A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

of low-temperature non-equilibrium calcite-water fractionation

In this paper we present the first detailed geochemical study of the world-famous actively forming Pamukkale and Karahayit travertines (Denizli Basin, SW-Turkey) and associated thermal waters. Sampling was performed along downstream sections through different depositional environments (vent, artificial channel and lake, terrace-pools and cascades of proximal slope, marshy environment of distal slope). delta C-13(travertine) values show significant increase (from +6.1 parts per thousand to +11.7 parts per thousand PDB) with increasing distance from the spring orifice, whereas the delta O-18(travertine) values show only slight increase downstream (from -10.7 parts per thousand to -9.1 parts per thousand PDB). Mainly the CO2 outgassing caused the positive downstream shift (similar to 6 parts per thousand) in the delta C-13(travertine) values. The high delta C-13 values of Pamukkale travertines located closest to the spring orifice (not affected by secondary processes) suggest the contribution of CO2 liberated by thermometamorphic decarbonation besides magmatic sources. Based on the gradual downstream increase of the concentration of the conservative Na+, K+, Cl-, evaporation was estimated to be 2-5%, which coincides with the moderate effect of evaporation on the water isotope composition. Stable isotopic compositions of the Pamukkale thermal water springs show of meteoric origin, and indicate a Local Meteoric Water Line of Denizli Basin to be between the Global Meteoric Water Line (Craig, 1961) and Western Anatolian Meteoric Water Line (Simsek, 2003). Detailed evaluation of several major and trace element contents measured in the water and in the precipitated travertine along the Pamukkale MM section revealed which elements are precipitated in the carbonate or concentrated in the detrital minerals.Former studies on the Hungarian Egerszalok travertine (Kele et al., 2008a, b, 2009) had shown that the isotopic equilibrium is rarely maintained under natural conditions during calcite precipitation in the temperature range between 41 and 67 degrees C. In this paper, besides the detailed geochemical analyses along downstream sections, we present new evidences of non-equilibrium calcite-water fractionation in lower temperature range (13.3 to 51.3 degrees C). Our measurements and calculations on natural hot water travertine precipitations at Pamukkale and Egerszalok revealed that the delta O-18(travertine) is equal with the delta O-18(HCO3) at the orifice of the thermal springs, which means that practically there is no oxygen isotope fractionation between these two phases. High rate of CO2 degassing with rapid precipitation of carbonate could be responsible for this as it was theoretically supposed by O'Neil et al. (1969). Thus, for the determination of the deposition temperature of a fossil travertine deposit we propose to use the water-bicarbonate oxygen isotope equilibrium fractionation instead of the water-travertine fractionation, which can result 8-9 degrees C difference in the calculated values. Our study is the first detailed empirical proof of O'Neil's hypothesis on a natural carbonate depositing system. The presented observations can be used to identify more precisely the deposition temperature of fossil travertines during paleoclimate studies. (C) 2011 Elsevier B.V. All rights reserved

Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells.

Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls) induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe