Gossypol Interferes with Both Type I and Type II Topoisomerase Activities Without Generating Strand Breaks

A considerable number of agents with chemotherapeutic potentials reported over the past years were shown to interfere with the reactions of DNA topoisomerases, the essential enzymes that regulate conformational changes in DNA topology. Gossypol, a naturally occurring bioactive phytochemical is a chemopreventive agent against various types of cancer cell growth with a reported activity on mammalian topoisomerase II. The compounds targeting topoisomerases vary in their mode of action; class I compounds act by stabilizing covalent topoisomerase-DNA complexes resulting in DNA strand breaks while class II compounds interfere with the catalytic function of topoisomerases without generating strand breaks. In this study, we report Gossypol as the interfering agent with type I topoisomerases as well. We also carried out an extensive set of assays to analyze the type of interference manifested by Gossypol on DNA topoisomerases. Our results strongly suggest that Gossypol is a potential class II inhibitor as it blocked DNA topoisomerase reactions with no consequently formed strand breaks. © 2012 Springer Science+Business Media New York

A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation

Saturated Fats: A Perspective from Lactation and Milk Composition

For recommendations of specific targets for the absolute amount of saturated fat intake, we need to know what dietary intake is most appropriate? Changing agricultural production and processing to lower the relative quantities of macronutrients requires years to accomplish. Changes can have unintended consequences on diets and the health of subsets of the population. Hence, what are the appropriate absolute amounts of saturated fat in our diets? Is the scientific evidence consistent with an optimal intake of zero? If not, is it also possible that a finite intake of saturated fats is beneficial to overall health, at least to a subset of the population? Conclusive evidence from prospective human trials is not available, hence other sources of information must be considered. One approach is to examine the evolution of lactation, and the composition of milks that developed through millennia of natural selective pressure and natural selection processes. Mammalian milks, including human milk, contain 50% of their total fatty acids as saturated fatty acids. The biochemical formation of a single double bond converting a saturated to a monounsaturated fatty acid is a pathway that exists in all eukaryotic organisms and is active within the mammary gland. In the face of selective pressure, mammary lipid synthesis in all mammals continues to release a significant content of saturated fatty acids into milk. Is it possible that evolution of the mammary gland reveals benefits to saturated fatty acids that current recommendations do not consider

A reappraisal of the impact of dairy foods and milk fat on cardiovascular disease risk

Background This review provides a reappraisal of the potential effects of dairy foods, including dairy fats, on cardiovascular disease (CVD)/coronary heart disease (CHD) risk. Commodities and foods containing saturated fats are of particular focus as current public dietary recommendations are directed toward reducing the intake of saturated fats as a means to improve the overall health of the population. A conference of scientists from different perspectives of dietary fat and health was convened in order to consider the scientific basis for these recommendations. Aims This review and summary of the conference focus on four key areas related to the biology of dairy foods and fats and their potential impact on human health: (a) the effect of dairy foods on CVD in prospective cohort studies; (b) the impact of dairy fat on plasma lipid risk factors for CVD; (c) the effects of dairy fat on non-lipid risk factors for CVD; and (d) the role of dairy products as essential contributors of micronutrients in reference food patterns for the elderly. Conclusions Despite the contribution of dairy products to the saturated fatty acid composition of the diet, and given the diversity of dairy foods of widely differing composition, there is no clear evidence that dairy food consumption is consistently associated with a higher risk of CVD. Thus, recommendations to reduce dairy food consumption irrespective of the nature of the dairy product should be made with cautionJ. Bruce German, Robert A. Gibson, Ronald M. Krauss, Paul Nestel, Benoît Lamarche, Wija A. van Staveren, Jan M. Steijns, Lisette C. P. G. M. de Groot, Adam L. Lock and Frédéric Destaillat

Evaluation of the interactions of the Sunitinib malate with topoisomerase enzymes by in vitro enzyme and molecular docking analyses

Today, we live with the fact that anti-cancer drugs, which are in medical use and have been identified to have many mechanisms of action, only allow the treatment of a certain number of cancer types, and despite the research of many molecules with potential anti-cancer properties, not all types of cancer can be treated. Tyrosine kinase inhibitors (TKIs) mostly destroy certain types of cancer cells and many TKIs are currently being investigated in phase stages. Determining their use for various types of cancer is especially important for cases of acquired resistance in cancer. In our study, we investigated whether Sunitinib malate molecule, a multi-target receptor tyrosine kinase inhibitor, targets the topoisomerase I enzyme in addition to its known targets. In our study, we investigated whether Sunitinib malate molecule, a multi-target receptor tyrosine kinase inhibitor, targets the topoisomerase I enzyme in addition to its known targets. The interactions of Sunitinib malate with topoisomerase enzyme I were evaluated by in vitro enzyme activity tests, and Sunitinib malate was shown to inhibit topoisomerase I enzyme in a concentration-dependent manner, and when used in combination with Camptothecin, the potential for inhibition effects was evaluated by in vitro enzyme assays and molecular docking analysis

Neonatal line on fetus and infant teeth An indicator of live birth and mode of delivery

Dagalp, Rukiye/0000-0002-7335-8578; Dagalp, Rukiye E/0000-0002-7335-8578;WOS: 000339149600002PubMed: 24951074Background: The neonatal line (NL) is an important issue in forensic odontology. It is the sign of a developmental birth defect, which is caused by the effect of metabolic stress on tooth structures when the fetus passes to extrauterine life. Aims: The aim of this research is to determine the existence and thickness of NL in teeth, as it is a legal necessity to indicate the signs of viability at birth in a forensic examination of a fetus or infant case. Study design and subjects: This research was conducted on 48 lower left and right lateral teeth, which were taken from 24 autopsy cases (46% female and 54% male). Left lateral teeth were sectioned in a vertical plane and right lateral teeth were sectioned in a horizontal plane. The NL thickness was measured with a scanning electron microscope (SEM). These cases comprised three conditions as: 70.3% normal birth, 16.7% caesarean sections, and 12.5% still birth cases under the legal and ethical permission. Outcome measures: The mean NL thickness of normal birth cases was higher than caesarean cases as 7.7 mu m and 2.5 mu m, respectively. Results and conclusions: The results showed a statistical significance between all birth conditions. NL does not exist in still birth cases (p < 0.001). Not only is the presence of NL a sign of live birth, but also its thickness is an indicator of the delivery mode where NL thickness of normal birth was found thicker than the caesarean cases. (C) 2014 Elsevier Ireland Ltd. All rights reserved