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881.
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Maternal diabetes adversely affects AMP-activated protein kinase activity and cellular metabolism in murine oocytes 总被引:1,自引:0,他引:1
Ratchford AM Chang AS Chi MM Sheridan R Moley KH 《American journal of physiology. Endocrinology and metabolism》2007,293(5):E1198-E1206
Maternal diabetes is associated with an increased risk of miscarriages and congenital anomalies. Preovulatory oocytes in murine models also experience maturational delay and greater granulosa cell apoptosis. The objective of this study was to examine whether maternal diabetes influences preovulatory oocyte metabolism and impacts meiotic maturation. Streptozotocin-induced diabetic B6SJLF1 mice were superovulated, and oocytes were collected at 0, 2, and 6 h after human chorionic gonadotropin (hCG) injection. Individual oocyte concentrations of ATP, 5'-AMP, glycogen, and fructose-1,6-phosphate (FBP) and enzyme activities of glucose-6-phosphate dehydrogenase (G6PDH), adenylate kinase, hydroxyacyl-CoA dehydrogenase (Hadh2), and glutamic pyruvate transaminase (Gpt2) were measured. Protein levels of phosphorylated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) were also measured. ATP levels were significantly lower in oocytes from diabetic mice, and the percent change in the AMP-to-ATP ratio was significantly higher in these oocytes. In contrast, activities of Hadh2 and Gpt2, two enzymes activated by AMPK, were significantly less in these oocytes. Additionally, glycogen and FBP levels, both endogenous inhibitors of AMPK, were elevated. Phosphorylated ACC, a downstream target of AMPK, and phosphorylated AMPK were both decreased in diabetic oocytes, thus confirming decreased AMPK activity. Finally, addition of the activator AICAR to the in vitro maturation assay restored AMPK activity and corrected the maturation defect experienced by the oocytes from diabetic mice. In conclusion, maternal diabetes adversely alters cellular metabolism leading to abnormal AMPK activity in murine oocytes. Increasing AMPK activity in these oocytes during the preovulatory phase reverses the metabolic changes and corrects delays in meiotic maturation. 相似文献
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Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli 总被引:5,自引:0,他引:5
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Objective
Choosing to undertake a CT scan relies on balancing risk versus benefit, however risks associated with CT scanning have generally been limited to broad anatomical locations, which do not provided adequate information to evaluate risk against benefit. Our study aimed to determine differences in radiation dose and risk estimates associated with modern CT scanning examinations when computed for clinical protocols compared with those using anatomical area.Methods
Technical data were extracted from a tertiary hospital Picture Archiving Communication System for random samples of 20–40 CT examinations per adult clinical CT protocol. Organ and whole body radiation dose were calculated using ImPACT Monte Carlo simulation software and cancer incidence and mortality estimated using BEIR VII age and gender specific lifetime attributable risk weights.Results
Thirty four unique CT protocols were identified by our study. When grouped according to anatomic area the radiation dose varied substantially, particularly for abdominal protocols. The total estimated number of incident cancers and cancer related deaths using the mean dose of anatomical area were 86 and 69 respectively. Using more specific protocol doses the estimates rose to 214 and 138 incident cancers and cancer related deaths, at least doubling the burden estimated.Conclusions
Modern CT scanning produces a greater diversity of effective doses than much of the literature describes; where a lack of focus on actual scanning protocols has produced estimates that do not reflect the range and complexity of modern CT practice. To allow clinicians, patients and policy makers to make informed risk versus benefit decisions the individual and population level risks associated with modern CT practices are essential. 相似文献888.
Background
It has been hypothesized that human milk oligosaccharides (HMOs) confer systemic health benefits to breastfed infants; however, plausible mechanisms for some effects, such as systemic immunomodulation, require HMOs to access the bloodstream of the developing infant. While small concentrations of HMOs have been detected in the urine of breastfed infants there are no published studies of these oligosaccharides accessing the plasma compartment of breastfed infants. Here we determined the relative fractions of several ingested HMOs in infant urine and plasma. Plasma from formula-fed infants was used as a control.Methods
Using gas chromatography/mass spectrometry (GC/MS), liquid chromatography/mass spectrometry/tandem mass spectrometry (LC/MS/MS), and high performance liquid chromatography (HPLC), we analyzed the urine and plasma from 17 healthy formula-fed infants and 16 healthy breast-fed infants (and the milk from their mothers).Results
Multiple HMOs were detected in the urine and plasma of breastfed infants, but not in formula-fed infants. Levels of 2′-fucosyllactose (2′FL), 3FL and lacto-N-neotetraose (LNnT) in both plasma (r = 0.98, p<0.001; r = 0.75, p = 0.002; r = 0.71, p = 0.004) and urine (r = 0.81, p<0.001; r = 0.56, p = 0.026; NS) correlated significantly with concentrations in the corresponding breast milk. The relative fractions of HMOs were low, 0.1% of milk levels for plasma and 4% of milk levels for urine. Within the breastfed cohort, there were significant differences between secretor and nonsecretor groups in levels of several fucosylated HMOs.Conclusion
At least some ingested HMOs are absorbed intact into the circulation and excreted in the urine and their concentrations in these fluids correlate with levels of the corresponding mother''s milk. While relative fractions of absorbed HMOs were low, these levels have been shown to have biological effects in vitro, and could explain some of the postulated benefits of human milk. 相似文献889.
Rachael E. Stebbing Susan C. Irvin Efraín E. Rivera-Serrano Karl W. Boehme Mine Ikizler Jeffrey A. Yoder Terence S. Dermody Barbara Sherry 《Journal of virology》2014,88(5):2572-2583
Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: μ2, σ2, and λ2. We demonstrate for the first time that μ2 is phosphorylated, contains a functional ITAM, and activates NF-κB. Specifically, μ2 and μNS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the μ2 ITAM. Moreover, both the μ2 ITAM and Syk are required for maximal μ2 activation of NF-κB. A mutant virus lacking the μ2 ITAM activates NF-κB less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-β) than does wild-type virus despite similar replication. Notably, the consequences of these μ2 ITAM effects are cell type specific. In fibroblasts where NF-κB is required for reovirus-induced apoptosis, the μ2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-κB is not required for apoptosis, the μ2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the μ2 ITAM on viral spread reflects the cell type-specific effects of NF-κB and IFN-β. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host. 相似文献
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Kalliolias GD Gordon RA Ivashkiv LB 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(11):7047-7056
IL-27 is a pleiotropic cytokine with both activating and inhibitory functions on innate and acquired immunity. IL-27 is expressed at sites of inflammation in cytokine-driven autoimmune/inflammatory diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and sarcoidosis. However, its role in modulating disease pathogenesis is still unknown. In this study, we found that IL-27 production is induced by TNF-α in human macrophages (MΦ) and investigated the effects of IL-27 on the responses of primary human MΦ to the endogenous inflammatory cytokines TNF-α and IL-1. In striking contrast to IL-27-mediated augmentation of TLR-induced cytokine production, we found that IL-27 suppressed MΦ responses to TNF-α and IL-1β, thus identifying an anti-inflammatory function of IL-27. IL-27 blocked the proximal steps of TNF-α signaling by downregulating cell-surface expression of the signaling receptors p55 and p75. The mechanism of inhibition of IL-1 signaling was downregulation of the ligand-binding IL-1RI concomitant with increased expression of the receptor antagonist IL-1Ra and the decoy receptor IL-1RII. These findings provide a mechanism for suppressive effects of IL-27 on innate immune cells and suggest that IL-27 regulates inflammation by limiting activation of MΦ by inflammatory cytokines while preserving initial steps in host defense by augmenting responses to microbial products. 相似文献