Are the BPA analogues an alternative to classical BPA? Comparison between 2D and alternative 3D in vitro neuron model to assess cytotoxic and genotoxic effects.

BPA is used in a wide range of consumer products with very concern toxicological properties. The European Union has restricted its use to protect human health. Industry has substituted BPA by BPA analogues. However, there is a lack of knowledge about their impacts. In this work, BPA and 5 BPA analogues (BPS, BPAP, BPAF, BPFL and BPC) have been studied in classical SH-SY5Y and the alternative 3D in vitro models after 24 and 96 h of exposure. Cell viability, percentage of ROS, cell cycle phases as well as the morphology of the spheroids were measured. The 2D model was more sensitive than the 3D models with differences in cell viability higher than 60% after 24 h of exposure, and different mechanisms of ROS production. After chronic exposure, both models were more affected in comparison to the 24 h exposure. After a recovery time (96 h), the spheroids exposed to 2.5-40 µM were able to recover cell viability and the morphology. Among the BPs tested, BPFL>BPAF>BPAP and >BPC revealed higher toxicological effects, while BPS was the only one with lower effects than BPA. To conclude, the SH-SY5Y 3D model is a suitable candidate to perform more reliable in vitro neurotoxicity tests.

Beneficial Effects of Olive Oil Enriched with Lycopene on the Plasma Antioxidant and Anti-Inflammatory Profile of Hypercholesterolemic Patients.

Olive oil and lycopene are foods that have potent antioxidant activity. The objective was to determine the effects of consumption of olive oil enriched with lycopene on oxidative stress biomarkers in hypercholesterolemic subjects. We examined the effects of oil enriched with lycopene extract daily intake during 1 month on plasma antioxidant capacity, lipids profile (triacylgycerols, total cholesterol, cHDL; cLDL, ox-LDL), biomarkers of oxidative stress, and inflammatory markers related with atherosclerosis risk (C-reactive protein (CRP), IL-6; sDC4L) in subjects hypercholesteremics (cholesterol > 220 mg/dL). In the group consuming olive oil-lycopene, significant increases (p < 0.05) in the levels of plasma lycopene concentration (0.146 ± 0.03 versus 0.202 ± 0.04 (µmol/L)), α-carotene (0.166 ± 0.064 versus 0.238 ± 0.07) and in ß-carotene (0.493 ± 0.187 versus 0.713 ± 0.221) were observed. These results are linked with the increases of plasma antioxidants and decreases biomarkers of oxidative stress (carbonyl groups, malondialdehyde and 8-hydroxy-deoxiguanosine) observed in hypercholesterolemic group. In relation to lipid profile, a significant decrease was observed in the levels of ox-LDL (781 ± 302 versus 494 ± 200), remaining unchanged the levels of TG, cholesterol, HDL and LDL-c. Regarding inflammatory biomarkers, the levels of CRP and IL-6 decreased significantly. The positive results obtained in this study support the use of olive oil enriched with lycopene to reduce the risk of coronary disease.

Influence of the packaging systems on the phenolic profile and antioxidant properties of wine pomace used as seasoning in chicken meat.

White wine pomace products (wWPP) represent an innovative strategy as a functional food ingredient to be used as a seasoning both for their technological and functional properties. Nevertheless, the bioactive compounds of wWPP used as a seasoning could be modified during storage. The seasoning in the meat, regardless of the storage method used, modified its phenolic profile and in its bioaccessible fractions, while maintaining a high total antioxidant capacity and total polyphenol content. The contact of the seasoning with the meat can be considered safe as it does not show cytotoxicity in the Caco-2 cells. Additionally, the ability to modulate the cell oxidative stress of the bioaccessible fractions and the potential benefits on microbiota by the colonic fermentation fraction, suggest its potential use as a functional ingredient, without being affected by storage. These results are novel and may help to establish the value of this product as a functional ingredient.

Multi-omic alterations of the SWI/SNF complex define a clinical subgroup in lung adenocarcinoma.

SWI/SNF complexes are major targets of mutations in cancer. Here, we combined multiple "-omics" methods to assess SWI/SNF composition and aberrations in LUAD. Mutations in lung SWI/SNF subunits were highly recurrent in our LUAD cohort (41.4%), and over 70% of the mutations were predicted to have functional impact. Furthermore, SWI/SNF expression in LUAD suffered an overall repression that could not be explained exclusively by genetic alterations. Finally, SWI/SNF mutations were associated with poorer overall survival in TCGA-LUAD. We propose SWI/SNF-mutant LUAD as a separate clinical subgroup with practical implications.

From winery by-product to healthy product: bioavailability, redox signaling and oxidative stress modulation by wine pomace product.

The wine pomace is the main winery by-products that suppose an economic and environmental problem and their use as a functional ingredient are being increasingly recognized as a good and inexpensive source of bioactive compounds. In this sense, it is known the potential health properties of wine pomace products in the prevention of disorders associated with oxidative stress and inflammation such as endothelial dysfunction, hypertension, hyperglycemia, diabetes, obesity. Those effects are due to the bioactive compounds of wine pomace and the mechanisms concern especially modulation of antioxidant/prooxidant activity, improvement of nitric oxide bioavailability, reduction of pro-inflammatory cytokines and modulation of antioxidant/inflammatory signal pathways. This review mainly summarizes the mechanisms of wine pomace products as modulators of oxidative status involved in cell pathologies as well as their potential therapeutic use for cardiovascular diseases. For this purpose, the review provides an overview of the findings related to the wine pomace bioactive compounds profile, their bioavailability and the action mechanisms for maintaining the redox cell balance involved in health benefits. The review suggests an important role for wine pomace product in cardiovascular diseases prevention and their regular food intake may attenuate the development and progression of comorbidities associated with cardiovascular diseases.

Wine Pomace Product Inhibit Listeria monocytogenes Invasion of Intestinal Cell Lines Caco-2 and SW-480.

Red wine pomace products (WPP) have antimicrobial activities against human pathogens, and it was suggested that they have a probable anti-Listeria effect. This manuscript evaluates the intestinal cell monolayer invasive capacity of Listeria monocytogenes strains obtained from human, salmon, cheese, and L. innocua treated with two WPP (WPP-N and WPP-C) of different polyphenol contents using Caco-2 and SW480 cells. The invasion was dependent of the cell line, being higher in the SW480 than in the Caco-2 cell line. Human and salmon L. monocytogenes strains caused cell invasion in both cell lines, while cheese and L. innocua did not cause an invasion. The phenolic contents of WPP-N are characterized by high levels of anthocyanin and stilbenes and WPP-C by a high content of phenolic acids. The inhibitory effect of the WPPs was dependent of the strain and of the degree of differentiation of the intestinal cells line. The inhibition of Listeria invasion by WPPs in the SW480 cell line, especially with WPP-C, were higher than the Caco-2 cell line inhibited mainly by WPP-N. This effect is associated with the WPPs' ability to protect the integrity of the intestinal barrier by modification of the cell-cell junction protein expression. The gene expression of E-cadherin and occludin are involved in the L. monocytogenes invasion of both the Caco-2 and SW480 cell lines, while the gene expression of claudin is only involved in the invasion of SW480. These findings suggest that WPPs have an inhibitory L. monocytogenes invasion effect in gastrointestinal cells lines.

Bioavailable wine pomace attenuates oxalate-induced type II epithelial mesenchymal transition and preserve the differentiated phenotype of renal MDCK cells.

The functional renal epithelium is composed of differentiated and polarized tubular cells with a strong actin cortex and specialized cell-cell junctions. If, under pathological conditions, these cells have to resist higher kidney osmolarity, they need to activate diverse mechanisms to survive external nephrotoxic agents such as inflammation and oxidative stress. Wine pomace polyphenols exert protective effects on renal cells. In this study, two wine-pomace products and their protective effects upon promotion and preservation of normal cell differentiation and attenuation of oxalate-induced type II epithelial mesenchymal transition (EMT) are evaluated. Treatment with gastrointestinal and colonic bioavailable fractions from red (rWPP) and white (wWPP) wine pomaces, both in the presence and the absence of oxalate, showed similar cell numbers and nuclear size than the non-treated differentiated MDCK cells. Immunofluorescence analysis showed the reduction of morphological changes and the preservation of cellular junctions for the rWPP and wWPP pre-treatment of cells exposed to oxalate injury. Hence, both rWPP and wWPP attenuated oxalate type II EMT in MDCK cells that conserved their epithelial morphology and cellular junctions through the antioxidant activities of grape pomace polyphenols.

The value of lncRNA FENDRR and FOXF1 as a prognostic factor for survival of lung adenocarcinoma.

It is increasingly evident that non-coding RNAs play a significant role in tumour development. However, we still have a limited knowledge of the clinical significance of long non-coding RNAs (lncRNAs) in lung cancer. The FENDRR is a long coding RNA (also named FOXF1-AS1) located in the vicinity of the protein-coding gene FOXF1 at 16q24.1 chromosomal region. The present study aimed to define the clinic pathological significance of the long-non-coding RNA FENDRR in lung adenocarcinomas. FENDRR expression measured by quantitative PCR was found significantly downregulated (p<0.001) in lung adenocarcinoma samples in comparison with their normal adjacent tissues (n=70). RNA in situ hybridization (RNA-FISH) corroborated independently the down-regulation of FENDRR. Interestingly, the expression of FENDRR correlated positively (p<0.001) with the expression of its protein-coding neighbor gene FOXF1. Additionally, FOXF1 expression was also found downregulated in adenocarcinomas compared to normal samples (p<0.001) and its expression was significantly correlated with overall survival alone (p=0.003) or in combination with FENDRR expression (p=0.01). In conclusion, our data support that FENDRR and FOXF1 expression is decreased in lung adenocarcinoma and should be considered as new potential diagnostic/prognosis biomarkers.

The dose-response effect on polyphenol bioavailability after intake of white and red wine pomace products by Wistar rats.

Wine pomace by-products are an important source of phenolic acids with significant health benefits. However, phenolic acid bioavailability in vivo has been little studied and there are few comparative studies on bioavailability between red and white wine pomace and the effect of intake of different doses. The qualitative and quantitative profile of phenolic acid metabolites in plasma and urine samples from Wistar rats was obtained by gas chromatography/mass detection, after oral administration of four doses (50, 100, 150, and 300 mg) of both the red and the white wine pomace products (rWPP and wWPP, respectively). The antioxidant capacity of the plasma samples assessed by both the ABTS and the FRAP levels was also evaluated. The results showed that neither the bioavailability nor the antioxidant capacity in vivo of the rWPP increased at high doses. However, both parameters were dependent on the intake of the wWPP.

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non-Small Cell Lung Carcinoma: the ROSING Study.

INTRODUCTION: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. METHODS: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). RESULTS: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). CONCLUSIONS: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm.

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines.

Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-CuII complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO2)]n compound (1) (HPTSC=pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu(PTSC*)(ONO2)}2] derivative (2, HPTSC*=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of CuI ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands.

Irrigation water consumption modelling of a soilless cucumber crop under specific greenhouse conditions in a humid tropical climate / Modelação de consumo de água de irrigação de pepino sem solo em condições específicas de uma casa de vegetação em um clima tropical húmido

ABSTRACT: The irrigation water consumption of a soilless cucumber crop under greenhouse conditions in a humid tropical climate has been evaluated in this paper in order to improve the irrigation water and fertilizers management in these specific conditions. For this purpose, a field experiment was conducted. Two trials were carried out during the years 2011 and 2014 in an experimental farm located in Vinces (Ecuador). In each trial, the complete growing cycle of a cucumber crop grown under a greenhouse was evaluated. Crop development was monitored and a good fit to a sigmoidal Gompertz type growth function was reported. The daily water uptake of the crop was measured and related to the most relevant indoor climate variables. Two different combination methods, namely the Penman-Monteith equation and the Baille equation, were applied. However, the results obtained with these combination methods were not satisfactory due to the poor correlation between the climatic variables, especially the incoming radiation, and the crop's water uptake (WU). On contrary, a good correlation was reported between the crop's water uptake and the leaf area index (LAI), especially in the initial crop stages. However, when the crop is fully developed, the WU stabilizes and becomes independent from the LAI. A preliminary model to simulate the water uptake of the crop was adjusted using the data obtained in the first experiment and then validated with the data of the second experiment.

RESUMO: Com o objetivo de melhorar a gestão da água de irrigação e fertilizantes em condições específicas, foi avaliado, neste trabalho, o consumo de água de irrigação de pepinos cultivados sem solo em casa de vegetação. Para avaliar este efeito, conduziu-se um experimento de campo. O trabalho de pesquisa foi composto de dois ensaios realizados durante os anos de 2011 e 2014 em Vinces (Equador), onde predomina o clima tropical. Em cada ensaio, avaliou-se o ciclo de crescimento completo da cultura do pepino cultivada em estufa.O desenvolvimento da cultura foi monitorado e um bom ajuste para a função de crescimento tipo sigmoidal Gompertz foi encontrado. A absorção de água diária da cultura foi medida e relacionada às variáveis climáticas mais relevantes. Com o objetivo de modelar o consumo de água das culturas, dois métodos de combinação diferentes, isto é, a equação de Penman-Monteith e a equação Baille, foram aplicadas. No entanto, os resultados obtidos com estes métodos de combinação não foram satisfatórios devido a fraca correlação entre as variáveis climáticas, especialmente, a radiação incidente e absorção de água pela cultura (WU). Por outro lado, foi encontrada uma boa correlação entre a captação de água da cultura e o índice de área foliar (LAI), especialmente, nos estágios iniciais da cultura. No entanto, quando a cultura está completamente desenvolvida, o WU estabiliza e torna-se independente do LAI. Um modelo preliminar para simular a absorção de água da cultura foi ajustado e utilizado e, os dados obtidos do primeiro experimento foram comparados com os dados do segundo.

Coffee component 3-caffeoylquinic acid increases antioxidant capacity but not polyphenol content in experimental cerebral infarction.

Although coffee has antioxidant capacity, it is not known which of its bioactive compounds is responsible for it, nor has it been analyzed in experimental cerebral infarction. We studied the effect one of its compounds, 3-caffeoylquinic acid (3-CQA), at doses of 4, 25 and 100 µg on plasma antioxidant capacity and plasma polyphenol content, measuring the differences before and after inducing a cerebral infarction in an experimental rat model. We compared them with 3-caffeoylquinic-free controls. The increase in total antioxidant capacity was only higher than in controls in 3-CQA treated animals with the highest dose. This increase in antioxidant capacity was not due to an increase in polyphenols. No differences between the experimental and control group were found regarding polyphenol content and cerebral infarction volume. In conclusion, this increase in antioxidant capacity in the group that received the highest dose of 3-CQA was not able to reduce experimental cerebral infarction.

Changes in the levels of thioredoxin and indoleamine-2,3-dioxygenase activity in plasma of patients with colorectal cancer treated with chemotherapy.

Increased oxidative stress and indoleamine-2,3-dioxygenase (IDO) activity have been reported in cancer, but their relationship with chemotherapy remains unknown. The aim of the present study was to examine wether the chemotherapy treatments used in colorectal cancer had an additional effect on oxidative stress and on IDO activity. Plasma samples were collected from 27 colorectal cancer patients on cytostatic treatment, 27 with cytostatic drugs plus monoclonal antibodies (cytostatic-Mabs) and 15 non-treated patients. All patients with colorectal cancer had high plasma malondialdehyde (MDA), thioredoxin (Trx) levels, and elevated IDO activity in plasma (IDOp) and in dendritic cells (IDOc). This study shows that treatment with cytostatics have an effect on oxidative stress by increasing MDA levels and by decreasing Trx levels and IDO activity. However, treatment with cytostatic-Mabs showed no effect on MDA levels but decreased Trx levels, and the IDO activity showed values similar to the healthy group. Significant correlations between plasma IDO activity and the levels of Trx (r = 0.2062, p < 0.05) and MDA (r = 0.2873, p < 0.005) were observed. Furthermore, our study suggests that IDO activity measured as kynurenine levels could be used as a marker of the response to the chemotherapy treatments, although further studies are necessary.

Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study.

BACKGROUND: This study was designed to evaluate and compare antioxidant capacity and radical scavenging activity of naringin and its aglycone by different in vitro assays. The effects of flavanones on lipid peroxidation, glutathione (GSH) oxidation and DNA cleavage were also assessed. RESULTS: The results showed that naringenin exhibited higher antioxidant capacity and hydroxyl and superoxide radical scavenger efficiency than naringin. Our results evidenced that glycosylation attenuated the efficiency in inhibiting the enzyme xanthine oxidase and the aglycone could act like a more active chelator of metallic ions than the glycoside. Additionally, naringenin showed a greater effectiveness in the protection against oxidative damage to lipids in a dose-dependent manner. Both flavanones were equally effective in reducing DNA damage. However, they show no protective effect on oxidation of GSH. CONCLUSION: The data obtained support the importance of characterizing the ratio naringin/naringenin in foods when they are evaluated for their health benefits.

TAp73 is one of the genes responsible for the lack of response to chemotherapy depending on B-Raf mutational status.

BACKGROUND: Although there have been many studies on the p73 gene, some of its functions still remain unclear. There is little research on the relationship between p73 gene transcription and its protein expression and the response to certain drugs such as oxaliplatin and cetuximab, which are drugs currently used in colorectal cancer.The purpose of this study was to evaluate the impact of TAp73 expression on oxaliplatin and cetuximab-based chemotherapy in colorectal cancer cell lines with different K-Ras and B-Raf mutational status. METHODS: TAp73 was analyzed in three colorectal tumor cell lines HT-29, SW-480 and Caco-2. mRNA TAp73 was determined using Real time PCR; TAp73 protein by immunoblotting and cell viability was analyzed by the MTT method. RESULTS: We found that mRNA and TAp73 protein were decreased in cells treated with oxaliplatin (in monotherapy or combined with cetuximab) when B-Raf is mutated. This was statistically significant and was also associated with higher cell viability after the treatment. CONCLUSIONS: Here, for the first time we report, that there is a signaling loop between B-Raf activation and p73 function.Low expression of TAp73 in colorectal cancer cell lines with mutated B-Raf may be involved in the lack of response to oxaliplatin in monotherapy or combined with cetuximab.

Metastatic non-small-cell lung carcinoma successfully treated with pre-operative chemotherapy and bilateral adrenalectomy.

Metastatic non-small-cell lung cancer is a common condition with a dismal prognosis. Although palliative chemotherapy improves survival and quality of life, nearly all patients die of progressive disease. Metastatic involvement of adrenal glands is not rare, but usually reflects widespread dissemination. Selected patients with single adrenal metastasis may be cured with surgery, although the level of evidence comes from single cases reports and short retrospective series. Here we report a patient with bilateral adrenal metastases from previously resected non-small-cell lung cancer, who remains free of disease four years after pre-operative chemotherapy and bilateral adrenalectomy.

Streptococcus pyogenes: sensibilidad a penicilina y eritromicina en las ciudades de Neuquen y Cipolletti / Streptococcus pyogenes: penicillin and erythromycin susceptibility in the cities of Neuquen and Cipolletti

Hasta la fecha no se ha detectado resistencia a penicilina en Streptococcus pyogenes. No obstante se ha registrado un aumento en la resistencia a macrólidos en varios países del mundo. En la Argentina se han observado escasos porcentajes de resistencia a eritromicina, a excepción de un 11.1 por ciento registrado en Mendoza. El objetivo del presente trabajo fue estudiar la sensibilidad in vitro a penicilina y eritromicina de 251 aislamientos sucesivos de S. pyogenes obtenidos en cuatro centros asistenciales localizados en las ciudades de Neuquén y Cipolletti durante el período abril-diciembre de 1998. Se empleó el método de difusión con discos de penicilina y el método del doble disco (eritromicina 15 µg y clindamicina 2 µg) para observar la resistencia a macrólidos y el mecanismo involucrado. Los aislamientos resistentes a macrólidos fueron estudiados por E-test (AB Biodisk, Solna, Suecia) para establecer los niveles de sensibilidad a eritromicina, y por dilución en agar para penicilina, eritromicina, ceftriaxona, azitromicina y clindamicina. Todos los aislamientos fueron sensibles a penicilina y treinta de ellos (12.0 por ciento) fueron resistentes a eritromicina. Estos últimos mostraron el fenotipo M, característico del mecanismo de eflujo activo. Todos los aislamientos resistentes a eritromicina (CIM entre 8 y 16 mg/l) también resultaron resistentes a azitromicina, pero sensibles a clindamicina, penicilina y ceftriaxona. De acuerdo a estos resultados concluimos que S. pyogenes continúa siendo sensible a la penicilina, pero creemos que en nuestra zona es necesario realizar estudios rutinarios de pruebas de sensibilidad a macrólidos debido al relativamente elevado porcentaje de resistencia a eritromicina observado.