Although it has been known for over more than forty years that selenium is essential for the mammalian organism, our knowledge of the metabolism and the functions of the element is still incomplete. In order to investigate some of the still unanswered questions, several studies have been carried out on rats. The animals were either supplied with adequate amounts of selenium or were depleted by feeding with a seleniumdeficient diet over longer periods of time, sometimes for several generations. By combining methods for trace element analysis, tracer techniques and various biochemical procedures, the distribution of selenium was determined among tissues, tissue fractions, certain types of cells, subcellular compartments and proteins. In this way information was obtained on the regulation of selenium and on new selenium-containing proteins and their sites of action. Our main findings in these two areas of research will be presented and discussed.
As almost all of the selenium present in the mammalian organism is protein-bound, speciation is mostly concerned with the determination of the different selenium-containing proteins. Information on their distribution and their concentrations in the different tissues of the rat was obtained by means of tracer procedures which, after application of 75Se-selenite with a very high specific activity to selenium-depleted animals and electrophoretic separation of the labelled proteins, allow the determination of these compounds in the pmol to fmos range. A method was developed for the determination of selenocysteine and selenomethionine in the selenium-containing proteins. The identification of specific selenoproteins was achieved by analysis of their selenoamino acid residues and by studies on their characteristics and possible biological functions. This is being followed by the development of methods for the quantitative analysis of the selenoproteins in questions in the tissues of animals and man. In this paper the strategies and procedures used in the identification, characterization and determination of the selenium species present in the mammalian organism will be discussed.
Background: The objective of this study was to investigate the performance of a newly developed decision support system for the establishment of tight glycemic control in medical intensive care unit (ICU) patients for a period of 72 hours. Methods: This was a single-center, open, non-controlled feasibility trial including 10 mechanically ventilated ICU patients. The CS-1 decision support system (interacting infusion pumps with integrated enhanced model predictive control algorithm and user interface) was used to adjust the infusion rate of administered insulin to normalize blood glucose. Efficacy and safety were assessed by calculating the percentage of values within the target range (80-110 mg/dl), hyperglycemic index, mean glucose, and hypoglycemic episodes (<40 mg/dl).
The insufficient penetration through the cell membranes is one of the major drawbacks of chemotherapeutics such as 5-fluorouracil (5-FU; 1). To improve the penetration, a useful strategy is the attachment of lipophilic moieties. Thus, we have synthesized a series of nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or at the 2',3'-O position, i.e., 3a, 3b, 4-7, and tested their cytostatic/cytotoxic activities towards three carcinoma cell lines (colon (HT-29), hepatocellular (HepG2), and renal (RENCA)) in comparison with 5-FU (1) and 5-FUrd (2a). After 48 h of incubation, four derivatives, 3a, 3b, 5, and 7, showed inhibitory effects on the survival of HT-29, HepG2, and RENCA cells. Additionally, to differentiate between anticancer and side-effects, we tested the cytotoxicity of the derivatives in human macrophages. Interestingly, the derivatives 4, 5, and 6 did not exhibit any effects on survival of THP-1 macrophages. Furthermore, we investigated the apoptosis induction of compound 1 and 2a, and the above-mentioned derivatives in HT-29 cells. Derivative 5 showed the highest significant (p<0.05; p<0.01) increase of the apoptosis at 80 μM after 2-h or 4-h treatment, as well as after 6-h incubation at 40 μM (p<0.05). Real-time PCR revealed that 40-μM derivative 5 showed a 1.8-fold increase of the pro-apoptotic caspase-3 gene and a twofold significant increase (p<0.01 and p<0.05 vs. control and 1, resp.) of the tumor suppressor TP53 gene, whereas the other compounds did not show any effect. We demonstrated that some 5-FUrd derivatives such as compound 5 are more effective than 5-FU or 5-FUrd concerning a cytotoxic (vs. cytostatic (5-FU, 5-FUrd)) effect on different cancer cell lines, but without cytotoxic side-effects on differentiated macrophages. Thus, compound 5 is suggested as a novel potent cytotoxic multi-anti-cancer drug.
One of the major drawbacks of chemotherapeutics is their insufficient penetration through cell membranes due to a high hydrophobicity. Thus, we have synthesized a series of selected nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or in the 2',3'-O-position (i.e., 3a-7a and 3c), and tested their cytostatic/cytotoxic activities using HT-29 human colon carcinoma cells, in comparison with, e.g., 5-FU (1) and 5-FUrd (2a). Incorporation and intracellular localization of the substances under test were performed after conjugation with the fluorochrome Atto 425. We showed that all 5'-O-labelled Atto 425 derivatives were incorporated by the human HT-29 cells and accumulated in their cytoplasm. Moreover, after 24-h treatment of HT-29 human colon carcinoma cells, 1 or 2a (10, 20, 40, or 80 μM) revealed a significant (14-23 or 33-45%, resp.) decrease of the viability in comparison with the (negative) control. Interestingly, derivatives 3a and 3c (40 and 80 μM) led to a significant (77-95 or 89-96%, resp.) inhibition of survival of human HT29 cells, i.e., these two substances were ca. 63-72% or ca. 75%, respectively more effective than 5-FU (1; positive control). Furthermore, derivative 5a showed a significant, i.e., 30 and 86%, inhibition of the survival at 40 and 80 μM, respectively in comparison with the (negative) control. Some synthesized 5-FUrd derivatives turned out to be more effective than 5-FU (1) or 5-FUrd (2a).
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