No abstract

We deduce that SCFAs and MCFAs are suitable and safe sources of energy under inflammatory conditions with the capability to partly restore mitochondrial respiration.

In 42 patients with septic shock, 29 of whom underwent substitution with antithrombin Ill concentrate and fresh frozen plasma for coagulation disorders, the proteinase-inhibitor complexes thrombin-antithrombin I11 and neutrophil elastasealpha, proteinase inhibitor, were elevated on admission. On admission, the elastase complex was significantly higher in the patients receiving substitution (p = 0.0039). but at the endpoint it was higher in the non-survivors (p = 0.0040). The elastase decrease was confined to the substitution group with the thrombin complex decreasing in both groups. Initially the thrombin complex correlated with prothrombin times and factor XIII, while the elastase complex correlated with creatinine, thrombocyte count and prothrombin times in the late stages. Hemostatic disturbance, thrombin generation and neutrophil elastase release were favorably influenced by substitution. Furthermore, in this uncontrolled pilot study, the survival rate was higher in the treated (16 of 29) than in the untreated (1 of 13) patients, although the treated patients initially had pronounced hemostatic disturbances.

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).