New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma

The anti-epileptic drug valproic acid is also under trial as an anti-cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti-neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA-derivatives (ACS2, ACS33) on pre-clinical prostate cancer models. PC3 and DU-145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up-regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU-145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti-tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer

Nucleosomes indicate the in vitro radiosensitivity of irradiated bronchoepithelial and lung cancer cells

Nucleosomes, which are typical cell death products, are elevated in the serum of cancer patients and are known to rapidly increase during radiotherapy. As both normal and malignant cells are damaged by irradiation, we investigated to which extent both cell types contribute to the release of nucleosomes. We cultured monolayers of normal bronchoepithelial lung cells (BEAS-2B, n = 18) and epithelial lung cancer cells (EPLC, n = 18), exposed them to various radiation doses (0, 10 and 30 Gy) and observed them for 5 days. Culture medium was changed every 24 h. Subsequently, nucleosomes were determined in the supernatant by the Cell Death Detection-ELISA(plus) ( Roche Diagnostics). Additionally, the cell number was estimated after harvesting the cells in a second preparation. After 5 days, the cell number of BEAS-2B cultures in the irradiated groups (10 Gy: median 0.03 x 10(6) cells/culture, range 0.02-0.08 x 10(6) cells/culture; 30 Gy: median 0.08 x 10(6) cells/culture, range 0.02-0.14 x 10(6) cells/culture) decreased significantly (10 Gy: p = 0.005; 30 Gy p = 0.005; Wilcoxon test) compared to the non-irradiated control group (median 4.81 x 10(6) cells/culture, range 1.50-9.54 x 10(6) cells/culture). Consistently, nucleosomes remained low in the supernatant of nonirradiated BEAS-2B. However, at 10 Gy, BEAS-2B showed a considerably increasing release of nucleosomes, with a maximum at 72 h ( before irradiation: 0.24 x 10(3) arbitrary units, AU, range 0.13-4.09 x 10(3) AU, and after 72 h: 1.94 x 10(3) AU, range 0.11-5.70 x 10(3) AU). At 30 Gy, the release was even stronger, reaching the maximum earlier (at 48 h, 11.09 x 10(3) AU, range 6.89-18.28 x 10(3) AU). In non-irradiated EPLC, nucleosomes constantly increased slightly. At 10 Gy, we observed a considerably higher release of nucleosomes in EPLC, with a maximum at 72 h (before irradiation: 2.79 x 10(3) AU, range 2.42-3.80 x 10(3) AU, and after 72 h: 7.16 x 10(3) AU, range 4.30-16.20 x 10(3) AU), which was more than 3.5 times higher than in BEAS-2B. At 30 Gy, the maximum (6.22 x 10(3) AU, range 5.13-9.71 x 10(3) AU) was observed already after 24 h. These results indicate that normal bronchoepithelial and malignant lung cancer cells contribute to the release of nucleosomes during irradiation in a dose-and time-dependent manner with cancer cells having a stronger impact at low doses. Copyright (C) 2004 S. Karger AG, Basel

Amelioration Of Snap Bean Growth, Yield, Quantity And Nutritional Status Under Salinity Stress By Using Spirulina Algae Extract And Amino Acids

Salinity stress is a major abiotic stress that limits agricultural production and threatens global food security due to rapid climate change. Salt stress negatively affects the growth, yield and quality of crops.  Amino Acids and Spirulina Algae Extract are well-known biostimulants that have positive effects on plant growth and productivity and significantly reduce damage caused by abiotic stress. Therefore, this study investigated the effect of several treatments with spirulina extract and amino acids on snap bean plant growing under saline soil stress. Field experiment was carried out during the two successive summer seasons of 2021 and 2022 under saline soil at private farm in Faqus - Sharkia Governorate, to study the effect of spirulina algae and amino acid concentrations as foliar spray on growth, yield quantity and quality and nutritional status of snap bean cv, Bronco. The experiment was executed in split plot design, three rates of spirulina algae extracts (0, 1 and 2 cm3 L-1) were distributed on main plot and another three level of amino acids (0, 500 and 1000 mg L-1) were arranged on subplot. Finally, main and subplot were replicated three times. The results can be summarized as follows: Under saline soil condition, spraying snap bean plants with different concentrations of spirulina extract and amino acids three times led to an improvement in plant growth, crop quantity and quality as well as nutritional status, compared to the experimental treatment in which both were not used. The highest values of growth, yield and content of nitrogen, phosphorus and potassium were obtained by spraying 2 cm3 L-1 of spirulina extract with 1000 mg L-1 of amino acids under two consecutive seasons. Thus, it can be said that Therefore, the spirulina algae extract and amino acids are considered one of the safe solutions to get rid of the effect of soil salinity on the  snap bean plant, and then obtain a high yield and also high quality

Correlation between anthropometric measurements and blood pressure in a population of Palestinian adults.

This manuscript is part of the PhD research developed by Moath Abu Ejheisheh, included in the Official PhD Program of Clinical Medicine and Public Health at the University of Granada, Spain. The authors in this study would like to extend her appreciation to the study participants for their time.Obesity can be a major problem due to its potential to cause a number of health issues, including high blood pressure and diabetes. Many reports have come out of Palestine on overweight and obesity and their direct link to non-communicable diseases, although there is only limited evidence available on the connection between obesity and hypertension in Palestinian adults. We aimed to look at the associations between anthropometric and body composition variables and blood pressure in a large population of Palestinian adults (1337 subjects) and determine which anthropometric indices most strongly correlate with high blood pressure. Anthropometric measurements including height, waist circumference (WC), hip circumference (HC), body mass index (BMI), and total body fat (TBF) were assessed. A body composition analyzer was used to measure body weight, fat mass and fat-free mass. Systolic (SBP) and diastolic (DBP) blood pressure were measured using a Dinamap vital signs monitor. In both males and females, all the anthropometric measurements showed significant strong positive correlations with mean SBP and mean DBP (p < 0.01). SBP correlated the most strongly with waist circumference in all subjects (r = 0.444 in females, r = 0.422 in males), while DBP correlated the most strongly with WC in males (r = 0.386), but with TBF in females (r = 0.256). By controlling fat percentage, WC, HC, and BMI, which are affected by extra weight and lack of exercise, blood pressure levels can be regulated.The author(s) received no financial support for the research, authorship, and/or publication of this article

Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial

Altered histone deacetylase (HDAC) activity has been identified in several types of cancer. This study was designed to determine the safety and maximum tolerated dose (MTD) of valproic acid (VPA) as an HDAC inhibitor in cancer patients. Twenty-six pre-treated patients with progressing solid tumours were enrolled in dose-escalating three-patient cohorts, starting at a dose of VPA 30 mg kg−1 day−1. VPA was administered as an 1-h infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile, with grade 3 or 4 neurological side effects occurring in 8 out of 26 patients. No grade 3 or 4 haematological toxicity was observed. The MTD of infusional VPA was 60 mg kg−1 day−1. Biomonitoring of peripheral blood lymphocytes demonstrated the induction of histone hyperacetylation in the majority of patients and downmodulation of HDAC2. Pharmacokinetic studies showed increased mean and maximum serum VPA concentrations >120 and >250 mg l−1, respectively, in the 90 and 120 mg kg−1 cohorts, correlating well with the incidence of dose-limiting toxicity (DLT). Neurotoxicity was the main DLT of infusional VPA, doses up to 60 mg kg−1 day−1 for 5 consecutive days are well tolerated and show detectable biological activity. Further investigations are warranted to evaluate the effectivity of VPA alone and in combination with other cytotoxic drugs

Anthracycline rechallenge using pegylated liposomal doxorubicin in patients with metastatic breast cancer: a pooled analysis using individual data from four prospective trials

BACKGROUND: The aim of this study was to determine the activity of anthracycline rechallenge using pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) previously treated with conventional anthracyclines. METHODS: Pooled individual data from four prospective trials were used, and the primary end point of the pooled analysis was clinical benefit rate (CBR). The studies comprised 935 patients, of whom 274 had received PLD in the metastatic setting after prior exposure to conventional anthracyclines (rechallenge population). RESULTS: The majority of patients were heavily pretreated. Previous anthracycline therapy was administered in the adjuvant (14%) or metastatic setting (46%), or both (40%). The overall CBR from rechallenge with PLD was 37.2% (95% CI, 32.4-42.0). In univariate analyses, the CBR was significantly higher in patients with less exposure to prior chemotherapy, in taxane-naive patients, and in patients with a favourable Eastern Cooperative Group performance status of 0 vs 1 vs 2 (53.3 vs 35.5 vs 18.2%; P<0.001). In multivariate analyses, performance status proved to be the only independent predictor of the CBR achieved with PLD rechallenge (P=0.038). There was no statistically significant difference in CBR regarding the setting, cumulative dose of and/or resistance to prior anthracyclines, or time since prior anthracycline administration. CONCLUSION: Anthracycline rechallenge using PLD is effective in patients with MBC who have a favourable performance status, regardless of setting, resistance, cumulative dose or time since prior conventional anthracycline therapy. British Journal of Cancer (2010) 103, 1518-1523. doi:10.1038/sj.bjc.6605961 www.bjcancer.com Published online 26 October 2010 (C) 2010 Cancer Research U

The effect of electronic cigarettes exposure on learning and memory functions: behavioral and molecular analysis

Objective: Electronic cigarettes (ECIGs) are battery-powered devices that emit vaporized solutions for the user to inhale. ECIGs are marketed as a less harmful alternative to combustible cigarettes. The current study examined the effects of ECIG aerosol exposure on learning and memory, expression of brain derived neurotrophic factor (BDNF), and the activity of antioxidant enzymes in the hippocampus. Methods: Male Wistar rats were exposed to ECIG aerosol, by a whole-body exposure system, 1 h/day for 1 week, 4 weeks, and 12 weeks. Spatial learning and memory were tested using the Radial Arm Water Maze (RAWM). Hippocampal BDNF protein level, and oxidative stress biomarkers (GPx, SOD, GSH, GSSG, GSH/GSSG ratio) were also assessed. Results: ECIG aerosol exposure for 4 and 12 weeks impaired both short- and long- term memory and induced reductions in the hippocampus BDNF, SOD and GPx activities, and GSH/GSSG ratio (p 0.05). Conclusions: ECIG aerosol exposure impaired functional memory and elicited changes in brain chemistry that are consistent with reduced function and oxidative stress. © 2021 Informa UK Limited, trading as Taylor & Francis Group