Cholesterol metabolism,pancreatic β-cell function and diabetes

Cholesterol plays an essential role in determining cell membrane physico-chemical characteristics and functions. A proper membrane structure is critical in pancreatic β-cells for glucose-mediated insulin secretion, and alterations in cellular cholesterol content may negatively affect this process, leading to β-cell dysfunction. The low density lipoprotein receptor (LDL-R) appears to play a relevant role in ß-cell dysfunction due to cholesterol accumulation. This observation raised the question of whether hypocholesterolemic drugs which increase LDL-R expression might bear diabetogenic properties, thus increasing the risk of new-onset diabetes or worsen glycaemic parameters in diabetic patients.Being at higher cardiovascular risk, diabetic patients are usually treated with hypolipidemic drugs to correct the atherogenic dyslipidemia characteristic of this pathological condition. Statin therapy has been associated with an increased incidence of new-onset diabetes (NOD), being the diabetogenic effect depending on the type and dose of statin. However, it is worth noting that the benefits on cardiovascular mortality largely exceed the increased risk associated with the development of diabetes. Although genetic variants associated with lower levels of LDL-C are also associated with an increased NOD risk, clinical trials with lipid-lowering drugs other than statins, namely ezetimibe or monoclonal antibodies against PCSK9, did not observe an increase of developing diabetes.In summary, molecular evidence clearly points to a key role for cholesterol homeostasis in pancreatic β-cell function which, in humans, is negatively affected by statins. Available data exclude that this could be the case for other hypocholesterolemic approaches, but long-term studies are warranted to explore this critical aspect.     

Life time—circadian clocks,mitochondria and metabolism

A functional circadian clock has long been considered a selective advantage. Accumulating evidence shows that the clock coordinates a variety of physiological processes in order to schedule them to the optimal time of day and thus to synchronize metabolism to changes in external conditions. In mitochondria, both metabolic and cellular defense mechanisms are carefully regulated. Abnormal clock function, might influence mitochondrial function, resulting in decreased fitness of an organism.     

α-Synuclein and dopamine metabolism

α-Synuclein (α-Syn), a 140-amino-acid protein richly expressed in presynaptic terminals in the central nervous system, has been shown to play a central role in the pathogenesis of Parkinson’s disease. Although the normal functions of α-Syn remain elusive, accumulating evidence shows that the molecule is involved in multiple steps related to dopamine metabolism, including dopamine synthesis, storage, release, and uptake. The regulatory effect of α-Syn on dopamine metabolism is likely to tone down the amount of cytoplasmic dopamine at nerve terminals, thereby limiting its conversion to highly reactive oxidative molecules. Formation of α-Syn protofibrils triggered by factors such as gene mutations and environmental toxins can make the molecule lose its normal functions, leading to disrupted homeostasis of dopamine metabolism, increased cytoplasmic dopamine levels, and enhanced oxidative stress in dopaminergic neurons. The enhanced oxidative stress will, in turn, exacerbate the formation of α-Syn protofibrils and drive the neurons into a vicious cycle, which will finally result in the selective degeneration of the dopaminergic neurons associated with Parkinson’s disease.     

Lipids,lipid metabolism and Kaposi’s sarcoma-associated herpesvirus pathogenesis

Lipids are essential for mammalian cells to maintain many physiological functions. Emerging evidence has shown that cancer cells can develop specific alterations in lipid biosynthesis and metabolism to facilitate their survival and various malignant behaviors. To date, the precise role of cellular lipids and lipid metabolism in viral oncogenesis is still largely unclear with only a handful of literature covering this topic to implicate lipid metabolism in oncogenic virus associated pathogenesis. In this review, we focus on the role of lipid biosynthesis and metabolism in the pathogenesis of the Kaposi’s sarcoma-associated herpesvirus, a common causative factor for cancers arising in the immunocompromised settings.

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Are there connections between phenol metabolism,ascorbate metabolism and membrane integrity in leaves of boron-deficient sunflower plants?

The influence of soluble phenol concentration and polyphenoloxidase activity in leaves of both B‐deficient and B‐sufficient sunflower plants ( Helianthus annuus L. cv. Frankasol) on plasma membrane permeability was investigated, A study was also undertaken as to whether or not the incubation of B‐deficient leaves in ascorbate‐ and calcium‐containing solutions has a beneficial effect on plasma membrane integrity. Plants were cultivated under controlled environmental conditions with deficient and sufficient B supply and different light intensity to provoke changes in phenol metabolism. Analysis of membrane permeability (measured by potassium efflux), soluble phenol concentration and polyphenoloxidase (EC 1.10.3.1) activity of leaves showed that there was no correlation between these parameters. Furthermore, incubation in solutions containing ascorbate and calcium did not decrease the enhanced membrane permeability due to B deficiency, which could, however, be lowered by boric acid application. In summary, the results suggest that B does not maintain plasma membrane integrity by complexing phenols or inhibiting polyphenoloxidase activity, thereby preventing damage by oxygen free radicals. Ascorbate metabolism or calcium‐related disorders seem also not to be involved. It is therefore likely that B has a direct function at the membrane, possibly by stimulating membrane‐related enzymes, or in a structural role similar to that reported for the cell wall.     

Acetate and hydrogen metabolism in intact and disintegrated granules from an acetate-fed, 55° C,UASB reactor

Summary To investigate mass-transfer resistance in granules, the effect of disintegration on the specific methanogenic activity (SMA) of acetate-grown anaerobic, thermophilic (55°C) granules was measured. Four different methods of disintegration were used; vortex mixing, ultra-sound, blending and repeated syrine aspiration. When H₂/CO₂ was used as the substrate, disintegrated granules showed a higher SMA than intact granules. However, with acetate as substrate, no effect was observed when granules disintegrated using a vortex mixer or ultra-sound, whereas both the blender- and syringe-treated granules had lower SMAs compared to intact granules. An effectiveness factor, , the ratio of the SMA of disintegrated granules to the SMA of intact granules, was presented and found useful for describing the effectiveness of disintegration to relieve mass-transfer limitation on the granules. Offprint requests to: B. K. Ahring     

Microbial metabolism of quorum-sensing molecules acyl-homoserine lactones, γ-heptalactone and other lactones

The cell-to-cell communication of microorganisms is known to be via exertion of certain chemical compounds (signal molecules) and is referred to as quorum sensing (QS). QS phenomenon is widespread in microbial communities. Several Gram-positive and Gram-negative bacteria and fungi use lactone-containing compounds (e.g. acyl-homoserine lactones (AHLs), γ-heptalactone, butyrolactone-I) as signalling molecules. The ability of microorganisms to metabolise these compounds and the mechanisms they employ for this purpose are not clearly understood. Many studies, however, have focused on identifying AHL and other lactone-degrading enzymes produced by bacteria and fungi. Various strains that are able to utilise these signalling molecules as carbon and energy sources have also been isolated. In addition, several reports have provided evidence on the involvement of lactones and lactone-degrading enzymes in numerous biological functions. These studies, although focused on processes other than metabolism of lactone signalling molecules, still provide insights into further understanding of the mechanisms employed by various microorganisms to metabolise the QS compounds. In this review, we consider conceivable microbial strategies to metabolise AHL and other lactone-containing signalling molecules such as γ-heptalactones.     

Nematode numbers,biomass and respiratory metabolism in a beech woodland—Wytham Woods,Oxford

Summary The mean annual population density of nematodes in the litter and upper 6 cm of soil was found to be 368,000 m^-2. Mean individual live weight biomass approximated 0.2 g and mean biomass was calculated to be 74.6 mg live weight m^-2. No evidence of seasonal vertical migration between the litter, 0–3 cm and 3–6 cm strata was found and on average these strata contained 21.9, 46.2 and 31.9% respectively of the total number of nematodes recovered. The equivalent biomass values were 26.14, 56.57, and 17.29%. Total numbers revealed a general picture of low densities in spring and high ones in early winter, whereas biomass m^-2 was low in late summer — autumn and high in winter. The annual oxygen consumption of the extracted nematodes was calculated to approximate 0.211 m^-2 (4.0 kJ m^-2) but when corrected for the effect of individual biomass (weight specific oxygen uptake) was equivalent to an energy expenditure 6.0 kJ m^-2 which in its turn, because of the efficiencies of extraction, probably accounts for only 87% of the total energy expenditure by the nematode fauna. The nematodes were estimated to be responsible for a minimum of 0.11% to a maximum of 0.13% of the total soil respiration. A production/biomass ratio of 5.16 was estimated as was a net population production efficiency of 36.63%.     

Snail numbers,biomass and respiratory metabolism in a beech woodland — Wytham Woods,Oxford

Summary Two methods of extraction were used in the estimation of snail population densities in woodland litter. The time-consuming-Vágvölgyi technique proved to be 6.25 times more efficient than infra-red heat extraction but it was shown that the results obtained by the latter method could be easily corrected to conform with those of the former.Snail density varied with season (Winter, 1,000–1,250 m^-2, Summer, 50–600 m^-2), the annual mean density being 645 m^-2. The annual mean ash-free dry weight biomass was 176 mg m^-2 while annual population metabolism equalled 0.8941 O₂ (=17.84 kJ m^-2 yr^-1).Two independent estimates of the energy equivalent of food consumption gave rise to values of 25.37 and 57.98 kJ m^-2 yr^-1, these respectively account for 0.54 and 1.23% of the known ground litter disappearance of 4,716.58 kJ (=235 g dry wt. m^-2 yr^-1).     

Intestinal absorption and metabolism of a soluble flavonoid, αG-rutin,in portal cannulated rats

A highly soluble quercetin glycoside, αG-rutin, is a glucose adduct of insoluble rutin, and intestinal absorption and metabolism of αG-rutin has not been known. We investigated the intestinal absorption and metabolism of αG-rutin by using portal and duodenal cannulated rats and the isolated rat intestinal mucosa. After a duodenal instillation of αG-rutin (150 μmol), intact αG-rutin, rutin and quercetin were appeared in the portal blood and these concentrations were similarly increased at 15 min. Portal quercetin reached a peak value at 60 min, and the value was higher than those of αG-rutin and rutin at that time. Quercetin-conjugates were also increased 30 min after the instillation. The remaining of αG-rutin metabolites, mainly rutin, in the intestine were 58% of instilled αG-rutin after 150 min. In the experiment by using the isolated mucosa of the jejunum, ileum and cecum, αG-rutin and rutin, but not quercetin, appeared in the serosal sides of all segments, and they were increased linearly from 10 to 100 mmol/l of mucosal αG-rutin. We also showed portal injected αG-rutin was very rapidly cleared from the blood, and appeared a large amount of conjugates. In conclusion, a soluble flavonoid-glycoside, αG-rutin, was absorbed as glycosides into the portal blood. A part of αG-rutin was hydrolyzed to rutin, but not to aglycone, through the intestine.     

Incorporation and metabolism of stearic,oleic, linoleic andα-linolenic acids in Minimal Deviation Hepatoma 7288 C cells

Summary Minimal Deviation Hepatoma 7288 C cells were cultured in confluent layer with labeled stearic, oleic, linoleic and-linolenic acids. The kinetics of incorporation and conversion to higher homologs was studied. The maximum amounts incorporated in nmoles per mg of cellular protein for stearic, oleic, linoleic and-linolenic acids were 39, 115.6, 90 and 230 respectively.-linolenic acid was converted to octadeca-6,9,12,15-tetraenoic acid (18:4), eicosa-11,14,17-trienoic acid (20:3), eicosa-8,11,14,17 and 5,11,14,17-tetraenoic acids (20:4) and eicosa-5,8,11,14,17-pentaenoic acid (20:5), and also to myristic, palmitic, palmitoleic, stearic and oleic acids. By a mathematical approach, the endogenous pool size of-linolenic acid available for conversion to eicosa-5,8,11,14,17-pentaenoic acid, and the capacity of the cell to convert-linolenic acid to eicosa-5,8,11,14,17-pentaenoic acid, were calculated. Both values decreased when the cells were preincubated with unlabeled-linolenic acid.Dedicated to ProfessorLuis F. Leloir on the occasion of his 70th birthday.     

An isotope-dilution,GC–MS assay for formate and its application to human and animal metabolism

Formate, a crucial component of one-carbon metabolism, is increasingly recognized as an important intermediate in production and transport of one-carbon units. Unlike tetrahydrofolate-linked intermediates, it is not restricted to the intracellular milieu so that circulating levels of formate can provide insight into cellular events. We report a novel isotope-dilution, GC–MS assay employing derivatization by 2,3,4,5,6-pentafluorobenzyl bromide for the determination of formate in biological samples. This assay is robust and sensitive; it may be applied to the measurement of formate in serum, plasma and urine. We demonstrate how this method may be applied by providing the first characterization of formate levels in a human population; formate levels were higher in males than in females. We also show how this procedure may be applied for the measurement of in vivo kinetics of endogenous formate production in experimental animals.     

β-Alanine metabolism and high salinity stress in the sea anemone,Bunodosoma cavernata

Summary During high salinity stress, -alanine accumulates to high levels in the sea anemone,Bunodosoma cavernata. Following a salinity increase from 26 to 40 -alanine increased 28-fold from 1.5 to 41.9 moles/g dry weight. Both whole animal studies and experiments with cell free homogenates indicate that under high salinity conditions an increase in the rate of -alanine synthesis from aspartic acid as well as a decrease in the rate of -alanine oxidation are responsible for the observed accumulation of -alanine. The rate of aspartic acid decarboxylation to -alanine is about 3 times greater in anemones acclimated to 40 than for those in normal salinity water (26). -alanine oxidation to CO₂ and acetyl-CoA proceeds 2.5 to 3 times slower in high salinity adaptedB. cavernata than in those acclimated to normal salinity. There is always a rapid degradation of uracil to -alanine, but this does not change with salinity.Abbreviations CASF cold acid soluble fraction - FAA free amino acids - MES 2(N-morpholino) ethane sulfonic acid - NPS ninhydrin positive substances - PCA perchloric acid - TCA trichloroacetic acid     

Origin of sucrose metabolism in higher plants: when,how and why?

Since the discovery of sucrose biosynthesis, considerable advances have been made in understanding its regulation and crucial role in the functional biology of plants. However, important aspects of this metabolism are still an enigma. Studies in cyanobacteria and the publication of the sequences of several complete genomes have recently significantly increased our knowledge of the structures of proteins involved in sucrose metabolism and given us new insights into their origin and further evolution.