Protective and antigenotoxic effect of Ulva rigida C. Agardh in experimental hypothyroid

The presence of chromosomal damage in bone marrow cells affected by several diseases such as thyroid, cancer etc., was detected by the micronucleus (MN) assay. The present study was designed to evaluate: i) volatile components of Ulva rigida, ii) effects of hypothyroidism on bone marrow MN frequency, iii) effects of oral administration of Ulva rigida ethanolic extract (URE) on MN frequency produced by hypothyroidism, and iv) thyroid hormone levels in normal and 6-n-Propylthiouracil (PTU)-induced hypothyroid rats. The volatile components of Ulva rigida was studied using a direct thermal desorption (DTD) technique with comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOF/MS). UREadministration was of no significant impact on thyroid hormone levels in control group, while PTU administration decreased thyroid hormone levels compared to control group (p < 0.001). Moreover, UREsupplementation resulted in a significant decrease in MN frequency in each thyroid group (p < 0.0001). This is the first in vivo study that shows the strong antigenotoxic and protective effect of UREagainst the genotoxicity produced by hypothyroidism

Genotoxic, Cytotoxic, and Apoptotic Effects of Hypogymnia physodes (L.) Nyl. on Breast Cancer Cells

The aim of this study is to determine the chemical composition, and evaluate the genotoxic, and anti-growth potency of the methanol extracts of lichen species Hypogymnia physodes (L.) Nyl. (HPE). Anti-growth effect was tested in two different human breast cancer cell lines (MCF-7 and MDA-MB-231) by the MTT and ATP viability assays and apoptosis was assayed by the caspase-cleaved cytokeratin 18 (M30-antigen). Genotoxic activity of HPE was studied using chromosome aberration and micronuclei tests in human lymphocytes culture in vitro. The chemical composition of H. physodes was analyzed by using direct thermal desorption method coupled with comprehensive gas chromatography-time of flight mass spectrometry (GCXGC-TOF/MS). Our results indicate that HPE has an anti-growth effect at relatively lower concentrations, while relatively higher concentrations are required for genotoxic activity. HPE, therefore, seems to represent a therapeutic potential and poses new challenges for medicinal chemistry. (C) 2012 Wiley Periodicals, Inc

Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells

Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.Fil: Ozcan, Selahattin C.. Koc University Research Center For Translational Medici; TurquíaFil: Mutlu, Aydan. Bursa Uludag University; TurquíaFil: Altunok, Tugba H.. Bursa Uludag University; TurquíaFil: Gurpinar, Yunus. Bursa Uludag University; TurquíaFil: Sarioglu, Aybike. Bursa Uludag University; TurquíaFil: Guler, Sabire. Bursa Uludag University; TurquíaFil: Muchut, Robertino José. Universidad Nacional del Litoral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Iglesias, Alberto Alvaro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral; ArgentinaFil: Celikler, Serap. Bursa Uludag University; TurquíaFil: Campbell, Paul M.. The Marvin and Concetta Greenberg Pancreatic Cancer Institute; Estados UnidosFil: Yalcin, Abdullah. Bursa Uludag University; Turquí