Author: BioactiveCompoundLibrary

The current literature is mixed with regard to the efficacy of increased meal frequency regimens in causing metabolic alterations, particularly in relation to weight management. Increasing eating frequency has been postulated to increase metabolism, reduce hunger and food cravings, improve glucose and insulin control, and reduce body weight and body fat storage. However, there are suggestions from experimental studies to date as well as from cross-sectional epidemiological studies, in which energy intake underreporting is taken into account, that greater eating frequency may promote positive energy balance in free-living adults. On the other hand, well-controlled intervention studies do not support an association between eating frequency and body weight. Eating three meals a day is suggested to result in a higher postprandial insulin peak due to the higher carbohydrate intake and thereby increasing cellular glucose uptake and oxidation. As a consequence, dietary fat is primarily stored in the adipose LY294002 PI3K inhibitor tissue during the postprandial phase. In between meals, the fasting state, when insulin levels are decreased and lipolysis is activated this substrate flux is reversed. Very well-controlled trials are necessary to resolve speculation that the current increase in snacking habits contribute by its metabolic changes during the day to the escalating obesity epidemic. For that reason, the aim of the present study was to investigate the mechanistic effects of meal frequency on 24 hr insulin, glucose profiles, appetite profiles and substrate partitioning under well-controlled energy balance conditions. We hypothesized that in an energy balanced situation eating 3 meals a day gives better opportunities to turn the metabolic flux into a prolonged fasting state with a higher fat oxidation compared to eating 14 meals a day where subjects remain in a continuous postprandial status. Increasing meal frequency resulted in significantly lower peaks, higher troughs and constant glucose and insulin values compared with the LFr diet under isoenergetic wellcontrolled conditions in lean healthy males. Nevertheless, no effect of meal frequency was observed on substrate partitioning of CHO and fat. Protein oxidation, RMR and appetite control increased significantly in the LFr diet compared with the HFr diet. Our results are in accordance with findings from Solomon et al., who found that 2 meals per day led to greater fluctuations in glucose, insulin, and ghrelin responses compared with the 12 meals per day assessed throughout an 8-h period. Nevertheless, the lower AUC of glucose in the LFr indicates glycemic improvements, we suggest that this can lead to a better body weight control on the long term. The CGMS data showed the glycemic excursions and clearly indicated the differences between the two diets during the day. However, baseline values are somewhat lower than the glucose levels measured at the fixed time points. The accuracy of the sensor has been discussed and discrepancies occasionally were seen between interstitial tissue and blood glucose levels in detecting low glucose values.

The two systems are not equally activated in response to stress, and recent studies demonstrate that the HPA axis response is stronger to socialevaluative types of stress, while the SNS is stronger in response to stressors causing anxiety and fear. These CPI-613 measures are thus frequently included in stress studies. It can be expected that there is a cross-talk between the two stress systems, i.e. that they interact in relation to the perception and processing of psychosocial stress. However, no systematic studies have looked at this interaction – specifically what happens to one system if the other one failed to respond has to the best of our knowledge not been previously investigated. The aim of the present study was thus to investigate the interaction between the HPA and SNS systems by blocking the acute HPA axis response and then exposing the subject to an acute stressful situation. The research question led to the development of a new stress paradigm: a combination of the dexamethasone suppression test and the TSST, termed “The combined Dexamethasone/TSST paradigm.” The DST is commonly used to test negative feedback inhibition of the HPA axis. As a potent synthetic glucocorticoid, dexamethasone primarily binds to GC receptors in the periphery, and the pituitary, resulting in an almost complete suppression of pituitary release of ACTH for several hours, lasting into the morning following DEX administration the evening before. The lack of ACTH then leads further to almost complete absence of cortisol since the adrenal cortex is not stimulated. It is important to differentiate the effects of a low to moderate administration of DEX between the brain and the periphery. DEX does not cross the blood-brain barrier and thus will not reach receptors above the level of the pituitary in the central nervous system, thus depriving the CNS from any stimulation with glucocorticoids, and causing a hypocorticoid state. In contrast, the amounts typically used in the DST lead to a flooding of receptors in the periphery, causing a hypercorticoid state in the body. In the combined Dexamethasone/TSST paradigm, subjects are exposed to the TSST after DEX has been given the night before, and thus this paradigm allows to test the response of the individual to an acute and strong stressor at the psychological level and the physiological level, in the absence of an HPA axis stress response. Given the role of the HPA system in coping with stress, and the interaction between the different stress systems in the human organism, we hypothesized that the blockade of a cortisol response to acute stress will result in an increased perception of psychological stress, and an increased activity of the SNS. The goal of the present study was investigate the effects of suppressing the HPA axis system in the presence of an acute stressor on blood pressure, heart rate, alpha-amylase, and the subjective experience of stress. In order to do so, we applied an HPA axis suppressant prior to administering acute psychosocial stress.

Increased ROS production is common to different models of cellular insulin resistance, including those induced by TNF-a, insulin and palmitate treatments. Moreover, mitochondria-targeted Wortmannin antioxidant treatment partially preserves insulin sensitivity both in vivo and in vitro. In the present study, we observed that both urinary F2-isoprostane and skeletal muscle protein carbonyls were increased, with the latter increased as early as 3 days of overfeeding. This finding suggests that increased oxidative stress may be an early event during over-nutrition in humans. Protein carbonylation is a nonreversible modification by highly reactive aldehydes, by-products of lipid peroxidation that cause loss of function or trigger degradation of proteins with a cysteine, histidine or lysine side chain, typically enzymes. Carbonylated proteins, including the antioxidants thioredoxin, thioredoxin reductase, glutathione peroxidase, fatty acid binding protein and cytosolic and mitochondrial NADP+ -dependent isocitrate dehydrogenase isoforms, were 2–3 fold higher in adipose tissue collected from high fat-high sucrose fed mice compared to chow fed mice. We speculate that antioxidants and enzymes involved in oxidative stress and/or insulin action in skeletal muscle may also be potential targets for carbonylation and degradation during the overfeeding diet. Also, in the postprandial state, fat and carbohydrate have a differential effect on the oxidative stress response. Importantly, participants in the present study were placed on the same snacks, rich in both sugar and fat, to increase their energy intake and thus we cannot differentiate the effect of particular macronutrients on the outcomes. The two principal sites of superoxide generation in mitochondria are complexes I and III of the electron transport chain. In this study, we observed an increase in protein content of complex I, but not complex III, at day 3 of overfeeding. Superoxide leaking from the mitochondrial complexes is dismutated rapidly into hydrogen peroxide by MnSOD and Cu/ZnSOD in the mitochondrial matrix and the inter-membrane space, respectively. Consistent with this, it has previously been shown that MnSOD transgenic mice are partially protected from high fat feeding-induced insulin resistance. In the present study, we observed that MnSOD was increased transiently, possibly in an attempt to limit oxidative damage. We speculate that the lack of a sustained induction of the anti-oxidative systems, including MnSOD and UCP3 may have contributed to the increase in oxidative stress that was observed following overfeeding in this study. Previous studies have shown that high fat diet increased UCP3 protein in rodent mitochondria and isocaloric 65% fat diet increased UCP3 mRNA expression in lean, but not obese humans. However, to our knowledge protein content of UCP3 during overfeeding has not previously been investigated. Pre-diabetes and type 2 diabetes are characterized by reduced expression and protein levels of PGC1a, a master metabolic regulator of mitochondrial biogenesis. However, it is unclear whether this is a cause or consequence of insulin resistance. In the present study, the protein levels of PGC1a and the complexes of the mitochondrial electron transport chain were increased at day 3, but these returned to basal at day 28.

Spearman’s correlation coefficent was employed to assess whether the abundances of two taxa were independent or associated. Obesity is closely linked with insulin resistance, and increasing evidence suggests that reactive oxygen species generated in muscle mitochondria may impair insulin signalling in animal and cellular models. These studies have also shown that over – expression of muscle-specific antioxidant enzymes, or treatment with the mitochondrial superoxide dismutase mimetics and mitochondria-specific free radical scavengers, protects rodents from developing insulin resistance following high fat overfeeding. Whether sustained high fat overfeeding will elevate these markers in non-obese humans is not yet clear, although a single high fat meal increases mitochondrial ROS emission in lean and obese humans. Moreover, both systemic markers of oxidative stress and ROS production in skeletal muscle mitochondria are reported to be elevated in human obesity. A reduction in skeletal muscle mitochondrial number and/or maximal oxidative capacity is also reported in human obesity, aging and type 2 diabetes and is postulated to be causal in the development of obesity-associated insulin resistance. The mitochondrial dysfunction hypothesis of insulin resistance has arisen SCH772984 mainly from studies showing reduced expression of genes involved in mitochondrial biogenesis or reduced ATP production in healthy relatives of type 2 diabetes individuals. Reduced expression of genes involved in mitochondrial biogenesis is also observed following isocaloric high fat diet, or following prolonged lipid infusion with the parallel induction of peripheral insulin resistance in healthy humans. However, other studies have shown that mitochondrial dysfunction is not a prerequisite for insulin resistance in humans. Rodents that are fed a high fat diet for 4–20 weeks have increases in the more functional measures of skeletal muscle oxidative capacity, despite developing insulin resistance and diabetes. Together, these findings challenge the role of mitochondrial dysfunction as a primary factor in the development of insulin resistance. We, and others, have previously shown that short term overfeeding decreases the glucose infusion rate necessary to maintain euglycemia during a hyperinsulinemic-euglycemic clamp. In this study, we focused on factors in skeletal muscle that may contribute to the insulin resistance that was observed during overfeeding. The specific aims were to determine the effects of 3 and 28 days of overfeeding on skeletal muscle markers of oxidative stress, and mitochondrial content and function. We hypothesized that overfeeding would increase oxidative stress and this would be associated with a reduction in markers of mitochondrial content and function. Short term overfeeding reduces insulin sensitivity in healthy non-obese individuals, however the mechanisms underlying this are unclear. In this study, we report that whilst the reduction in insulin sensitivity following overfeeding was modest, it occurred without a reduction in any of the markers of mitochondrial content and function examined. However, we observed that systemic and skeletal muscle markers of oxidative stress were increased, and therefore may have contributed to the insulin resistance observed. The role of ROS in mediating insulin resistance is debated.

This is of particular interest because PMNs are the primary leukocyte involved in clearing bacteria corneal infections. Interestingly, it was shown that Staphylococcus aureus cells coated with serratamolide were also protected from PMN phagocytosis. This leads us to speculate that the presence of S. marcescens-derived serratamolide in contact lens cases or on lenses may better enable other pathogenic bacteria to establish ocular infections. It was noted that swrW was found in,35% of the tested ocular clinical isolates, and 40% of the swrW containing isolates were hemolysis positive on blood agar plates, suggesting that hemolytic strains express swrW sufficiently to produce hemolysis. In support of this premise, mutation of swrW in three out of five hemolysis positive strains severely reduced or eliminated hemolysis zones on blood agar plates. Of the swrW negative strains, 42% were hemolysis positive, indicating that other mechanisms of hemolysis are present in ocular clinical isolates. Another gene, swrA, present in some strains of S. marcescens is necessary for production of serrawettin W2, may account for the hemolysis positive phenotype of swrW negative strains. There is genetic evidence that the swrA-dependent product serrawettin W2, a structurally distinct surfactant, can act as a hemolytic agent. Serrawettin W2, consisting of five amino acids with a single acyl chain, is detected by Caenorhabditis elegans as a chemical signal to avoid S. marcescens colonies. Transposon mutation of the swrA gene, in strain Db10, led to the loss of hemolysis zones on blood agar plates that was correlated with the loss of serrawettin W2. Whereas the hemolysis and cytotoxicity data presented here suggest that serratamolide may contribute to bacterial infections, the absence of the swrW gene in many pathogenic and contact lens associated strains indicate that SwrW is not a requirement for colonization of contact lenses or for causing ocular diseases. Serratamolide may be more relevant in environmental settings than for human infections, as the majority of pigmented strains tested had the swrW gene, and pigmentation is generally associated with environmental isolates, whereas clinical isolates are almost exclusively non-pigmented. In an environmental setting serratamolide could contribute to the competitiveness of S. marcescens as it is a broad spectrum antibiotic. Furthermore, it was shown that a surfactant produced by Serratia sp. ATCC 39006 facilitates the dispersal of the antibiotic pigment prodigiosin, and serratamolide may act in an analogous fashion. Serratamolide has shown promise as an anticancer agent for its proapoptotic effect upon breast cancer and B-cell chronic lymphocytic leukemia cells. Therefore, understanding the pathways that control serratamolide production may yield improved ways to generate this cyclodepsipeptide. Further studies will focus on determining the regulatory pathway by which CRP regulates serratamolide production, and characterizing the role this surfactant plays in host-pathogen interactions. The life cycle of Plasmodium takes place in a Torin 1 vertebrate and in an insect host. When the mosquito takes up a bloodmeal from an infected host, it ingests sexual stages of Plasmodium, the gametocytes. In the mosquito, the gametocytes develop into gametes which fertilise to form a zygote.