Impacts on Sirtuin Function and Bioavailability of the Dietary Bioactive Compound Dihydrocoumarin

The plant secondary metabolite and common food additive dihydrocoumarin (DHC) is an inhibitor of the Sirtuin family of NAD⁺-dependent deacetylases. Sirtuins are key regulators of epigenetic processes that maintain silent chromatin in yeast and have been linked to gene expression, metabolism, apoptosis, tumorogenesis and age-related processes in multiple organisms, including humans. Here we report that exposure to the polyphenol DHC led to defects in several Sirtuin-regulated processes in budding yeast including the establishment and maintenance of Sir2p-dependent silencing by causing disassembly of silent chromatin, Hst1p-dependent repression of meiotic-specific genes during the mitotic cell cycle. As both transient and prolonged exposure to environmental and dietary factors have the potential to lead to heritable alterations in epigenetic states and to modulate additional Sirtuin-dependent phenotypes, we examined the bioavailability and digestive stability of DHC using an in vivo rat model and in vitro digestive simulator. Our analyses revealed that DHC was unstable during digestion and could be converted to melilotic acid (MA), which also caused epigenetic defects, albeit less efficiently. Upon ingestion, DHC was observed primarily in intestinal tissues, but did not accumulate over time and was readily cleared from the animals. MA displayed a wider tissue distribution and, in contrast to DHC, was also detected in the blood plasma, interstitial fluid, and urine, implying that the conversion of DHC to the less bioactive compound, MA, occurred efficiently in vivo.     

End Stage Renal Disease Predicts Increased Risk of Death in First Degree Relatives in the Norwegian Population

BackgroundIncreased risk of end stage renal disease (ESRD) and death in Norwegian living kidney donors has been reported, most of the donors were related to the recipient. The present study investigates risk of death in first degree relatives of ESRD patients.MethodsThe Norwegian Population Registry, The Norwegian Cause of Death Registry and the Norwegian Renal Registry were linked. All citizens born in Norway, alive in 1960 and with at least one registered first degree relative were included; individuals who died during the first year of life were excluded. A cohort-design was used, ESRD in a first degree relative was the main exposure variable and death and causes of death were the main outcome variables. Cox regression statistics were used to investigate mortality risks.Results5 130 600 individuals were included, 27 508 had at least one first degree relative with ESRD. 828 022 died during follow-up, of whom 4105 had a first degree relative with ESRD. Adjusted hazard ratio (aHR) for death was 1.13 (1.09–1.16) in individuals with a relative with ESRD compared to those without a relative with ESRD. Excluding known hereditary renal disease, aHR decreased to 1.12 (1.09–1.15). Cardiovascular death aHR was 1.15 (1.10–1.21), of which cerebrovascular death 1.34 (1.22–1.50). aHR for death due to non-hereditary renal/ureteric disease was 2.29 (1.81–2.91) with renal failure 1.80 (1.26–2.56) and glomerular disease 5.69 (3.88–8.34) as main contributors. Diabetes mellitus death aHR was 1.68 (1.35–2.10). Absolute mortality risks increased most for the oldest cohorts with excess mortality of 148 per 100.000 person years for the cohort born 1920–39 and 218 for the cohort born 1900–1919.ConclusionsESRD in first degree relatives was associated with increased hazard ratio for death. Death due to cardiovascular disease, renal disease and diabetes mellitus increased the most.     

An ODE Model of Early Stages of Atherosclerosis: Mechanisms of the Inflammatory Response

Atherosclerosis is a chronic disease of the large arteries, characterized by fatty cholesterol-filled streaks and plaque build-up within the artery wall. Within the past decade, inflammation has been determined as a crucial factor in all stages of lesion formation, however, many of the mechanisms involved are not yet fully understood. We present a simplified ODE model that explores the role of inflammation in atherosclerosis. The model incorporates two of the main lesion constituents, cholesterol-carrying modified Low Density Lipoproteins (LDLs) and macrophage foam cells. Their complex interactions are combined into general functions, and the long-term model behaviour is investigated through phase plane analysis and simulations. Our results indicate that the underlying mechanisms of macrophage uptake of modified LDL can have a deep impact on the cellular dynamics in the lesion. Our model demonstrates that it is macrophage proliferation and constant signalling to the endothelial cells, rather than an increasing influx of modified LDL, that drives lesion instability.     

The membrane transport system responsible for multidrug resistance is operating in nonresistant cells

Cultured hamster fibroblasts of the DM-15 cell line stained by rhodamine 123 gradually release the dye when placed in dye-free medium. Here we demonstrate that reserpine, verapamil, and trifluoperazine are capable of blocking this release. We also show that reserpine can inhibit the efflux of another dye, phosphine 3R, from DM-15 cells and the release of rhodamine 123 from mouse embryo fibroblasts, four mouse cell lines, and MDCK cells. The three substances that block the release of the dyes are potent inhibitors of the membrane transport system implicated in the phenomenon of multidrug resistance (MDR). By using this system MDR cells can pump many structurally unrelated drugs and dyes, including rhodamine 123 and phosphine 3R, from the cytoplasm to the outer medium. It appears from our results that the membrane transport system responsible for MDR operates slowly in nonresistant cells and can play a role in normal cell physiology.     

Trends in mortality statistics in England and Wales with particular reference to AIDS from 1984 to April 1987

Death certification should be able to provide accurate data on the number of deaths due to AIDS as a basis for predicting future deaths from the syndrome. Trends in deaths from other causes may identify conditions that have not been recognised to be associated with HIV infection. Mortality statistics with reference to AIDS in England and Wales were completed from death certificates. Increases in deaths from selected causes likely to be associated with AIDS or HIV infection suggested that in some patients with HIV infection, AIDS was not stated on the death certificate or subsequently notified by the doctor who signed the certificate. From calculations of excess deaths between the beginning of 1985 and the end of April 1987, compared with 1984 at least 495 deaths possibly associated with HIV infection were estimated to have occurred among men aged 15-54 during that period. In 261 AIDS or HIV infection was stated on the original or amended death entry as the cause of death, and of these 198 were included in the estimated number of excess deaths.Accurate notification of the underlying cause of death and associated diseases is required for the precise monitoring of trends in mortality from AIDS and possible identification of unrecognised conditions associated with HIV infection.