absolute percentage error (MAPE) values and correlation coefficient ‘r’. The proposed ANN results accurately predict the experimental data with correlation coefficients of 0.991 and 0.997. Further due to its simplicity, reliability as well as its efficient computational capability the proposed ANN model permits relatively fast, cost effective and objective estimates to be made of serving in this industry.Peer reviewe

Prediction of pilling grade of alkali-treated regenerated cellulosic fabric using fuzzy inference system

Fabric pilling is formed due to the entanglement of fibers during mechanical actions including abrasion, domestic washing process, and wearing cycles. Pilling resistance is one of the important aesthetic property of fabrics controlling the appearance of fabric quality. Pilling can be controlled by different methods; alkali treatment is one of the methods for the lyocell fabric. In this study, the prediction of pilling resistance on the alkali treated lyocell fabric has been done through a fuzzy inference system (FIS). In general, conventional pilling measurements has some hindrance due to human error and time consuming. This work utilizes the algorithm to provide accurate quantitative values of pilling grades. The correlation coefficient 'r' between predicted and experimental values shows 0.93 for TmAH and 0.81 for NaOH treatments. The forecast between experimental and predicted data sets of pilling grades were evaluated by mean absolute percentage error (MAPE) method and observed the values for NaOH, KOH, LiOH, and TmAH treatments as 16.6%, 18.87%, 21.09%, and 8.72% respectively.Peer reviewe

Adaptive Neuro-Fuzzy Inference System to Predict the Release of Microplastic Fibers during Domestic Washing

Publisher Copyright: Copyright © 2021 by ASTM International.Micro plastic particles are a burgeoning population crisis in marine environments. This work is to predict the release of micro plastic fibers from jeans made from polyester during domestic washing by using of adaptive neuro-fuzzy inference system (ANFIS) model. The advantage of the ANFIS model is to predict the variations between the randomly chosen parameters. This prediction model can be cost-effective and slowed down to study behavior more closely. The consequence of washing duration, temperature, spin speed, detergent types, and conditioner usage was investigated against the micro plastic fiber release. The washing temperature, washing duration, spin speed, detergent types, and addition of conditioner are the main factors for this research work. The forecast presentations have been exposed by having a considerably lowered root mean square error value of 3.23 compared with the variant of the experiment as exposed by its standard deviation for the ANFIS version. This ANFIS model will be able to provide a theoretical understanding to enhance and inhibit micro plastic fiber release from jeans.Peer reviewe

Pollution Source Identification and Suitability Assessment of Groundwater Quality for Drinking Purposes in Semi-Arid Regions of the Southern Part of India

The quality of groundwater plays an important role in human health, and it majorly influences the agricultural process in the southern part of India. The present study mainly focused on evaluating the quality of groundwater used for domestic purpose in semi-arid regions of the southern part of India. The samples were collected in 36 locations, covering the entire investigation zone. The collected samples were analyzed for various physical and chemical characteristics of groundwater and compared with the world health organization standards. The entropy-weighted water quality index (EWQI) of the groundwater revealed that 16.67% of the samples required primary-level treatment before they could be used for drinking purposes. About 72.23% of the samples were in the good-to-medium category for drinking purposes, as was identified through weighted overlay analysis. The ionic relationship plot was used to identify the source of contamination and it revealed that carbonate weathering and anthropogenic activities are the primary sources of groundwater contamination. The present results show the contaminated zones and offer more helpful solutions to strengthen the water management policy in the study region