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81.
Raf kinase inhibitory protein (RKIP or PEBP) is an inhibitor of the Raf/MEK/MAP kinase signaling cascade and a suppressor of cancer metastasis. We now show that RKIP associates with centrosomes and kinetochores and regulates the spindle checkpoint in mammalian cells. RKIP depletion causes decreases in the mitotic index, the number of metaphase cells, and traversal times from nuclear envelope breakdown to anaphase, and an override of mitotic checkpoints induced by spindle poisons. Raf-1 depletion or MEK inhibition reverses the reduction in the mitotic index, whereas hyperactivation of Raf mimics the RKIP-depletion phenotype. Finally, RKIP depletion or Raf hyperactivation reduces kinetochore localization and kinase activity of Aurora B, a regulator of the spindle checkpoint. These results indicate that RKIP regulates Aurora B kinase and the spindle checkpoint via the Raf-1/MEK/ERK cascade and demonstrate that small changes in the MAP kinase (MAPK) pathway can profoundly impact the fidelity of the cell cycle. 相似文献
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83.
Summary The acute effect of insulin on 3H incorporation into lipid from glucose was measured in 3T3-L1 fatty fibroblasts cultured with and without insulin at 10 µg/ml for 7 days. Basal lipid synthesis did not differ between control cells and cells treated chronically with insulin. There was no insulin stimulation in treated cells while 3H incorporation into lipid in control cells increased from a basal level of 1.39 to 3.85 nmol/dish/90 min with a maximally-stimulating concentration of insulin. This is the first study of 3T3-L1 fatty fibroblasts which describes a lack of acute insulin responsiveness in cells exposed chronically to insulin as compared to control cells.Abbreviations KRP buffer
Kreb's Ringer phosphate buffer
- BSA
bovine serum albumin
Dr. Pohl is the recipient of Research Career Development Award AM 00183. 相似文献
84.
Oil sands mining is a major disturbance to boreal landscapes in north-eastern Alberta, Canada. Freshwater peatlands dominate the landscape prior to mining, but the post-mining reclamation landscape will have wetlands that span a salinity gradient. Little is known about the native vegetation communities in subsaline and saline marshes in the boreal region, yet these communities offer the best potential for reclamation of wetlands after oil sands mining. The overall intent of this study is to provide information on natural wetland communities along a gradient of salinities that can be used to enhance oil sands wetland reclamation. Our specific study objectives were to: (1) characterize environmental conditions of industrial and natural wetlands, (2) characterize vegetation communities (composition and diversity) in these wetlands, (3) and explore how vegetation communities (composition and diversity) may be influenced by environmental conditions. We surveyed vegetation communities and environmental variables in 25 natural boreal wetlands along a salinity gradient and in 10 industrial marshes in the oil sands mining region. We observed an electrical conductivity (EC) range of 0.5-28 mS cm−1 in the wetlands, indicating that salinity similar to or higher than anticipated for oil sands reclamation is naturally present in some boreal wetlands. We observed low species richness in both industrial and natural wetlands. There were 101 plant species observed in all the wetlands, with 82 species recorded in the natural wetlands and 44 species in industrial wetlands. At the plot level, richness decreased with increasing EC and pH, but increased with soil organic matter. Using Cluster Analysis and indicator species analysis we defined 16 distinct vegetation community types, each dominated by one or two species of graminoid vegetation. In general these communities resembled those of boreal or prairie marshes. Electrical conductivity, pH, and water depth were important factors correlating with community composition of the wetlands, however peat depth and soil organic content did not differ among community types. Not all community types were present in industrial wetlands, indicating that these communities may need to be planted to enhance overall diversity in future reclaimed oil sands wetlands. 相似文献
85.
Sara Borniquel Emmelie Å. Jansson Marsha P. Cole Bruce A. Freeman Jon O. Lundberg 《Free radical biology & medicine》2010,48(4):499-505
Nitric oxide and its metabolites undergo nitration reactions with unsaturated fatty acids during oxidative inflammatory conditions, forming electrophilic nitro-fatty acid derivatives. These endogenous electrophilic mediators activate anti-inflammatory signaling reactions, serving as high-affinity ligands for peroxisome proliferator-activated receptor γ (PPARγ). Here we examined the therapeutic effects of 9- or 10-nitro-octadecenoic oleic acid (OA-NO2) and native oleic acid (OA) in a mouse model of colitis. OA-NO2 reduced the disease activity index and completely prevented dextran sulfate sodium-induced colon shortening and the increase in colonic p65 expression. Increased PPARγ expression was observed in colon samples as well as in cells after OA-NO2 administration, whereas no effect was seen with OA. This induction of PPARγ expression was completely abolished by the PPARγ antagonist GW9662. 5-Aminosalicylic acid, an anti-inflammatory drug routinely used in the management of inflammatory bowel disease, also increased PPARγ expression but to a lesser extent. Altogether, these findings demonstrate that administration of OA-NO2 attenuates colonic inflammation and improves clinical symptoms in experimental inflammatory bowel disease. This protection involves activation of colonic PPARγ. 相似文献
86.
Nicholas K.H. Khoo Volker Rudolph Marsha P. Cole Franca Golin-Bisello Francisco J. Schopfer Steven R. Woodcock Carlos Batthyany Bruce A. Freeman 《Free radical biology & medicine》2010,48(2):230-239
Reactive oxygen species mediate a decrease in nitric oxide (NO) bioavailability and endothelial dysfunction, with secondary oxidized and nitrated by-products of these reactions contributing to the pathogenesis of numerous vascular diseases. While oxidized lipids and lipoproteins exacerbate inflammatory reactions in the vasculature, in stark contrast the nitration of polyunsaturated fatty acids and complex lipids yields electrophilic products that exhibit pluripotent anti-inflammatory signaling capabilities acting via both cGMP-dependent and -independent mechanisms. Herein we report that nitro-oleic acid (OA-NO2) treatment increases expression of endothelial nitric oxide synthase (eNOS) and heme oxygenase 1 (HO-1) in the vasculature, thus transducing vascular protective effects associated with enhanced NO production. Administration of OA-NO2 via osmotic pump results in a significant increase in eNOS and HO-1 mRNA in mouse aortas. Moreover, HPLC-MS/MS analysis showed that NO2-FAs are rapidly metabolized in cultured endothelial cells (ECs) and treatment with NO2-FAs stimulated the phosphorylation of eNOS at Ser1179. These posttranslational modifications of eNOS, in concert with elevated eNOS gene expression, contributed to an increase in endothelial NO production. In aggregate, OA-NO2-induced eNOS and HO-1 expression by vascular cells can induce beneficial effects on endothelial function and provide a new strategy for treating various vascular inflammatory and hypertensive disorders. 相似文献
87.
Kristen Page John R Ledford Ping Zhou Krista Dienger Marsha Wills-Karp 《Respiratory research》2010,11(1):62
Background
Allergic asthma is on the rise in developed countries. A common characteristic of allergens is that they contain intrinsic protease activity, and many have been shown to activate protease-activated receptor (PAR)-2 in vitro. The role for PAR-2 in mediating allergic airway inflammation has not been assessed using a real world allergen.Methods
Mice (wild type or PAR-2-deficient) were sensitized to German cockroach (GC) feces (frass) or protease-depleted GC frass by either mucosal exposure or intraperitoneal injection and measurements of airway inflammation (IL-5, IL-13, IL-17A, and IFNγ levels in the lung, serum IgE levels, cellular infiltration, mucin production) and airway hyperresponsiveness were performed.Results
Following systemic sensitization, GC frass increased airway hyperresponsiveness, Th2 cytokine release, serum IgE levels, cellular infiltration and mucin production in wild type mice. Interestingly, PAR-2-deficient mice had similar responses as wild type mice. Since these data were in direct contrast to our finding that mucosal sensitization with GC frass proteases regulated airway hyperresponsiveness and mucin production in BALB/c mice (Page et. al. 2007 Resp Res 8:91), we backcrossed the PAR-2-deficient mice into the BALB/c strain. Sensitization to GC frass could now occur via the more physiologically relevant method of intratracheal inhalation. PAR-2-deficient mice had significantly reduced airway hyperresponsiveness, Th2 and Th17 cytokine release, serum IgE levels, and cellular infiltration compared to wild type mice when sensitization to GC frass occurred through the mucosa. To confirm the importance of mucosal exposure, mice were systemically sensitized to GC frass or protease-depleted GC frass via intraperitoneal injection. We found that removal of proteases from GC frass had no effect on airway inflammation when administered systemically.Conclusions
We showed for the first time that allergen-derived proteases in GC frass elicit allergic airway inflammation via PAR-2, but only when allergen was administered through the mucosa. Importantly, our data suggest the importance of resident airway cells in the initiation of allergic airway disease, and could make allergen-derived proteases attractive therapeutic targets. 相似文献88.
89.
Ward DS Dowda M Trost SG Felton GM Dishman RK Pate RR 《Obesity (Silver Spring, Md.)》2006,14(1):97-105
Objective: This study compared correlates of physical activity (PA) among African‐American and white girls of different weight groups to guide future interventions. Research Methods and Procedures: Participants were 1015 girls (mean age, 14.6 years; 45% African‐American) from 12 high schools in South Carolina who served as control subjects for a school‐based intervention. Post‐intervention measures obtained at the end of ninth grade were used. PA was measured using the Three‐Day PA Recall, and a questionnaire measured social‐cognitive and environmental variables thought to mediate PA. Height and weight were measured, and BMI was calculated. Girls were stratified by race and categorized into three groups, based on BMI percentiles for girls from CDC growth charts: normal (BMI < 85th percentile), at risk (BMI, 85th to 94th percentile), and overweight (BMI ≥ 95th percentile). Girls were further divided into active and low‐active groups, based on a vigorous PA standard (average of one or more 30‐minute blocks per day per 3‐day period). Mixed‐model ANOVA was used to compare factors among groups, treating school as a random effect Results: None of the social‐cognitive or environmental variables differed by weight status for African‐American or white girls. Perceived behavioral control and sports team participation were significantly higher in girls who were more active, regardless of weight or race group. In general, social‐cognitive variables seem to be more related to activity in white girls, whereas environmental factors seem more related to activity in African‐American girls. Discussion: PA interventions should be tailored to the unique needs of girls based on PA levels and race, rather than on weight status alone. 相似文献
90.
Celine S. Lages Ian Lewkowich Alyssa Sproles Marsha Wills‐Karp Claire Chougnet 《Aging cell》2010,9(5):785-798
Programmed cell death‐1 (PD‐1) is a newly characterized negative regulator of immune responses. The interaction of PD‐1 with its ligands (PD‐L1 and PD‐L2) inhibits T‐cell proliferation and cytokine production in young mice. Increased PD‐1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD‐1 may contribute to age‐associated T‐cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD‐1‐expressing T cells and the level of expression of PD‐Ls was increased on dendritic cell subsets and T cells; (ii) PD‐1+ T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine‐producing capacity; (iii) the expression of PD‐1 was up‐regulated after T‐cell receptor‐mediated activation of CD8+ T cells, but not of CD4+ T cells; (iv) blockade of the PD‐1/PD‐L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD‐1/PD‐L1 pathway did not restore function of PD‐1+ T cells; its effect appeared to be exclusively mediated by increased functionality of the PD‐1? T cells. Our data thus suggest that blockade of the PD‐1/PD‐L1 is not likely to be efficient at restoring exhausted T‐cell responses in aged hosts, although improving the responses of PD‐1? T cells may prove to be a helpful strategy in enhancing primary responses. 相似文献