Effects of fatty acids on hepatic amino acid catabolism and fibrinogen synthesis in young healthy volunteers

Increased synthesis rate of fibrinogen, an independent risk factor for cardiovascular disease, was recently reported in obese insulin-resistant female adolescents with chronic elevated nonesterified fatty acids (NEFA). It is unknown whether a short-term change of NEFA concentrations controls hepatic fibrinogen synthesis. Therefore, 10 healthy male volunteers (24.5 +/- 3.3 yr, body mass index 23.5 +/- 2.9 kg/m2) were investigated in random order under basal and elevated NEFA for 8 h. Leucine metabolism, the fractional synthesis rates (FSR) of plasma fibrinogen, and endogenous urea production rates were measured during primed, continuous infusion of [1-13C]leucine and [15N2]urea, respectively. Plasma alpha-[13C]ketoisocaproic acid and [15N2]urea enrichment values were measured with GC-MS. Plasma fibrinogen was isolated with the beta-alanine method, and fibrinogen-related [13C]leucine enrichment was analyzed by GC-CIRMS. Lipofundin infusion and subcutaneous heparin tripled NEFA and triglycerides in the tests. Plasma glucose, circulating insulin, human C-peptide, and plasma glucagon were not changed by the study procedure. Fibrinogen FSR were significantly lower in tests with NEFA elevation (18.44 +/- 4.67%) than in control tests (21.48 +/- 4.32%; P < 0.05). Plasma fibrinogen concentrations measured were not significantly different (NEFA test subjects: 1.85 +/- 0.33, controls: 1.97 +/- 0.54 g/l). Parameters of leucine metabolism, such as leucine rate of appearance, leucine oxidation, and nonoxidative leucine disposal, were not influenced by NEFA elevation, and endogenous urea production remained unchanged. NEFA contributes to short-term regulation of fibrinogen FSR in healthy volunteers under unchanged hormonal status, leucine metabolism, and overall amino acid catabolism. Its contribution might be of relevance at least after fat-rich meals, counteracting by reduction of FSR the blood viscosity increase implied by hyperlipidemia.     

Furanocoumarins from Dorsteniafoetida

The linear furanocoumarins 5-(2,3-epoxy-3-methyl-butoxy)-chalepensin, 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen-diacetate (7), 5-methoxy-3-[3-(β-d-glucopyranosyloxy)-2-acetyloxy-3-methyl-butyl]-psoralen and 5-(3-methyl-2,3-dihydroxybutyloxy)-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-psoralen, and the coumarin derivative 7-hydroxy-5-methoxy-6-carboxymethyl-3-[3-(β-d-glucopyranosyloxy)-2-hydroxy-3-methyl-butyl]-coumarin were isolated from the leaves of Dorstenia foetida (Moraceae) along with the known compounds psoralen, bergapten, isopimpinellin, phellopterin, 5-methoxychalepensin and turbinatocoumarin. Further furanocoumarins were characterized by ESI-MS/MS investigations. The nonpolar extracts of D. foetida exhibit antifungal, antibacterial and cytotoxic activity, however, no anthelminthic activity.     

DPP-4 inhibition increases GIP and decreases GLP-1 incretin effects during intravenous glucose tolerance test in Wistar rats

GIP metabolite [GIP (3-42)] and GLP-1 metabolite [GLP-1 (9-36) amide] have been reported to differ with regard to biological actions. Systemic DPP-4 inhibition can therefore reveal different actions of GIP and GLP-1. In catheter wearing Wistar rats, insulinotropic effects of equipotent doses of GIP (2.0 nmol/kg) and GLP-1 (7-36) amide (4.0 nmol/kg) and vehicle were tested in the absence/presence of DPP-4 inhibition. Blood glucose and insulin were frequently sampled. DPP-4 inhibitor was given at -20 min, the incretin at -5 min and the intravenous glucose tolerance test (0.4 g glucose/kg) commenced at 0 min. G-AUC and I-AUC, insulinogenic index and glucose efflux, were calculated from glucose and insulin curves. Systemic DPP-4 inhibition potentiated the acute GIP incretin effects: I-AUC (115±34 vs. 153±39 ng·min/ml), increased the insulinogenic index (0.74±0.24 vs. 0.99±0.26 ng/mmol), and improved glucose efflux (19.8±3.1 vs. 20.5±5.0 min?1). The GLP-1 incretin effects were diminished: I-AUC (124±18 vs. 106±38 ng·min/ml), the insulinogenic index was decreased (0.70±0.18 vs. 0.50±0.19 ng/mmol), and glucose efflux declined (14.9±3.1 vs. 11.1±3.7 min?1). GLP-1 and GIP differ remarkably in their glucoregulatory actions in healthy rats when DPP-4 is inhibited. These previously unrecognized actions of DPP-4 inhibitors could have implications for future use in humans.     

A novel arginine methyltransferase inhibitor with cellular activity

Via virtual screening we identified a thioglycolic amide as an arginine methyltransferase (PRMT) inhibitor and tested it and related compounds against the fungal PRMT RmtA and human PRMT1. Compound RM65 was the most potent druglike inhibitor (IC(50)-PRMT1: 55.4 microM) and showed histone hypomethylation in HepG2 cells. Docking studies proposed binding at the substrate and SAM cofactor binding pocket. It may serve as a lead for further PRMT inhibitors useful for the treatment for hormone dependent cancers.     

Circular structure of the genome of phage ?H in a lysogenic Halobacterium halobium

Summary Phage H is a temperate phage, i.e., it can establish lysogeny in the archaebacterium Halobacterium halobium. H-lysogens are immune to phage infection and phage production is spontaneously induced at a rate of about 10^-7. In the prophage state. H DNA exists as a covalently closed circle of 57 kb.The frequent occurrence of clones carrying the phage genome but unable to produce phage is another proof of the high variability of DNA in H. halobium. In one such strain, R₁-3, the phage genome has undergone a structural change which may have abolished an essential phage gene.     

Die postnatale Funktionsentwicklung der Nebenniere beim Goldhamster (Mesocricetus auratus)

Zusammenfassung An 80 Nebennieren des Goldhamsters (Mesocricetus auratus) wird die Funktionsentwicklung des Markorgans mit Hilfe der Chromat- und Jodatreaktion untersucht.Chromatpositive Granula als Zeichen des Vorhandenseins von Catecholaminen können erstmalig einen Tag postnatal, jodatpositive als Zeichen der Existenz von Noradrenalin erst am 17. Tag post partum nachgewiesen werden. Das Verteilungsmuster chromat- und jodatpositiver Zellen wird beschrieben. Die Befunde werden diskutiert.

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Summary With the help of the iodate- and chromate-reaction the functional development of the medulla of the suprarenal gland ist investigated in 80 suprarenal glands of golden hamsters (Mesocricetus auratus).Chromate-positive granules, indicating the presence of catecholamines, can be observed one day post natum, whereas iodate-positive granules, indicating the presence of noradrenalin, appear only on the 17th day post partum. The distribution pattern of the chromate- and iodate-positive cells is described. The results are discussed.

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Mit Unterstützung durch die Deutsche Forschungsgemeinschaft.