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Sample records for metabolism exacerbates palmitate

  1. CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate.

    PubMed

    Lu, Z; Li, Y; Brinson, C W; Kirkwood, K L; Lopes-Virella, M F; Huang, Y

    2017-03-01

    We reported that high-fat diet (HFD)-induced metabolic syndrome (MetS) exacerbates lipopolysaccharide (LPS)-stimulated periodontitis and palmitate, the major saturated fatty acid in the HFD, amplified LPS-stimulated gene expression in vitro. As CD36 is a major receptor for fatty acids, we investigated periodontal CD36 expression in mice with periodontitis and MetS, and the role of CD36 in inflammatory gene expression in macrophages stimulated by palmitate. MetS and periodontitis were induced in mice by HFD and periodontal injection of LPS, respectively. The periodontal CD36 expression and its relationship with alveolar bone loss were studied using immunohistochemistry, real-time PCR, and correlation analysis. The role of CD36 in upregulation of inflammatory mediators by LPS and palmitate in macrophages was assessed using pharmacological inhibitor and small interfering RNA. Periodontal CD36 expression was higher in mice with both MetS and periodontitis than that in mice with periodontitis or MetS alone and was correlated with osteoclastogenesis and alveolar bone loss. In vitro studies showed that CD36 expression in macrophages was upregulated by LPS and palmitate, and targeting CD36 attenuated palmitate-enhanced gene expression. CD36 expression is upregulated in mice with periodontitis and MetS and involved in gene expression in macrophages stimulated by palmitate and LPS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes.

    PubMed

    Hamlin, Allyson N; Basford, Joshua E; Jaeschke, Anja; Hui, David Y

    2016-08-05

    LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocyte-specific LRP1 knock-out (hLrp1(-/-)) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1(-/-) mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1(+/+) hepatocytes. Palmitate-treated hLrp1(-/-) hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1(+/+) hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1(-/-) hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1(-/-) hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomal-mitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Physical activity is associated with retained muscle metabolism in human myotubes challenged with palmitate.

    PubMed

    Green, C J; Bunprajun, T; Pedersen, B K; Scheele, C

    2013-09-15

      The aim of this study was to investigate whether physical activity is associated with preserved muscle metabolism in human myotubes challenged with saturated fatty acids. Human muscle satellite cells were isolated from sedentary or active individuals and differentiated into myocytes in culture. Metabolic differences were then investigated in the basal state or after chronic palmitate treatment. At basal, myocytes from sedentary individuals exhibited higher CD36 and HSP70 protein expression as well as elevated phosphorylation of c-Jun NH2-terminal kinase (JNK) and insulin receptor substrate 1 (IRS1) serine(307) compared to myocytes from active individuals. Despite equal lipid accumulation following palmitate treatment, myocytes from sedentary individuals exhibited delayed acetyl coenzyme A carboxylase phosphorylation compared to the active group. Myocytes from sedentary individuals had significantly higher basal glucose uptake and palmitate promoted insulin resistance in sedentary myocytes. Importantly, myocytes from active individuals were partially protected from palmitate-induced insulin resistance. Palmitate treatment enhanced IRS1 serine307 phosphorylation in myocytes from sedentary individuals and correlated positively to JNK phosphorylation. In conclusion, muscle satellite cells retain metabolic differences associated with physical activity. Physical activity partially protects myocytes from fatty acid-induced insulin resistance and inactivity is associated with dysregulation of metabolism in satellite cells challenged with palmitate. Although the benefits of physical activity on whole body physiology have been well investigated, this paper presents novel findings that both diet and exercise impact satellite cells directly. Given the fact that satellite cells are important for muscle maintenance, a dysregulated function could have profound effects on health. Therefore the effects of lifestyle on satellite cells needs to be delineated.

  4. Palmitate acutely raises glycogen synthesis in rat soleus muscle by a mechanism that requires its metabolization (Randle cycle).

    PubMed

    Massao Hirabara, Sandro; de Oliveira Carvalho, Carla Roberta; Mendonça, José Roberto; Piltcher Haber, Esther; Fernandes, Luiz Claudio; Curi, Rui

    2003-04-24

    The acute effect of palmitate on glucose metabolism in rat skeletal muscle was examined. Soleus muscles from Wistar male rats were incubated in Krebs-Ringer bicarbonate buffer, for 1 h, in the absence or presence of 10 mU/ml insulin and 0, 50 or 100 microM palmitate. Palmitate increased the insulin-stimulated [(14)C]glycogen synthesis, decreased lactate production, and did not alter D-[U-(14)C]glucose decarboxylation and 2-deoxy-D-[2,6-(3)H]glucose uptake. This fatty acid decreased the conversion of pyruvate to lactate and [1-(14)C]pyruvate decarboxylation and increased (14)CO(2) produced from [2-(14)C]pyruvate. Palmitate reduced insulin-stimulated phosphorylation of insulin receptor substrate-1/2, Akt, and p44/42 mitogen-activated protein kinases. Bromopalmitate, a non-metabolizable analogue of palmitate, reduced [(14)C]glycogen synthesis. A strong correlation was found between [U-(14)C]palmitate decarboxylation and [(14)C]glycogen synthesis (r=0.99). Also, palmitate increased intracellular content of glucose 6-phosphate in the presence of insulin. These results led us to postulate that palmitate acutely potentiates insulin-stimulated glycogen synthesis by a mechanism that requires its metabolization (Randle cycle). The inhibitory effect of palmitate on insulin-stimulated protein phosphorylation might play an important role for the development of insulin resistance in conditions of chronic exposure to high levels of fatty acids.

  5. Effect of. cap alpha. -ketobutyrate on the metabolism of pyruvate and palmitate in isolated rat hepatocytes

    SciTech Connect

    Brass, E.P.

    1986-05-01

    Alpha-ketobutyrate (..cap alpha..KB), an intermediate in the catabolism of threonine and methionine, is decarboxylated to propionyl-CoA. The authors have reported that propionate (PROP) inhibits oxidative metabolism in rate hepatocytes. Based on these observations, the present study examined the effects of ..cap alpha..KB on pyruvate and palmitate metabolism in hepatocytes isolated from fed rats. Similar to PROP, ..cap alpha..KB (10mM) inhibited palmitate oxidation and this inhibition was diminished when 10mM carnitine (CN) was added (35 +/- 6% inhibition without CN, 22 +/- 8% with CN). ..cap alpha..KB inhibited the conversion of 3-/sup 14/C-pyruvate to glucose and CO/sub 2/. Inhibition of pyruvate metabolism by ..cap alpha..KB was concentration-dependent. At equal concentrations, ..cap alpha..KB inhibited pyruvate metabolism to a greater extent than PROP. Addition of CN partially reversed the effects of PROP on pyruvate metabolism, but not those of ..cap alpha..KB despite the generation of propionylcarnitine when ..cap alpha..KB and CN were included in the incubation. These results demonstrate that accumulation of ..cap alpha..KB can impair normal hepatocyte metabolism. While some of the effects of ..cap alpha..KB can be explained on the basis of propionyl-CoA formation, ..cap alpha..KB has effects on pyruvate metabolism not explainable by this mechanism.

  6. Thiazide diuretics exacerbate fructose-induced metabolic syndrome.

    PubMed

    Reungjui, Sirirat; Roncal, Carlos A; Mu, Wei; Srinivas, Titte R; Sirivongs, Dhavee; Johnson, Richard J; Nakagawa, Takahiko

    2007-10-01

    Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome. Thiazide diuretics are frequently used in these patients for treatment of hypertension, but they also exacerbate metabolic syndrome. Rats on high-fructose diets that are given thiazides exhibit potassium depletion and hyperuricemia. Potassium supplementation improves their insulin resistance and hypertension, whereas allopurinol reduces serum levels of uric acid and ameliorates hypertension, hypertriglyceridemia, hyperglycemia, and insulin resistance. Both potassium supplementation and treatment with allopurinol also increase urinary nitric oxide excretion. We suggest that potassium depletion and hyperuricemia in rats exacerbates endothelial dysfunction and lowers the bioavailability of nitric oxide, which blocks insulin activity and causes insulin resistance during thiazide usage. Addition of potassium supplements and allopurinol with thiazides might be helpful in the management of metabolic syndrome.

  7. Uncoupling effect of palmitate is exacerbated in skeletal muscle mitochondria of sea-acclimatized king penguins (Aptenodytes patagonicus).

    PubMed

    Rey, Benjamin; Duchamp, Claude; Roussel, Damien

    2017-09-01

    In king penguin juveniles, the environmental transition from a terrestrial to a marine habitat, occurring at fledging, drastically stimulates lipid catabolism and the remodelling of muscle mitochondria to sustain extensive swimming activity and thermoregulation in the cold circumpolar oceans. However, the exact nature of these mechanisms remains only partially resolved. Here we investigated, in vitro, the uncoupling effect of increasing doses of fatty acids in pectoralis muscle intermyofibrillar mitochondria isolated, either from terrestrial never-immersed or experimentally cold water immersed pre-fledging king penguins or from sea-acclimatized fledged penguins. Mitochondria exhibited much greater palmitate-induced uncoupling respiration and higher maximal oxidative capacity after acclimatization to marine life. Such effects were not reproduced experimentally after repeated immersions in cold water, suggesting that the plasticity of mitochondrial characteristics may not be primarily driven by cold exposure per se but by other aspects of sea acclimatization. Copyright © 2017. Published by Elsevier Inc.

  8. The heart-liver metabolic axis: defective communication exacerbates disease

    PubMed Central

    Baskin, Kedryn K; Bookout, Angie L; Olson, Eric N

    2014-01-01

    The heart has been recognized as an endocrine organ for over 30 years (de Bold, 2011); however, little is known about how the heart communicates with other organs in the body, and even less is known about this process in the diseased heart. In this issue of EMBO Molecular Medicine, Magida and Leinwand (2014) introduce the concept that a primary genetic defect in the heart results in aberrant hepatic lipid metabolism, which consequently exacerbates hypertrophic cardiomyopathy (HCM). This study provides evidence in support of the hypothesis that crosstalk occurs between the heart and liver, and that this becomes disrupted in the diseased state. PMID:24623378

  9. Invited review: palmitic and stearic acid metabolism in lactating dairy cows.

    PubMed

    Loften, J R; Linn, J G; Drackley, J K; Jenkins, T C; Soderholm, C G; Kertz, A F

    2014-01-01

    Energy is the most limiting nutritional component in diets for high-producing dairy cows. Palmitic (C16:0) and stearic (C18:0) acids have unique and specific functions in lactating dairy cows beyond a ubiquitous energy source. This review delineates their metabolism and usage in lactating dairy cows from diet to milk production. Palmitic acid is the fatty acid (FA) found in the greatest quantity in milk fat. Dietary sources of C16:0 generally increase milk fat yield and are used as an energy source for milk production and replenishing body weight loss during periods of negative energy balance. Stearic acid is the most abundant FA available to the dairy cow and is used to a greater extent for milk production and energy balance than C16:0. However, C18:0 is also intimately involved in milk fat production. Quantifying the transfer of each FA from diet into milk fat is complicated by de novo synthesis of C16:0 and desaturation of C18:0 to oleic acid in the mammary gland. In addition, incorporation of both FA into milk fat appears to be limited by the cow's requirement to maintain fluidity of milk, which requires a balance between saturated and unsaturated FA. Oleic acid is the second most abundant FA in milk fat and likely the main unsaturated FA involved in regulating fluidity of milk. Because the mammary gland can desaturate C18:0 to oleic acid, C18:0 appears to have a more prominent role in milk production than C16:0. To understand metabolism and utilization of these FA in lactating dairy cows, we reviewed production and milk fat synthesis studies. Additional and longer lactation studies on feeding both FA to lactating dairy cows are required to better delineate their roles in optimizing milk production and milk FA composition and yield.

  10. Determination of Fatty Acid Metabolism with Dynamic 11C-Palmitate Positron Emission Tomography of Mouse Heart In Vivo

    PubMed Central

    Li, Yinlin; Huang, Tao; Zhang, Xinyue; Zhong, Min; Walker, Natalie N.; He, Jiang; Berr, Stuart S.; Keller, Susanna R.; Kundu, Bijoy K.

    2015-01-01

    The goal of this study was to establish a quantitative method for measuring FA metabolism with partial volume (PV) and spill-over (SP) corrections using dynamic 11C-palmitate PET images of mouse heart in vivo. Methods Twenty-minute dynamic 11C-palmitate PET scans of four 18–20 week old male C57BL/6 mice under isoflurane anesthesia were performed using a Focus 120 PET scanner. A model corrected blood input function (MCIF), by which the input function with SP and PV corrections and the metabolic rate constants (k1−k5) are simultaneously estimated from the dynamic 11C-palmitate PET images of mouse hearts in a 4-compartment tracer kinetic model, was used to determine rates of myocardial FA oxidation (MFAO), myocardial FA esterification (MFAE), myocardial FA utilization (MFAU) and myocardial FA uptake (MFAUp). Results The MFAO thus measured in C57BL/6 mice was 375.03±43.83 nmoles/min/g. This compares well with the MFAO measured in perfused working C57BL/6 mouse hearts ex vivo of about 350 nmoles/g/min and 400 nmoles/min/g. Conclusions FA metabolism was measured for the first time in mouse heart in vivo using dynamic 11C-palmitate PET in a 4-compartment tracer kinetic model. MFAO obtained with this model were validated by results previously obtained with mouse hearts ex vivo. PMID:26462138

  11. Manganese accumulation in membrane fractions of primary astrocytes is associated with decreased γ-aminobutyric acid (GABA) uptake, and is exacerbated by oleic acid and palmitate.

    PubMed

    Fordahl, Steve C; Erikson, Keith M

    2014-05-01

    Manganese (Mn) exposure interferes with GABA uptake; however, the effects of Mn on GABA transport proteins (GATs) have not been identified. We sought to characterize how Mn impairs GAT function in primary rat astrocytes. Astrocytes exposed to Mn (500 μM) had significantly reduced (3)H-GABA uptake despite no change in membrane or cytosolic GAT3 protein levels. Co-treatment with 100 μM oleic or palmitic acids (both known to be elevated in Mn neurotoxicity), exacerbated the Mn-induced decline in (3)H-GABA uptake. Mn accumulation in the membrane fraction of astrocytes was enhanced with fatty acid administration, and was negatively correlated with (3)H-GABA uptake. Furthermore, control cells exposed to Mn only during the experimental uptake had significantly reduced (3)H-GABA uptake, and the addition of GABA (50 μM) blunted cytosolic Mn accumulation. These data indicate that reduced GAT function in astrocytes is influenced by Mn and fatty acids accumulating at or interacting with the plasma membrane. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice.

    PubMed

    Cheng, Licai; Yu, Yinghua; Szabo, Alexander; Wu, Yizhen; Wang, Hongqin; Camer, Danielle; Huang, Xu-Feng

    2015-05-01

    The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Efficacy and safety of once-monthly injection of paliperidone palmitate in hospitalized Asian patients with acute exacerbated schizophrenia: an open-label, prospective, noncomparative study

    PubMed Central

    Li, HuaFang; Turkoz, Ibrahim; Zhang, Fan

    2016-01-01

    Introduction This single-group, open-label, prospective, noncomparative, multicenter, Phase IV study explored the efficacy and tolerability of paliperidone palmitate (PP) in hospitalized patients with acute exacerbation of schizophrenia. Methods Asian patients of either sex, between 18 and 65 years of age, diagnosed with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) with acute exacerbations within the previous 4 weeks, were enrolled. Intramuscular PP was initiated at doses of 150 milligram equivalent (mg eq) (day 1) and 100 mg eq (day 8), followed by a monthly maintenance dose between 75 mg eq and 150 mg eq (days 36 and 64). Primary efficacy endpoint was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score (last-observation-carried-forward) at week 13. Results Of the 212 enrolled patients, 152 (71.7%) completed the 13-week treatment; withdrawal of consent (24 [11.3%] patients) was the most common reason for study discontinuation. Mean (standard deviation) PANSS total score from baseline (90.0 [17.41]) improved significantly at day 4 (−6.1 [9.27]; 95% confidence interval: −7.38, −4.85; P<0.001) and week 13 endpoint (−23.9 [23.24]; 95% confidence interval: −27.10, −20.78; P<0.001). Similarly, the secondary endpoints (Clinical Global Impression-Severity, Physical and Social Performance, each PANSS subscale, and Marder factor scores) improved significantly from baseline to week 13 endpoint (P<0.001 for all). At week 13, 112/210 (53.3%) patients had a 40% improvement in the PANSS total score (responder rate), and 133/212 (62.7%) patients were ready for hospital discharge. Overall, 139 (65.6%) patients experienced at least one treatment-emergent adverse event (TEAE). Most common (>5%) TEAEs were hyperprolactinemia, constipation, nasopharyngitis, insomnia, increased weight, and tremor. Worsening of schizophrenia (3.3%) and sinus bradycardia (2.0%) were serious TEAEs; no deaths were

  14. Astrocyte arachidonate and palmitate uptake and metabolism is differentially modulated by dibutyryl-cAMP treatment.

    PubMed

    Seeger, D R; Murphy, C C; Murphy, E J

    2016-07-01

    Astrocytes play a vital role in brain lipid metabolism; however the impact of the phenotypic shift in astrocytes to a reactive state on arachidonic acid metabolism is unknown. Therefore, we determined the impact of dibutyryl-cAMP (dBcAMP) treatment on radiolabeled arachidonic acid ([1-(14)C]20:4n-6) and palmitic acid ([1-(14)C]16:0) uptake and metabolism in primary cultured murine cortical astrocytes. In dBcAMP treated astrocytes, total [1-(14)C]20:4n-6 uptake was increased 1.9-fold compared to control, while total [1-(14)C]16:0 uptake was unaffected. Gene expression of long-chain acyl-CoA synthetases (Acsl), acyl-CoA hydrolase (Acot7), fatty acid binding protein(s) (Fabp) and alpha-synuclein (Snca) were determined using qRT-PCR. dBcAMP treatment increased expression of Acsl3 (4.8-fold) and Acsl4 (1.3-fold), which preferentially use [1-(14)C]20:4n-6 and are highly expressed in astrocytes, consistent with the increase in [1-(14)C]20:4n-6 uptake. However, expression of Fabp5 and Fabp7 were significantly reduced by 25% and 45%, respectively. Acot7 (20%) was also reduced, suggesting dBcAMP treatment favors acyl-CoA formation. dBcAMP treatment enhanced [1-(14)C]20:4n-6 (2.2-fold) and [1-(14)C]16:0 (1.6-fold) esterification into total phospholipids, but the greater esterification of [1-(14)C]20:4n-6 is consistent with the observed uptake through increased Acsl, but not Fabp expression. Although total [1-(14)C]16:0 uptake was not affected, there was a dramatic decrease in [1-(14)C]16:0 in the free fatty acid pool as esterification into the phospholipid pool was increased, which is consistent with the increase in Acsl3 and Acsl4 expression. In summary, our data demonstrates that dBcAMP treatment increases [1-(14)C]20:4n-6 uptake in astrocytes and this increase appears to be due to increased expression of Acsl3 and Acsl4 coupled with a reduction in Acot7 expression.

  15. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity.

    PubMed

    Drager, Luciano F; Li, Jianguo; Reinke, Christian; Bevans-Fonti, Shannon; Jun, Jonathan C; Polotsky, Vsevolod Y

    2011-11-01

    Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6-8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.

  16. Intermittent Hypoxia Exacerbates Metabolic Effects of Diet-Induced Obesity

    PubMed Central

    Drager, Luciano F.; Li, Jianguo; Reinke, Christian; Bevans-Fonti, Shannon; Jun, Jonathan C.; Polotsky, Vsevolod Y.

    2015-01-01

    Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6–8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity. PMID:21799478

  17. [The positional isomers of triglycerides in oils, fats and apoB-100 lipoproteins: palmitic and oleic modes of metabolism of fatty acids-substrates for energy acquiring].

    PubMed

    Kotkina, T I; Titov V N

    2014-01-01

    Even total resemblance of content of fatty acids in triglycerides has both no standing for their functional unity nor even identity of their physical chemical characteristics. The etherification of fatty acids in various positions of three-atomic glycerin separates triglycerides on palmitic and oleic substrates for energy acquiring by cells. The kinetic parameters of biochemical reactions under palmitic mode of metabolism of fatty acids are always low. The myocytes in biological reaction of exotrophy experience deficiency of exogenous fatty acids which in vivo is to permanently supply through activation of biological reaction of endotrophy--enhancement of lipolysis in adipocytes. The biological role of insulin is to prevent formation in vivo of palmitic mode of metabolism of saturated and monoenic fatty acids. Under this condition, the necessity to activate lipolysis and to increase in blood plasma concentration of unesteritied fatty acids forms syndrome of resistance to insulin. The surplus of palmitic fatty acid in food and deficiency of insulin show in vivo unidirectional a physiologic action. The formation of palmitic mode of metabolism of energy substrates--portion of pathogenesis of atherosclerosis, metabolic syndrome, obesity, non-alcoholic fatty infiltration of liver and partiallly essential arterial hypertension.

  18. Regulation of intestinal IgA responses by dietary palmitic acid and its metabolism.

    PubMed

    Kunisawa, Jun; Hashimoto, Eri; Inoue, Asuka; Nagasawa, Risa; Suzuki, Yuji; Ishikawa, Izumi; Shikata, Shiori; Arita, Makoto; Aoki, Junken; Kiyono, Hiroshi

    2014-08-15

    Enhancement of intestinal IgA responses is a primary strategy in the development of oral vaccine. Dietary fatty acids are known to regulate host immune responses. In this study, we show that dietary palmitic acid (PA) and its metabolites enhance intestinal IgA responses. Intestinal IgA production was increased in mice maintained on a PA-enriched diet. These mice also showed increased intestinal IgA responses against orally immunized Ag, without any effect on serum Ab responses. We found that PA directly stimulates plasma cells to produce Ab. In addition, mice receiving a PA-enriched diet had increased numbers of IgA-producing plasma cells in the large intestine; this effect was abolished when serine palmitoyltransferase was inhibited. These findings suggest that dietary PA regulates intestinal IgA responses and has the potential to be a diet-derived mucosal adjuvant.

  19. Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation.

    PubMed

    Quan-Jun, Yang; Jian-Ping, Zhang; Jian-Hua, Zhang; Yong-Long, Han; Bo, Xin; Jing-Xian, Zhang; Bona, Dai; Yuan, Zhang; Cheng, Guo

    2017-03-01

    Inhaled budesonide and salbutamol represent the most important and frequently used drugs in asthmatic children during acute exacerbation. However, there is still no consensus about their resulting metabolic derangements; thus, this study was conducted to determine the distinct metabolic profiles of these two drugs. A total of 69 children with asthma during acute exacerbation were included, and their serum and urine were investigated using high-resolution nuclear magnetic resonance (NMR). A metabolomics analysis was performed using a principal component analysis and orthogonal signal correction-partial least squares using SIMCA-P. The different metabolites were identified, and the distinct metabolic profiles were analysed using MetPA. A high-resolution NMR-based serum and urine metabolomics approach was established to study the overall metabolic changes after inhaled budesonide and salbutamol in asthmatic children during acute exacerbation. The perturbed metabolites included 22 different metabolites in the serum and 21 metabolites in the urine. Based on an integrated analysis, the changed metabolites included the following: increased 4-hydroxybutyrate, lactate, cis-aconitate, 5-hydroxyindoleacetate, taurine, trans-4-hydroxy-l-proline, tiglylglycine, 3-hydroxybutyrate, 3-methylhistidine, glucose, cis-aconitate, 2-deoxyinosine and 2-aminoadipate; and decreased alanine, glycerol, arginine, glycylproline, 2-hydroxy-3-methylvalerate, creatine, citrulline, glutamate, asparagine, 2-hydroxyvalerate, citrate, homoserine, histamine, sn-glycero-3-phosphocholine, sarcosine, ornithine, creatinine, glycine, isoleucine and trimethylamine N-oxide. The MetPA analysis revealed seven involved metabolic pathways: arginine and proline metabolism; taurine and hypotaurine metabolism; glycine, serine and threonine metabolism; glyoxylate and dicarboxylate metabolism; methane metabolism; citrate cycle; and pyruvate metabolism. The perturbed metabolic profiles suggest potential metabolic

  20. Metabolism of palmitic acid in the subcellular fractions of mouse brain.

    PubMed

    Sun, G Y; Horrocks, L A

    1973-03-01

    After an intracerebral injection of [(14)C]palmitic acid to C57BL/10J mice, the radioactivity in the brains decreased rapidly with time. The incorporated radioactivity was primarily in the 16:0 acyl groups of the diacyl phosphoglycerides at 1 and 3 days after injection. At longer times, increasing proportions of the radioactivity were found in cerebrosides, alkenyl groups, and other acyl groups. The specific radioactivities of the phosphoglycerides were highest in the microsomal fraction at 1 day after injection. The exchange of the diacyl glycerophosphorylcholines and diacyl glycerophosphorylethanolamines between the microsomes and the myelin required 8-14 days. When calculated on the basis of the radioactivity in the 16:0 acyl groups, the half-lives for both of these phosphoglycerides were 6-8 days in all subcellular fractions during the period from 14 to 30 days after injection. The radioactivity in the total lipids from the purified myelin fraction did not decline until more than 14 days after injection because of the reutilization of labeled 16:0 acyl groups for lipid biosynthesis. Recycling of the acyl groups explains the long half-lives reported for myelin phosphoglycerides after injection of [(14)C]acetic acid. Lipids with a relatively high specific radioactivity were lost from the myelin fraction during the purification procedure. The most likely source of these lipids is the most recently formed myelin that is not consolidated into the myelin sheath.

  1. Body mass index and metabolic parameters in patients with schizophrenia during long-term treatment with paliperidone palmitate

    PubMed Central

    2014-01-01

    Background There is a strong association between weight gain and metabolic events in patients with schizophrenia receiving many of the second-generation antipsychotic agents. We explored the relationship between body mass index (BMI) and metabolic events in patients with schizophrenia receiving long-acting injectable paliperidone palmitate (PP) in a long-term trial. Methods We conducted a post hoc analysis of data from a PP study that included a 33-week open-label transition (TR) and maintenance phase; a variable duration, randomized, double-blind (DB), placebo-controlled phase and a 52-week open-label extension (OLE) phase. Overall, 644 patients received PP continuously from study entry through discontinuation or study completion and were grouped by baseline BMI (kg/m2): underweight (BMI <19; n = 29, 4.5%), normal-weight (BMI 19- < 25; n = 229, 35.6%), overweight (BMI 25- < 30; n = 232, 36.0%) and obese (BMI ≥30; n = 154, 23.9%). Metabolic treatment-emergent adverse events (TEAEs) and changes in related laboratory results from TR baseline were analyzed. Results PP exposure was similar across BMI groups; overall mean (SD) dose/month was 70.3 (17.17) mg eq. [109.6 (26.78) mg]; median duration of exposure was 204 days (6 to 1009 days). Occurrences of metabolic TEAEs overall by group were 0% (underweight), 14.9% (normal-weight), 14.7% (overweight), and 24.0% (obese). The most common (≥2%) metabolic TEAE were weight gain and elevated blood levels of glucose, lipids, and insulin. Mean BMI and weight increased in normal-weight and overweight groups at DB endpoint, and in underweight, normal-weight and overweight groups at OLE endpoint (p ≤0.05). No consistent trend for increased metabolic-related laboratory values by baseline BMI group was observed. Homeostatic model assessments for insulin resistance indicated preexisting insulin resistance at baseline, with minimal changes at OLE endpoint across baseline BMI groups. Conclusion

  2. Secondary hypoxia exacerbates acute disruptions of energy metabolism in rats resulting from fluid percussion injury.

    PubMed

    Bauman, Richard A; Widholm, John; Long, Joseph B

    2005-05-07

    The purpose of these experiments was to determine whether secondary hypoxia exacerbates the metabolic consequences of fluid percussion injury (FPI). In Experiment I, rats were trained to press a lever for their entire daily ration of food at any time during a 12-h light/dark cycle and run in an activity wheel. After food intake and body weight stabilized, rats were surgically prepared, assigned to one of four groups [FPI+Hypoxia (IH), FPI+Normoxia (IN), Sham Injury+Hypoxia (SH), Sham Injury+Normoxia (SN)] and, after recovery from surgery, anesthetized with halothane delivered by a 21% O2 source. Immediately after injury or sham injury, the O2 source was switched to 13% for rats in Groups IH and SH for 30 min. Post-traumatic hypoxemia exacerbated the ensuing FPI-induced reductions of food intake and body weight, but did not change FPI-induced reduction in wheel running. In Experiment II, rats were assigned to one of three groups (SH, IN, or IH) and subjected to sham injury and 13% O2 or FPI and either 13 or 21% O2. Immediately after 30 min of hypoxia or normoxia, rats were confined to metabolism cages that were used to quantify rates of oxygen consumption (VO2), carbon dioxide production (VCO2), and heat production (H). Post-traumatic hypoxia exacerbated the FPI-induced increases in VO2, VCO2, and H. The results of Experiments I and II provide convergent confirmation that secondary hypoxemia exacerbates the FPI-induced hypermetabolic state in rats and therefore might significantly exacerbate the brain injury-induced disruptions of energy metabolism in humans.

  3. High anger expression exacerbates the relationship between age and metabolic syndrome.

    PubMed

    Boylan, Jennifer Morozink; Ryff, Carol D

    2015-01-01

    Building on prior work linking high anger expression to poor health, this cross-sectional study addressed whether anger expression exacerbated age-related risk for metabolic syndrome in a national sample of adults, known as MIDUS (Midlife in the United States). Respondents reported anger expression via survey assessments and completed an overnight clinic visit. Unadjusted metabolic syndrome prevalence was 40.6%. Men, less educated individuals, and those who reported not getting regular physical activity were at significantly higher risk for metabolic syndrome. Anger expression did not predict higher risk for metabolic syndrome in main effects models, but it moderated the relationship between age and metabolic syndrome. Age-associated risk for metabolic syndrome was significant only for adults with high anger expression. Among older adults, anger expression predicted higher prevalence of metabolic syndrome. Older adults reporting low anger expression had metabolic syndrome rates comparable to younger adults. Results highlight that failing to show the frequently observed decline in anger expression with age may have pernicious health concomitants. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. High Anger Expression Exacerbates the Relationship Between Age and Metabolic Syndrome

    PubMed Central

    Ryff, Carol D.

    2015-01-01

    Objective. Building on prior work linking high anger expression to poor health, this cross-sectional study addressed whether anger expression exacerbated age-related risk for metabolic syndrome in a national sample of adults, known as MIDUS (Midlife in the United States). Method. Respondents reported anger expression via survey assessments and completed an overnight clinic visit. Results. Unadjusted metabolic syndrome prevalence was 40.6%. Men, less educated individuals, and those who reported not getting regular physical activity were at significantly higher risk for metabolic syndrome. Anger expression did not predict higher risk for metabolic syndrome in main effects models, but it moderated the relationship between age and metabolic syndrome. Age-associated risk for metabolic syndrome was significant only for adults with high anger expression. Discussion. Among older adults, anger expression predicted higher prevalence of metabolic syndrome. Older adults reporting low anger expression had metabolic syndrome rates comparable to younger adults. Results highlight that failing to show the frequently observed decline in anger expression with age may have pernicious health concomitants. PMID:24077742

  5. The production of ω-hydroxy palmitic acid using fatty acid metabolism and cofactor optimization in Escherichia coli.

    PubMed

    Sung, Changmin; Jung, Eunok; Choi, Kwon-Young; Bae, Jin-Hyung; Kim, Minsuk; Kim, Joonwon; Kim, Eun-Jung; Kim, Pyoung Il; Kim, Byung-Gee

    2015-08-01

    Hydroxylated fatty acids (HFAs) are used as important precursors for bulk and fine chemicals in the chemical industry. Here, to overproduce long-chain (C16-C18) fatty acids and hydroxy fatty acid, their biosynthetic pathways including thioesterase (Lreu_0335) from Lactobacillus reuteri DSM20016, β-hydroxyacyl-ACP dehydratase (fabZ) from Escherichia coli, and a P450 system (i.e., CYP153A from Marinobacter aquaeolei VT8 and camA/camB from Pseudomonas putida ATCC17453) were overexpressed. Acyl-CoA synthase (fadD) involved in fatty acid degradation by β-oxidation was also deleted in E. coli BW25113. The engineered E. coli FFA4 strain without the P450 system could produce 503.0 mg/l of palmitic (C16) and 508.4 mg/l of stearic (C18) acids, of which the amounts are ca. 1.6- and 2.3-fold higher than those of the wild type. On the other hand, the E. coli HFA4 strain including the P450 system for ω-hydroxylation could produce 211.7 mg/l of ω-hydroxy palmitic acid, which was 42.1 ± 0.1 % of the generated palmitic acid, indicating that the hydroxylation reaction was the rate-determining step for the HFA production. For the maximum production of ω-hydroxy palmitic acid, NADH, i.e., an essential cofactor for P450 reaction, was overproduced by the integration of NAD(+)-dependent formate dehydrogenase (FDH) from Candida boidinii into E. coli chromosome and the deletion of alcohol dehydrogenase (ADH). Finally, the NADH-level-optimized E. coli strain produced 610 mg/l of ω-hydroxy palmitic acid (ω-HPA), which was almost a threefold increase in its yield compared to the same strain without NADH overproduction.

  6. Metabolism of U/sup 14/C palmitic and 1-/sup 14/C caproic acids by lettuce seeds during early germination

    SciTech Connect

    Salon, C.; Raymond, P.; Pradet, A.

    1986-04-01

    Germinating lettuce embryos (before radicule emergence) were fed with either U/sup 14/C palmitic acid or 1/sup 14/C caproic acid until a metabolic steady state was reached. The bulk of labelled caproate was evolved as respiratory CO/sub 2/ (52%) and incorporated into organic and amino acids (38%) and only a small part incorporated into lipids whereas most of labelled palmitic acid was found into lipids (92%) and only 8% evolved as CO/sub 2/ and incorporated into organic and amino acids. The label distribution at steady state in intermediates linked to the T.C.A. cycle was interpreted using a metabolic model. They found that the two fatty acids were degraded by ..beta..-oxidation and incorporated into the T.C.A. cycle as acetylCoA suggesting that ..beta..-oxidation is located in the mitochondria. The results also indicate that lipids contribute for at least 90% to the carbon supply to respiration.

  7. Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status?

    PubMed

    Mills, James L; Carter, Tonia C; Scott, John M; Troendle, James F; Gibney, Eileen R; Shane, Barry; Kirke, Peadar N; Ueland, Per M; Brody, Lawrence C; Molloy, Anne M

    2011-08-01

    In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12-related metabolic abnormalities. We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population.

  8. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice.

    PubMed

    Dubois, Vanessa; Laurent, Michaël R; Jardi, Ferran; Antonio, Leen; Lemaire, Katleen; Goyvaerts, Lotte; Deldicque, Louise; Carmeliet, Geert; Decallonne, Brigitte; Vanderschueren, Dirk; Claessens, Frank

    2016-02-01

    Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men.

  9. High density lipoprotein (HDL) reverses palmitic acid induced energy metabolism imbalance by switching CD36 and GLUT4 signaling pathways in cardiomyocyte.

    PubMed

    Wen, Su-Ying; Velmurugan, Bharath Kumar; Day, Cecilia Hsuan; Shen, Chia-Yao; Chun, Li-Chin; Tsai, Yi-Chieh; Lin, Yueh-Min; Chen, Ray-Jade; Kuo, Chia-Hua; Huang, Chih-Yang

    2017-11-01

    In our previous study palmitic acid (PA) induced lipotoxicity and switches energy metabolism from CD36 to GLUT4 in H9c2 cells. Low level of high density lipoprotein (HDL) is an independent risk factor for cardiac hypertrophy. Therefore, we in the present study investigated whether HDL can reverse PA induced lipotoxicity in H9c2 cardiomyoblast cells. In this study, we treated H9c2 cells with PA to create a hyperlipidemia model in vitro and analyzed for CD36 and GLUT4 metabolic pathway proteins. CD36 metabolic pathway proteins (phospho-AMPK, SIRT1, PGC1α, PPARα, CPT1β, and CD36) were decreased by high PA (150 and 200 μg/μl) concentration. Interestingly, expression of GLUT4 metabolic pathway proteins (p-PI3K and pAKT) were increased at low concentration (50 μg/μl) and decreased at high PA concentration. Whereas, phospho-PKCζ, GLUT4 and PDH proteins expression was increased in a dose dependent manner. PA treated H9c2 cells were treated with HDL and analyzed for cell viability. Results showed that HDL treatment induced cell proliferation efficiency in PA treated cells. In addition, HDL reversed the metabolic effects of PA: CD36 translocation was increased and reduced GLUT4 translocation, but HDL treatment significantly increased CD36 metabolic pathway proteins and reduced GLUT4 pathway proteins. Rat neonatal cardiomyocytes showed similar results. In conclusion, HDL reversed palmatic acid-induced lipotoxicity and energy metabolism imbalance in H9c2 cardiomyoblast cells and in neonatal rat cardiomyocyte cells. © 2017 Wiley Periodicals, Inc.

  10. Restraint stress exacerbates cardiac and adipose tissue pathology via β-adrenergic signaling in rats with metabolic syndrome.

    PubMed

    Matsuura, Natsumi; Nagasawa, Kai; Minagawa, Yuji; Ito, Shogo; Sano, Yusuke; Yamada, Yuichiro; Hattori, Takuya; Watanabe, Shogo; Murohara, Toyoaki; Nagata, Kohzo

    2015-05-15

    Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and β-adrenergic receptor (β-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the β-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate β-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS.

  11. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells.

    PubMed

    Luo, Yi; Rana, Payal; Will, Yvonne

    2012-06-01

    Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients.

  12. Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells

    SciTech Connect

    Luo, Yi Rana, Payal; Will, Yvonne

    2012-06-01

    Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA-induced toxicity and worsen the outcome in transplant patients. -- Highlights: ► Palmitic acid and cyclosporine (CsA) synergistically increased cytotoxicity. ► The impairment of mitochondrial functions may contribute to the enhanced toxicity. ► Inhibition of JNK activity attenuated

  13. Intramuscular paliperidone palmitate.

    PubMed

    Hoy, Sheridan M; Scott, Lesley J; Keating, Gillian M

    2010-03-01

    Intramuscular paliperidone palmitate is a long-acting, atypical antipsychotic that is indicated in the US for the acute and maintenance therapy of adult patients with schizophrenia. Paliperidone is the major active metabolite of risperidone. The noninferiority of flexible doses of intramuscular paliperidone palmitate 39-156 mg to flexible doses of intramuscular long-acting risperidone 25-50 mg was not established in an initial 53-week study. However, these data were utilized to optimize the intramuscular paliperidone palmitate dosage regimen. In four randomized, double-blind studies, intramuscular paliperidone palmitate 39-234 mg was generally effective in the treatment of adult patients with acute schizophrenia, inducing significantly greater improvements from baseline in the mean Positive and Negative Syndrome Scale (PANSS) total score than placebo (primary endpoint). In general, intramuscular paliperidone palmitate recipients achieved significantly better outcomes than placebo recipients with regard to the PANSS subscale, PANSS factor, Personal and Social Performance scale and Clinical Global Impressions-Severity scale scores. As maintenance therapy, intramuscular paliperidone palmitate 39-156 mg was significantly more effective than placebo in delaying the time to the first relapse of schizophrenia symptoms in adult patients, according to the results of a randomized, double-blind study. The beneficial effects of intramuscular paliperidone palmitate therapy on the PANSS total score were sustained in a 52-week noncomparative extension phase of the maintenance therapy study. Intramuscular paliperidone palmitate 39-234 mg was generally well tolerated in adult patients with schizophrenia.

  14. Metabolism in humans of cis-12,trans-15-octadecadienoic acid relative to palmitic, stearic, oleic and linoleic acids

    SciTech Connect

    Emken, E.A.; Rohwedder, W.K.; Adlof, R.O.; Rakoff, H.; Gulley, R.M.

    1987-07-01

    Mixtures of triglycerides containing deuterium-labeled hexadecanoic acid (16:0), octadecanoic acid (18:0), cis-9-octadecenoic acid (9c-18:1), cis-9,cis-12-octadecadienoic acid (9c, 12c-18:2) and cis-12,trans-15-octadecadienoic acid (12c,15t-18:2) were fed to two young-adult males. Plasma lipid classes were isolated from samples collected periodically over 48 hr. Incorporation and turnover of the deuterium-labeled fats in plasma lipids were followed by gas chromatography-mass spectrometry (GC-MS) analysis of the methyl ester derivatives. Absorption of the deuterated fats was followed by GC-MS analysis of chylomicron triglycerides isolated by ultracentrifugation. Results were the following: (i) endogenous fat contributed about 40% of the total fat incorporated into chylomicron triglycerides; (ii) elongation, desaturation and chain-shortened products from the deuterated fats were not detected; (iii) the polyunsaturated isomer 12c,15t-18:2 was metabolically more similar to saturated and 9c-18:1 fatty acids than to 9c,12c-18:2; (iv) relative incorporation of 9c,12c-18:2 into phospholipids did not increase proportionally with an increase of 9c,12c-18:2 in the mixture of deuterated fats fed; (v) absorption of 16:0, 18:0, 9c-18:1, 9c,12c-18:2 and 12c,15t-18:2 were similar; and (vi) data for the 1- and 2-acyl positions of phosphatidylcholine and for cholesteryl ester fractions reflected the known high specificity of phosphatidylcholine acyltransferase and lecithin:cholesteryl acyltransferase for 9c,12c-18:2. These results illustrate that incorporation of dietary fatty acids into human plasma lipid classes is selectively controlled and that incorporation of dietary 9c,12c-18:2 is limited.

  15. Vitamin D deficiency exacerbates atypical antipsychotic-induced metabolic side effects in rats: involvement of the INSIG/SREBP pathway.

    PubMed

    Dang, Ruili; Jiang, Pei; Cai, Hualin; Li, Huande; Guo, Ren; Wu, Yanqin; Zhang, Lihong; Zhu, Wenye; He, Xin; Liu, Yiping; Xu, Ping

    2015-08-01

    Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

  16. Ethanol diversely alters palmitate, stearate and oleate metabolism in the liver and pancreas of rats using the deuterium oxide single tracer

    PubMed Central

    Boros, Laszlo G.; Deng, Qinggao; Pandol, Stephen J.; Tsukamoto, Hidekazu; Go, Vay Liang W.; Lee, Wai-Nang Paul

    2015-01-01

    Objective To determine tissue specific effects of alcohol on fatty acid synthesis and distribution as related to functional changes in triglyceride transport and membrane formation. Methods Tissue fatty acid profile, and de novo lipogenesis were determined in adult male Wistar rats after 5 weeks of ethanol feeding using deuterated water and GC/MS. Liver and pancreas fatty acid profiles and new synthesis fractions were compared with those from control rats on an isocaloric diet. Results Fatty acid ratios in the liver indicated that there was an over two-fold accumulation of stearate to that of palmitate, with an apparent decrease in oleate content. On the other hand, in the pancreas there was a 17% decrease in the stearate to palmitate ratio, while oleate to palmitate ratio was increased by 30%. The fractions of deuterium labeled palmitate and stearate were substantially reduced in the liver and pancreas of the alcohol treated animals. Deuterium labeling of oleate was reduced in the liver but not in the pancreas consistent with the oleate/stearate ratios in these tissues. Conclusions Long-term alcohol exposure results in opposite effects on the desaturase activity in the liver and pancreas limiting fatty acid transport in the liver but promoting the exocrine function of the pancreas. PMID:19248221

  17. Effects of sn-2 palmitic acid-fortified vegetable oil and fructooligosaccharide on calcium metabolism in growing rats fed casein based diet

    PubMed Central

    Lee, Yeon-Sook; Kang, Eun-Young; Park, Mi-Na; Choi, You-Young; Jeon, Jeong-Wook

    2008-01-01

    This study was carried out to investigate the efficacy of sn-2 palmitic acid-fortified vegetable oil (Sn2PA) on calcium absorption and to confirm the synergistic effects of fructooligosaccharide on calcium absorption. Male SD rats were fed 6 kinds of casein based diets containing vegetable oil (control), sn-2 palmitic acid-fortified vegetable oil (Sn2PA) and Sn2PA with fructooligosaccharide(Sn2PAFO) in two levels of calcium (normal 0.5% and high 1.0%) for 3 weeks. Total lipids, cholesterol, triglyceride and calcium in blood were measured. Feces were collected using cages for 4 days. Serum concentrations of total lipids and calcium were not significantly different among groups. However, serum triglyceride was significantly decreased by fructooligosaccharide supplementation regardless of dietary calcium level. The lipid absorption was not significantly different among experimental groups. Calcium absorption was significantly higher in Sn2PAFO group than other groups. Calcium solubility of intestine was increased by sn-2 palmitic acid supplementation. These results suggest that sn-2 palmitic acid and fructooligosaccharide supplementation could be beneficial for baby foods including infant formula, with regard to increasing absorption of calcium by more soluble calcium in the small intestinal content. PMID:20126357

  18. Ethanol diversely alters palmitate, stearate, and oleate metabolism in the liver and pancreas of rats using the deuterium oxide single tracer.

    PubMed

    Boros, Laszlo G; Deng, Qinggao; Pandol, Stephen J; Tsukamoto, Hidekazu; Go, Vay Liang W; Lee, Wai-Nang Paul

    2009-03-01

    To determine tissue-specific effects of alcohol on fatty acid synthesis and distribution as related to functional changes in triglyceride transport and membrane formation. Tissue fatty acid profile and de novo lipogenesis were determined in adult male Wistar rats after 5 weeks of ethanol feeding using deuterated water and gas chromatography/mass spectrometry. Liver and pancreas fatty acid profiles and new synthesis fractions were compared with those from control rats on an isocaloric diet. Fatty acid ratios in the liver indicated that there was a more than 2-fold accumulation of stearate to that of palmitate, with an apparent decrease in oleate content. On the other hand, in the pancreas, there was a 17% decrease in the stearate-to-palmitate ratio, whereas the oleate-to-palmitate ratio was increased by 30%. The fractions of deuterium-labeled palmitate and stearate were substantially reduced in the liver and pancreas of the alcohol-treated animals. Deuterium labeling of oleate was reduced in the liver but not in the pancreas, consistent with the oleate/stearate ratios in these tissues. Long-term alcohol exposure results in opposite effects on the desaturase activity in the liver and pancreas, limiting fatty acid transport in the liver but promoting the exocrine function of the pancreas.

  19. Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model.

    PubMed

    Ressler, Ilana B; Grayson, Bernadette E; Ulrich-Lai, Yvonne M; Seeley, Randy J

    2015-06-15

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors. Copyright © 2015 the American Physiological Society.

  20. The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape.

    PubMed

    Curtis, Meredith M; Hu, Zeping; Klimko, Claire; Narayanan, Sanjeev; Deberardinis, Ralph; Sperandio, Vanessa

    2014-12-10

    The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape

    PubMed Central

    Curtis, Meredith M.; Hu, Zeping; Klimko, Claire; Narayanan, Sanjeev; Deberardinis, Ralph; Sperandio, Vanessa

    2014-01-01

    SUMMARY The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor, Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility. PMID:25498343

  2. Diet composition exacerbates or attenuates soman toxicity in rats: implied metabolic control of nerve agent toxicity.

    PubMed

    Myers, Todd M; Langston, Jeffrey L

    2011-06-01

    To evaluate the role of diet composition on nerve agent toxicity, rats were fed four distinct diets ad libitum for 28 d prior to challenge with 110 μg/kg (1.0 LD(50), sc) soman. The four diets used were a standard rodent diet, a choline-enriched diet, a glucose-enriched diet, and a ketogenic diet. Body weight was recorded throughout the study. Toxic signs and survival were evaluated at key times for up to 72 h following soman exposure. Additionally, acquisition of discriminated shuttlebox avoidance performance was characterized beginning 24h after soman challenge and across the next 8 d (six behavioral sessions). Prior to exposure, body weight was highest in the standard diet group and lowest in the ketogenic diet group. Upon exposure, differences in soman toxicity as a function of diet became apparent within the first hour, with mortality in the glucose-enriched diet group reaching 80% and exceeding all other groups (in which mortality ranged from 0 to 6%). At 72 h after exposure, mortality was 100% in the glucose-enriched diet group, and survival approximated 50% in the standard and choline-enriched diet groups, but equaled 87% in the ketogenic diet group. Body weight loss was significantly reduced in the ketogenic and choline-enriched diet groups, relative to the standard diet group. At 1 and 4h after exposure, rats in the ketogenic diet group had significantly lower toxic sign scores than all other groups. The ketogenic diet group performed significantly better than the standard diet group on two measures of active avoidance performance. The exacerbated soman toxicity observed in the glucose-enriched diet group coupled with the attenuated soman toxicity observed in the ketogenic diet group implicates glucose availability in the toxic effects of soman. This increased glucose availability may enhance acetylcholine synthesis and/or utilization, thereby exacerbating peripheral and central soman toxicity. Published by Elsevier B.V.

  3. Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status?123

    PubMed Central

    Mills, James L; Carter, Tonia C; Scott, John M; Troendle, James F; Gibney, Eileen R; Shane, Barry; Kirke, Peadar N; Ueland, Per M; Brody, Lawrence C; Molloy, Anne M

    2011-01-01

    Background: In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12–related metabolic abnormalities. Objective: We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. Design: In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. Results: In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. Conclusions: In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population. PMID:21653798

  4. Palmitic Acid and Health: Introduction.

    PubMed

    Agostoni, Carlo; Moreno, Luis; Shamir, Raanan

    2016-09-09

    Interest in the dietary role and metabolic effect of saturated fatty acids has been recently renewed on the basis of epidemiologic observations and economical approach to health and well-being. Saturated fats may favorably increase blood HDL-Cholesterol levels without significant changes of the total cholesterol/HDL-Cholesterol ratio. Also, the negative effect of saturated fat on cardiovascular diseases risk has recently been challenged. Palmitic acid, among all, may have special structural and functional roles in utero and in infancy, and indeed is it is being delivered in a unique form in human milk. Future research should include objective cost-benefit analyses when disentangling the role of saturated fats in dietary recommendations.

  5. In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses.

    PubMed

    Shukla, Shivendra D; Aroor, Annayya R; Restrepo, Ricardo; Kharbanda, Kusum K; Ibdah, Jamal A

    2015-11-20

    Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.

  6. Cigarette smoking exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis: the Bogalusa Heart Study.

    PubMed

    Li, Shengxu; Yun, Miaoying; Fernandez, Camilo; Xu, Jihua; Srinivasan, Sathanur R; Chen, Wei; Berenson, Gerald S

    2014-01-01

    Age and metabolic syndrome are major risk factors for atherosclerosis. However, limited information is available regarding whether cigarette smoking, another major, modifiable risk factor, has synergistic effects with age and metabolic syndrome on subclinical atherosclerosis, particularly in young adults. This aspect was examined in 1,051 adults (747 whites and 304 blacks; aged 24-43 years) from the Bogalusa Heart Study. General linear models were used to examine the effects of cigarette smoking and its interactive effects with age and metabolic syndrome on carotid intima-media thickness (CIMT). After adjusting for age, race, and sex, current smokers had lower BMI (mean ± SE: 27.4 ± 0.4, 29.3 ± 0.5, and 29.9 ± 0.3 kg/m2 in current, former, and never smokers, respectively; p<0.0001) and lower levels of fasting glucose (82.8 ± 0.9, 89.5 ± 2.3, and 87.1 ± 1.1 mg/dL, respectively; p = 0.001) and insulin (10.6 ± 0.4, 14.2 ± 1.0, 13.6 ± 0. 6 µU/ml, respectively; p<0.0001). Despite being lean and having favorable levels of glucose and insulin, current smokers had greater CIMT (0.850 ± 0.012, 0.808 ± 0.011, and 0.801 ± 0.006 mm, respectively; p = 0.0004). Importantly, cigarette smoking showed significant interactions with age and metabolic syndrome on CIMT: Age-related change in CIMT in current smokers was significantly greater (0.013 ± 0.002 mm/year) than in nonsmokers (former and never smokers combined) (0.008 ± 0.001 mm/year) (p for interaction = 0.005); the difference in CIMT between those with and without metabolic syndrome was significantly greater in current smokers (0.154 ± 0.030 mm, p<0.0001) than in nonsmokers (0.031 ± 0.014 mm, p = 0.03) (p for interaction<0.0001). In conclusion, cigarette smoking significantly exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis in young adults, which underscores the importance of prevention and cessation of cigarette smoking behavior in the young.

  7. Cigarette Smoking Exacerbates the Adverse Effects of Age and Metabolic Syndrome on Subclinical Atherosclerosis: The Bogalusa Heart Study

    PubMed Central

    Fernandez, Camilo; Xu, Jihua; Srinivasan, Sathanur R.; Chen, Wei; Berenson, Gerald S.

    2014-01-01

    Age and metabolic syndrome are major risk factors for atherosclerosis. However, limited information is available regarding whether cigarette smoking, another major, modifiable risk factor, has synergistic effects with age and metabolic syndrome on subclinical atherosclerosis, particularly in young adults. This aspect was examined in 1,051 adults (747 whites and 304 blacks; aged 24–43 years) from the Bogalusa Heart Study. General linear models were used to examine the effects of cigarette smoking and its interactive effects with age and metabolic syndrome on carotid intima-media thickness (CIMT). After adjusting for age, race, and sex, current smokers had lower BMI (mean±SE: 27.4±0.4, 29.3±0.5, and 29.9±0.3 kg/m2 in current, former, and never smokers, respectively; p<0.0001) and lower levels of fasting glucose (82.8±0.9, 89.5±2.3, and 87.1±1.1 mg/dL, respectively; p = 0.001) and insulin (10.6±0.4, 14.2±1.0, 13.6±0. 6 µU/ml, respectively; p<0.0001). Despite being lean and having favorable levels of glucose and insulin, current smokers had greater CIMT (0.850±0.012, 0.808±0.011, and 0.801±0.006 mm, respectively; p = 0.0004). Importantly, cigarette smoking showed significant interactions with age and metabolic syndrome on CIMT: Age-related change in CIMT in current smokers was significantly greater (0.013±0.002 mm/year) than in nonsmokers (former and never smokers combined) (0.008±0.001 mm/year) (p for interaction = 0.005); the difference in CIMT between those with and without metabolic syndrome was significantly greater in current smokers (0.154±0.030 mm, p<0.0001) than in nonsmokers (0.031±0.014 mm, p = 0.03) (p for interaction<0.0001). In conclusion, cigarette smoking significantly exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis in young adults, which underscores the importance of prevention and cessation of cigarette smoking behavior in the young. PMID:24789040

  8. APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease

    PubMed Central

    Maulik, Mahua; Peake, Kyle; Chung, JiYun; Wang, Yanlin; Vance, Jean E.; Kar, Satyabrata

    2015-01-01

    Amyloid-β (Aβ) peptides originating from β-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aβ peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aβ metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal–lysosomal system, a major site of Aβ production, on APP/Aβ metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (α-CTF/β-CTF) and Aβ peptides, but not APP mRNA/protein or soluble APPα/APPβ, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of γ-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Aβ levels may result from a combination of increased production and decreased turnover. APP-CTFs and Aβ peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aβ peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced β-CTF/Aβ levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aβ metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology. PMID:26433932

  9. Post-traumatic hypoxia exacerbates neurological deficit, neuroinflammation and cerebral metabolism in rats with diffuse traumatic brain injury

    PubMed Central

    2011-01-01

    Background The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles. Methods Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O2/88% N2) or normoxic (22% O2/78% N2) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique. Results TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels. Conclusion Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction. PMID

  10. APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease.

    PubMed

    Maulik, Mahua; Peake, Kyle; Chung, JiYun; Wang, Yanlin; Vance, Jean E; Kar, Satyabrata

    2015-12-15

    Amyloid-β (Aβ) peptides originating from β-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aβ peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aβ metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. Using this unique bigenic ANPC mice and complementary stable N2a cells, we have examined the functional consequences of cellular cholesterol sequestration in the endosomal-lysosomal system, a major site of Aβ production, on APP/Aβ metabolism and its relation to neuronal viability. Levels of APP C-terminal fragments (α-CTF/β-CTF) and Aβ peptides, but not APP mRNA/protein or soluble APPα/APPβ, were increased in ANPC mouse brains and N2a-ANPC cells. These changes were accompanied by reduced clearance of peptides and an increased level/activity of γ-secretase, suggesting that accumulation of APP-CTFs is due to decreased turnover, whereas increased Aβ levels may result from a combination of increased production and decreased turnover. APP-CTFs and Aβ peptides were localized primarily in early-/late-endosomes and to some extent in lysosomes/autophagosomes. Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aβ peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced β-CTF/Aβ levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aβ metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology. © The Author 2015. Published by Oxford University Press. All rights reserved. For

  11. Cerebral microvascular dysfunction in metabolic syndrome is exacerbated by ischemia-reperfusion injury.

    PubMed

    Obadia, Nathalie; Lessa, Marcos Adriano; Daliry, Anissa; Silvares, Raquel Rangel; Gomes, Fabiana; Tibiriçá, Eduardo; Estato, Vanessa

    2017-09-08

    Metabolic syndrome (MetS) is associated with an increased risk of cerebrovascular diseases, including cerebral ischemia. Microvascular dysfunction is an important feature underlying the pathophysiology of cerebrovascular diseases. In this study, we aimed to investigate the impacts of ischemia and reperfusion (IR) injury on the cerebral microvascular function of rats with high-fat diet-induced MetS. We examined Wistar rats fed a high-fat diet (HFD) or normal diet (CTL) for 20 weeks underwent 30 min of bilateral carotid artery occlusion followed by 1 h of reperfusion (IR) or sham surgery. Microvascular blood flow was evaluated on the parietal cortex surface through a cranial window by laser speckle contrast imaging, functional capillary density, endothelial function and endothelial-leukocyte interactions by intravital videomicroscopy. Lipid peroxidation was assessed by TBARs analysis, the expression of oxidative enzymes and inflammatory markers in the brain tissue was analyzed by real-time PCR. The cerebral IR in MetS animals induced a functional capillary rarefaction (HFD IR 117 ± 17 vs. CTL IR 224 ± 35 capillary/mm(2); p < 0.05), blunted the endothelial response to acetylcholine (HFD IR -16.93% vs. CTL IR 16.19% from baseline inner diameter p < 0.05) and increased the endothelial-leukocyte interactions in the venules in the brain. The impact of ischemia on the cerebral microvascular blood flow was worsened in MetS animals, with a marked reduction of cerebral blood flow, exposing brain tissue to a higher state of hypoxia. Our results demonstrate that during ischemia and reperfusion, animals with MetS are more susceptible to alterations in the cerebral microcirculation involving endothelial dysfunction and oxidative stress events.

  12. Concurrent presence of inflammation and obstructive sleep apnea exacerbates the risk of metabolic syndrome

    PubMed Central

    Kim, Jinkwan; Yoon, Dae Wui; Lee, Seung Ku; Lee, Seunggwan; Choi, Kyung-Mee; Robert, Thomas J.; Shin, Chol

    2017-01-01

    Abstract Obstructive sleep apnea (OSA) leads to multiple end-organ morbidities that are mediated by the cumulative burden of oxidative stress and inflammation. Both OSA and inflammation play key roles in increased risk of cardiovascular disease (CVD). Thus, we hypothesized that the combination of inflammation and OSA could accelerate the development of metabolic syndrome (MetS) in a large cohort study. A total of 1835 participants were randomly selected from the ongoing Korean Genome and Epidemiology Study for the years between 2007 and 2015. Overnight polysomnography was performed on each participant. Blood was drawn for biochemical analyses. Participants with high or low inflammation were divided by high-sensitivity C-reactive protein (hsCRP). MetS was defined using the criteria of the modified National Cholesterol Education Program, Adult Treatment Panel III. The prevalence of MetS was higher among the subjects with OSA and high hsCRP levels than among the other corresponding groups. The incidence of MetS among the 4 groups stratified by OSA and inflammation status at the 6-year follow-up was 11.8%, 19.9%, 25.8%, and 36.0% (HsCRP[−]/OSA[−] vs HsCRP[+]/OSA[−] vs HsCRP[−]/OSA[+] vs HsCRP[+]/OSA[+], P < 0.01). After adjusting for age, sex, smoking, alcohol status, BMI, and change in BMI (ΔBMI) in a multiple logistic regression, the subjects with OSA and high hsCRP levels at follow-up had a 2.22-fold risk of developing MetS, as compared with those with no-OSA and low hsCRP levels (P < 0.01). MetS is more prevalent in the concurrent presence of inflammation and OSA. The combination of these conditions is associated with higher risk of MetS. Additional research is needed to help further define the significance of the combined effect of OSA and subclinical inflammation on the development of MetS in the context of reduction of CVD risk. PMID:28207497

  13. Comparison of enriched palmitic acid and calcium salts of palm fatty acids distillate fat supplements on milk production and metabolic profiles of high-producing dairy cows.

    PubMed

    Rico, D E; Ying, Y; Harvatine, K J

    2014-09-01

    A variable response to fat supplementation has been reported in dairy cows, which may be due to cow production level, environmental conditions, or diet characteristics. In the present experiment, the effect of a high palmitic acid supplement was investigated relative to a conventional Ca salts of palm fatty acids (Ca-FA) supplement in 16 high-producing Holstein cows (46.6±12.4kg of milk/d) arranged in a crossover design with 14-d periods. The experiment was conducted in a non-heat-stress season with 29.5% neutral detergent fiber diets. Treatments were (1) high palmitic acid (PA) supplement fed as free FA [1.9% of dry matter (DM); 84.8% C16:0] and (2) Ca-FA supplement (2.3% of DM; 47.7% C16:0, 35.9% C18:1, and 8.4% C18:2). The PA supplement tended to increase DM intake, and increased the yields of milk and energy-corrected milk. Additionally, PA increased the yields of milk fat, protein, and lactose, whereas milk concentrations of these components were not affected. The yields of milk de novo and 16-C FA were increased by PA compared with Ca-FA (7 and 20%, respectively), whereas the yield of preformed FA was higher in Ca-FA. A reduction in milk fat concentration of de novo and 16-C FA and a marginal elevation in trans-10 C18:1 in Ca-FA is indicative of altered ruminal biohydrogenation and increased risk of milk fat depression. No effect of treatment on plasma insulin was observed. A treatment by time interaction was detected for plasma nonesterified fatty acids (NEFA), which tended to be higher in Ca-FA than in PA before feeding. Overall, the palmitic acid supplement improved production performance in high-producing cows while posing a lower risk for milk fat depression compared with a supplement higher in unsaturated FA.

  14. Palmitic acid interferes with energy metabolism balance by adversely switching the SIRT1-CD36-fatty acid pathway to the PKC zeta-GLUT4-glucose pathway in cardiomyoblasts.

    PubMed

    Chen, Yeh-Peng; Tsai, Chia-Wen; Shen, Chia-Yao; Day, Cecilia-Hsuan; Yeh, Yu-Lan; Chen, Ray-Jade; Ho, Tsung-Jung; Padma, V Vijaya; Kuo, Wei-Wen; Huang, Chih-Yang

    2016-05-01

    Metabolic regulation is inextricably linked with cardiac function. Fatty acid metabolism is a significant mechanism for creating energy for the heart. However, cardiomyocytes are able to switch the fatty acids or glucose, depending on different situations, such as ischemia or anoxia. Lipotoxicity in obesity causes impairments in energy metabolism and apoptosis in cardiomyocytes. We utilized the treatment of H9c2 cardiomyoblast cells palmitic acid (PA) as a model for hyperlipidemia to investigate the signaling mechanisms involved in these processes. Our results show PA induces time- and dose-dependent lipotoxicity in H9c2 cells. Moreover, PA enhances cluster of differentiation 36 (CD36) and reduces glucose transporter type 4 (GLUT4) pathway protein levels following a short period of treatment, but cells switch from CD36 back to the GLUT4 pathway after during long-term exposure to PA. As sirtuin 1 (SIRT1) and protein kinase Cζ (PKCζ) play important roles in CD36 and GLUT4 translocation, we used the SIRT1 activator resveratrol and si-PKCζ to identify the switches in metabolism. Although PA reduced CD36 and increased GLUT4 metabolic pathway proteins, when we pretreated cells with resveratrol to activate SIRT1 or transfected si-PKCζ, both were able to significantly increase CD36 metabolic pathway proteins and reduce GLUT4 pathway proteins. High-fat diets affect energy metabolism pathways in both normal and aging rats and involve switching the energy source from the CD36 pathway to GLUT4. In conclusion, PA and high-fat diets cause lipotoxicity in vivo and in vitro and adversely switch the energy source from the CD36 pathway to the GLUT4 pathway.

  15. Decreased serum obestatin consequent upon TRIB3 Q84R polymorphism exacerbates carotid atherosclerosis in subjects with metabolic syndrome

    PubMed Central

    2012-01-01

    Background Functional TRIB3 Q84R polymorphism has been associated with insulin resistance. Obestatin, improving insulin resistance, exerts obscure effects on metabolic syndrome (MetS) and carotid atherosclerosis. Aims to investigate whether the prevalent TRIB3 Q84R polymorphism has profound implications for alterations of serum obestatin and what effect obestatin exerts on carotid atherosclerosis. Methods A total of 518 unrelated Chinese subjects consisted of control (n = 258) and MetS (n = 260) groups. Clinical and biochemical characteristics were collected. The level of serum obestatin was measured. Genotype the functional TRIB3 Q84R polymorphism. All subjects underwent ultrasonography to determine carotid intima-media thickness (IMT). Results Serum obestatin was significantly decreased in MetS as compared with the control group (P = 0.042). Among the MetS group participants possessing RR84 genotype had significantly lower levels of serum obestatin than those with QQ84 or QR84 genotypes (P = 0.008, P = 0.043) with similar significant difference among the control group. Factorial analyses showed statistically significant interactions between MetS and RR84 genotype (P = 0.009 for interaction for obestatin). On correlation analysis, obestatin correlated negatively with homeostasis model assessment insulin resistance (r = -0.163, P = 0.010) and IMT (r = -0.256, P = 0.011). On partial analyses, obestatin negatively correlated with IMT(r = -0.259, P = 0.024) after controlling for the confounding factors. Conclusion MetS individuals with TRIB3 RR84 genotype demonstrated further decreased serum obestatin. Decreased serum obestatin might in part exacerbate insulin resistance and carotid atherosclerosis. PMID:23245314

  16. Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    PubMed

    Mailloux, Ryan J; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co

  17. Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

    PubMed Central

    Mailloux, Ryan J.; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C.; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G.; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co

  18. Palmitic acid stimulates energy metabolism and inhibits insulin/PI3K/AKT signaling in differentiated human neuroblastoma cells: The role of mTOR activation and mitochondrial ROS production.

    PubMed

    Calvo-Ochoa, Erika; Sánchez-Alegría, Karina; Gómez-Inclán, Cecilia; Ferrera, Patricia; Arias, Clorinda

    2017-09-15

    The high consumption of saturated lipids has been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance in peripheral tissues. However, how neurons develop insulin resistance in response to lipid overload is not fully understood. Here, we used cultured rat cortical neurons and differentiated human neuroblastoma cells to demonstrate that PA blocks insulin-induced metabolic activation, inhibits the activation of the insulin/PI3K/Akt pathway and activates mTOR kinase downstream of Akt. Despite the fact that fatty acids are not normally used as a significant source of fuel by neural cells, we also found that short-term neuronal exposure to PA reduces the NAD(+)/NADH ratio, indicating that PA modifies the neuronal energy balance. Finally, inhibiting mitochondrial ROS production with mitoTEMPO prevented the deleterious effect of PA on insulin signaling. This work provides novel evidence of the mechanisms behind saturated fatty acid-induced insulin resistance and its metabolic consequences on neuronal cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Berberine Attenuates Development of the Hepatic Gluconeogenesis and Lipid Metabolism Disorder in Type 2 Diabetic Mice and in Palmitate-Incubated HepG2 Cells through Suppression of the HNF-4α miR122 Pathway.

    PubMed

    Wei, Shengnan; Zhang, Ming; Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M

    2016-01-01

    Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122

  20. Berberine Attenuates Development of the Hepatic Gluconeogenesis and Lipid Metabolism Disorder in Type 2 Diabetic Mice and in Palmitate-Incubated HepG2 Cells through Suppression of the HNF-4α miR122 Pathway

    PubMed Central

    Yu, Yang; Lan, Xiaoxin; Yao, Fan; Yan, Xin; Chen, Li; Hatch, Grant M.

    2016-01-01

    Berberine (BBR) has been shown to exhibit protective effects against diabetes and dyslipidemia. Previous studies have indicated that BBR modulates lipid metabolism and inhibits hepatic gluconeogensis by decreasing expression of Hepatocyte Nuclear Factor-4α (HNF-4α). However, the mechanism involved in this process was unknown. In the current study, we examined the mechanism of how BBR attenuates hepatic gluconeogenesis and the lipid metabolism alterations observed in type 2 diabetic (T2D) mice and in palmitate (PA)-incubated HepG2 cells. Treatment with BBR for 4 weeks improve all biochemical parameters compared to T2D mice. Treatment of T2D mice for 4 weeks or treatment of PA-incubated HepG2 cells for 24 h with BBR decreased expression of HNF-4α and the microRNA miR122, the key gluconeogenesis enzymes Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) and the key lipid metabolism proteins Sterol response element binding protein-1 (SREBP-1), Fatty acid synthase-1 (FAS-1) and Acetyl-Coenzyme A carboxylase (ACCα) and increased Carnitine palmitoyltransferase-1(CPT-1) compared to T2D mice or PA-incubated HepG2 cells. Expression of HNF-4α in HepG2 cells increased expression of gluconeogenic and lipid metabolism enzymes and BBR treatment or knock down of miR122 attenuated the effect of HNF-4α expression. In contrast, BBR treatment did not alter expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. In addition, miR122 mimic increased expression of gluconeogenic and lipid metabolism enzymes in HepG2 cells with knockdown of HNF-4α. These data indicate that miR122 is a critical regulator in the downstream pathway of HNF-4α in the regulation of hepatic gluconeogenesis and lipid metabolism in HepG2 cells. The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4α and is regulated downstream of miR122. Our data provide new evidence to support HNF-4α and miR122

  1. LNK deficiency aggravates palmitate-induced preadipocyte apoptosis.

    PubMed

    Du, Jie-Yi; Jin, Chen-Chen; Wang, Guo-Hao; Huang, Xiong-Qing; Cheng, Jian-Ding; Wen, Xue-Jun; Zhao, Xiao-Miao; Wang, Guan-Lei

    2017-08-19

    LNK (SH2B3) is an intracellular adaptor protein that negatively regulates cellular proliferation or self-renewal of hematopoietic stem cells and some other progenitor cells. LNK is also recognized as a key regulator of insulin resistance and inflammatory responses in several tissues and organs. The function of LNK in adipose tissue is unknown. We previously demonstrated that type 2 diabetes mellitus (T2DM) mouse model had elevated serum free fatty acids (FFAs) levels and increased preadipocyte apoptosis in visceral fat tissue, showing the occurrence of lipotoxicity. Herein, when compared to control mice, the protein expression of LNK decreased in epididymal fat tissue from the high-sucrose/fat diet, low-dose streptozotocin induced T2DM mouse model. We thus investigated whether LNK could regulate palmitate-induced preadipocyte apoptosis in an in vitro apoptotic model in 3T3-L1 preadipocytes. LNK specific siRNA exacerbated palmitate-induced apoptosis and increased pro-apoptotic protein levels of cleaved caspase-3, Bax and cytochrome C; while overexpression of LNK cDNA exhibited significant anti-apoptotic effects. Consistently, LNK specific siRNA further decreased the Akt Ser-473 phosphorylation reduced by palmitate and located on upstream of Bax and cytochrome C. The siRNA-mediated LNK knockdown exacerbated mitochondrial membrane depolarization and mitochondrial-derived reactive oxygen species production induced by palmitate, whereas overexpression of LNK attenuated that. These results indicated that LNK plays a regulatory role in the palmitate-related preadipocyte apoptosis and might be involved in adipose tissue dysfunction. Copyright © 2017. Published by Elsevier Inc.

  2. Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia.

    PubMed

    Schreiner, Andreas; Aadamsoo, Kaire; Altamura, A Carlo; Franco, Manuel; Gorwood, Philip; Neznanov, Nikolaj G; Schronen, Juan; Ucok, Alp; Zink, Mathias; Janik, Adam; Cherubin, Pierre; Lahaye, Marjolein; Hargarter, Ludger

    2015-12-01

    Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention. Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability. In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249 days (P=0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P=0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P=0.021) and a trend at endpoint (P=0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified. The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness. Copyright © 2015 Janssen Pharmaceutica NV. Published by Elsevier B.V. All rights reserved.

  3. Effects of dichloroacetate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro and on extraction of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo

    PubMed Central

    McAllister, Anthony; Allison, S. P.; Randle, Philip J.

    1973-01-01

    1. The extractions of glucose, lactate, pyruvate and free fatty acids by dog heart in vivo were calculated from measurements of their arterial and coronary sinus blood concentration. Elevation of plasma free fatty acid concentrations by infusion of intralipid and heparin resulted in increased extraction of free fatty acids and diminished extractions of glucose, lactate and pyruvate by the heart. It is suggested that metabolism of free fatty acids by the heart in vivo, as in vitro, may impair utilization of these substrates. These effects of elevated plasma free fatty acid concentrations on extractions by the heart in vivo were reversed by injection of dichloroacetate, which also improved extraction of lactate and pyruvate by the heart in vivo in alloxan diabetes. 2. Sodium dichloroacetate increased glucose oxidation and pyruvate oxidation in hearts from fed normal or alloxan-diabetic rats perfused with glucose and insulin. Dichloroacetate inhibited oxidation of acetate and 3-hydroxybutyrate and partially reversed inhibitory effects of these substrates on the oxidation of glucose. In rat diaphragm muscle dichloroacetate inhibited oxidation of acetate, 3-hydroxybutyrate and palmitate and increased glucose oxidation and pyruvate oxidation in diaphragms from alloxan-diabetic rats. Dichloroacetate increased the rate of glycolysis in hearts perfused with glucose, insulin and acetate and evidence is given that this results from a lowering of the citrate concentration within the cell, with a consequent activation of phosphofructokinase. 3. In hearts from normal rats perfused with glucose and insulin, dichloroacetate increased cell concentrations of acetyl-CoA, acetylcarnitine and glutamate and lowered those of aspartate and malate. In perfusions with glucose, insulin and acetate, dichloroacetate lowered the cell citrate concentration without lowering the acetyl-CoA or acetylcarnitine concentrations. Measurements of specific radioactivities of acetyl-CoA, acetylcarnitine

  4. Studies on the fate of labelled palmitic acid in rat lung.

    PubMed

    Miras, F; Hernandez, J; de la Higuera Torres, J; Nuñez, J; Martin, A; de la Higuera Rojas, J

    1983-01-01

    1. Pulmonary palmitic acid metabolism was studied in rats in basal conditions and after experimental talcosis. 2. Palmitic acid was rapidly incorporated into phospholipids and stored in the form of esterified cholesterol. 3. During the experiment a de novo synthesis of triglycerides was not detected.

  5. Palmitate Inhibits SIRT1-Dependent BMAL1/CLOCK Interaction and Disrupts Circadian Gene Oscillations in Hepatocytes

    PubMed Central

    Tong, Xin; Zhang, Deqiang; Arthurs, Blake; Li, Pei; Durudogan, Leigh; Gupta, Neil; Yin, Lei

    2015-01-01

    Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes during the development of obesity. However, it remains unclear whether palmitate directly impacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstream metabolic outputs. Here we presented evidence that the molecular clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhibits the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein interaction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes. PMID:26075729

  6. Olestra ingestion and retinyl palmitate absorption in humans.

    PubMed

    Daher, G C; Cooper, D A; Zorich, N L; King, D; Riccardi, K A; Peters, J C

    1997-08-01

    This study examined the effect of olestra, a zero-calorie fat replacement, on the absorption of retinyl palmitate in humans. After a 30-d adaptation period during which they consumed 10 g olestra/d in potato chips under free-living conditions, 68 healthy male subjects were housed in a metabolic ward and given a single dose of retinyl palmitate (0.33 RDA) containing a trace amount of 3H-retinyl palmitate with a breakfast that contained 0, 8, 20 or 32 g of olestra and about 38 g of triglyceride. Blood was collected at defined intervals for 48 h and plasma analyzed for 3H-retinyl esters by HPLC and liquid scintillation spectrometry. There was no significant effect on retinyl palmitate absorption as determined from the area under the plasma 3H-retinyl esters concentration-time curve. However, an area under the plasma concentration-time curve in the 32-g olestra group that was 81% (mean value) or 70% (median value) of the area under the curve for the placebo group suggested that olestra may have affected retinyl palmitate absorption. Inclusion or exclusion of 13 high responders did not change the results.

  7. 21 CFR 186.1771 - Sodium palmitate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Sodium palmitate. 186.1771 Section 186.1771 Food... of Specific Substances Affirmed as GRAS § 186.1771 Sodium palmitate. (a) Sodium palmitate (C16H31O2Na, CAS Reg. No. 408-35-5) is the sodium salt of palmitic acid (hexadecanoic acid). It exists as a...

  8. 21 CFR 186.1771 - Sodium palmitate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Sodium palmitate. 186.1771 Section 186.1771 Food... GRAS § 186.1771 Sodium palmitate. (a) Sodium palmitate (C16H31O2Na, CAS Reg. No. 408-35-5) is the sodium salt of palmitic acid (hexadecanoic acid). It exists as a white to yellow powder....

  9. 21 CFR 186.1771 - Sodium palmitate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Sodium palmitate. 186.1771 Section 186.1771 Food... of Specific Substances Affirmed as GRAS § 186.1771 Sodium palmitate. (a) Sodium palmitate (C16H31O2Na, CAS Reg. No. 408-35-5) is the sodium salt of palmitic acid (hexadecanoic acid). It exists as a...

  10. 21 CFR 186.1771 - Sodium palmitate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Sodium palmitate. 186.1771 Section 186.1771 Food... of Specific Substances Affirmed as GRAS § 186.1771 Sodium palmitate. (a) Sodium palmitate (C16H31O2Na, CAS Reg. No. 408-35-5) is the sodium salt of palmitic acid (hexadecanoic acid). It exists as a...

  11. 21 CFR 186.1771 - Sodium palmitate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Sodium palmitate. 186.1771 Section 186.1771 Food... of Specific Substances Affirmed as GRAS § 186.1771 Sodium palmitate. (a) Sodium palmitate (C16H31O2Na, CAS Reg. No. 408-35-5) is the sodium salt of palmitic acid (hexadecanoic acid). It exists as a...

  12. Metabolic syndrome’ in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition

    PubMed Central

    Agrawal, Rahul; Gomez-Pinilla, Fernando

    2012-01-01

    We pursued studies to determine the effects of the metabolic syndrome (MetS) on brain, and the possibility of modulating these effects by dietary interventions. In addition, we have assessed potential mechanisms by which brain metabolic disorders can impact synaptic plasticity and cognition. We report that high-dietary fructose consumption leads to an increase in insulin resistance index, and insulin and triglyceride levels, which characterize MetS. Rats fed on an n-3 deficient diet showed memory deficits in a Barnes maze, which were further exacerbated by fructose intake. In turn, an n-3 deficient diet and fructose interventions disrupted insulin receptor signalling in hippocampus as evidenced by a decrease in phosphorylation of the insulin receptor and its downstream effector Akt. We found that high fructose consumption with an n-3 deficient diet disrupts membrane homeostasis as evidenced by an increase in the ratio of n-6/n-3 fatty acids and levels of 4-hydroxynonenal, a marker of lipid peroxidation. Disturbances in brain energy metabolism due to n-3 deficiency and fructose treatments were evidenced by a significant decrease in AMPK phosphorylation and its upstream modulator LKB1 as well as a decrease in Sir2 levels. The decrease in phosphorylation of CREB, synapsin I and synaptophysin levels by n-3 deficiency and fructose shows the impact of metabolic dysfunction on synaptic plasticity. All parameters of metabolic dysfunction related to the fructose treatment were ameliorated by the presence of dietary n-3 fatty acid. Results showed that dietary n-3 fatty acid deficiency elevates the vulnerability to metabolic dysfunction and impaired cognitive functions by modulating insulin receptor signalling and synaptic plasticity. PMID:22473784

  13. Beta-palmitate - a natural component of human milk in supplemental milk formulas.

    PubMed

    Havlicekova, Zuzana; Jesenak, Milos; Banovcin, Peter; Kuchta, Milan

    2016-03-17

    The composition and function of human milk is unique and gives a basis for the development of modern artificial milk formulas that can provide an appropriate substitute for non-breastfed infants. Although human milk is not fully substitutable, modern milk formulas are attempting to mimic human milk and partially substitute its complex biological positive effects on infants. Besides the immunomodulatory factors from human milk, research has been focused on the composition and structure of human milk fat with a high content of β-palmitic acid (sn-2 palmitic acid, β-palmitate). According to the available studies, increasing the content of β-palmitate added to milk formulas promotes several beneficial physiological functions. β-palmitate positively influences fatty acid metabolism, increases calcium absorption, improves bone matrix quality and the stool consistency, and has a positive effect on the development of the intestinal microbiome.

  14. Stevioside counteracts the alpha-cell hypersecretion caused by long-term palmitate exposure.

    PubMed

    Hong, J; Chen, L; Jeppesen, P B; Nordentoft, I; Hermansen, K

    2006-03-01

    Long-term exposure to fatty acids impairs beta-cell function in type 2 diabetes, but little is known about the chronic effects of fatty acids on alpha-cells. We therefore studied the prolonged impact of palmitate on alpha-cell function and on the expression of genes related to fuel metabolism. We also investigated whether the antihyperglycemic agent stevioside was able to counteract these effects of palmitate. Clonal alpha-TC1-6 cells were cultured with palmitate in the presence or absence of stevioside. After 72 h, we evaluated glucagon secretion, glucagon content, triglyceride (TG) content, and changes in gene expression. Glucagon secretion was dose-dependently increased after 72-h culture, with palmitate at concentrations >or=0.25 mM (P< 0.05). Palmitate (0.5 mM) enhanced TG content of alpha-cells by 73% (P< 0.01). Interestingly, stevioside (10(-8) and 10(-6) M) reduced palmitate-stimulated glucagon release by 22 and 45%, respectively (P< 0.01). There was no significant change in glucagon content after 72-h culture with palmitate and/or stevioside. Palmitate increased carnitine palmitoyltransferase I (CPT I) mRNA level, whereas stevioside enhanced CPT I, peroxisome proliferator-activated receptor-gamma, and stearoyl-CoA desaturase gene expressions in the presence of palmitate (P<0.05). In conclusion, long-term exposure to elevated fatty acids leads to a hypersecretion of glucagon and an accumulation of TG content in clonal alpha-TC1-6 cells. Stevioside was able to counteract the alpha-cell hypersecretion caused by palmitate and enhanced the expression of genes involved in fatty acid metabolism. This indicates that stevioside may be a promising antidiabetic agent in treatment of type 2 diabetes.

  15. Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an “obesogenic” diet

    PubMed Central

    Fullston, Tod; McPherson, Nicole O; Owens, Julie A; Kang, Wan Xian; Sandeman, Lauren Y; Lane, Michlle

    2015-01-01

    Obesity and related comorbidities are becoming increasingly prevalent globally. In mice preconception paternal exposure to a high fat diet (HFD) impairs the metabolic and reproductive health of male offspring, despite their control diet (CD) consumption. However, offspring share lifestyle, including diet, with parents. We assessed if male offspring from HFD fathers have a heightened susceptibility to HFD-induced metabolic and reproductive derangements. This 2 × 2 design saw founder males (F0) and their offspring (F1) fed either a HFD or a nutritionally matched CD. Regardless of paternal diet, HFD fed male offspring had greater total body weight and adiposity. Offspring sired by a HFD male and fed a HFD were the heaviest, had the greatest adiposity and had the greatest concentration of serum cholesterol, triglyceride, HDL, and NEFA compared with CD sired/fed littermates. A synergistic increase in serum insulin was unmasked by both father/son HFD consumption, concomitant with increased sera glucose. Either a paternal or offspring HFD was associated with similar reductions to offspring sperm motility. Whereas sperm ROS concentrations and sperm–oocyte binding saw detrimental effects of both F0 HFD and F1 HFD with an interaction evident between both, culminating in the most impaired sperm parameters in this group. This indicates that metabolic and fertility disturbances in male offspring sired by HFD fathers are exacerbated by a “second-hit” of exposure to the same obesogenic environment postnatally. If translatable to human health, this suggests that adverse reproductive and metabolic outcomes may be amplified across generations through a shared calorie dense diet, relevant to the current worldwide obesity epidemic. PMID:25804263

  16. Involvement of iron depletion in palmitate-induced lipotoxicity of beta cells.

    PubMed

    Jung, Ik-Rak; Choi, Sung-E; Jung, Jong-Gab; Lee, Sang-A; Han, Seung Jin; Kim, Hae Jin; Kim, Dae Jung; Lee, Kwan-Woo; Kang, Yup

    2015-05-15

    High levels of plasma free fatty acid are thought to contribute to the loss of pancreatic beta-cells in type 2 diabetes. In particular, saturated fatty acid such as palmitate or stearate can induce apoptosis in cultured beta cells (lipotoxicity). Endoplasmic reticulum stress is a critical mediator of free fatty acid-induced lipotoxicity. Recently, disorders in mitochondrial respiratory metabolism have been linked to lipotoxicity. Since iron is a critical component of respiratory metabolism, this study is initiated to determine whether abnormal iron metabolism is involved in palmitate-induced beta cell death. Immunoblotting analysis showed that treatment of INS-1 beta cells with palmitate reduced the level of transferrin receptor 1 (TfR1), but increased the level of heavy chain ferritin (FTH). In addition, palmitate reduced intracellular labile iron pool. Whereas iron depletion through treatment with iron-chelators deferoxamine or deferasirox augmented palmitate-induced cell death, iron supplementation with ferric chloride, ferrous sulfate, or holo-transferrin significantly protected cells against palmitate-induced death. Furthermore, overexpression of TfR1 reduced palmitate-induced cell death, whereas knockdown of TfR1 augmented cell death. In particular, treatment with deferoxamine increased the level of endoplasmic reticulum (ER) stress markers phospho-PERK, phospho-eIF2α, CHOP and phospho-c-Jun N-terminal kinase. Treatment with chemical chaperone significantly protected cells against deferoxamine-induced apoptosis. Iron supplementation also protected cells against palmitate-induced primary islet death. These data suggest that iron depletion plays an important role in palmitate-induced beta cell death through inducing ER stress. Therefore, attempts to block iron depletion might be able to prevent beta cell loss in type 2 diabetes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis.

    PubMed

    Grant, Ryan; Nguyen, Kim Y; Ravussin, Anthony; Albarado, Diana; Youm, Yun-Hee; Dixit, Vishwa Deep

    2014-05-16

    Successful adaptation to periods of chronic caloric excess is a highly coordinated event that is critical to the survival and propagation of species. Transcription factor C/ebp homologous protein (Chop) is thought to be an important molecular mediator that integrates nutrient signals to endoplasmic reticulum (ER) stress and innate immune activation. Given that aberrant ER stress response is implicated in inducing metabolic inflammation and insulin resistance, we hypothesized that ER stress target gene Chop integrates immune and metabolic systems to adapt to chronic positive energy balance. Here we report that inactivation of Chop in mice fed a high fat diet led to significant increase in obesity caused by a reduction in energy expenditure without any change in food intake. Importantly, ablation of Chop does not induce metabolically healthy obesity, because Chop-deficient mice fed a high fat diet had increased hepatic steatosis with significantly higher insulin resistance. Quantification of adipose tissue leukocytosis revealed that elimination of Chop during obesity led to substantial increase in number of adipose tissue T and B lymphocytes. In addition, deficiency of Chop led to increase in total number of myeloid subpopulations like neutrophils and F4/80(+) adipose tissue macrophages without any alterations in the frequency of M1- or M2-like adipose tissue macrophages. Further investigation of inflammatory mechanisms revealed that ablation of Chop increases the sensitivity of macrophages to inflammasome-induced activation of IL-β in macrophages. Our findings indicate that regulated expression of Chop during obesity is critical for adaptation to chronic caloric excess and maintenance of energy homeostasis via integration of metabolic and immune systems. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Retinol and Retinyl Palmitate in Foetal Lung Mice: Sexual Dimorphism

    PubMed Central

    Carvalho, Olga; Gonçalves, Carlos

    2013-01-01

    In this work, we evaluate the lung retinoids content to study the possible difference between male and female mice during prenatal development and to comprehend if the vitamin A metabolism is similar in both genders. The study occurred between developmental days E15 and E19, and the retinol and retinyl palmitate lung contents were determined by HPLC analysis. We established two main groups: the control, consisting of foetuses obtained from pregnant females without any manipulation, and vitamin A, composed of foetuses from pregnant females submitted to vitamin A administration on developmental day E14. Each of these groups was subdivided by gender, establishing the four final groups. In the lung of control group, retinol was undetected in both genders and retinyl palmitate levels exhibited a sexual dimorphism. In the vitamin A group, we detected retinol and retinyl palmitate in both genders, and we observed a more evident sexual dimorphism for both retinoids. Our study also indicates that, from developmental day E15 to E19, there is an increase in the retinoids content in foetal lung and a gender difference in the retinoids metabolism. In conclusion, there is a sexual dimorphism in the lung retinoids content and in its metabolism during mice development. PMID:23365730

  19. Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes.

    PubMed

    Kuzmicic, Jovan; Parra, Valentina; Verdejo, Hugo E; López-Crisosto, Camila; Chiong, Mario; García, Lorena; Jensen, Michael D; Bernlohr, David A; Castro, Pablo F; Lavandero, Sergio

    2014-10-01

    Metabolic and cardiovascular disease patients have increased plasma levels of lipids and, specifically, of palmitate, which can be toxic for several tissues. Trimetazidine (TMZ), a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, its mechanism of action is controversial. Given the fact that TMZ is able to alter mitochondrial metabolism, we evaluated the protective role of TMZ on mitochondrial morphology and function in an in vitro model of lipotoxicity induced by palmitate. We treated cultured rat cardiomyocytes with BSA-conjugated palmitate (25 nM free), TMZ (0.1-100 μM), or a combination of both. We evaluated mitochondrial morphology and lipid accumulation by confocal fluorescence microscopy, parameters of mitochondrial metabolism (mitochondrial membrane potential, oxygen consumption rate [OCR], and ATP levels), and ceramide production by mass spectrometry and indirect immunofluorescence. Palmitate promoted mitochondrial fission evidenced by a decrease in mitochondrial volume (50%) and an increase in the number of mitochondria per cell (80%), whereas TMZ increased mitochondrial volume (39%), and decreased mitochondrial number (56%), suggesting mitochondrial fusion. Palmitate also decreased mitochondrial metabolism (ATP levels and OCR), while TMZ potentiated all the metabolic parameters assessed. Moreover, pretreatment with TMZ protected the cardiomyocytes from palmitate-induced mitochondrial fission and dysfunction. TMZ also increased lipid accumulation in cardiomyocytes, and prevented palmitate-induced ceramide production. Our data show that TMZ protects cardiomyocytes by changing intracellular lipid management. Thus, the beneficial effects of TMZ on patients with different cardiovascular pathologies can be related to modulation of the mitochondrial morphology and function.

  20. A review of paliperidone palmitate.

    PubMed

    Chue, Pierre; Chue, James

    2012-12-01

    Risperidone long-acting injection (RLAI) was the first second-generation antipsychotic available as a long-acting injection. Paliperidone (9-hydroxyrisperidone) is the active metabolite of risperidone, introduced initially as an extended release oral (ORal Osmotic System, OROS®, Alza Corporation) formulation (Invega®, Janssen). Paliperidone long-acting injection (PLAI) has now been developed as a suspension of paliperidone palmitate nanocrystals in an aqueous formulation (Invega Sustenna®, Xeplion®), administered monthly by intramuscular injection (deltoid or gluteal). Doses of PLAI can be expressed either in milligram equivalents (mg eq) of paliperidone palmitate or in milligrams of the active fraction of paliperidone. The recommended initiation regimen of 150 mg eq (234 mg) on day 1 and 100 mg eq (156 mg) on day 8 (both administered in the deltoid) achieves therapeutic blood levels rapidly and without the necessity of oral supplementation. No refrigeration or reconstitution prior to administration is required. PLAI has been shown in to be effective in controlling the acute symptoms of schizophrenia as well as delaying time to relapse. Safety and tolerability are comparable to RLAI with no new safety signals. Thus, PLAI may represent the rational development of RLAI with greater ease of use.

  1. The saturated fatty acid, palmitic acid, induces anxiety-like behavior in mice

    PubMed Central

    Moon, Morgan L.; Joesting, Jennifer J.; Lawson, Marcus A.; Chiu, Gabriel S.; Blevins, Neil A.; Kwakwa, Kristin A.; Freund, Gregory G.

    2014-01-01

    Objectives Excess fat in the diet can impact neuropsychiatric functions by negatively affecting cognition, mood and anxiety. We sought to show that the free fatty acid (FFA), palmitic acid, can cause adverse biobehaviors in mice that lasts beyond an acute elevation in plasma FFAs. Methods Mice were administered palmitic acid or vehicle as a single intraperitoneal (IP) injection. Biobehaviors were profiled 2 and 24 hrs after palmitic acid treatment. Quantification of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their major metabolites was performed in cortex, hippocampus and amygdala. FFA concentration was determined in plasma. Relative fold change in mRNA expression of unfolded protein response (UPR)-associated genes was determined in brain regions. Results In a dose-dependent fashion, palmitic acid rapidly reduced mouse locomotor activity by a mechanism that did not rely on TLR4, MyD88, IL-1, IL-6 or TNFα but was dependent on fatty acid chain length. Twenty-four hrs after palmitic acid administration mice exhibited anxiety-like behavior without impairment in locomotion, food intake, depressive-like behavior or spatial memory. Additionally, the serotonin metabolite 5-HIAA was increased by 33% in the amygdala 24 hrs after palmitic acid treatment. Conclusions Palmitic acid induces anxiety-like behavior in mice while increasing amygdala-based serotonin metabolism. These effects occur at a time point when plasma FFA levels are no longer elevated. PMID:25016520

  2. Adiposity and glucose intolerance exacerbate components of metabolic syndrome in children consuming sugar-sweetened beverages: QUALITY cohort study.

    PubMed

    Wang, J W; Mark, S; Henderson, M; O'Loughlin, J; Tremblay, A; Wortman, J; Paradis, G; Gray-Donald, K

    2013-08-01

    Sugar-sweetened beverage (SSB) consumption is linked to weight gain and metabolic syndrome (MetS) components in children, but whether these associations are modified by excess weight and glucose tolerance status in children is not known. The objective of this study was to examine the cross-sectional associations between SSB intake and MetS components among children above and below the 85th body mass index (BMI) percentile and those with and without impaired glucose tolerance (IGT). Data were from the QUébec Adiposity and Lifestyle InvesTigation in Youth study (2005-2008). Caucasian children aged 8-10 years (n = 632) were recruited from 1040 primary schools in Québec, Canada. SSB consumption was assessed by three 24-h dietary recalls, body fat mass by dual-energy absorptiometry, physical activity by 7-d accelerometer. Multivariate linear regressions were used, with age, sex, fat mass index and physical activity as covariates, including waist circumference (WC), systolic blood pressure (SBP), concentrations of triglyceride and high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance (HOMA-IR) as outcome variables. Among overweight children, a 100-mL higher SSB consumption was associated with a 0.1-unit higher HOMA-IR (P = 0.009) and a 1.1-mm Hg higher SBP (P = 0.001). In children with IGT, a 100-mL higher SSB consumption was associated with a 1.4-mm Hg higher SBP and a 4.0-cm higher WC (P < 0.001). These associations were not observed among children <85th BMI percentile. Our results suggest that the association between higher SSB consumption and MetS components is more evident in overweight/obese and glucose-intolerant children. © 2012 The Authors. Pediatric Obesity © 2012 International Association for the Study of Obesity.

  3. Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation*

    PubMed Central

    Lizárraga-Mollinedo, Esther; Fernández-Millán, Elisa; García-San Frutos, Miriam; de Toro-Martín, Juan; Fernández-Agulló, Teresa; Ros, Manuel; Álvarez, Carmen; Escrivá, Fernando

    2015-01-01

    Human studies have suggested that early undernutrition increases the risk of obesity, thereby explaining the increase in overweight among individuals from developing countries who have been undernourished as children. However, this conclusion is controversial, given that other studies do not concur. This study sought to determine whether rehabilitation after undernutrition increases the risk of obesity and metabolic disorders. We employed a published experimental food-restriction model. Wistar female rats subjected to severe food restriction since fetal stage and controls were transferred to a moderately high-fat diet (cafeteria) provided at 70 days of life to 6.5 months. Another group of undernourished rats were rehabilitated with chow. The energy intake of undernourished animals transferred to cafeteria formula exceeded that of the controls under this regime and was probably driven by hypothalamic disorders in insulin and leptin signal transduction. The cafeteria diet resulted in greater relative increases in both fat and lean body mass in the undernourished rats when compared with controls, enabling the former group to completely catch up in length and body mass index. White adipose tissues of undernourished rats transferred to the high-lipid regime developed a browning which, probably, contributed to avoid the obesigenic effect observed in controls. Nevertheless, the restricted group rehabilitated with cafeteria formula had greater accretion of visceral than subcutaneous fat, showed increased signs of macrophage infiltration and inflammation in visceral pad, dyslipidemia, and ectopic fat accumulation. The data indicate that early long-term undernutrition is associated with increased susceptibility to the harmful effects of nutritional rehabilitation, without causing obesity. PMID:26105051

  4. Combination of Alcohol and Fructose Exacerbates Metabolic Imbalance in Terms of Hepatic Damage, Dyslipidemia, and Insulin Resistance in Rats

    PubMed Central

    Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and

  5. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

    PubMed

    Alwahsh, Salamah Mohammad; Xu, Min; Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (P<0.05). Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and

  6. Attenuation of cold stress-induced exacerbation of cardiac and adipose tissue pathology and metabolic disorders in a rat model of metabolic syndrome by the glucocorticoid receptor antagonist RU486

    PubMed Central

    Nagasawa, K; Matsuura, N; Takeshita, Y; Ito, S; Sano, Y; Yamada, Y; Uchinaka, A; Murohara, T; Nagata, K

    2016-01-01

    Objectives: Chronic stress affects the central nervous system as well as endocrine, metabolic and immune systems. However, the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We recently characterized DahlS.Z-Leprfa/Leprfa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of MetS. We have now investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology as well as on metabolic parameters in this model. Methods: DS/obese rats were exposed to cold stress (immersion in ice-cold water to a depth of 1–2 cm for 2 h per day) with or without subcutaneous injection of the GR antagonist RU486 (2 mg kg−1day−1) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr+/Lepr+) littermates served as a control. Results: Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction in DS/obese rats in a manner sensitive to RU486 treatment. Cold stress with or without RU486 did not affect body weight or fat mass. In contrast, cold stress further increased cardiac oxidative stress as well as macrophage infiltration and proinflammatory gene expression in LV and visceral fat tissue, with all of these effects being attenuated by RU486. Cold stress also further increased GR and 11β-hydroxysteroid dehydrogenase type 1 mRNA and protein abundance in LV and visceral adipose tissue, and these effects were again inhibited by RU486. In addition, RU486 ameliorated the stress-induced aggravation of dyslipidemia, glucose intolerance and insulin resistance in DS/obese rats. Conclusions: Our results implicate GR signaling in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as of abnormal glucose and lipid metabolism in a rat model of MetS. PMID:27110688

  7. β cells keep bad epigenetic memories of palmitate.

    PubMed

    Fradin, Delphine; Bougnères, Pierre

    2014-06-23

    Palmitic acid, or hexadecanoic acid, a 16-carbon saturated fatty acid (FA), accounts for approximately 38% of the total circulating FA in lean or obese humans. In an article published in BMC Medicine, Hall et al. report that cultured islets from healthy donors, when exposed to palmitate, undergo changes in CpG methylation that are associated with modifications of expression in 290 genes. Their results provide a first look at the mechanisms used by the endocrine pancreas of humans to keep a durable genomic imprint from their exposure to FA that can influence gene expression and possibly cell phenotype in the long term. It is likely that such studies will help understand the epigenetic response of β cells to a disturbed metabolic environment, especially one created by obesity.

  8. 21 CFR 182.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Ascorbyl palmitate. 182.3149 Section 182.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 182.3149 Ascorbyl palmitate. (a) Product. Ascorbyl...

  9. Free Fatty Acid Palmitate Impairs the Vitality and Function of Cultured Human Bladder Smooth Muscle Cells

    PubMed Central

    Oberbach, Andreas; Schlichting, Nadine; Heinrich, Marco; Till, Holger; Stolzenburg, Jens-Uwe; Neuhaus, Jochen

    2012-01-01

    Background Incidence of urinary tract infections is elevated in patients with diabetes mellitus. Those patients show increased levels of the saturated free fatty acid palmitate. As recently shown metabolic alterations induced by palmitate include production and secretion of the pro-inflammatory cytokine interleukine-6 (IL-6) in cultured human bladder smooth muscle cells (hBSMC). Here we studied the influence of palmitate on vital cell properties, for example, regulation of cell proliferation, mitochondrial enzyme activity and antioxidant capacity in hBSMC, and analyzed the involvement of major cytokine signaling pathways. Methodology/Principal Findings HBSMC cultures were set up from bladder tissue of patients undergoing cystectomy and stimulated with palmitate. We analyzed cell proliferation, mitochondrial enzyme activity, and antioxidant capacity by ELISA and confocal immunofluorescence. In signal transduction inhibition experiments we evaluated the involvement of NF-κB, JAK/STAT, MEK1, PI3K, and JNK in major cytokine signaling pathway regulation. We found: (i) palmitate decreased cell proliferation, increased mitochondrial enzyme activity and antioxidant capacity; (ii) direct inhibition of cytokine receptor by AG490 even more strongly suppressed cell proliferation in palmitate-stimulated cells, while counteracting palmitate-induced increase of antioxidant capacity; (iii) in contrast knockdown of the STAT3 inhibitor SOCS3 increased cell proliferation and antioxidant capacity; (iv) further downstream JAK/STAT3 signaling cascade the inhibition of PI3K or JNK enhanced palmitate induced suppression of cell proliferation; (v) increase of mitochondrial enzyme activity by palmitate was enhanced by inhibition of PI3K but counteracted by inhibition of MEK1. Conclusions/Significance Saturated free fatty acids (e.g., palmitate) cause massive alterations in vital cell functions of cultured hBSMC involving distinct major cytokine signaling pathways. Thereby, certain

  10. COPD exacerbations . 2: aetiology.

    PubMed

    Sapey, E; Stockley, R A

    2006-03-01

    Exacerbations of COPD are thought to be caused by complex interactions between the host, bacteria, viruses, and environmental pollution. These factors increase the inflammatory burden in the lower airways, overwhelming the protective anti-inflammatory defences leading to tissue damage. Frequent exacerbations are associated with increased morbidity and mortality, a faster decline in lung function, and poorer health status, so prevention or optimal treatment of exacerbations is a global priority. In order to evolve new treatment strategies there has been great interest in the aetiology and pathophysiology of exacerbations, but progress has been hindered by the heterogeneous nature of these episodes, vague definitions of an exacerbation, and poor stratification of known confounding factors when interpreting results. We review how an exacerbation should be defined, its inflammatory basis, and the importance of exacerbations on disease progression. Important aetiologies, with their potential underlying mechanisms, are discussed and the significance of each aetiology is considered.

  11. Isosteviol Has Beneficial Effects on Palmitate-Induced α-Cell Dysfunction and Gene Expression

    PubMed Central

    Chen, Xiaoping; Hermansen, Kjeld; Xiao, Jianzhong; Bystrup, Sara Kjaergaard; O'Driscoll, Lorraine; Jeppesen, Per Bendix

    2012-01-01

    Background Long-term exposure to high levels of fatty acids impairs insulin secretion and exaggerates glucagon secretion. The aim of this study was to explore if the antihyperglycemic agent, Isosteviol (ISV), is able to counteract palmitate-induced α-cell dysfunction and to influence α-cell gene expression. Methodology/Principal Findings Long-term incubation studies with clonal α-TC1–6 cells were performed in the presence of 0.5 mM palmitate with or without ISV. We investigated effects on glucagon secretion, glucagon content, cellular triglyceride (TG) content, cell proliferation, and expression of genes involved in controlling glucagon synthesis, fatty acid metabolism, and insulin signal transduction. Furthermore, we studied effects of ISV on palmitate-induced glucagon secretion from isolated mouse islets. Culturing α-cells for 72-h with 0.5 mM palmitate in the presence of 18 mM glucose resulted in a 56% (p<0.01) increase in glucagon secretion. Concomitantly, the TG content of α-cells increased by 78% (p<0.01) and cell proliferation decreased by 19% (p<0.05). At 18 mM glucose, ISV (10−8 and 10−6 M) reduced palmitate-stimulated glucagon release by 27% (p<0.05) and 27% (p<0.05), respectively. ISV (10−6 M) also counteracted the palmitate-induced hypersecretion of glucagon in mouse islets. ISV (10−6 M) reduced α-TC1–6 cell proliferation rate by 25% (p<0.05), but ISV (10−8 and 10−6 M) had no effect on TG content in the presence of palmitate. Palmitate (0.5 mM) increased Pcsk2 (p<0.001), Irs2 (p<0.001), Fasn (p<0.001), Srebf2 (p<0.001), Acaca (p<0.01), Pax6 (p<0.05) and Gcg mRNA expression (p<0.05). ISV significantly (p<0.05) up-regulated Insr, Irs1, Irs2, Pik3r1 and Akt1 gene expression in the presence of palmitate. Conclusions/Significance ISV counteracts α-cell hypersecretion and apparently contributes to changes in expression of key genes resulting from long-term exposure to palmitate. ISV apparently acts as a glucagonostatic drug with

  12. Determination of protein-bound palmitate turnover rates using a three-compartment model that formally incorporates [3H]palmitate recycling.

    PubMed

    Qanbar, Riad; Bouvier, Michel

    2004-09-28

    The observation that the palmitoylation state of certain proteins can be biologically modulated led to the proposal that it could, much like phosphorylation, be an important dynamic regulator of protein function. However, based on single-phase exponential decay analysis of data from [(3)H]palmitate pulse/chase experiments, the measured protein-bound palmitate turnover rates were often found to be too slow to account for rapid physiological responses. This paper reports that exponential decay does not adequately describe the results of such experiments because it fails to account for the recycling of [(3)H]palmitate from cellular lipids to palmitoyl CoA. Taking this recycling into account, a three-compartment model was used to deduce the time-dependent changes of cellular [(3)H]palmitoyl CoA and to infer the time course for the incorporation of [(3)H]palmitate into proteins. The validity of the inferences made by the model was checked against data obtained by metabolic labeling of endogenous HEK293 cell proteins. In addition, the model could account for reported anomalies, discrepancies, and apparently paradoxical observations obtained by traditional analysis of data from pulse/chase experiments. Including the recycling of cellular palmitate in the formal description of the system offers a new tool for quantitative assessment of protein-bound palmitate turnover rates. Through the re-evaluation of these rates, the model provides a means for the reassessment of the potential physiological implications of dynamic palmitoylation. The model may also be generally applicable to other areas of research where recycling of tracer is a concern.

  13. Exacerbations of COPD

    PubMed Central

    Pavord, Ian D; Jones, Paul W; Burgel, Pierre-Régis; Rabe, Klaus F

    2016-01-01

    Exacerbations of chronic obstructive pulmonary disease (COPD) are defined as sustained worsening of a patient’s condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization. Exacerbations have a significant and prolonged impact on health status and outcomes, and negative effects on pulmonary function. A significant proportion of exacerbations are unreported and therefore left untreated, leading to a poorer prognosis than those treated. COPD exacerbations are heterogeneous, and various phenotypes have been proposed which differ in biologic basis, prognosis, and response to therapy. Identification of biomarkers could enable phenotype-driven approaches for the management and prevention of exacerbations. For example, several biomarkers of inflammation can help to identify exacerbations most likely to respond to oral corticosteroids and antibiotics, and patients with a frequent exacerbator phenotype, for whom preventative treatment is appropriate. Reducing the frequency of exacerbations would have a beneficial impact on patient outcomes and prognosis. Preventative strategies include modification of risk factors, treatment of comorbid conditions, the use of bronchodilator therapy with long-acting β2-agonists or long-acting muscarinic antagonists, and inhaled corticosteroids. A better understanding of the mechanisms underlying COPD exacerbations will help to optimize use of the currently available and new interventions for preventing and treating exacerbations. PMID:26937187

  14. Erdosteine for COPD exacerbations.

    PubMed

    2008-10-01

    The mucolytic drug erdosteine (Erdotin - Galen) is licensed in the UK as treatment for up to 10 days "for the symptomatic treatment of acute exacerbations of chronic bronchitis in adults". This indication differs from that for carbocisteine and mecysteine, two older mucolytic drugs that are licensed for adjunctive treatment in respiratory disorders characterised by viscous mucus, and typically used for longer to prevent exacerbations of chronic obstructive pulmonary disease (COPD). Does erdosteine have a role for people with COPD exacerbations?

  15. 21 CFR 182.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ascorbyl palmitate. 182.3149 Section 182.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 182.3149...

  16. 21 CFR 182.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Ascorbyl palmitate. 182.3149 Section 182.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 182.3149...

  17. 21 CFR 582.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Ascorbyl palmitate. 582.3149 Section 582.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 582...

  18. 21 CFR 582.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Ascorbyl palmitate. 582.3149 Section 582.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 582...

  19. 21 CFR 582.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Ascorbyl palmitate. 582.3149 Section 582.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 582...

  20. 21 CFR 182.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Ascorbyl palmitate. 182.3149 Section 182.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 182.3149...

  1. 21 CFR 182.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Ascorbyl palmitate. 182.3149 Section 182.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 182.3149...

  2. 21 CFR 582.3149 - Ascorbyl palmitate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Ascorbyl palmitate. 582.3149 Section 582.3149 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Chemical Preservatives § 582...

  3. Free fatty acid receptor 1 (FFAR1/GPR40) signaling affects insulin secretion by enhancing mitochondrial respiration during palmitate exposure.

    PubMed

    Kristinsson, Hjalti; Bergsten, Peter; Sargsyan, Ernest

    2015-12-01

    Fatty acids affect insulin secretion via metabolism and FFAR1-mediated signaling. Recent reports indicate that these two pathways act synergistically. Still it remains unclear how they interrelate. Taking into account the key role of mitochondria in insulin secretion, we attempted to dissect the metabolic and FFAR1-mediated effects of fatty acids on mitochondrial function. One-hour culture of MIN6 cells with palmitate significantly enhanced mitochondrial respiration. Antagonism or silencing of FFAR1 prevented the palmitate-induced rise in respiration. On the other hand, in the absence of extracellular palmitate FFAR1 agonists caused a modest increase in respiration. Using an agonist of the M3 muscarinic acetylcholine receptor and PKC inhibitor we found that in the presence of the fatty acid mitochondrial respiration is regulated via Gαq protein-coupled receptor signaling. The increase in respiration in palmitate-treated cells was largely due to increased glucose utilization and oxidation. However, glucose utilization was not dependent on FFAR1 signaling. Collectively, these results indicate that mitochondrial respiration in palmitate-treated cells is enhanced via combined action of intracellular metabolism of the fatty acid and the Gαq-coupled FFAR1 signaling. Long-term palmitate exposure reduced ATP-coupling efficiency of mitochondria and deteriorated insulin secretion. The presence of the FFAR1 antagonist during culture did not improve ATP-coupling efficiency, however, it resulted in enhanced mitochondrial respiration and improved insulin secretion after culture. Taken together, our study demonstrates that during palmitate exposure, integrated actions of fatty acid metabolism and fatty acid-induced FFAR1 signaling on mitochondrial respiration underlie the synergistic action of the two pathways on insulin secretion.

  4. 21 CFR 582.5936 - Vitamin A palmitate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Vitamin A palmitate. 582.5936 Section 582.5936 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Supplements 1 § 582.5936 Vitamin A palmitate. (a) Product. Vitamin A palmitate. (b) Conditions of use....

  5. 21 CFR 582.5936 - Vitamin A palmitate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Vitamin A palmitate. 582.5936 Section 582.5936 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Supplements 1 § 582.5936 Vitamin A palmitate. (a) Product. Vitamin A palmitate. (b) Conditions of use....

  6. 21 CFR 582.5936 - Vitamin A palmitate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Vitamin A palmitate. 582.5936 Section 582.5936 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Supplements 1 § 582.5936 Vitamin A palmitate. (a) Product. Vitamin A palmitate. (b) Conditions of use....

  7. 21 CFR 582.5936 - Vitamin A palmitate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Vitamin A palmitate. 582.5936 Section 582.5936 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Supplements 1 § 582.5936 Vitamin A palmitate. (a) Product. Vitamin A palmitate. (b) Conditions of use....

  8. 21 CFR 582.5936 - Vitamin A palmitate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Vitamin A palmitate. 582.5936 Section 582.5936 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... Supplements 1 § 582.5936 Vitamin A palmitate. (a) Product. Vitamin A palmitate. (b) Conditions of use....

  9. Acute exacerbation of COPD.

    PubMed

    Ko, Fanny W; Chan, Ka Pang; Hui, David S; Goddard, John R; Shaw, Janet G; Reid, David W; Yang, Ian A

    2016-10-01

    The literature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is fast expanding. This review focuses on several aspects of acute exacerbation of COPD (AECOPD) including epidemiology, diagnosis and management. COPD poses a major health and economic burden in the Asia-Pacific region, as it does worldwide. Triggering factors of AECOPD include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. Disruption in the dynamic balance between the 'pathogens' (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. The diagnostic approach to AECOPD varies based on the clinical setting and severity of the exacerbation. After history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest X-ray and blood tests for inflammatory markers. Arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. Depending on the severity, the acute management of AECOPD involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. Hospitalization may be required, for severe exacerbations. Nonpharmacological interventions including disease-specific self-management, pulmonary rehabilitation, early medical follow-up, home visits by respiratory health workers, integrated programmes and telehealth-assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent AECOPD. Pharmacological approaches to reducing risk of future exacerbations include long-acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long-term macrolides. Further studies are needed to assess the cost-effectiveness of these interventions in preventing COPD exacerbations.

  10. Lipotoxic Palmitate Impairs the Rate of β-Oxidation and Citric Acid Cycle Flux in Rat Neonatal Cardiomyocytes.

    PubMed

    Haffar, Taha; Akoumi, Ali; Bousette, Nicolas

    2016-01-01

    Diabetic hearts exhibit intracellular lipid accumulation. This suggests that the degree of fatty acid oxidation (FAO) in these hearts is insufficient to handle the elevated lipid uptake. We previously showed that palmitate impaired the rate of FAO in primary rat neonatal cardiomyocytes. Here we were interested in characterizing the site of FAO impairment induced by palmitate since it may shed light on the metabolic dysfunction that leads to lipid accumulation in diabetic hearts. We measured fatty acid oxidation, acetyl-CoA oxidation, and carnitine palmitoyl transferase (Cpt1b) activity. We measured both forward and reverse aconitase activity, as well as NAD+ dependent isocitrate dehydrogenase activity. We also measured reactive oxygen species using the 2', 7'-Dichlorofluorescin Diacetate (DCFDA) assay. Finally we used thin layer chromatography to assess diacylglycerol (DAG) levels. We found that palmitate significantly impaired mitochondrial β-oxidation as well as citric acid cycle flux, but not Cpt1b activity. Palmitate negatively affected net aconitase activity and isocitrate dehydrogenase activity. The impaired enzyme activities were not due to oxidative stress but may be due to DAG mediated PKC activation. This work demonstrates that palmitate, a highly abundant fatty acid in human diets, causes impaired β-oxidation and citric acid cycle flux in primary neonatal cardiomyocytes. This metabolic defect occurs prior to cell death suggesting that it is a cause, rather than a consequence of palmitate mediated lipotoxicity. This impaired mitochondrial metabolism can have important implications for metabolic diseases such as diabetes and obesity. © 2016 The Author(s) Published by S. Karger AG, Basel.

  11. Short-term effects of palmitate and 2-bromopalmitate on the lipolytic activity of rat adipocytes.

    PubMed

    Szkudelski, Tomasz; Szkudelska, Katarzyna

    2011-09-26

    Fatty acids are involved in the regulation of lipolysis in adipocytes; however, this regulatory action is unclear. The present study aimed to determine the short-term influence of palmitate and its non-metabolisable analogue, 2-bromopalmitate, on the lipolytic activity of adipocytes. Freshly isolated rat adipocytes were exposed to lipolytic modulators with or without palmitate or 2-bromopalmitate. Glycerol released from cells was determined as an indicator of lipolysis. Moreover, cAMP, ATP and changes in mitochondrial membrane potential were measured in cells treated with 2-bromopalmitate. It was demonstrated that glycerol release from adipocytes incubated with epinephrine alone or epinephrine with insulin was unchanged by palmitate. However, 2-bromopalmitate was found to significantly decrease lipolysis stimulated by epinephrine or dibutyryl-cAMP. The inhibitory effect of 2-bromopalmitate on lipolysis was accompanied by reduced cAMP in adipocytes. Moreover, 2-bromopalmitate diminished hyperpolarisation of the inner mitochondrial membrane. Adipocyte exposure to 2-bromopalmitate also resulted in a substantial ATP depletion. The effects of 2-bromopalmitate on lipolysis and on ATP content were prevented neither by high glucose nor by alanine in the incubation medium. These findings demonstrate that short-term adipocyte exposure to palmitate disturbs neither the lipolytic action of epinephrine nor the antilipolytic action of insulin. However, 2-bromopalmitate significantly decreases lipolysis probably due to impaired metabolic activity of mitochondria. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Covalent modification of platelet proteins by palmitate

    SciTech Connect

    Muszbek, L.; Laposata, M. )

    1989-09-01

    Covalent attachment of fatty acid to proteins plays an important role in association of certain proteins with hydrophobic membrane structures. In platelets, the structure of many membrane glycoproteins (GPs) has been examined in detail, but the question of fatty acid acylation of platelet proteins has not been addressed. In this study, we wished to determine (a) whether platelet proteins could be fatty acid acylated; and, if so, (b) whether these modified proteins were present in isolated platelet membranes and cytoskeletal fractions; and (c) if the pattern of fatty acid acylated proteins changed on stimulation of the platelets with the agonist thrombin. We observed that in platelets allowed to incorporate 3H-palmitate, a small percentage (1.37%) of radioactivity incorporated into the cells became covalently bound to protein. Selective cleavage of thioester, thioester plus O-ester, and amide-linked 3H-fatty acids from proteins, and their subsequent analysis by high-performance liquid chromatography (HPLC) indicated that the greatest part of 3H-fatty acid covalently bound to protein was thioester-linked 3H-palmitate. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fluorography, at least ten major radiolabeled proteins were detected. Activation of platelets by thrombin greatly increased the quantity of 3H-palmitoylated proteins associated with the cytoskeleton. Nearly all radiolabeled proteins were recovered in the membrane fraction, indicating that these proteins are either integral or peripheral membrane proteins or proteins tightly associated to membrane constituents. Components of the GPIIb-IIIa complex were not palmitoylated. Thus, platelet proteins are significantly modified posttranslationally by 3H-palmitate, and incorporation of palmitoylated proteins into the cytoskeleton is a prominent component of the platelet response to thrombin stimulation.

  13. The Estrogen Metabolite 16αOHE Exacerbates BMPR2-Associated PAH Through miR-29-Mediated Modulation of Cellular Metabolism

    PubMed Central

    Chen, Xinping; Talati, Megha; Fessel, Joshua P.; Hemnes, Anna R.; Gladson, Santhi; French, Jaketa; Shay, Sheila; Trammel, Aaron; Phillips, John A.; Hamid, Rizwan; Cogan, Joy D.; Dawson, Elliott P.; Womble, Kristie E.; Hedges, Lora K.; Martinez, Elizabeth G.; Wheeler, Lisa A.; Loyd, James E.; Majka, Susan J.; West, James; Austin, Eric D.

    2015-01-01

    Background Pulmonary arterial hypertension (PAH) is a proliferative disease of the pulmonary vasculature which preferentially affects females. Estrogens, such as the metabolite 16α-hydroxyestrone (16αOHE), may contribute to PAH pathogenesis; and, alterations in cellular energy metabolism associate with PAH. We hypothesized that 16αOHE promotes heritable PAH (HPAH) via miR-29 family upregulation, and that antagonism of miR-29 would attenuate pulmonary hypertension in transgenic mouse models of Bmpr2 mutation. Methods and Results MicroRNA (miR) array profiling of human lung tissue found elevation of miRs associated with energy metabolism, including the miR-29 family, among HPAH patients. miR-29 expression was 2-fold higher in Bmpr2 mutant mice lungs at baseline compared to controls, and 4 to 8-fold higher in Bmpr2 mice exposed to 16αOHE 1.25 μg/hr for 4 weeks. Blot analyses of Bmpr2 mouse lung protein showed significant reductions in PPARγ and CD36 in those mice exposed to 16αOHE, as well as from protein derived from HPAH lungs compared to controls. Bmpr2 mice treated with anti-miR-29 (α-miR29) (20mg/kg injections for 6 weeks) had improvements in hemodynamic profile, histology, and markers of dysregulated energy metabolism compared to controls. PASMCs derived from Bmpr2 murine lungs demonstrated mitochondrial abnormalities, which improved with α-miR29 transfection in vitro; endothelial-like cells derived from HPAH patient iPS cell lines were similar, and improved with α-miR29 treatment. Conclusions 16αOHE promotes the development of HPAH via upregulation of miR-29, which alters molecular and functional indices of energy metabolism. Antagonism of miR-29 improves in vivo and in vitro features of HPAH, and reveals a possible novel therapeutic target. PMID:26487756

  14. Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis.

    PubMed

    Pillon, Nicolas J; Azizi, Paymon M; Li, Yujin E; Liu, Jun; Wang, Changsen; Chan, Kenny L; Hopperton, Kathryn E; Bazinet, Richard P; Heit, Bryan; Bilan, Philip J; Lee, Warren L; Klip, Amira

    2015-07-01

    Obesity is associated with inflammation and immune cell recruitment to adipose tissue, muscle and intima of atherosclerotic blood vessels. Obesity and hyperlipidemia are also associated with tissue insulin resistance and can compromise insulin delivery to muscle. The muscle/fat microvascular endothelium mediates insulin delivery and facilitates monocyte transmigration, yet its contribution to the consequences of hyperlipidemia is poorly understood. Using primary endothelial cells from human adipose tissue microvasculature (HAMEC), we investigated the effects of physiological levels of fatty acids on endothelial inflammation and function. Expression of cytokines and adhesion molecules was measured by RT-qPCR. Signaling pathways were evaluated by pharmacological manipulation and immunoblotting. Surface expression of adhesion molecules was determined by immunohistochemistry. THP1 monocyte interaction with HAMEC was measured by cell adhesion and migration across transwells. Insulin transcytosis was measured by total internal reflection fluorescence microscopy. Palmitate, but not palmitoleate, elevated the expression of IL-6, IL-8, TLR2 (Toll-like receptor 2), and intercellular adhesion molecule 1 (ICAM-1). HAMEC had markedly low fatty acid uptake and oxidation, and CD36 inhibition did not reverse the palmitate-induced expression of adhesion molecules, suggesting that inflammation did not arise from palmitate uptake/metabolism. Instead, inhibition of TLR4 to NF-κB signaling blunted palmitate-induced ICAM-1 expression. Importantly, palmitate-induced surface expression of ICAM-1 promoted monocyte binding and transmigration. Conversely, palmitate reduced insulin transcytosis, an effect reversed by TLR4 inhibition. In summary, palmitate activates inflammatory pathways in primary microvascular endothelial cells, impairing insulin transport and increasing monocyte transmigration. This behavior may contribute in vivo to reduced tissue insulin action and enhanced tissue

  15. Curcumin Improves Palmitate-Induced Insulin Resistance in Human Umbilical Vein Endothelial Cells by Maintaining Proteostasis in Endoplasmic Reticulum

    PubMed Central

    Ye, Mao; Qiu, Hong; Cao, Yingkang; Zhang, Min; Mi, Yan; Yu, Jing; Wang, Changhua

    2017-01-01

    Dysfunction of proteasome and autophagy will result in disturbance of endoplasmic reticulum (ER) proteostasis, and thus lead to long-term and chronic ER stress and subsequent unfolded protein response (UPR), which is implicated in the occurrence and development of insulin resistance. Curcumin exerts beneficial metabolic effects in in vitro cells and in vivo animal models of diabetes and diabetic complications including cardiovascular diseases, due to its powerful anti-oxidative and anti-inflammatory properties. However, its impacts on insulin resistance of endothelial cells and its underlying mechanism(s) remain ill-defined. Herein, we tested the hypothesis that curcumin action in ER protein quality control was related to improvement of insulin resistance in human umbilical vein endothelial cells (HUVECs) cultured with saturated fatty acid palmitate. We found that palmitate treatment induced insulin resistance of HUVECs and activated both the ubiquitin-proteasome system (UPS) and autophagy. Palmitate-stimulated activation of the UPS and autophagy was attenuated by pharmacological inhibition of ER stress. In addition, curcumin supplementation mitigated palmitate-induced insulin resistance, inhibited the UPS, and activated autophagy. Furthermore, curcumin administration suppressed palmitate-induced protein aggregation and ER stress. Genetic inhibition of autophagy by silencing autophagy protein 5 (Atg5) completely restored total protein ubiquitination and protein aggregation in HUVECs treated with combined curcumin and palmitate. Atg5-knockdown also abolished the beneficial effects of curcumin on palmitate-induced ER stress, JNK/IRS-1 pathway as well as insulin signaling. Our results reveal that curcumin-activated autophagy could maintain proteostasis in ER leading to attenuation of ER stress and subsequent inhibition of JNK/IRS-1 pathway and improvement of insulin resistance. PMID:28377722

  16. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts.

    PubMed

    Sokolova, Marina; Vinge, Leif Erik; Alfsnes, Katrine; Olsen, Maria Belland; Eide, Lars; Kaasbøll, Ole Jørgen; Attramadal, Håvard; Torp, May-Kristin; Fosshaug, Linn E; Rashidi, Azita; Lien, Egil; Finsen, Alexandra Vanessa; Sandanger, Øystein; Aukrust, Pål; Ranheim, Trine; Yndestad, Arne

    2017-02-01

    Palmitate triggers inflammatory responses in several cell types, but its effects on cardiac fibroblasts are at present unknown. The aims of the study were to (1) assess the potential of palmitate to promote inflammatory signaling in cardiac fibroblasts through TLR4 and the NLRP3 inflammasome and (2) characterize the cellular phenotype of cardiac fibroblasts exposed to palmitate. We examined whether palmitate induces inflammatory responses in cardiac fibroblasts from WT, NLRP3(-/-) and ASC(-/-)mice (C57BL/6 background). Exposure to palmitate caused production of TNF, IL-6 and CXCL2 via TLR4 activation. NLRP3 inflammasomes are activated in a two-step manner. Whereas palmitate did not prime the NLRP3 inflammasome, it induced activation in LPS-primed cardiac fibroblasts as indicated by IL-1β, IL-18 production and NLRP3-ASC co-localization. Palmitate-induced NLRP3 inflammasome activation in LPS-primed cardiac fibroblasts was associated with reduced AMPK activity, mitochondrial reactive oxygen species production and mitochondrial dysfunction. The cardiac fibroblast phenotype caused by palmitate, in an LPS and NLRP3 independent manner, was characterized by decreased cellular proliferation, contractility, collagen and MMP-2 expression, as well as increased senescence-associated β-galactosidase activity, and consistent with a state of cellular senescence. This study establishes that in vitro palmitate exposure of cardiac fibroblasts provides inflammatory responses via TLR4 and NLRP3 inflammasome activation. Palmitate also modulates cardiac fibroblast functionality, in a NLRP3 independent manner, resulting in a phenotype related to cellular senescence. These effects of palmitate could be of importance for myocardial dysfunction in obese and diabetic patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Asthma Outcomes: Exacerbations

    PubMed Central

    Fuhlbrigge, Anne; Peden, David; Apter, Andrea J.; Boushey, Homer A.; Camargo, Carlos; Gern, James; Heymann, Peter W.; Martinez, Fernando D.; Mauger, David; Teague, William G.; Blaisdell, Carol

    2013-01-01

    Background The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining “exacerbation,” or about how to characterize an episode’s severity. Objective National Institutes of Health (NIH) institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. Methods We utilized comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes, and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Results No dominant definition of “exacerbation” was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalization, and (3) use of short-acting β-agonists (SABAs) as quick-relief (sometimes referred to as “rescue” or “reliever”) medications. Conclusions The working group participants propose that the definition of “asthma exacerbation” be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome.” As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Further, they propose the development of a standardized, component-based definition of “exacerbation” with clear thresholds of severity for each component. PMID:22386508

  18. Palmitic acid, verified by lipid profiling using secondary ion mass spectrometry, demonstrates anti-multiple myeloma activity.

    PubMed

    Nagata, Yasuyuki; Ishizaki, Itsuko; Waki, Michihiko; Ide, Yoshimi; Hossen, Md Amir; Ohnishi, Kazunori; Miyayama, Takuya; Setou, Mitsutoshi

    2015-06-01

    Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 μM. The percentage of apoptotic cells increased from 24h after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells.

  19. High serum palmitic acid is associated with low antiviral effects of interferon-based therapy for hepatitis C virus.

    PubMed

    Miyake, Teruki; Hiasa, Yoichi; Hirooka, Masashi; Tokumoto, Yoshio; Watanabe, Takao; Furukawa, Shinya; Ueda, Teruhisa; Yamamoto, Shin; Kumagi, Teru; Miyaoka, Hiroaki; Abe, Masanori; Matsuura, Bunzo; Onji, Morikazu

    2012-11-01

    Hepatitis C virus (HCV) infection alters fatty acid synthesis and metabolism in association with HCV replication. The present study examined the effect of serum fatty acid composition on interferon (IFN)-based therapy. Fifty-five patients with HCV were enrolled and received IFN-based therapy. Patient characteristics, laboratory data (including fatty acids), and viral factors that could be associated with the anti-HCV effects of IFN-based therapy were evaluated. The effects of individual fatty acids on viral replication and IFN-based therapy were also examined in an in-vitro system. Multivariate logistic regression analysis showed that the level of serum palmitic acid before treatment and HCV genotype were significant predictors for rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR). High levels of palmitic acid inhibited the anti-HCV effects of IFN-based therapy. HCV replication assays confirmed the inhibitory effects of palmitic acid on anti-HCV therapy. The concentration of serum palmitic acid is an independent predictive factor for RVR, EVR, and SVR in IFN-based antiviral therapy. These results suggest that the effect of IFN-based antiviral therapy in patients with HCV infection might be enhanced by treatment that modulates palmitic acid levels.

  20. Prior cadmium exposure improves glucoregulation in diabetic rats but exacerbates effects on metabolic dysregulation, oxidative stress, and hepatic and renal toxicity.

    PubMed

    Singh, Prem Kumar; Baxi, Darshee; Diwedi, Ruchi; Ramachandran, A V

    2012-04-01

    The present study was taken up to assess the role of subchronic exposure to an environmentally relevant dosage of cadmium in type l diabetes. Female rats of the Wistar strain were treated with cadmium (5.12 mg/kg body weight) for 45 days. On day 46, rats were made diabetic by alloxan. After 7 days, diabetes (i.e., animals with serum glucose greater than 300 mg/dL) in the alloxanized animals was confirmed and further experiments were conducted for 15 days. Cadmium pretreatment showed disturbed glucose homeostasis with attendant changes in carbohydrate metabolism, coupled with decrease in food and water intake. Disturbance in carbohydrate metabolism was indicated by altered tissue metabolite load, as marked by a decrease in protein and glycogen contents and increased cholesterol store. Poor glucose clearance subsequent to a glucose challenge under the glucose tolerance test was observed in these animals (0.48/min in control vs. 0.13/min in Cd animals). There was a significantly lower glucose elevation rate in the insulin response test subsequent to an insulin-induced decrease in glucose level in Cd-exposed animals. Elevated oxidative stress was marked by increased lipid peroxidation, decreased antioxidant (both nonenzymatic and enzymatic) levels, and serum markers of hepatic and renal damage. Decreased corticosterone levels, together with increased E2 and reduced P4 levels, were some of the hallmark changes in the serum hormone profile of Cd-exposed animals. Overall, the present results are novel and interesting to open more investigations on animal models of type 1 diabetes with a history of previous Cd exposure.

  1. Paliperidone Palmitate Intramuscular 3-Monthly Formulation: A Review in Schizophrenia.

    PubMed

    Lamb, Yvette N; Keating, Gillian M

    2016-10-01

    A 3-monthly formulation of intramuscular paliperidone palmitate (3-monthly paliperidone palmitate) has recently been approved for the maintenance treatment of schizophrenia in adult patients in the EU (Trevicta(®)), following earlier approval in the USA (Invega Trinza(®)). This narrative review discusses the clinical use of 3-monthly paliperidone palmitate in the maintenance treatment of schizophrenia in adult patients and summarizes its pharmacological properties. The efficacy of the 3-monthly paliperidone palmitate formulation as a maintenance treatment for schizophrenia has been demonstrated in well designed, phase III trials. Three-monthly paliperidone palmitate was more effective than placebo in delaying time to relapse and reducing relapse rates, and was noninferior to 1-monthly paliperidone palmitate in the proportion of patients that remained relapse-free. The 3-monthly formulation was also more effective than placebo in controlling the symptoms of schizophrenia, whilst not differing significantly from the 1-monthly formulation in terms of symptomatic control. Three-monthly paliperidone palmitate was generally well tolerated in clinical trials, with a tolerability profile consistent with that of the 1-monthly formulation. In conclusion, 3-monthly paliperidone palmitate is a useful treatment option for adult patients with schizophrenia who are adequately treated with the 1-monthly formulation, particularly for those who would prefer, or may benefit from, longer dosing intervals.

  2. Anaerobic biodegradation of oleic and palmitic acids: evidence of mass transfer limitations caused by long chain fatty acid accumulation onto the anaerobic sludge.

    PubMed

    Pereira, M A; Pires, O C; Mota, M; Alves, M M

    2005-10-05

    Palmitic acid was the main long chain fatty acids (LCFA) that accumulated onto the anaerobic sludge when oleic acid was fed to an EGSB reactor. The conversion between oleic and palmitic acid was linked to the biological activity. When palmitic acid was fed to an EGSB reactor it represented also the main LCFA that accumulated onto the sludge. The way of palmitic acid accumulation was different in the oleic and in the palmitic acid fed reactors. When oleic acid was fed, the biomass-associated LCFA (83% as palmitic acid) were mainly adsorbed and entrapped in the sludge that became "encapsulated" by an LCFA layer. However, when palmitic acid was fed, the biomass-associated LCFA (the totality as palmitic acid) was mainly precipitated in white spots like precipitates in between the sludge, which remained "non-encapsulated." The two sludges were compared in terms of the specific methanogenic activity (SMA) in the presence of acetate, propionate, butyrate, and H(2)CO(2), before and after the mineralization of similar amounts of biomass-associated LCFA (4.6 and 5.2 g COD-LCFA/g of volatile suspended solids (VSS), for the oleic and palmitic acid fed sludge, respectively). The "non-encapsulated," sludge exhibited a considerable initial methanogenic activity on all the tested substrates, with the single exception of butyrate. However, with the "encapsulated" sludge only methane production from ethanol and H(2)/CO(2) was detected, after a lag phase of about 50 h. After mineralization of the biomass-associated LCFA, both sludges exhibited activities of similar order of magnitude in the presence of the same individual substrates and significantly higher than before. The results evidenced that LCFA accumulation onto the sludge can create a physical barrier and hinder the transfer of substrates and products, inducing a delay on the initial methane production. Whatever the mechanism, metabolic or physical, that is behind this inhibition, it is reversible, being eliminated after the

  3. Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation.

    PubMed

    García-Martín, Rubén; Alexaki, Vasileia I; Qin, Nan; Rubín de Celis, María F; Economopoulou, Matina; Ziogas, Athanasios; Gercken, Bettina; Kotlabova, Klara; Phieler, Julia; Ehrhart-Bornstein, Monika; Bornstein, Stefan R; Eisenhofer, Graeme; Breier, Georg; Blüher, Matthias; Hampe, Jochen; El-Armouche, Ali; Chatzigeorgiou, Antonios; Chung, Kyoung-Jin; Chavakis, Triantafyllos

    2015-11-16

    Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction. Copyright © 2016 García-Martín et al.

  4. Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation

    PubMed Central

    Alexaki, Vasileia I.; Qin, Nan; Rubín de Celis, María F.; Economopoulou, Matina; Ziogas, Athanasios; Gercken, Bettina; Kotlabova, Klara; Phieler, Julia; Ehrhart-Bornstein, Monika; Bornstein, Stefan R.; Eisenhofer, Graeme; Breier, Georg; Blüher, Matthias; Hampe, Jochen; El-Armouche, Ali; Chatzigeorgiou, Antonios; Chung, Kyoung-Jin

    2015-01-01

    Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction. PMID:26572826

  5. Dark chocolate exacerbates acne.

    PubMed

    Vongraviopap, Saivaree; Asawanonda, Pravit

    2016-05-01

    The effects of chocolate on acne exacerbations have recently been reevaluated. For so many years, it was thought that it had no role in worsening acne. To investigate whether 99% dark chocolate, when consumed in regular daily amounts, would cause acne to worsen in acne-prone male subjects, twenty-five acne prone male subjects were asked to consume 25 g of 99% dark chocolate daily for 4 weeks. Assessments which included Leeds revised acne scores as well as lesion counts took place weekly. Food frequency questionnaire was used, and daily activities were recorded. Statistically significant changes of acne scores and numbers of comedones and inflammatory papules were detected as early as 2 weeks into the study. At 4 weeks, the changes remained statistically significant compared to baseline. Dark chocolate when consumed in normal amounts for 4 weeks can exacerbate acne in male subjects with acne-prone skin. © 2015 The International Society of Dermatology.

  6. Concurrent presence of inflammation and obstructive sleep apnea exacerbates the risk of metabolic syndrome: A KoGES 6-year follow-up study.

    PubMed

    Kim, Jinkwan; Yoon, Dae Wui; Lee, Seung Ku; Lee, Seunggwan; Choi, Kyung-Mee; Robert, Thomas J; Shin, Chol

    2017-02-01

    Obstructive sleep apnea (OSA) leads to multiple end-organ morbidities that are mediated by the cumulative burden of oxidative stress and inflammation. Both OSA and inflammation play key roles in increased risk of cardiovascular disease (CVD). Thus, we hypothesized that the combination of inflammation and OSA could accelerate the development of metabolic syndrome (MetS) in a large cohort study.A total of 1835 participants were randomly selected from the ongoing Korean Genome and Epidemiology Study for the years between 2007 and 2015. Overnight polysomnography was performed on each participant. Blood was drawn for biochemical analyses. Participants with high or low inflammation were divided by high-sensitivity C-reactive protein (hsCRP). MetS was defined using the criteria of the modified National Cholesterol Education Program, Adult Treatment Panel III.The prevalence of MetS was higher among the subjects with OSA and high hsCRP levels than among the other corresponding groups. The incidence of MetS among the 4 groups stratified by OSA and inflammation status at the 6-year follow-up was 11.8%, 19.9%, 25.8%, and 36.0% (HsCRP[-]/OSA[-] vs HsCRP[+]/OSA[-] vs HsCRP[-]/OSA[+] vs HsCRP[+]/OSA[+], P < 0.01). After adjusting for age, sex, smoking, alcohol status, BMI, and change in BMI (ΔBMI) in a multiple logistic regression, the subjects with OSA and high hsCRP levels at follow-up had a 2.22-fold risk of developing MetS, as compared with those with no-OSA and low hsCRP levels (P < 0.01).MetS is more prevalent in the concurrent presence of inflammation and OSA. The combination of these conditions is associated with higher risk of MetS. Additional research is needed to help further define the significance of the combined effect of OSA and subclinical inflammation on the development of MetS in the context of reduction of CVD risk.

  7. Nucleotides released from palmitate-challenged muscle cells through pannexin-3 attract monocytes.

    PubMed

    Pillon, Nicolas J; Li, Yujin E; Fink, Lisbeth N; Brozinick, Joseph T; Nikolayev, Alexander; Kuo, Ming-Shang; Bilan, Philip J; Klip, Amira

    2014-11-01

    Obesity-associated low-grade inflammation in metabolically relevant tissues contributes to insulin resistance. We recently reported monocyte/macrophage infiltration in mouse and human skeletal muscles. However, the molecular triggers of this infiltration are unknown, and the role of muscle cells in this context is poorly understood. Animal studies are not amenable to the specific investigation of this vectorial cellular communication. Using cell cultures, we investigated the crosstalk between myotubes and monocytes exposed to physiological levels of saturated and unsaturated fatty acids. Media from L6 myotubes treated with palmitate-but not palmitoleate-induced THP1 monocyte migration across transwells. Palmitate activated the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in myotubes and elevated cytokine expression, but the monocyte chemoattracting agent was not a polypeptide. Instead, nucleotide degradation eliminated the chemoattracting properties of the myotube-conditioned media. Moreover, palmitate-induced expression and activity of pannexin-3 channels in myotubes were mediated by TLR4-NF-κB, and TLR4-NF-κB inhibition or pannexin-3 knockdown prevented monocyte chemoattraction. In mice, the expression of pannexin channels increased in adipose tissue and skeletal muscle in response to high-fat feeding. These findings identify pannexins as new targets of saturated fatty acid-induced inflammation in myotubes, and point to nucleotides as possible mediators of immune cell chemoattraction toward muscle in the context of obesity.

  8. High fat-diet and saturated fatty acid palmitate inhibits IGF-1 function in chondrocytes.

    PubMed

    Nazli, S A; Loeser, R F; Chubinskaya, S; Willey, J S; Yammani, R R

    2017-09-01

    Insulin-like growth factor-1 (IGF-1) promotes matrix synthesis and cell survival in cartilage. Chondrocytes from aged and osteoarthritic cartilage have a reduced response to IGF-1. The purpose of this study was to determine the effect of free fatty acids (FFA) present in a high-fat diet on IGF-1 function in cartilage and the role of endoplasmic reticulum (ER) stress. C57BL/6 male mice were maintained on either a high-fat (60% kcal from fat) or a low-fat (10% kcal from fat) diet for 4 months. Mice were then sacrificed; femoral head cartilage caps were collected and treated with IGF-1 to measure proteoglycan (PG) synthesis. Cultured human chondrocytes were treated with 500 μM FFA palmitate or oleate, followed by stimulation with (100 ng/ml) IGF-1 overnight to measure CHOP (a protein marker for ER stress) and PG synthesis. Human chondrocytes were pre-treated with palmitate or 1 mM 4-phenyl butyric acid (PBA) or 1 μM C-Jun N terminal Kinase (JNK) inhibitor, and IGF-1 function (PG synthesis and signaling) was measured. Cartilage explants from mice on the high fat-diet showed reduced IGF-1 mediated PG synthesis compared to a low-fat group. Treatment of human chondrocytes with palmitate induced expression of CHOP, activated JNK and inhibited IGF-1 function. PBA, a small molecule chemical chaperone that alleviates ER stress rescued IGF-1 function and a JNK inhibitor rescued IGF-1 signaling. Palmitate-induced ER stress inhibited IGF-1 function in chondrocytes/cartilage via activating the mitogen-activated protein (MAP) kinase JNK. This is the first study to demonstrate that ER stress is metabolic factor that regulates IGF-1 function in chondrocytes. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  9. COPD exacerbation: lost in translation.

    PubMed

    Makris, Demosthenes; Bouros, Demosthenes

    2009-01-29

    The introduction and acceptance of a standard definition for exacerbations of COPD can be helpful in prompt diagnosis and management of these events. The latest GOLD executive committee recognised this necessity and it has now included a definition of exacerbation in the guidelines for COPD which is an important step forward in the management of the disease. This definition is pragmatic and compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication") in the definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiological process which characterizes exacerbations. It should be also noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions (i.e. congestive cardiac failure or pulmonary embolism) that can masquerade as exacerbations but they should not be considered as causes of them. The authors therefore suggest that an inclusion of the etiologic factors of COPD exacerbations in the definition. Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation and significant deterioration in lung function. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. The authors acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations meets certain difficulties related to performing lung function tests or to sampling during exacerbations. However, the introduction of a test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward in the management of

  10. Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1.

    PubMed

    Yang, Won-Mo; Min, Kyung-Ho; Lee, Wan

    2016-01-01

    Obesity is defined as the excessive accumulation of body fat that ultimately leads to chronic metabolic diseases. Diets rich in saturated fatty acids (SFA) exacerbate obesity and hepatic steatosis, which increase the risk of hepatic insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play an important role in a range of biological processes, the implications of SFA-induced miRNAs in metabolic dysregulation, particularly in the pathogenesis of hepatic insulin resistance, are not well understood. This study investigated the implications of miR-96, which is induced strongly by SFA, in the development of hepatic insulin resistance. The liver of HFD mice and the palmitate-treated hepatocytes exhibited an impairment of insulin signaling due to the significant decrease in INSR and IRS-1 expression. According to expression profiling and qRT-PCR analysis of the miRNAs, the expression level of miR-96 was higher in hepatocytes treated with palmitate. Moreover, miR-96 was also upregulated in the liver of HFD mice. Interestingly, miR-96 targeted the 3'UTRs of INSR and IRS-1 directly, and repressed the expression of INSR and IRS-1 at the post-transcriptional level. Accordingly, the overexpression of miR-96 was found to cause a significant decrease in INSR and IRS-1 expression, thereby leading to an impairment of insulin signaling and glycogen synthesis in hepatocytes. These results reveal a novel mechanism whereby miR-96 promotes the pathogenesis of hepatic insulin resistance resulted from SFA or obesity.

  11. Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1

    PubMed Central

    Yang, Won-Mo; Min, Kyung-Ho

    2016-01-01

    Obesity is defined as the excessive accumulation of body fat that ultimately leads to chronic metabolic diseases. Diets rich in saturated fatty acids (SFA) exacerbate obesity and hepatic steatosis, which increase the risk of hepatic insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play an important role in a range of biological processes, the implications of SFA-induced miRNAs in metabolic dysregulation, particularly in the pathogenesis of hepatic insulin resistance, are not well understood. This study investigated the implications of miR-96, which is induced strongly by SFA, in the development of hepatic insulin resistance. The liver of HFD mice and the palmitate-treated hepatocytes exhibited an impairment of insulin signaling due to the significant decrease in INSR and IRS-1 expression. According to expression profiling and qRT-PCR analysis of the miRNAs, the expression level of miR-96 was higher in hepatocytes treated with palmitate. Moreover, miR-96 was also upregulated in the liver of HFD mice. Interestingly, miR-96 targeted the 3’UTRs of INSR and IRS-1 directly, and repressed the expression of INSR and IRS-1 at the post-transcriptional level. Accordingly, the overexpression of miR-96 was found to cause a significant decrease in INSR and IRS-1 expression, thereby leading to an impairment of insulin signaling and glycogen synthesis in hepatocytes. These results reveal a novel mechanism whereby miR-96 promotes the pathogenesis of hepatic insulin resistance resulted from SFA or obesity. PMID:28036389

  12. Palmitic Acid in Early Human Development.

    PubMed

    Innis, Sheila M

    2016-09-09

    Palmitic acid (16:0) is a saturated fatty acid present in the diet and synthesized endogenously. Although often considered to have adverse effects on chronic disease in adults, 16:0 is an essential component of membrane, secretory, and transport lipids, with crucial roles in protein palmitoylation and signal molecules. At birth, the term infant is 13-15% body fat, with 45-50% 16:0, much of which is derived from endogenous synthesis in the fetus. After birth, the infant accumulates adipose tissue at high rates, reaching 25% body weight as fat by 4-5 months age. Over this time, human milk provides 10% dietary energy as 16:0, but in unusual triglycerides with 16:0 on the glycerol center carbon. This paper reviews the synthesis and oxidation of 16:0 and possible reasons why the infant is endowed with large amounts of fat and 16:0. The marked deviations in tissues with displacement of 16:0 that can occur in infants fed vegetable oil formulas is introduced. Assuming fetal fatty acid synthesis and the unusual delivery of 16:0 in human milk evolved to afford survival advantage to the neonate, it is timely to question if 16:0 is an essential component of tissue lipids whereby both deficiency and excess are detrimental.

  13. Palmitate attenuates osteoblast differentiation of fetal rat calvarial cells

    SciTech Connect

    Yeh, Lee-Chuan C.; Ford, Jeffery J.; Lee, John C.; Adamo, Martin L.

    2014-07-18

    Highlights: • Palmitate inhibits osteoblast differentiation. • Fatty acid synthase. • PPARγ. • Acetyl Co-A carboxylase inhibitor TOFA. • Fetal rat calvarial cell culture. - Abstract: Aging is associated with the accumulation of ectopic lipid resulting in the inhibition of normal organ function, a phenomenon known as lipotoxicity. Within the bone marrow microenvironment, elevation in fatty acid levels may produce an increase in osteoclast activity and a decrease in osteoblast number and function, thus contributing to age-related osteoporosis. However, little is known about lipotoxic mechanisms in intramembraneous bone. Previously we reported that the long chain saturated fatty acid palmitate inhibited the expression of the osteogenic markers RUNX2 and osteocalcin in fetal rat calvarial cell (FRC) cultures. Moreover, the acetyl CoA carboxylase inhibitor TOFA blocked the inhibitory effect of palmitate on expression of these two markers. In the current study we have extended these observations to show that palmitate inhibits spontaneous mineralized bone formation in FRC cultures in association with reduced mRNA expression of RUNX2, alkaline phosphatase, osteocalcin, and bone sialoprotein and reduced alkaline phosphatase activity. The effects of palmitate on osteogenic marker expression were inhibited by TOFA. Palmitate also inhibited the mRNA expression of fatty acid synthase and PPARγ in FRC cultures, and as with osteogenic markers, this effect was inhibited by TOFA. Palmitate had no effect on FRC cell proliferation or apoptosis, but inhibited BMP-7-induced alkaline phosphatase activity. We conclude that palmitate accumulation may lead to lipotoxic effects on osteoblast differentiation and mineralization and that increases in fatty acid oxidation may help to prevent these lipotoxic effects.

  14. Hydrothermal catalytic deoxygenation of palmitic acid over nickel catalyst

    SciTech Connect

    Miao, Chao; Marin-Flores, Oscar; Davidson, Stephen D.; Li, Tingting; Dong, Tao; Gao, Difeng; Wang, Yong; Garcia-Pérez, Manuel; Chen, Shulin

    2016-02-01

    Fatty acid has recently received considerable interest as a possible precursor for producing renewable hydrocarbon. In this study, we investigated hydrothermal catalytic deoxygenation of palmitic acid to produce paraffin over a Ni/ZrO2 catalyst with no or low-pressure (100 psi) external supply of H2. The results show that the presence of water greatly improved conversion of palmitic acid and paraffin yield. Significant improvement was attributed to the formation of in-situ H2. Without an external H2 supply, a 64.2 C% conversion of palmitic acid was achieved in the presence of water, while only a 17.2 C% conversion was achieved without water. The results also show that the presence of water suppressed the side reactions of palmitic acid, specifically ketonization and esterification. We concluded that, compared with decarboxylation and hydrodeoxygenation, decarbonylation was the major route for palmitic acid deoxygenation catalyzed by Ni/ZrO2. Varieties of shorter-chain paraffin (C8–C14) were formed through hydrogenolysis, which also produced a considerable amount of CH4. A viable reaction pathway for hydrothermal catalytic deoxygenation of palmitic acid in the presence of Ni/ZrO2 was suggested. The results show that hydrogenolysis and decarbonylation were the major reactions that occurred. This study demonstrates that this hydrothermal catalytic process is a promising approach for producing liquid paraffin (C8–C15) from fatty acids under no or low-pressure H2.

  15. ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice.

    PubMed

    Huang, Yun-Ying; Huang, Xiong-Qin; Zhao, Li-Yan; Sun, Fang-Yun; Chen, Wen-Liang; Du, Jie-Yi; Yuan, Feng; Li, Jie; Huang, Xue-Lian; Liu, Jie; Lv, Xiao-Fei; Guan, Yong-Yuan; Chen, Jian-Wen; Wang, Guan-Lei

    2014-11-01

    Palmitate, a common saturated free fatty acid (FFA), has been demonstrated to induce preadipocyte apoptosis in the absence of adipogenic stimuli, suggesting that preadipocytes may be prone to apoptosis under adipogenic insufficient conditions, like type 2 diabetes mellitus (T2DM). ClC-3, encoding Cl(-) channel or Cl(-)/H(+) antiporter, is critical for cell fate choices of proliferation versus apoptosis under diseased conditions. However, it is unknown whether ClC-3 is related with preadipocyte apoptosis induced by palmitate or T2DM. Palmitate, but not oleate, induced apoptosis and increase in ClC-3 protein expression and endoplasmic reticulum (ER) stress in 3T3-L1 preadipocyte. ClC-3 specific siRNA attenuated palmitate-induced apoptosis and increased protein levels of Grp78, ATF4, CHOP and phosphorylation of JNK1/2, whereas had no effects on increased phospho-PERK and phospho-eIF2α protein expression. Moreover, the enhanced apoptosis was shown in preadipocytes from high-sucrose/fat, low-dose STZ induced T2DM mouse model with hyperglycemia, hyperlipidemia (elevated serum TG and FFA levels) and insulin resistance. ClC-3 knockout significantly attenuated preadipocyte apoptosis and the above metabolic disorders in T2DM mice. These data demonstrated that ClC-3 deficiency prevent preadipocytes against palmitate-induced apoptosis via suppressing ER stress, and also suggested that ClC-3 may play a role in regulating cellular apoptosis and disorders of glucose and lipid metabolism during T2DM.

  16. Rhinosinusitis and aspirin-exacerbated respiratory disease.

    PubMed

    Garcia Cruz, Maria L; Jimenez-Chobillon, M Alejandro; Teran, Luis M

    2012-01-01

    Rhinosinusitis is a feature of aspirin-exacerbated respiratory disease (AERD), which in the initial phase is manifested as nasal congestion, mostly affecting females at the age of around 30 years on average. Subsequently, nasal inflammation progresses to chronic eosinophilic rhinosinusitis, asthma, nasal polyposis, and intolerance to aspirin and to other NSAIDs. While it has been long established that NSAIDs cause inhibition of cyclooxygenase-1 (COX-1), leading to excessive metabolism of arachidonic acid (AA) to cysteinyl-leukotrienes (cys-LTs), there is now evidence that both cytokines and staphylococcus superantigens amplify the inflammatory process exacerbating the disease. This paper gives a brief overview of the development of chronic rhinosinusitis (CRS) in sensitive patients, and we share our experience in the diagnosis and management of CRS in AERD.

  17. Rhinosinusitis and Aspirin-Exacerbated Respiratory Disease

    PubMed Central

    Garcia Cruz, Maria L.; Jimenez-Chobillon, M. Alejandro; Teran, Luis M.

    2012-01-01

    Rhinosinusitis is a feature of aspirin-exacerbated respiratory disease (AERD), which in the initial phase is manifested as nasal congestion, mostly affecting females at the age of around 30 years on average. Subsequently, nasal inflammation progresses to chronic eosinophilic rhinosinusitis, asthma, nasal polyposis, and intolerance to aspirin and to other NSAIDs. While it has been long established that NSAIDs cause inhibition of cyclooxygenase-1 (COX-1), leading to excessive metabolism of arachidonic acid (AA) to cysteinyl-leukotrienes (cys-LTs), there is now evidence that both cytokines and staphylococcus superantigens amplify the inflammatory process exacerbating the disease. This paper gives a brief overview of the development of chronic rhinosinusitis (CRS) in sensitive patients, and we share our experience in the diagnosis and management of CRS in AERD. PMID:22829846

  18. Asthma exacerbations · 3: Pathogenesis

    PubMed Central

    Wark, P A B; Gibson, P G

    2006-01-01

    Asthma exacerbations are an exaggerated lower airway response to an environmental exposure. Respiratory virus infection is the most common environmental exposure to cause a severe asthma exacerbation. Airway inflammation is a key part of the lower airway response in asthma exacerbation, and occurs together with airflow obstruction and increased airway responsiveness. The patterns of airway inflammation differ according to the trigger factor responsible for the exacerbation. The reasons for the exaggerated response of asthmatic airways are not completely understood, but recent studies have identified a deficient epithelial type 1 interferon response as an important susceptibility mechanism for viral infection. PMID:17008482

  19. Anti-inflammatory activity of methyl palmitate and ethyl palmitate in different experimental rat models

    SciTech Connect

    Saeed, Noha M.; El-Demerdash, Ebtehal; Abdel-Rahman, Hanaa M.; Algandaby, Mardi M.; Al-Abbasi, Fahad A.; Abdel-Naim, Ashraf B.

    2012-10-01

    Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). MP and EP decreased NF-κB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models. -- Highlights: ► Efficacy of MP and EP in combating inflammation was displayed in several models. ► MP and EP reduced carrageenan-induced rat paw edema and prostaglandin E2 level. ► MP and EP decreased TNF-α and IL-6 levels in experimental endotoxemia. ► MP and EP reduced NF-κB expression and histological changes in rat liver and lung. ► MP and EP reduced croton oil-induced ear edema and neutrophil infiltration.

  20. Anti-inflammatory activity of methyl palmitate and ethyl palmitate in different experimental rat models.

    PubMed

    Saeed, Noha M; El-Demerdash, Ebtehal; Abdel-Rahman, Hanaa M; Algandaby, Mardi M; Al-Abbasi, Fahad A; Abdel-Naim, Ashraf B

    2012-10-01

    Methyl palmitate (MP) and ethyl palmitate (EP) are naturally occurring fatty acid esters reported as inflammatory cell inhibitors. In the current study, the potential anti-inflammatory activity of MP and EP was evaluated in different experimental rat models. Results showed that MP and EP caused reduction of carrageenan-induced rat paw edema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In lipopolysaccharide (LPS)-induced endotoxemia in rats, MP and EP reduced plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). MP and EP decreased NF-κB expression in liver and lung tissues and ameliorated histopathological changes caused by LPS. Topical application of MP and EP reduced ear edema induced by croton oil in rats. In the same animal model, MP and EP reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In conclusion, this study demonstrates the effectiveness of MP and EP in combating inflammation in several experimental models.

  1. Betaine improves growth, but does not induce whole body or hepatic palmitate oxidation in swine (Sus scrofa domestica).

    PubMed

    Wray-Cahen, Diane; Fernández-Fígares, Ignacio; Virtanen, Erkki; Steele, Norman C; Caperna, Thomas J

    2004-01-01

    Dietary betaine may reduce carcass fat in growing pigs. We explored the effects of betaine on short-term growth and in vivo and in vitro fatty acid oxidation. Pigs were housed in metabolism crates and fed diets containing either 0% (control), 0.125% or 0.5% betaine at 80% of ad libitum energy intake. Fatty acid oxidation was measured during intravenous infusions of 1-(13)C-palmitate and in hepatocytes incubated in the presence or absence of betaine and carnitine. CO2 and palmitate isotopic enrichments were determined by mass spectrometry. Pigs consuming 0.125% and 0.5% betaine for at least 9 days had growth rates that were 38% and 12% greater than controls, respectively. Feed efficiency was also improved with betaine. Fasting increased palmitate oxidation rates 7-8-fold (P < 0.01), but betaine had no effect in either the fed or fasted state (P > 0.1). For hepatocytes, carnitine but not betaine enhanced palmitate oxidation. This response suggests that previously observed reduction in adipose accretion must be via a mechanism other than oxidation. Betaine had no effect on plasma non-esterified fatty acids or urea nitrogen. Under the confinement conditions in this study, dietary betaine improved animal growth responses, but it had no apparent effect on either whole body or hepatic fatty acid oxidation.

  2. Synergy Analysis Reveals Association between Insulin Signaling and Desmoplakin Expression in Palmitate Treated HepG2 Cells

    PubMed Central

    Yang, Xuerui; Portis, Amanda; Walton, S. Patrick; Chan, Christina

    2011-01-01

    The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a “gene-cooperativity” network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD). PMID:22132232

  3. Suppression of Grb2 expression improved hepatic steatosis, oxidative stress, and apoptosis induced by palmitic acid in vitro partly through insulin signaling alteration.

    PubMed

    Shan, Xiangxiang; Miao, Yufeng; Fan, Rengen; Song, Changzhi; Wu, Guangzhou; Wan, Zhengqiang; Zhu, Jian; Sun, Guan; Zha, Wenzhang; Mu, Xiangming; Zhou, Guangjun; Chen, Yan

    2013-09-01

    In this study, we aimed to study the role of growth factor receptor-bound protein 2 (Grb2) in palmitic acid-induced steatosis and other "fatty liver" symptoms in vitro. HepG2 cells, with or without stably suppressed Grb2 expression, were incubated with palmitic acid for 24 h to induce typical clinical "fatty liver" features, including steatosis, impaired glucose metabolism, oxidative stress, and apoptosis. MTT and Oil Red O assays were applied to test cell viability and fat deposition, respectively. Glucose uptake assay was used to evaluate the glucose utilization of cells. Quantitative polymerase chain reaction and Western blot were used to measure expressional changes of key markers of insulin signaling, lipid/glucose metabolism, oxidative stress, and apoptosis. After 24-h palmitic acid induction, increased fat accumulation, reduced glucose uptake, impaired insulin signaling, enhanced oxidative stress, and increased apoptosis were observed in HepG2 cells. Suppression of Grb2 in HepG2 significantly reduced fat accumulation, improved glucose metabolism, ameliorated oxidative stress, and restored the activity of insulin receptor substrate-1/Akt and MEK/ERK pathways. In addition, Grb2 deficiency attenuated hepatic apoptosis shown by reduced activation of caspase-3 and fluorescent staining. Modulation of Bcl-2 and Bak1 also contributed to reduced apoptosis. In conclusion, suppression of Grb2 expression in HepG2 cells improved hepatic steatosis, glucose metabolism, oxidative stress, and apoptosis induced by palmitic acid incubation partly though modulating the insulin signaling pathway.

  4. Switching away from pipotiazine palmitate: a naturalistic study

    PubMed Central

    Mustafa, Feras Ali

    2016-01-01

    Background: In March 2015, pipotiazine palmitate depot antipsychotic was globally withdrawn due to the shortage of its active ingredient. Thus, all patients receiving this medication had to be switched to an alternative antipsychotic drug. In this study we set to evaluate the process of switching away from pipotiazine palmitate within our clinical service, and its impact on hospitalization. Methods: Demographic and clinical data on patients who were receiving pipotiazine palmitate in Northamptonshire at the time of its withdrawal were anonymously extracted from their electronic records and analyzed using descriptive statistics. Results: A total of 17 patients were switched away from pipotiazine palmitate at the time of its withdrawal, all of whom had a prior history of nonadherence with oral treatment. A total of 14 patients were switched to another depot antipsychotic drug, while three patients chose an oral alternative which they subsequently discontinued resulting in relapse and hospitalization. There was a five-fold increase in mean hospitalization among patients who completed a year after the switch. Conclusion: Switching away from pipotiazine palmitate was associated with significant clinical deterioration in patients who switched to an oral antipsychotic, whereas most patients who switched to another depot treatment maintained stability. Clinicians should exercise caution when switching patients with schizophrenia away from depot antipsychotic drugs, especially in cases of patients with a history of treatment nonadherence who prefer to switch to oral antipsychotics. PMID:28101321

  5. Antioxidant effect of mogrosides against oxidative stress induced by palmitic acid in mouse insulinoma NIT-1 cells.

    PubMed

    Xu, Q; Chen, S Y; Deng, L D; Feng, L P; Huang, L Z; Yu, R R

    2013-11-18

    Excessive oxidative stress in pancreatic β cells, caused by glucose and fatty acids, is associated with the pathogenesis of type 2 diabetes. Mogrosides have shown antioxidant and antidiabetic activities in animal models of diabetes, but the underlying mechanisms remain unclear. This study evaluated the antioxidant effect of mogrosides on insulinoma cells under oxidative stress caused by palmitic acid, and investigated the underlying molecular mechanisms. Mouse insulinoma NIT-1 cells were cultured in medium containing 0.75 mM palmitic acid, mimicking oxidative stress. The effects of 1 mM mogrosides were determined with the dichlorodihydrofluorescein diacetate assay for intracellular reactive oxygen species (ROS) and FITC-Annexin V/PI assay for cell apoptosis. Expression of glucose transporter-2 (GLUT2) and pyruvate kinase was determined by semi-quantitative reverse-transcription polymerase chain reaction. Palmitic acid significantly increased intracellular ROS concentration 2-fold (P<0.05), and decreased expression of GLUT2 (by 60%, P<0.05) and pyruvate kinase (by 80%, P<0.05) mRNAs in NIT-1 cells. Compared with palmitic acid, co-treatment with 1 mM mogrosides for 48 h significantly reduced intracellular ROS concentration and restored mRNA expression levels of GLUT2 and pyruvate kinase. However, mogrosides did not reverse palmitic acid-induced apoptosis in NIT-1 cells. Our results indicate that mogrosides might exert their antioxidant effect by reducing intracellular ROS and regulating expression of genes involved in glucose metabolism. Further research is needed to achieve a better understanding of the signaling pathway involved in the antioxidant effect of mogrosides.

  6. Antioxidant effect of mogrosides against oxidative stress induced by palmitic acid in mouse insulinoma NIT-1 cells

    PubMed Central

    Xu, Q.; Chen, S.Y.; Deng, L.D.; Feng, L.P.; Huang, L.Z.; Yu, R.R.

    2013-01-01

    Excessive oxidative stress in pancreatic β cells, caused by glucose and fatty acids, is associated with the pathogenesis of type 2 diabetes. Mogrosides have shown antioxidant and antidiabetic activities in animal models of diabetes, but the underlying mechanisms remain unclear. This study evaluated the antioxidant effect of mogrosides on insulinoma cells under oxidative stress caused by palmitic acid, and investigated the underlying molecular mechanisms. Mouse insulinoma NIT-1 cells were cultured in medium containing 0.75 mM palmitic acid, mimicking oxidative stress. The effects of 1 mM mogrosides were determined with the dichlorodihydrofluorescein diacetate assay for intracellular reactive oxygen species (ROS) and FITC-Annexin V/PI assay for cell apoptosis. Expression of glucose transporter-2 (GLUT2) and pyruvate kinase was determined by semi-quantitative reverse-transcription polymerase chain reaction. Palmitic acid significantly increased intracellular ROS concentration 2-fold (P<0.05), and decreased expression of GLUT2 (by 60%, P<0.05) and pyruvate kinase (by 80%, P<0.05) mRNAs in NIT-1 cells. Compared with palmitic acid, co-treatment with 1 mM mogrosides for 48 h significantly reduced intracellular ROS concentration and restored mRNA expression levels of GLUT2 and pyruvate kinase. However, mogrosides did not reverse palmitic acid-induced apoptosis in NIT-1 cells. Our results indicate that mogrosides might exert their antioxidant effect by reducing intracellular ROS and regulating expression of genes involved in glucose metabolism. Further research is needed to achieve a better understanding of the signaling pathway involved in the antioxidant effect of mogrosides. PMID:24270904

  7. Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation.

    PubMed

    Tumova, Jana; Malisova, Lucia; Andel, Michal; Trnka, Jan

    2015-10-01

    Unsaturated free fatty acids (FFA) are able to prevent deleterious effects of saturated FFA in skeletal muscle cells although the mechanisms involved are still not completely understood. FFA act as endogenous ligands of peroxisome proliferator-activated receptors (PPAR), transcription factors regulating the expression of genes involved in lipid metabolism. The aim of this study was to determine whether activation of PPARδ, the most common PPAR subtype in skeletal muscle, plays a role in mediating the protective effect of unsaturated FFA on saturated FFA-induced damage in skeletal muscle cells and to examine an impact on mitochondrial respiration. Mouse C2C12 myotubes were treated for 24 h with different concentrations of saturated FFA (palmitic acid), unsaturated FFA (oleic, linoleic and α-linolenic acid), and their combinations. PPARδ agonist GW501516 and antagonist GSK0660 were also used. Both mono- and polyunsaturated FFA, but not GW501516, prevented palmitic acid-induced cell death. Mono- and polyunsaturated FFA proved to be effective activators of PPARδ compared to saturated palmitic acid; however, in combination with palmitic acid their effect on PPARδ activation was blocked and stayed at the levels observed for palmitic acid alone. Unsaturated FFA at moderate physiological concentrations as well as GW501516, but not palmitic acid, mildly uncoupled mitochondrial respiration. Our results indicate that although unsaturated FFA are effective activators of PPARδ, their protective effect on palmitic acid-induced toxicity is not mediated by PPARδ activation and subsequent induction of lipid regulatory genes in skeletal muscle cells. Other mechanisms, such as mitochondrial uncoupling, may underlie their effect.

  8. Palmitic acid-induced apoptosis in pancreatic β-cells is increased by liver X receptor agonist and attenuated by eicosapentaenoate.

    PubMed

    Liang, Huasheng; Zhong, Yuhua; Zhou, Shaobi; Li, Qingdi Quentin

    2011-01-01

    Saturated fatty acids are implicated in the development of diabetes via the impairment of pancreatic islet β-cell viability and function. Liver X receptors (LXRs) and eicosapentaenoate (EPA) are known regulators of fatty acid metabolism. However, their roles in the pathogenesis of diabetes remain incompletely understood. The aim of this study was to determine the effects of EPA and the LXR agonist T0901317 on saturated fatty acid (palmitic acid)-induced apoptosis in the insulinoma β-cell line INS-1, a model for insulin-secreting β-cells. T0901317 significantly promoted palmitic acid-induced apoptotic cell death in the INS-1 cells. Consistent with these results, caspase-3 activity and BAX and sterol regulatory element binding protein-1c (SREBP-1c) mRNA levels were markedly increased in INS-1 cells co-administered palmitic acid and T0901317. The production of reactive oxygen species was considerably higher in the cells cultured concurrently with T0901317 and palmitic acid than in the cells incubated with either agent alone. EPA treatment attenuated the cellular death promoted by palmitic acid and T0901317 in the INS-1 cells, disclosing a possible mediating mechanism involving the inhibition of SREBP-1c. Finally, T0901317 up-regulated the palmitic acid-induced expression of p27(KIP1), transforming growth factor beta 1, and SMAD3 proteins in INS-1 cells. These results demonstrate that palmitic acid-induced apoptosis in β-cells is enhanced by T0901317 via the activation of LXRs and is blocked by EPA via the inhibition of SREBP-1c, suggesting that the regulation of lipogenesis and lipotoxicity affecting pancreatic β-cell viability and insulin production may be a unique strategy for diabetes therapy.

  9. Improvement of efficiency in the enzymatic synthesis of lactulose palmitate.

    PubMed

    Bernal, Claudia; Illanes, Andres; Wilson, Lorena

    2015-04-15

    Sugar esters are considered as surfactants due to its amphiphilic balance that can lower the surface tension in oil/water mixtures. Enzymatic syntheses of these compounds are interesting both from economic and environmental considerations. A study was carried out to evaluate the effect of four solvents, temperature, substrate molar ratio, biocatalyst source, and immobilization methodology on the yield and specific productivity of lactulose palmitate monoester synthesis. Lipases from Pseudomonas stutzeri (PsL) and Alcaligenes sp. (AsL), immobilized in porous silica functionalized with octyl groups (adsorption immobilization, OS) and with glyoxyl-octyl groups (both adsorption and covalent immobilization, OGS), were used. The highest lactulose palmitate yields were obtained at 47 °C in acetone, for all biocatalysts, while the best lactulose:palmitic acid molar ratio differed according to the immobilization methodology, being 1:1 for AsL-OGS biocatalyst (20.7 ± 3%) and 1:3 for the others (30-50%).

  10. A Guide to the George Palmiter River Restoration Techniques.

    DTIC Science & Technology

    1982-03-01

    AD-Ri34 232 A GUIDE TO THE GEORGE PRLMITER RIVER RESTORATION TECHNIQUES (U) MTRMI UNIY OXFORD OH INST OF ENVIRONMENTAL SCIENCES C N HERBKERSMAN MAR 82...Water Resources A Guide to the George Palmiter River Restoration Techniques "DTIC T 3 1 1983 C-) This docurne1’ hc p crt O"ed for p\\."Ai e...Subtitle) 5. TYPE OF REPORT & PERIOD COVERED Contributing Report A Guide to the George Palmiter Rivei Restorat ion March 1982 Techniques 6. PERFORMING

  11. Regional cerebral incorporation of plasma (/sup 14/C)palmitate, and cerebral glucose utilization, in water-deprived Long-Evans and Brattleboro rats

    SciTech Connect

    Noronha, J.G.; Larson, D.M.; Rapoport, S.I.

    1989-03-01

    Regional rates of incorporation into brain of intravenously administered (/sup 14/C)palmitate and regional cerebral metabolic rates for glucose (rCMRglc) were measured in water-provided (WP) and water-deprived (WD) homozygous (DI) and heterozygous (HZ) Brattleboro rats, a mutant strain unable to synthesize vasopressin, and in the parent Long-Evans (LE) strain. Following 15 h or 4 days of water deprivation, rCMRglc was elevated threefold in the pituitary neural lobe of LE-WD and DI-WD as compared with LE-WP rats, and in the paraventricular nucleus of LE-WD, and the supraoptic nucleus of DI-WD rats. However, incorporation of (/sup 14/C)palmitate into these regions was not specifically altered. The results indicate that water deprivation for up to 4 days increases rCMRglc in some brain regions involved with vasopressin, but does not alter (/sup 14/C)palmitate incorporation into these regions. Incorporation of plasma (/sup 14/C)palmitate is independent of unlabeled plasma palmitate at brain regions which have an intact blood-brain barrier, but at nonbarrier regions falls according to saturation kinetics as cold plasma concentration rises, with a mean half-saturation constant (Km) equal to 0.136 mumol.ml-1.

  12. Defective (U-14 C) palmitic acid oxidation in Duchenne muscular dystrophy

    SciTech Connect

    Carroll, J.E.; Norris, B.J.; Brooke, M.H.

    1985-01-01

    Compared with normal skeletal muscle, muscle from patients with Duchenne dystrophy had decreased (U-14 C) palmitic acid oxidation. (1-14 C) palmitic acid oxidation was normal. These results may indicate a defect in intramitochondrial fatty acid oxidation.

  13. Metabolism

    MedlinePlus

    Metabolism refers to all the physical and chemical processes in the body that convert or use energy, ... Tortora GJ, Derrickson BH. Metabolism. In: Tortora GJ, Derrickson ... Physiology . 14th ed. Hoboken, NJ: John Wiley & Sons; 2014:chap ...

  14. Metabolism

    MedlinePlus

    ... El metabolismo Metabolism Basics Our bodies get the energy they need from food through metabolism, the chemical ... that convert the fuel from food into the energy needed to do everything from moving to thinking ...

  15. 21 CFR 520.390c - Chloramphenicol palmitate oral suspension.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Chloramphenicol palmitate oral suspension. 520.390c Section 520.390c Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  16. 21 CFR 520.390c - Chloramphenicol palmitate oral suspension.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Chloramphenicol palmitate oral suspension. 520.390c Section 520.390c Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... Not for use in animals that are raised for food production. Must not be used in meat-, egg-, or...

  17. Cysteine aggravates palmitate-induced cell death in hepatocytes

    PubMed Central

    Dou, Xiaobing; Wang, Zhigang; Yao, Tong; Song, Zhenyuan

    2011-01-01

    Aims Lipotoxicity, defined as cell death induced by excessive fatty acids, especially saturated fatty acids, is critically involved in the development of non-alcoholic steatohepatitis (NASH). Recent studies report that plasma cysteine concentrations is elevated in the subjects with either alcoholic steatohepatitis (ASH) or NASH than normal subjects. The present study was conducted to determine if elevation of cysteine could be a deleterious factor in palmitate-induced hepatocyte cell death. Main methods HepG2 and Hep3B cells were treated with palmitate with/without the inclusion of cysteine in the media for 24 hours. The effects of cysteine inclusion on palmitate induced cell death were determined by lactate dehydrogenase (LDH) release and MTT assay. Oxidative stress was evaluated by intracellular glutathione (GSH) level, malondialdehyde (MDA) formation, and DCFH-DA assay. Western blotting was performed to detect the changes of endoplasmic reticulum(ER) stress markers: C/EBP homologous transcription factor (CHOP), GRP-78, and phosphorylated c-jun N-terminal kinase (p-JNK). Key findings Elevated intracellular cysteine aggravates hepatocytes to palmitate-induced cell death. Enhancement of ER stress, specifically increased activation of JNK pathway, contributed to this cell death process. Significance Increase of plasma cysteine levels, as observed in both ASH and NASH patients, may play a pathological role in the development of the liver diseases. Manipulation of dietary amino acids supplementation could be a therapeutic choice. PMID:22008477

  18. Biosysthesis of corn starch palmitate by lipase Novozym 435.

    PubMed

    Xin, Jia-Ying; Wang, Yan; Liu, Tie; Lin, Kai; Chang, Le; Xia, Chun-Gu

    2012-01-01

    Esterification of starch was carried out to expand the usefulness of starch for a myriad of industrial applications. Lipase B from Candida antarctica, immobilized on macroporous acrylic resin (Novozym 435), was used for starch esterification in two reaction systems: micro-solvent system and solvent-free system. The esterification of corn starch with palmitic acid in the solvent-free system and micro-solvent system gave a degree of substitution (DS) of 1.04 and 0.0072 respectively. Esterification of corn starch with palmitic acid was confirmed by UV spectroscopy and IR spectroscopy. The results of emulsifying property analysis showed that the starch palmitate with higher DS contributes to the higher emulsifying property (67.6%) and emulsion stability (79.6%) than the native starch (5.3% and 3.9%). Modified starch obtained by esterification that possesses emulsifying properties and has long chain fatty acids, like palmitic acid, has been widely used in the food, pharmaceutical and biomedical applications industries.

  19. Beta Palmitate Improves Bone Length and Quality during Catch-Up Growth in Young Rats

    PubMed Central

    Bar-Maisels, Meytal; Gabet, Yankel; Shamir, Raanan; Hiram-Bab, Sahar; Pasmanik-Chor, Metsada; Phillip, Moshe; Bar-Yoseph, Fabiana

    2017-01-01

    Palmitic acid (PA) is the most abundant saturated fatty acid in human milk, where it is heavily concentrated in the sn-2-position (termed beta palmitate, BPA) and as such is conserved in all women, regardless of their diet or ethnicity, indicating its physiological and metabolic importance. We hypothesized that BPA improves the efficiency of nutrition-induced catch up growth as compared to sn-1,3 PA, which is present in vegetable oil. Pre-pubertal male rats were subjected to a 17 days food restriction followed by re-feeding for nine days with 1,3 PA or BPA-containing diets. We measured bone length, epiphyseal growth plate height (EGP, histology), bone quality (micro-CT and 3-point bending assay), and gene expression (Affymetrix). The BPA-containing diet improved most growth parameters: humeri length and EGP height were greater in the BPA-fed animals. Further analysis of the EGP revealed that the hypertrophic zone was significantly higher in the BPA group. In addition, Affymetrix analysis revealed that the diet affected the expression of several genes in the liver and EGP. Despite the very subtle difference between the diets and the short re-feeding period, we found a small but significant improvement in most growth parameters in the BPA-fed rats. This pre-clinical study may have important implications, especially for children with growth disorders and children with special nutritional needs. PMID:28718808

  20. The effect of DL-2-bromopalmitate on the utilization of palmitic acid by rat granular pneumocytes.

    PubMed

    Heinemann, H O; Pietra, G G; Wagner, M; Minda, M

    1979-02-06

    The effect of DL-2-bromopalmitate (BrPA), an analogue of palmitic acid (PA), on the utilization of this fatty acid by rat lungs was investigated by a combination of anatomic and biochemical methods. The experiments were performed in vitro on two types of preparations, isolated perfused lungs and lung slices. In the isolated lung preparation the substrate reached the lung via the capillaries, in lung slices via the alveolar epithelium. Electron microscope autoradiography showed that BrPA depressed uptake of PA by granular pneumocytes. Radioactivity recovered by tissue analysis and capture of CO2 established that PA oxidation and incorporation into phospholipids and triglycerides was depressed by BrPA. A close correlation was found between the reduction in radioactivity in phospholipids and the grain density over lamellar bodies. The study shows that BrPA reversibly interferes with the uptake and utilization of long chain fatty by granular pneumocytes. BrPA appears as a useful tool to study palmitate metabolism and surfactant production by the lung.

  1. Manipulating catalytic pathways: deoxygenation of palmitic acid on multifunctional catalysts.

    PubMed

    Peng, Baoxiang; Zhao, Chen; Kasakov, Stanislav; Foraita, Sebastian; Lercher, Johannes A

    2013-04-08

    The mechanism of the catalytic reduction of palmitic acid to n-pentadecane at 260 °C in the presence of hydrogen over catalysts combining multiple functions has been explored. The reaction involves rate-determining reduction of the carboxylic group of palmitic acid to give hexadecanal, which is catalyzed either solely by Ni or synergistically by Ni and the ZrO2 support. The latter route involves adsorption of the carboxylic acid group at an oxygen vacancy of ZrO2 and abstraction of the α-H with elimination of O to produce the ketene, which is in turn hydrogenated to the aldehyde over Ni sites. The aldehyde is subsequently decarbonylated to n-pentadecane on Ni. The rate of deoxygenation of palmitic acid is higher on Ni/ZrO2 than that on Ni/SiO2 or Ni/Al2O3, but is slower than that on H-zeolite-supported Ni. As the partial pressure of H2 is decreased, the overall deoxygenation rate decreases. In the absence of H2, ketonization catalyzed by ZrO2 is the dominant reaction. Pd/C favors direct decarboxylation (-CO2), while Pt/C and Raney Ni catalyze the direct decarbonylation pathway (-CO). The rate of deoxygenation of palmitic acid (in units of mmol moltotal metal(-1) h(-1)) decreases in the sequence r(Pt black) ≈r(Pd black) >r(Raney Ni) in the absence of H2 . In situ IR spectroscopy unequivocally shows the presence of adsorbed ketene (C=C=O) on the surface of ZrO2 during the reaction with palmitic acid at 260 °C in the presence or absence of H2.

  2. Preparation of starch-stabilized silver nanoparticles from amylose-sodium palmitate inclusion complexes

    USDA-ARS?s Scientific Manuscript database

    Starch-stabilized silver nanoparticles were prepared from amylose-sodium palmitate complexes by first converting sodium palmitate to silver palmitate by reaction with silver nitrate and then reducing the silver ion to metallic silver. This process produced water solutions that could be dried and the...

  3. Effect of amylopectin on the rheological properties of aqueous dispersions of starch-sodium palmitate complexes

    USDA-ARS?s Scientific Manuscript database

    Aqueous dispersions of normal and high-amylose corn starch were steam jet cooked and blended with aqueous solutions of sodium palmitate to form amylose inclusion complexes. Partial conversion of complexed sodium palmitate to palmitic acid by addition of acetic acid led to the formation of gels. Bl...

  4. Lipid Mediators in Aspirin-Exacerbated Respiratory Disease.

    PubMed

    Parker, Andrew R; Ayars, Andrew G; Altman, Matthew C; Henderson, William R

    2016-11-01

    Aspirin-exacerbated respiratory disease (AERD) is a syndrome of severe asthma and rhinosinusitis with nasal polyposis with exacerbations of baseline eosinophil-driven and mast cell-driven inflammation after nonsteroidal antiinflammatory drug ingestion. Although the underlying pathophysiology is poorly understood, dysregulation of the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism is thought to be key. Central features of AERD pathogenesis are overproduction of proinflammatory and bronchoconstrictor cysteinyl leukotrienes and prostaglandin (PG) D2 and inhibition of bronchoprotective and antiinflammatory PGE2. Imbalance in the ratio of these lipid mediators likely leads to the increased eosinophilic and mast cell inflammatory responses in the respiratory tract.

  5. Selective use of palmitic acid over stearic acid for synthesis of phosphatidylcholine and phosphatidylglycerol in lung

    SciTech Connect

    Tsao, F.H.

    1986-11-01

    The incorporation of (/sup 3/H)palmitic acid and (/sup 14/C)stearic acid into phospholipids in rabbit lung tissue was studied. Under equal molar concentrations of palmitate and stearate, palmitate was incorporated to the 1- and 2-positions of phosphatidylcholine (PC) and phosphatidylglycerol (PG) 2-3 times more than stearate. By contrast, palmitate was 30% less than stearate in phosphatidylethanolamine, phosphatidylinositol and phosphatidylserine. These results suggest that preferential utilization of palmitate over stearate, rather than substrate availability, determines the high content of palmitoyl at the 1- and 2-positions of PC and PG in lung.

  6. Susceptibility of podocytes to palmitic acid is regulated by stearoyl-CoA desaturases 1 and 2.

    PubMed

    Sieber, Jonas; Weins, Astrid; Kampe, Kapil; Gruber, Stefan; Lindenmeyer, Maja T; Cohen, Clemens D; Orellana, Jana M; Mundel, Peter; Jehle, Andreas W

    2013-09-01

    Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.

  7. Susceptibility of Podocytes to Palmitic Acid Is Regulated by Stearoyl-CoA Desaturases 1 and 2

    PubMed Central

    Sieber, Jonas; Weins, Astrid; Kampe, Kapil; Gruber, Stefan; Lindenmeyer, Maja T.; Cohen, Clemens D.; Orellana, Jana M.; Mundel, Peter; Jehle, Andreas W.

    2014-01-01

    Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid–induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid–induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid–derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death. PMID:23867797

  8. Palmitate-induced ER stress increases trastuzumab sensitivity in HER2/neu-positive breast cancer cells.

    PubMed

    Baumann, Jan; Wong, Jason; Sun, Yan; Conklin, Douglas S

    2016-07-27

    HER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment. Transcriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines. Exogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and

  9. Physical Inactivity Differentially Alters Dietary Oleate and Palmitate Trafficking

    PubMed Central

    Bergouignan, Audrey; Trudel, Guy; Simon, Chantal; Chopard, Angèle; Schoeller, Dale A.; Momken, Iman; Votruba, Susanne B.; Desage, Michel; Burdge, Graham C.; Gauquelin-Koch, Guillemette; Normand, Sylvie; Blanc, Stéphane

    2009-01-01

    OBJECTIVE— Obesity and diabetes are characterized by the incapacity to use fat as fuel. We hypothesized that this reduced fat oxidation is secondary to a sedentary lifestyle. RESEARCH DESIGN AND METHODS— We investigated the effect of a 2-month bed rest on the dietary oleate and palmitate trafficking in lean women (control group, n = 8) and the effect of concomitant resistance/aerobic exercise training as a countermeasure (exercise group, n = 8). Trafficking of stable isotope–labeled dietary fats was combined with muscle gene expression and magnetic resonance imaging–derived muscle fat content analyses. RESULTS— In the control group, bed rest increased the cumulative [1-13C]oleate and [d31]palmitate appearance in triglycerides (37%, P = 0.009, and 34%, P = 0.016, respectively) and nonesterified fatty acids (NEFAs) (37%, P = 0.038, and 38%, P = 0.002) and decreased muscle lipoprotein lipase (P = 0.043) and fatty acid translocase CD36 (P = 0.043) mRNA expressions. Plasma NEFA-to-triglyceride ratios for [1-13C]oleate and [d31]palmitate remained unchanged, suggesting that the same proportion of tracers enters the peripheral tissues after bed rest. Bed rest did not affect [1-13C]oleate oxidation but decreased [d31]palmitate oxidation by −8.2 ± 4.9% (P < 0.0001). Despite a decreased spontaneous energy intake and a reduction of 1.9 ± 0.3 kg (P = 0.001) in fat mass, exercise training did not mitigate these alterations but partially maintained fat-free mass, insulin sensitivity, and total lipid oxidation in fasting and fed states. In both groups, muscle fat content increased by 2.7% after bed rest and negatively correlated with the reduction in [d31]palmitate oxidation (r2 = 0.48, P = 0.003). CONCLUSIONS— While saturated and monounsaturated fats have similar plasma trafficking and clearance, physical inactivity affects the partitioning of saturated fats toward storage, likely leading to an accumulation of palmitate in muscle fat. PMID:19017764

  10. Aspirin-Exacerbated Respiratory Disease.

    PubMed

    Walgama, Evan S; Hwang, Peter H

    2017-02-01

    Aspirin-exacerbated respiratory disease (AERD) is characterized by the triad of asthma, sinonasal polyposis, and aspirin intolerance. The hallmark of the disease is baseline overproduction of cysteinyl leukotrienes via the 5-lipoxygenase pathway, exacerbated by ingestion of aspirin. Patients with AERD have high rates of recidivistic polyposis following sinus surgery, although the improvement in quality of life following surgery is similar to aspirin-tolerant patients. The diagnosis is secured by a positive aspirin provocation test, usually administered by a medical allergist. Aspirin therapy is a unique treatment consideration for patients with AERD.

  11. Palmitic acid exerts pro-inflammatory effects on vascular smooth muscle cells by inducing the expression of C-reactive protein, inducible nitric oxide synthase and tumor necrosis factor-α.

    PubMed

    Wu, Di; Liu, Juntian; Pang, Xiaoming; Wang, Shuyue; Zhao, Jingjing; Zhang, Xiaolu; Feng, Liuxin

    2014-12-01

    Atherosclerosis is a chronic inflammatory disease in the vessel, and inflammatory cytokines play an important role in the inflammatory process of atherosclerosis. A high level of free fatty acids (FFAs) produced in lipid metabolism disorders are known to participate in the formation of atherosclerosis through multiple bioactivities. As the main saturated fatty acid in FFAs, palmitic acid stimulates the expression of inflammatory cytokines in macrophages. However, it is unclear whether palmitic acid exerts a pro-inflammatory effect on vascular smooth muscle cells (VSMCs). The purpose of the present study was to observe the effect of palmitic acid on the expression of C-reactive protein (CRP), tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) in VSMCs. Rat VSMCs were cultured, and palmitic acid was used as a stimulant for CRP, TNF-α and iNOS expression. mRNA expression was assayed with reverse transcription-polymerase chain reaction, and protein expression was detected with western blot analysis and immunocytochemistry. The results showed that palmitic acid significantly stimulated mRNA and protein expression of CRP, TNF-α and iNOS in VSMCs in time- and concentration-dependent manners, and therefore, palmitic acid is able to exert a pro-inflammatory effect on VSMCs via stimulating CRP, TNF-α and iNOS expression. The findings provide a novel explanation for the direct pro-inflammatory and atherogenic effects of palmitic acid, and for the association with metabolic syndrome, such as type 2 diabetes mellitus, obesity and atherosclerosis. Therefore, the intervention with anti-inflammatory agents may effectively delay the formation and progression of atherosclerosis in patients with metabolic syndrome.

  12. Amelioration of palmitate-induced insulin resistance in C₂C₁₂ muscle cells by rooibos (Aspalathus linearis).

    PubMed

    Mazibuko, S E; Muller, C J F; Joubert, E; de Beer, D; Johnson, R; Opoku, A R; Louw, J

    2013-07-15

    Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the glucose disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C₂C₁₂ skeletal muscle cells. Palmitate-induced insulin resistant C₂C₁₂ cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood glucose lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). Glucose uptake and mitochondrial activity were measured using 2-deoxy-[³H]-D-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to glucose metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside. Both rooibos extracts increased glucose uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing glucose uptake and ATP production. At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the glucose transporter (GLUT4) involved in glucose transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in

  13. Urea biosensors based on PVC membrane containing palmitic acid.

    PubMed

    Karakuş, Emine; Pekyardimci, Sule; Esma, Kiliç

    2005-01-01

    A new urea biosensor was prepared by immobilizing urease with four different procedures on poly(vinylchloride) (PVC) ammonium membrane electrode containing palmitic acid by using nonactine as an ammonium-ionophore. The analytical characteristics were investigated and were compared those of the biosensor prepared by using carboxylated PVC. The effect of pH, buffer concentration, temperature, urease concentration, stirring rate and enzyme immobilization procedures on the response to urea of the enzyme electrode were investigated. The linear working range and sensitivity of the biosensor were also determined. The urea biosensor prepared by using the PVC membranes containing palmitic acid showed more effective performance than those of the carboxylated PVC based biosensors. Additionally, urea assay in serum was successfully carried out by using the standard addition method.

  14. Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD).

    PubMed

    Narayanankutty, Arun; Reséndiz-Hernández, Juan Manuel; Falfán-Valencia, Ramcés; Teran, Luis M

    2013-05-01

    Aspirin exacerbated respiratory disease (AERD) is a distinct clinical entity characterized by eosinophilic rhinosinusitis, asthma and often nasal polyposis. Exposure to aspirin or other nonsteroid anti-inflammatory drugs (NSAIDs) exacerbates bronchospasms with asthma and rhinitis. Disease progression suggests a skewing towards TH2 type cellular response along with moderate to severe eosinophil and mast cell infiltration. Alterations in upper and lower airway cellular milieu with abnormalities in eicosanoid metabolism and altered eicosanoid receptor expression are the key features underlying AERD pathogenesis. Dysregulation of arachidonic acid (AA) metabolism, notably reduced prostaglandin E2 (PGE2) synthesis compared to their aspirin tolerant counterpart and relatively increased PGD2 production, a TH2/eosinophil chemoattractant are reported in AERD. Underproduced PGE2 is metabolized by overexpression of 15 prostaglandin dehydrogenase (15-PGDH) to inactive products further reducing PGE2 at real time. This relives the inhibitory effect of PGE2 on 5-lipoxygenase (5-LOX) resulting in overproduction of cysteinyl leukotrienes (CysLTs). Diminished formation of CysLT antagonists called lipoxins (LXs) also augments CysLTs responsiveness. Occasional intake of NSAIDs favors even more 5-LOX product formation, further narrowing the bronchoconstrictive bottle neck, resulting in acute asthmatic exacerbations along with increased mucus production. This review focuses on abnormalities in biochemical and molecular mechanisms in eicosanoid biosynthesis, eicosanoid receptor dysregulation and associated polymorphisms with special reference to arachidonic acid metabolism in AERD.

  15. Temperature induced modulation of lipid oxidation and lipid accumulation in palmitate-mediated 3T3-L1 adipocytes and 3T3-L1 adipocytes.

    PubMed

    Lin, Xiaofen; Li, Yi; Leung, Polly Hangmei; Li, Jiashen; Hu, Junyan; Liu, Xuan; Li, Zhi

    2016-05-01

    Human skin temperature can vary widely depending on anatomical location and ambient temperature. It is also known that local changes in skin and subcutaneous temperature can affect fat metabolism. This study aimed to explore the potential effects of surrounding thermal environment on fat by investigating cell viability, lipid oxidation, and lipid accumulation in 3T3-L1 adipocytes and palmitate-treated adipocytes after 4h incubation. No significant differences of viability in 3T3-L1 adipocytes were detected under different temperature conditions. Despite no significant increase being observed under warm temperature (39°C) conditions, a similarly significant suppression of intracellular reactive oxygen species (ROS) and lipid peroxidation were found in 3T3-L1 adipocytes and palmitate-treated adipocytes under 4h exposure to cooler temperatures of 31-33°C (P<0.01). ROS, chemically reactive molecules containing oxygen, are currently understood to be a major contributor to oxidantive stress in obesity. Additionally, cooler temperatures (31-33°C) could improve the size of lipid droplets in 3T3-L1 adipocytes (P<0.01), but no significant effect was generated by temperature change on lipid droplets in palmitate-treated adipocytes. In the palmitate-induced adiposity model, although excessive ROS and lipid peroxidation has been attenuated by temperature decrease (P<0.01), it still does not positively modulate lipid droplet size (P>0.05) and remedy the palmitate damage induced cell death (P<0.01). These findings provide preliminary support for potential interventions based on temperature manipulation for cell metabolism of adipocytes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Metabolism

    MedlinePlus

    ... symptoms. Metabolic diseases and conditions include: Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism is caused ... or through surgery or radiation treatments. Hypothyroidism (pronounced: hi-po-THIGH-roy-dih-zum). Hypothyroidism is caused ...

  17. COPD exacerbations: causes, prevention, and treatment.

    PubMed

    Mackay, Alex J; Hurst, John R

    2012-07-01

    The mechanisms of COPD exacerbation are complex. Respiratory viruses (in particular rhinovirus) and bacteria play a major role in the causative etiology of COPD exacerbations. In some patients, noninfective environmental factors may also be important. Data recently published from a large observational study identified a phenotype of patients more susceptible to frequent exacerbations. Many current therapeutic strategies can reduce exacerbation frequency. Future studies may target the frequent exacerbator phenotype, or those patients colonized with potential bacterial pathogens, for such therapies as long-term antibiotics, thus preventing exacerbations by decreasing bacterial load or preventing new strain acquisition in the stable state. Respiratory viral infections are also an important therapeutic target for COPD. Further work is required to develop new anti-inflammatory agents for exacerbation prevention, and novel acute treatments to improve outcomes at exacerbation. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Palmitic acid is the major fatty acid responsible for significant anti-N-methyl-N'-nitro-N-nitroguanidine (MNNG) activity in yogurt.

    PubMed

    Nadathur, S R; Carney, J R; Gould, S J; Bakalinsky, A T

    1996-04-04

    We describe here the isolation and identification of palmitic acid as being responsible for significant anti-N-methyl-N'-nitro-N-nitroguanidine (MNNG) activity in yogurt. The Ames test (Salmonella typhimurium TA100) was used to direct fractionation of activity. Yogurt was freeze-dried and extracted with acetone to yield a crude extract. The crude extract was purified by normal phase silica gel, Sephadex LH-20, and reversed phase medium pressure liquid chromatographies. The major compound in the active medium pressure liquid chromatographic fractions was determined to be palmitic acid on GC and high pressure liquid chromatography (HPLC) systems, and by nuclear magnetic resonance (NMR) analysis. Other saturated straight chain and methyl branched fatty acids were detected by GC/MS and were later shown to possess anti-MNNG activity. Of the straight chain fatty acids, palmitic acid had the highest anti-MNNG activity. All omega - 1 methyl branched fatty acids tested were more active than their straight chain counterparts. A trace amount of isopalmitic acid (14-methyl pentadecanoic acid), a minor milk lipid, was detected in one of the active fractions, and was later shown to be five times more active than palmitic acid. Isopalmitic acid also inhibited mutagenesis induced 4-nitroquinoline-N-oxide (4NQO), and 7, 12-dimethyl benz[a]anthracene (DMBA), and was found to inhibit the metabolic activation of DMBA.

  19. Rosiglitazone, but not epigallocatechin-3-gallate, attenuates the decrease in PGC-1α protein levels in palmitate-induced insulin-resistant C2C12 cells.

    PubMed

    Karimfar, Mohammad Hassan; Haghani, Karimeh; Babakhani, Azar; Bakhtiyari, Salar

    2015-06-01

    Alteration of lipid metabolism is an important mechanism for the treatment of insulin resistance. PGC-1α, a key regulator of mitochondrial biogenesis and function, plays an important role in the improvement of insulin sensitivity by increasing fatty acids β-oxidation. In the present study, the effects of epigallocatechin-3-gallate (EGCG), an anti-obesity agent and enhancer of lipid catabolism, on PGC-1α protein expression was examined and compared with anti-diabetic drug rosiglitazone (RGZ). After differentiation of C2C12 myoblasts to myotubes, insulin resistance was induced by palmitate treatment. Then the expression of the PGC-1a gene and glucose uptake were evaluated before and after treatment with RGZ and EGCG. Palmitate treatment significantly decreased PGC-1α protein expression in C2C12 cells (P < 0.05). RGZ could restore the expression of PGC-1α in palmitate treated cells (P > 0.05), while EGCG had no significant effect on the expression of this gene (P < 0.05). RGZ and EGCG significantly improved glucose uptake (by 2- and 1.54-fold, respectively) in myotubes treated with palmitate. These data suggest that RGZ and EGCG both exert their anti-diabetic activity by increasing insulin sensitivity, but with different molecular mechanisms. This effect of RGZ, unlike EGCG, is mediated, at least partly, by increasing PGC-1α protein expression.

  20. Exacerbation phenotyping in chronic obstructive pulmonary disease.

    PubMed

    MacDonald, Martin; Korman, Tony; King, Paul; Hamza, Kais; Bardin, Philip

    2013-11-01

    Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are crucial events but causes remain poorly defined. A method to clinically 'phenotype' AECOPD have been proposed, and 52 hospitalized chronic obstructive pulmonary disease exacerbations according to underlying aetiology have now been prospectively phenotyped. Multiple exacerbation phenotypes were identified. A subpopulation coinfected with virus and bacteria had a significantly longer length of hospital stay, and this pilot study indicates that exacerbation phenotyping may be advantageous.

  1. Antitumor activity of palmitic acid found as a selective cytotoxic substance in a marine red alga.

    PubMed

    Harada, Hideki; Yamashita, Uki; Kurihara, Hideyuki; Fukushi, Eri; Kawabata, Jun; Kamei, Yuto

    2002-01-01

    In a previous report, we discussed an extract from a marine red alga, Amphiroa zonata, which shows selective cytotoxic activity to human leukemic cells, but no cytotoxicity to normal human dermal fibroblast (HDF) cells in vitro. In this study, we identified palmitic acid, a selective cytotoxic substance from the marine algal extract, and investigated its biological activities. At concentrations ranging from 12.5 to 50 micrograms/ml, palmitic acid shows selective cytotoxicity to human leukemic cells, but no cytotoxicity to normal HDF cells. Furthermore, palmitic acid induces apoptosis in the human leukemic cell line MOLT-4 at 50 micrograms/ml. Palmitic acid also shows in vivo antitumor activity in mice. One molecular target of palmitic acid in tumor cells is DNA topoisomerase I, however, interestingly, it does not affect DNA topoisomerase II, suggesting that palmitic acid may be a lead compound of anticancer drugs.

  2. Localization of viable, ischemic myocardium by positron-emission tomography with /sup 11/C-palmitate

    SciTech Connect

    Lerch, R.A.; Ambos, H.D.; Bergmann, S.R.; Welch, M.J.; Ter-Pogossian, M.M.; Sobel, B.E.

    1981-10-01

    A study was performed to determine whether viable, but ischemic, tissue could be detected and localized in vivo based on external detection of impaired fatty acid metabolism. Accordingly, regional clearance of /sup 11/C-palmitate was assessed by sequential PET in 15 anesthetized dogs. Clearance was consistently monoexponential from 5-15 minutes after administration of the tracer. In the absence of coronary stenosis (n = 7), clearance was homogeneous throughout the heart, with an average rate constant (k) of -0.060 +/- 0.005 min/sup -1/ (+/- SEM) and a coefficient of variation (CV) of 11.1 +/- 2.1% in each heart. Homogeneity persisted when the heart rate was increased from 84.4 +/- 6.0 to 202.7 +/- 11.5 beats/min with atropine (CV 13.2 +/- 3.5%). With left circumflex coronary stenosis (less than or equal to70% reduction in vessel diameter), homogeneity of /sup 11/C-clearance under control conditions and with tachycardia did not differ from clearance in hearts without coronary stenosis. However, with stenosis >70% sufficient to induce ischemia without gross infarction, regional clearance of /sup 11/C became markedly heterogeneous under control conditions (CV 28.1 +/- 5.5%, p <0.01 compared with normal hearts) and with tachycardia (CV 34.8 +/- 5.4%, p <0.01). The heterogeneity resulted from reduced clearance of /sup 11/C in regions supplied by the stenotic vessel (k = -0.044 +/- 0.011 min/sup -1/) compared with clearance in well perfused regions (k = -0.064 +/- 0.011 min/sup -1/, p <0.025), a difference accentuated by tachycardia. Thus, sequential PET after i.v. injection of /sup 11/C-palmitate delineates zones of viable, ischemic myocardium that characteristically exhibit impaired oxidation of extracted fatty acid.

  3. Investigation of the interaction of naringin palmitate with bovine serum albumin: spectroscopic analysis and molecular docking.

    PubMed

    Zhang, Xia; Li, Lin; Xu, Zhenbo; Liang, Zhili; Su, Jianyu; Huang, Jianrong; Li, Bing

    2013-01-01

    Bovine serum albumin (BSA) contains high affinity binding sites for several endogenous and exogenous compounds and has been used to replace human serum albumin (HSA), as these two compounds share a similar structure. Naringin palmitate is a modified product of naringin that is produced by an acylation reaction with palmitic acid, which is considered to be an effective substance for enhancing naringin lipophilicity. In this study, the interaction of naringin palmitate with BSA was characterised by spectroscopic and molecular docking techniques. The goal of this study was to investigate the interactions between naringin palmitate and BSA under physiological conditions, and differences in naringin and naringin palmitate affinities for BSA were further compared and analysed. The formation of naringin palmitate-BSA was revealed by fluorescence quenching, and the Stern-Volmer quenching constant (KSV ) was found to decrease with increasing temperature, suggesting that a static quenching mechanism was involved. The changes in enthalpy (ΔH) and entropy (ΔS) for the interaction were detected at -4.11 ± 0.18 kJ·mol(-1) and -76.59 ± 0.32 J·mol(-1)·K(-1), respectively, which indicated that the naringin palmitate-BSA interaction occurred mainly through van der Waals forces and hydrogen bond formation. The negative free energy change (ΔG) values of naringin palmitate at different temperatures suggested a spontaneous interaction. Circular dichroism studies revealed that the α-helical content of BSA decreased after interacting with naringin palmitate. Displacement studies suggested that naringin palmitate was partially bound to site I (subdomain IIA) of the BSA, which was also substantiated by the molecular docking studies. In conclusion, naringin palmitate was transported by BSA and was easily removed afterwards. As a consequence, an extension of naringin applications for use in food, cosmetic and medicinal preparations may be clinically and practically significant

  4. Paliperidone palmitate use in pregnancy in a woman with schizophrenia.

    PubMed

    Özdemir, Aslı Karadağ; Pak, Şima Ceren; Canan, Fatih; Geçici, Ömer; Kuloğlu, Murat; Gücer, Mustafa Kadri

    2015-10-01

    Long-acting antipsychotic use in schizophrenia has become an advantage for treatment compliance and convenient administration of the drugs. There is no data on paliperidone palmitate (PP) use in pregnancy, which is the longest-acting (i.e., 1 month) atypical antipsychotic. In this case report, we aim to present a patient diagnosed with schizophrenia who had been using PP before and during her pregnancy until week 28 of gestation and gave birth to a male baby that weighed 3000 g at 39 weeks. As far as we know, this is the first case report on PP use during pregnancy.

  5. Intermittent Hypoxia Exacerbates Pancreatic β-Cell Dysfunction in A Mouse Model of Diabetes Mellitus

    PubMed Central

    Sherwani, Shariq I.; Aldana, Carolyn; Usmani, Saif; Adin, Christopher; Kotha, Sainath; Khan, Mahmood; Eubank, Timothy; Scherer, Philipp E.; Parinandi, Narasimham; Magalang, Ulysses J.

    2013-01-01

    Study Objectives: The effects of intermittent hypoxia (IH) on pancreatic function in the presence of diabetes and the underlying mechanisms are unclear. We hypothesized that IH would exacerbate pancreatic β-cell dysfunction and alter the fatty acids in the male Tallyho/JngJ (TH) mouse, a rodent model of type 2 diabetes. Design: TH mice were exposed for 14 d to either 8 h of IH or intermittent air (IA), followed by an intraperitoneal glucose tolerance test (IPGTT) and tissue harvest. The effect of IH on insulin release was determined by using a β3-adrenergic receptor (AR) agonist. Measurements and Results: During IH, pancreatic tissue pO2 decreased from 20.4 ± 0.9 to 5.7 ± 2.6 mm Hg, as determined by electron paramagnetic resonance oximetry. TH mice exposed to IH exhibited higher plasma glucose levels during the IPGTT (P < 0.001) while the insulin levels tended to be lower (P = 0.06). Pancreatic islets of the IH group showed an enhancement of the caspase-3 staining (P = 0.002). IH impaired the β-AR agonist-mediated insulin release (P < 0.001). IH increased the levels of the total free fatty acids and saturated fatty acids (palmitic and stearic acids), and decreased levels of the monounsaturated fatty acids in the pancreas and plasma. Ex vivo exposure of pancreatic islets to palmitic acid suppressed insulin secretion and decreased islet cell viability. Conclusions: Intermittent hypoxia increases pancreatic apoptosis and exacerbates dysfunction in a polygenic rodent model of diabetes. An increase in free fatty acids and a shift in composition towards long chain saturated fatty acid species appear to mediate these effects. Citation: Sherwani SI; Aldana C; Usmani S; Adin C; Kotha S; Khan M; Eubank T; Scherer PE; Parinandi N; Magalang UJ. Intermittent hypoxia exacerbates pancreatic β-cell dysfunction in a mouse model of diabetes mellitus. SLEEP 2013;36(12):1849-1858. PMID:24293759

  6. Dietary oleic and palmitic acids modulate the ratio of triacylglycerols to cholesterol in postprandial triacylglycerol-rich lipoproteins in men and cell viability and cycling in human monocytes.

    PubMed

    López, Sergio; Bermúdez, Beatriz; Pacheco, Yolanda M; López-Lluch, Guillermo; Moreda, Wenceslao; Villar, José; Abia, Rocío; Muriana, Francisco J G

    2007-09-01

    The postprandial metabolism of dietary fats produces triacylglycerol (TG)-rich lipoproteins (TRL) that could interact with circulating cells. We investigated whether the ratios of oleic:palmitic acid and monounsaturated fatty acids (MUFA):SFA in the diet affect the ratio of TG:cholesterol (CHOL) in postprandial TRL of healthy men. The ability of postprandial TRL at 3 h (early postprandial period) and 5 h (late postprandial period) to affect cell viability and cycle in the THP-1 human monocytic cell line was also determined. In a randomized, crossover experiment, 14 healthy volunteers (Caucasian men) ate meals enriched (50 g/m(2) body surface area) in refined olive oil, high-palmitic sunflower oil, butter, and a mixture of vegetable and fish oils, which had ratios of oleic:palmitic acid (MUFA:SFA) of 6.83 (5.43), 2.36 (2.42), 0.82 (0.48), and 13.81 (7.08), respectively. The ratio of TG:CHOL in postprandial TRL was inversely correlated (r = -0.89 to -0.99) with the ratio of oleic:palmitic acid and with the MUFA:SFA ratio in the dietary fats (P < 0.05). Postprandial TRL at 3 h preferentially increased the proportion of necrotic cells, whereas postprandial TRL at 5 h increased the proportion of apoptotic cells (P < 0.05). Cell cycle analysis showed that postprandial TRL blocked the human monocytes in S-phase. Our findings suggest that the level of TG and CHOL into postprandial TRL is associated with the ratios of oleic:palmitic acid and MUFA:SFA in dietary fats, which determines the ability of postprandial TRL to induce cytotoxicity and disturb the cell cycle in THP-1 cells.

  7. The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review.

    PubMed

    Toy, Edmond L; Gallagher, Kevin F; Stanley, Elizabeth L; Swensen, Andrine R; Duh, Mei Sheng

    2010-06-01

    Chronic obstructive pulmonary disease (COPD) poses a significant economic burden on society, and a substantial portion is related to exacerbations of COPD. A literature review of the direct and indirect costs of COPD exacerbations was performed. A systematic search of the MEDLINE database from 1998-2008 was conducted and supplemented with searches of conference abstracts and article bibliographies. Articles that contained cost data related to COPD exacerbations were selected for in-depth review. Eleven studies examining healthcare costs associated with COPD exacerbations were identified. The estimated costs of exacerbations vary widely across studies: $88 to $7,757 per exacerbation (2007 US dollars). The largest component of the total costs of COPD exacerbations was typically hospitalization. Costs were highly correlated with exacerbation severity. Indirect costs have rarely been measured. The wide variability in the cost estimates reflected cross-study differences in geographic locations, treatment patterns, and patient populations. Important methodological differences also existed across studies. Researchers have used different definitions of exacerbation (e.g., symptom- versus event-based definitions), different tools to identify and measure exacerbations, and different classification systems to define exacerbation severity. Unreported exacerbations are common and may influence the long-term costs of exacerbations. Measurement of indirect costs will provide a more comprehensive picture of the burden of exacerbations. Evaluation of pharmacoeconomic analyses would be aided by the use of more consistent and comprehensive approaches to defining and measuring COPD exacerbations.

  8. Retinyl palmitate flexible polymeric nanocapsules: characterization and permeation studies.

    PubMed

    Teixeira, Zaine; Zanchetta, Beatriz; Melo, Bruna A G; Oliveira, Luciana L; Santana, Maria H A; Paredes-Gamero, Edgar J; Justo, Giselle Z; Nader, Helena B; Guterres, Sílvia S; Durán, Nelson

    2010-11-01

    Polymeric nanocapsules with elastic characteristics were prepared by the pre-formed polymer interfacial deposition method. The system consists of an oily core of retinyl palmitate with Span 60 and a polymeric wall of poly(D,L-lactide) (PLA). A narrow size distribution (215 nm, P.D.I. 0.10) was showed by dynamic light scattering (DLS) analyses. Particle deformability was observed by transmission electron microscopy (TEM) images and permeation of the particles through two superposed membranes of smaller pore diameters. Permeation studies were achieved using plastic surgery abdominal human skin by Franz diffusion cell. Retinyl palmitate permeates into deep skin layers. Besides, a PLA fluorescent derivative conjugated with Nile blue dye by an amide covalent bound was additionally obtained. Permeation profile of the nanocapsules with the fluorescent polymer was evaluated by confocal laser scanning microscopy (CLSM). The CLSM showed that nanocapsules were distributed uniformly, suggesting that the permeation mechanism through skin is intercellular. Thus, the use of these nanocapsules may be a feasible strategy to enhance the permeation of actives into the skin when delivery to deep layers is aimed.

  9. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes

    PubMed Central

    Ly, Luong Dai; Xu, Shanhua; Choi, Seong-Kyung; Ha, Chae-Myeong; Thoudam, Themis; Cha, Seung-Kuy; Wiederkehr, Andreas; Wollheim, Claes B; Lee, In-Kyu; Park, Kyu-Sang

    2017-01-01

    Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications. PMID:28154371

  10. Concerted action of p62 and Nrf2 protects cells from palmitic acid-induced lipotoxicity

    SciTech Connect

    Park, Jeong Su; Kang, Dong Hoon; Lee, Da Hyun; Bae, Soo Han

    2015-10-09

    Nonalcoholic fatty liver disease (NAFLD), frequently associated with obesity and diabetes mellitus, is caused by the accumulation of excess fatty acids within liver cells. Palmitic acid (PA), a common saturated fatty acid found in mammals, induces the generation of reactive oxygen species (ROS) and elicits apoptotic cell death, known as lipotoxicity. However, protective mechanisms against PA-induced lipotoxicity have not been elucidated. In this study, we aimed to clarify the role of p62, an adapter protein in the autophagic process, as well as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in protecting cells from PA-induced lipotoxicity. The Nrf2-Keap1 pathway is essential for the protection of cells from oxidative stress. p62 enhances its binding to Keap1 and leads to Nrf2 activation. Here, we show that PA potentiates Keap1 degradation and thereby activates the transcription of Nrf2 target genes partially through autophagy. Furthermore, this PA-mediated Keap1 degradation depends on p62. Correspondingly, a lack of p62 attenuates the PA-mediated Nrf2 activation and increases the susceptibility of cells to oxidative stress. These results indicate that p62 plays an important role in protecting cells against lipotoxicity through Keap1 degradation-mediated Nrf2 activation. - Highlights: • PA induces Keap1 downregulation and activates Nrf2 target gene transcription. • PA-induced Keap1 degradation is partly mediated by the autophagic pathway. • PA-induced Keap1 degradation depends on p62. • Ablation of p62 exacerbates PA-mediated apoptotic cell death.

  11. Aripiprazole Lauroxil Compared with Paliperidone Palmitate in Patients with Schizophrenia: An Indirect Treatment Comparison.

    PubMed

    Cameron, Chris; Zummo, Jacqueline; Desai, Dharmik N; Drake, Christine; Hutton, Brian; Kotb, Ahmed; Weiden, Peter J

    Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic recently approved for treatment of schizophrenia on the basis of a large-scale trial of two doses of AL versus placebo. There are no direct-comparison studies with paliperidone palmitate (PP; long-acting antipsychotic used most often in acute settings) for the acute psychotic episode. To indirectly compare efficacy and safety of the pivotal AL study with all PP studies meeting indirect comparison criteria. Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, PsycINFO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and gray literature were performed to identify randomized controlled trials of PP with similar designs to the AL trial. Bayesian network meta-analysis compared treatments with respect to symptom response and tolerability issues including weight gain, akathisia, parkinsonism, and likelihood of treatment-emergent adverse events. Three appropriate PP studies were identified for indirect comparison. Both doses of AL (441 mg and 882 mg monthly) were used and compared with two efficacious doses of PP (156 mg and 234 mg monthly). All four active-treatment conditions were associated with comparable reductions in acute symptoms (Positive and Negative Syndrome Scale) versus placebo and were of similar magnitude (range of mean difference -8.12 to -12.01, with overlapping 95% credible intervals). Between-group comparisons of active-treatment arms were associated with summary estimates of magnitude near 0. No clinically meaningful differences in selected safety or tolerability parameter incidence were found between active treatments. These results suggest that both AL and PP are effective for treatment of adults experiencing acute exacerbation of schizophrenia. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  12. In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency.

    PubMed

    Baumgartner, Jeannine; Smuts, Cornelius M; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K; Bianco, Laura E; Boekschoten, Mark V; Müller, Michael; Langhans, Wolfgang; Hurrell, Richard F; Zimmermann, Michael B

    2012-08-01

    Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamines and related gene expression) and spatial working and reference memory [by Morris water maze (MWM) testing] associated with deficiency. Using a 2 × 2 design, male rats with concurrent ID and (n-3)FAD [ID+(n-3)FAD] were fed an Fe+DHA/EPA, Fe+(n-3)FAD, ID+DHA/EPA, or ID+(n-3)FAD diet for 5 wk [postnatal d 56-91]. Biochemical measures and MWM performance after repletion were compared to age-matched control rats. The provision of Fe in combination with DHA/EPA synergistically increased Fe concentrations in the olfactory bulb (OB) (Fe x DHA/EPA interaction). Similarly, provision of DHA/EPA in combination with Fe resulted in higher brain DHA concentrations than provision of DHA alone in the frontal cortex (FC) and OB (P < 0.05). Dopamine (DA) receptor D1 was upregulated in the hippocampus of Fe+DHA/EPA rats (fold-change = 1.25; P < 0.05) and there were significant Fe x DHA/EPA interactions on serotonin (5-HT) in the OB and on the DA metabolite dihydroxyphenylacetic acid in the FC and striatum. Working memory performance was impaired in ID+DHA/EPA rats compared with controls (P < 0.05). In the reference memory task, Fe+DHA/EPA improved learning behavior, but Fe or DHA/EPA alone did not. These findings suggest that feeding either Fe or DHA/EPA alone to adult rats with both ID and (n-3)FAD affects the DA and 5-HT pathways differently than combined repletion and exacerbates the cognitive deficits associated with combined deficiency.

  13. Crude Saponins of Panax notoginseng Have Neuroprotective Effects To Inhibit Palmitate-Triggered Endoplasmic Reticulum Stress-Associated Apoptosis and Loss of Postsynaptic Proteins in Staurosporine Differentiated RGC-5 Retinal Ganglion Cells.

    PubMed

    Wang, Dan-dan; Zhu, Hua-zhang; Li, Shi-wei; Yang, Jia-ming; Xiao, Yang; Kang, Qiang-rong; Li, Chen-yang; Zhao, Yun-shi; Zeng, Yong; Li, Yan; Zhang, Jian; He, Zhen-dan; Ying, Ying

    2016-02-24

    Increased apoptosis of retinal ganglion cells (RGCs) contributes to the gradual loss of retinal neurons at the early phase of diabetic retinopathy (DR). There is an urgent need to search for drugs with neuroprotective effects against apoptosis of RGCs for the early treatment of DR. This study aimed to investigate the neuroprotective effects of saponins extracted from Panax notoginseng, a traditional Chinese medicine, on apoptosis of RGCs stimulated by palmitate, a metabolic factor for the development of diabetes and its complications, and to explore the potential molecular mechanism. We showed that crude saponins of P. notoginseng (CSPN) inhibited the increased apoptosis and loss of postsynaptic protein PSD-95 by palmitate in staurosporine-differentiated RGC-5 cells. Moreover, CSPN suppressed palmitate-induced reactive oxygen species generation and endoplasmic reticulum stress-associated eIF2α/ATF4/CHOP and caspase 12 pathways. Thus, our findings address the potential therapeutic significance of CSPN for the early stage of DR.

  14. A Post-hoc Comparison of Paliperidone Palmitate to Oral Risperidone During Initiation of Long-acting Risperidone Injection in Patients with Acute Schizophrenia

    PubMed Central

    Pandina, Gahan; Lane, Rosanne; Nuamah, Isaac; Remmerie, Bart; Coppola, Danielle; Hough, David

    2011-01-01

    Objective: First-month data of a 13-week acute schizophrenia study were used to compare paliperidone palmitate to oral risperidone during initiation of long-acting injectable risperidone. Design: Double-blind, randomized study. Setting: Outpatient or inpatient. Participants: Adults with established (≥1 year) schizophrenia. Those assigned to risperidone long-acting injectable (n=460) received 25mg on Days 8 and 22 with oral risperidone (l–6mg) supplementation for the first 28 days. The paliperidone palmitate group (n=453) received 150mg eq. on Day 1, l00mg eq. on Day 8, and oral placebo supplementation for the first 28 days. Measurements: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical Global Impression-Severity score, and responder rate (percentage of patients with ≥30% reduction in PANSS total score). An analysis of covariance model estimated least-square mean differences between treatment groups. A post-hoc analysis of efficacy data for the period of interest, i.e., at the time points before and after the first 28 days, was conducted. Results: Positive and Negative Syndrome Scale, Personal and Social Performance Scale, Clinical global Impression-Severity scores showed similar efficacy between the treatment groups during the first weeks of treatment, corresponding to the risperidone long-acting injection initiation period. Mean Positive and Negative Syndrome Scale total score at baseline was 84.7 for paliperidone palmitate and 84.4 for oral risperidone, on Day 22 was 73.6 and 74.1, respectively, and on Day 36 was 71.8 and 72.8, respectively. Overall incidence of adverse events in the first 28 days was generally similar (45% for paliperidone palmitate vs. 35% for oral risperidone), except for injection site pain (4.6% vs. 0.7%). Similar active moiety plasma concentrations were obtained during this period. Conclusion: During the first month, paliperidone palmitate without oral supplementation has similar efficacy and

  15. 21 CFR 178.3450 - Esters of stearic and palmitic acids.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Esters of stearic and palmitic acids. 178.3450 Section 178.3450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... SANITIZERS Certain Adjuvants and Production Aids § 178.3450 Esters of stearic and palmitic acids. The ester...

  16. Palmitate causes endoplasmic reticulum stress and apoptosis in human mesenchymal stem cells: prevention by AMPK activator.

    PubMed

    Lu, Jun; Wang, Qinghua; Huang, Lianghu; Dong, Huiyue; Lin, Lingjing; Lin, Na; Zheng, Feng; Tan, Jianming

    2012-11-01

    Elevated circulating saturated fatty acids concentration is commonly associated with poorly controlled diabetes. The highly prevalent free fatty acid palmitate could induce apoptosis in various cell types, but little is known about its effects on human mesenchymal stem cells (MSCs). Here, we report that prolonged exposure to palmitate induces human bone marrow-derived MSC (hBM-MSC) and human umbilical cord-derived MSC apoptosis. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cell apoptosis. Palmitate activated XBP1 splicing, elF2α (eukaryotic translation initiation factor 2α) phosphorylation, and CHOP, ATF4, BiP, and GRP94 transcription in hBM-MSCs. ERK1/2 and p38 MAPK phosphorylation were also induced by palmitate in hBM-MSCs. A selective p38 inhibitor inhibited palmitate activation of the ER stress, whereas the ERK1/2 inhibitors had no effect. The AMP-activated protein kinase activator aminoimidazole carboxamide ribonucleotide blocked palmitate-induced ER stress and apoptosis. These findings suggest that palmitate induces ER stress and ERK1/2 and p38 activation in hBM-MSCs, and AMP-activated protein kinase activator prevents the deleterious effects of palmitate by inhibiting ER stress and apoptosis.

  17. 21 CFR 178.3450 - Esters of stearic and palmitic acids.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Esters of stearic and palmitic acids. 178.3450 Section 178.3450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... SANITIZERS Certain Adjuvants and Production Aids § 178.3450 Esters of stearic and palmitic acids. The ester...

  18. New alleles of FATB-1A to reduce palmitic acid levels in soybean

    USDA-ARS?s Scientific Manuscript database

    In wild-type soybeans, palmitic acid typically constitutes 10% of the total seed oil. Palmitic acid is a saturated fat linked to increased cholesterol levels, and reducing levels of saturated fats in soybean oil has been a breeding target. To identify novel and useful variation that could help in re...

  19. 78 FR 73200 - Draft Guidance for Industry on Bioequivalence Recommendations for Paliperidone Palmitate Extended...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-05

    ... Recommendations for Paliperidone Palmitate Extended-Release Injectable Suspension; Availability AGENCY: Food and... extended-release injectable suspension. DATES: Although you can comment on any guidance at any time (see 21... paliperidone palmitate extended-release injectable suspension. New drug application 022264 for INVEGA...

  20. Autocrine effects of transgenic resistin reduce palmitate and glucose oxidation in brown adipose tissue.

    PubMed

    Pravenec, Michal; Mlejnek, Petr; Zídek, Václav; Landa, Vladimír; Šimáková, Miroslava; Šilhavý, Jan; Strnad, Hynek; Eigner, Sebastian; Eigner Henke, Kateřina; Škop, Vojtěch; Malínská, Hana; Trnovská, Jaroslava; Kazdová, Ludmila; Drahota, Zdeněk; Mráček, Tomáš; Houštěk, Josef

    2016-06-01

    Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin (Retn) transgene specifically in adipose tissue (SHR-Retn), we have observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles, and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances. In the current study, we have analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR-Retn vs. nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR-Retn transgenic rats compared with SHR controls showed a lower relative weight (0.71 ± 0.05 vs. 0.91 ± 0.08 g/100 g body wt, P < 0.05), significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids (658 ± 50 vs. 856 ± 45 and 864 ± 47 vs. 1,086 ± 35 nmol/g/2 h, P ≤ 0.01, respectively), and significantly decreased palmitate oxidation (37.6 ± 4.5 vs. 57 ± 4.1 nmol/g/2 h, P = 0.007) and glucose oxidation (277 ± 34 vs. 458 ± 38 nmol/g/2 h, P = 0.001). In addition, in vivo microPET imaging revealed significantly reduced (18)F-FDG uptake in BAT induced by exposure to cold in SHR-Retn vs. control SHR (232 ± 19 vs. 334 ± 22 kBq/ml, P < 0.05). Gene expression profiles in BAT identified differentially expressed genes involved in skeletal muscle and connective tissue development, inflammation and MAPK and insulin signaling. These results provide evidence that autocrine effects of resistin attenuate differentiation and activity of BAT and thus may play a role in the pathogenesis of insulin resistance in the rat.

  1. Seinpin knockout exacerbates cerebral ischemia/reperfusion damage in mice.

    PubMed

    Chen, Yong; Wei, Lili; Tian, Jing; Wang, Yu-Hui; Liu, George; Wang, Chun

    2016-05-27

    Seipin, which regulates adipocyte differentiation and lipolysis, inducing severe lipodystrophy and metabolic syndromes, is also highly expressed in the nervous system and affects some neurological diseases. However, the impacts of seipin in stroke remain unclear. In this study, we subjected seipin knockout mice to cerebral ischemia/reperfusion injury and found that seipin knockout mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by blood-brain barrier (BBB) damages. Furthermore, we showed that seipin knockout aggravated endoplasmic reticulum (ER) stress and significantly increased glucose levels, decreased leptin and adiponectin levels in mouse plasma. Our findings reveal that seipin knockout exacerbates cerebral I/R-induced damages by increasing BBB permeability, amplifying ER stress and increasing glucose levels, as well as decreasing leptin and adiponectin levels, indicating that seipin may be a potential therapeutic target for stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Kleptomania and Potential Exacerbating Factors

    PubMed Central

    2011-01-01

    Kleptomania is an impulse control disorder that can cause significant impairment and serious consequences. Often, the condition is kept secret by the patient, and usually help is sought only when confronted by the legal consequences of the impulsive behaviors. Historically, kleptomania has been viewed from a psychodynamic perspective, and the mainstay of treatment has been psychotherapy. Recently, attempts to explain kleptomania within a neuropsychiatric paradigm have highlighted the possible links between mood disorders, addictive behaviors, and brain injury with kleptomania. These associations with kleptomania can be extrapolated to pharmacological strategies that can potentially help in treating kleptomania. A case of kleptomania, which was potentially exacerbated by multiple factors, will be reviewed. Treatment modalities used in this case, including the use of the Yale-Brown Obsessive Compulsive Scale as a surrogate marker to gauge response to treatment, will be discussed. PMID:22132369

  3. SN2-Palmitate Reduces Fatty Acid Excretion in Chinese Formula-fed Infants

    PubMed Central

    Bar-Yoseph, Fabiana; Lifshitz, Yael; Cohen, Tzafra; Malard, Patrice; Xu, Chungdi

    2016-01-01

    ABSTRACT Objectives: Palmitic acid (PA) comprises 17% to 25% of human milk fatty acids, of which 70% to 75% are esterified to the SN2 position of the triglyceride (SN2-palmitate). In vegetable oils, which are commonly used in infant formulas, palmitate is primarily esterified to other positions, resulting in reduced calcium and fat absorption and hard stools. The aim of this study was to elucidate the effects of SN2-palmitate on nutrient excretion. Methods: In total, 171 Chinese infants were included (within 14 days of birth) in this multicenter study. Formula-fed infants were randomly assigned to receive either SN2-palmitate formula (INFAT, n = 57) or control formula (n = 57). The formulas (Biostime, China) differed only in their SN2 PA proportions. Stool was collected at 6 postnatal weeks. Results: The stool dry weight and fat content of the SN2-palmitate group were lower compared with the control group (dry weight 4.25 g vs 7.28 g, P < 0.05; fat 0.8 g vs 1.2 g, P < 0.05). The lipid component was also significantly lower for the SN2-palmitate group (0.79 g vs 1.19 g, P < 0.05). PA, representing ∼50% of the saponified fatty acids, was significantly lower in the SN2-palmitate group compared with the control group (0.3 g vs 0.7 g, P < 0.01). Breast-fed infants had a significantly lower stool dry weight, fat content, and saponified fat excretion compared with formula-fed infants (P < 0.01). Conclusions: Similar to breast milk, the SN2-palmitate infant formula primarily reduced calcium-saponified fat excretion. The results of this study further emphasize the nutritional importance of SN2-palmitate structured fat for infants. PMID:26334255

  4. Proteins altered by elevated levels of palmitate or glucose implicated in impaired glucose-stimulated insulin secretion

    PubMed Central

    Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter

    2009-01-01

    Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692

  5. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells[S

    PubMed Central

    Leamy, Alexandra K.; Egnatchik, Robert A.; Shiota, Masakazu; Ivanova, Pavlina T.; Myers, David S.; Brown, H. Alex; Young, Jamey D.

    2014-01-01

    High levels of saturated FAs (SFAs) are acutely toxic to a variety of cell types, including hepatocytes, and have been associated with diseases such as type 2 diabetes and nonalcoholic fatty liver disease. SFA accumulation has been previously shown to degrade endoplasmic reticulum (ER) function leading to other manifestations of the lipoapoptotic cascade. We hypothesized that dysfunctional phospholipid (PL) metabolism is an initiating factor in this ER stress response. Treatment of either primary hepatocytes or H4IIEC3 cells with the SFA palmitate resulted in dramatic dilation of the ER membrane, coinciding with other markers of organelle dysfunction. This was accompanied by increased de novo glycerolipid synthesis, significant elevation of dipalmitoyl phosphatidic acid, diacylglycerol, and total PL content in H4IIEC3 cells. Supplementation with oleate (OA) reversed these markers of palmitate (PA)-induced lipotoxicity. OA/PA cotreatment modulated the distribution of PA between lipid classes, increasing the flux toward triacylglycerols while reducing its incorporation into PLs. Similar trends were demonstrated in both primary hepatocytes and the H4IIEC3 hepatoma cell line. Overall, these findings suggest that modifying the FA composition of structural PLs can protect hepatocytes from PA-induced ER stress and associated lipotoxicity. PMID:24859739

  6. Virus/Allergen Interaction in Asthma Exacerbation

    PubMed Central

    2015-01-01

    Allergy and viral respiratory infections have long been recognized as two of the most important risk factors for exacerbations of asthma. These observations have raised questions regarding potential interactions between these two important risk factors. For example, does allergy diminish the antiviral response, thereby promoting exacerbations of asthma? Alternately, do viral respiratory infections potentiate ongoing allergic inflammation in the airway? The answers to these questions are likely to have implications regarding the prevention and treatment of exacerbations of asthma. This article reviews that clinical evidence linking viral infections and allergy to exacerbations of asthma, reviews potential interactions between these two risk factors, and discusses possible application of new insights in virus/allergen interactions to the prevention and treatment of exacerbations of asthma. PMID:26595729

  7. Palmitate potentiation of glucose-induced insulin release: a study using 2-bromopalmitate.

    PubMed

    Parker, S M; Moore, P C; Johnson, L M; Poitout, V

    2003-10-01

    The mechanisms whereby fatty acids (FA) potentiate glucose-induced insulin secretion from the pancreatic beta cell are incompletely understood. In this study, the effects of palmitate on insulin secretion were investigated in isolated rat islets. Palmitate did not initiate insulin secretion at nonstimulatory glucose concentrations, but markedly stimulated insulin release at concentrations of glucose > or = 5.6 mmol/L. At concentrations of palmitate > or =0.5 mmol/L, the important determinant of the potency of the FA was its unbound concentration. At total concentrations < or = 0.5 mmol/L, both the total and unbound concentrations appeared important. Surprisingly, 2-bromopalmitate did not affect palmitate oxidation, but significantly diminished palmitate esterification into cellular lipids. Neither methyl palmitate, which is not activated into a long-chain acyl-CoA ester, nor 2-bromopalmitate affected glucose-stimulated insulin release. Further, 2-bromopalmitate partly inhibited the potentiating effect of palmitate. These results support the concept that FA potentiation of insulin release is mediated by FA-derived signals generated in the esterification pathway.

  8. Methyl palmitate attenuates lipopolysaccharide-induced acute lung injury in mice.

    PubMed

    Kalemci, S; Zeybek, A; Intepe, Y S; Uner, A G; Acar, T; Yaylali, A; Aksun, S; Can, C; Gulaydin, A; Sütçü, R

    2013-01-01

    The study is aimed to determine the beneficial effects of methyl palmitate (MP) which has antioxidant and anti-inflammatory effects demonstrated on murine model of acute lung injury induced by lipopolysaccharide (LPS). Forty male BALB/C mice were randomly allocated into four groups (n=10, each): control group, methyl palmitate group (300 mg/kg), LPS group, and methyl palmitate -treated groups. Methyl palmitate or vehicle was given with an intraperitoneal administration 1 h before an intratracheal instillation of LPS (5 mg/kg). The severity of pulmonary injury was evaluated 6 h after LPS challenge. All experimental procedures complied with the requirements of the Animal Care and Ethics Committee of the Adnan Menderes University. Methyl palmitate pretreatment significantly attenuated LPS-induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. Methyl palmitate pretreatment also reduced the concentrations of malondialdehyde in lung tissues. This study indicates that methyl palmitate may have a protective effect against LPS-induced acute lung injury, and the potential mechanism of this action may involve the inhibition of NF-κB. activation.

  9. Effects of inhibition of. beta. -oxidation on tissue kinetics of C-11 palmitate in normal myocardium

    SciTech Connect

    Wijns, W.; Schwaiger, M.; Huang, S.C.; Selin, C.; Grover-McKay, M.; Hansen, H.; Phelps, M.; Schelbert, H.R.

    1985-05-01

    C-11 palmitate (CPA) clears from myocardium biexponentially. The late slow tissue clearance curve component is thought to represent tracer deposited in the endogenous lipid pool. The early rapid component is thought to be related to oxidation of CPA. The nature of the curve components can be clarified by specific inhibition of individual metabolic steps, e.g., ..beta..-oxidation. Therefore, 11 dogs were studied at control and again after inhibition of carnitine acyltransferase I with iv. tetradecylglycidic acid (TDGA; 10 mg/kg). CPA was injected into the coronary circulation. Myocardial time activity curves (TAC) were analyzed by least square fitting. After TDGA, the late slow phase was unchanged (RS=32 +- 9%; T=336 +- 146 min) but the early rapid phase was reduced (RS=18 +- 8%; T=2.9 +- 1.4 min) while 50 +- 9% of extracted CPA diffused back (T=10.8 +- 3.6 sec). Thus, inhibition of ..beta..-oxidation shifted substrate usage from FFA to carbohydrates, had no effect on esterification of CPA but enhanced its back diffusion from myocardium. As discussed in this paper the decline of the early rapid phase indicates its relationship to CPA oxidation.

  10. Role of orexin A signaling in dietary palmitic acid-activated microglial cells.

    PubMed

    Duffy, Cayla M; Yuan, Ce; Wisdorf, Lauren E; Billington, Charles J; Kotz, Catherine M; Nixon, Joshua P; Butterick, Tammy A

    2015-10-08

    Excess dietary saturated fatty acids such as palmitic acid (PA) induce peripheral and hypothalamic inflammation. Hypothalamic inflammation, mediated in part by microglial activation, contributes to metabolic dysregulation. In rodents, high fat diet-induced microglial activation results in nuclear translocation of nuclear factor-kappa B (NFκB), and increased central pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). The hypothalamic neuropeptide orexin A (OXA, hypocretin 1) is neuroprotective in brain. In cortex, OXA can also reduce inflammation and neurodegeneration through a microglial-mediated pathway. Whether hypothalamic orexin neuroprotection mechanisms depend upon microglia is unknown. To address this issue, we evaluated effects of OXA and PA on inflammatory response in immortalized murine microglial and hypothalamic neuronal cell lines. We demonstrate for the first time in microglial cells that exposure to PA increases gene expression of orexin-1 receptor but not orexin-2 receptor. Pro-inflammatory markers IL-6, TNF-α, and inducible nitric oxide synthase in microglial cells are increased following PA exposure, but are reduced by pretreatment with OXA. The anti-inflammatory marker arginase-1 is increased by OXA. Finally, we show hypothalamic neurons exposed to conditioned media from PA-challenged microglia have increased cell survival only when microglia were pretreated with OXA. These data support the concept that OXA may act as an immunomodulatory regulator of microglia, reducing pro-inflammatory cytokines and increasing anti-inflammatory factors to promote a favorable neuronal microenvironment.

  11. Nerve growth factor protects against palmitic acid-induced injury in retinal ganglion cells

    PubMed Central

    Yan, Pan-shi; Tang, Shu; Zhang, Hai-feng; Guo, Yuan-yuan; Zeng, Zhi-wen; Wen, Qiang

    2016-01-01

    Accumulating evidence supports an important role for nerve growth factor (NGF) in diabetic retinopathy. We hypothesized that NGF has a protective effect on rat retinal ganglion RGC-5 cells injured by palmitic acid (PA), a metabolic factor implicated in the development of diabetes and its complications. Our results show that PA exposure caused apoptosis of RGC-5 cells, while NGF protected against PA insult in a concentration-dependent manner. Additionally, NGF significantly attenuated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in RGC-5 cells. Pathway inhibitor tests showed that the protective effect of NGF was completely reversed by LY294002 (PI3K inhibitor), Akt VIII inhibitor, and PD98059 (ERK1/2 inhibitor). Western blot analysis revealed that NGF induced the phosphorylation of Akt/FoxO1 and ERK1/2 and reversed the PA-evoked reduction in the levels of these proteins. These results indicate that NGF protects RGC-5 cells against PA-induced injury through anti-oxidation and inhibition of apoptosis by modulation of the PI3K/Akt and ERK1/2 signaling pathways. PMID:28123432

  12. Investigation of the Interaction of Naringin Palmitate with Bovine Serum Albumin: Spectroscopic Analysis and Molecular Docking

    PubMed Central

    Zhang, Xia; Li, Lin; Xu, Zhenbo; Liang, Zhili; Su, Jianyu; Huang, Jianrong; Li, Bing

    2013-01-01

    Background Bovine serum albumin (BSA) contains high affinity binding sites for several endogenous and exogenous compounds and has been used to replace human serum albumin (HSA), as these two compounds share a similar structure. Naringin palmitate is a modified product of naringin that is produced by an acylation reaction with palmitic acid, which is considered to be an effective substance for enhancing naringin lipophilicity. In this study, the interaction of naringin palmitate with BSA was characterised by spectroscopic and molecular docking techniques. Methodology/Principal Findings The goal of this study was to investigate the interactions between naringin palmitate and BSA under physiological conditions, and differences in naringin and naringin palmitate affinities for BSA were further compared and analysed. The formation of naringin palmitate-BSA was revealed by fluorescence quenching, and the Stern-Volmer quenching constant (KSV) was found to decrease with increasing temperature, suggesting that a static quenching mechanism was involved. The changes in enthalpy (ΔH) and entropy (ΔS) for the interaction were detected at −4.11±0.18 kJ·mol−1 and −76.59±0.32 J·mol−1·K−1, respectively, which indicated that the naringin palmitate-BSA interaction occurred mainly through van der Waals forces and hydrogen bond formation. The negative free energy change (ΔG) values of naringin palmitate at different temperatures suggested a spontaneous interaction. Circular dichroism studies revealed that the α-helical content of BSA decreased after interacting with naringin palmitate. Displacement studies suggested that naringin palmitate was partially bound to site I (subdomain IIA) of the BSA, which was also substantiated by the molecular docking studies. Conclusions/Significance In conclusion, naringin palmitate was transported by BSA and was easily removed afterwards. As a consequence, an extension of naringin applications for use in food, cosmetic and medicinal

  13. Use of Paliperidone Palmitate Throughout a Schizoaffective Disorder Patient's Gestation Period.

    PubMed

    Zamora Rodríguez, F J; Benítez Vega, C; Sánchez-Waisen Hernández, M R; Guisado Macías, J A; Vaz Leal, F J

    2017-01-01

    Introduction: Paliperidone palmitate treatment of schizophrenia or schizoaffective disorder is effective and well tolerated, but there is almost no data on its safety during pregnancy. Case report: An analysis is made of the safety and tolerability of paliperidone palmitate treatment throughout the gestation period in a 34-year-old patient diagnosed with schizoaffective disorder. Discussion: Paliperidone palmitate treatment throughout the gestation period was safe and well tolerated by both mother and foetus, there being no malformations or other perinatal complications in the newborn to date. © Georg Thieme Verlag KG Stuttgart · New York.

  14. Diacylglycerol kinase δ phosphorylates phosphatidylcholine-specific phospholipase C-dependent, palmitic acid-containing diacylglycerol species in response to high glucose levels.

    PubMed

    Sakai, Hiromichi; Kado, Sayaka; Taketomi, Akinobu; Sakane, Fumio

    2014-09-19

    Decreased expression of diacylglycerol (DG) kinase (DGK) δ in skeletal muscles is closely related to the pathogenesis of type 2 diabetes. To identify DG species that are phosphorylated by DGKδ in response to high glucose stimulation, we investigated high glucose-dependent changes in phosphatidic acid (PA) molecular species in mouse C2C12 myoblasts using a newly established liquid chromatography/MS method. We found that the suppression of DGKδ2 expression by DGKδ-specific siRNAs significantly inhibited glucose-dependent increases in 30:0-, 32:0-, and 34:0-PA and moderately attenuated 30:1-, 32:1-, and 34:1-PA. Moreover, overexpression of DGKδ2 also enhanced the production of these PA species. MS/MS analysis revealed that these PA species commonly contain palmitic acid (16:0). D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), significantly inhibited the glucose-stimulated production of the palmitic acid-containing PA species. Moreover, PC-PLC was co-immunoprecipitated with DGKδ2. These results strongly suggest that DGKδ preferably metabolizes palmitic acid-containing DG species supplied from the PC-PLC pathway, but not arachidonic acid (20:4)-containing DG species derived from the phosphatidylinositol turnover, in response to high glucose levels. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Diacylglycerol Kinase δ Phosphorylates Phosphatidylcholine-specific Phospholipase C-dependent, Palmitic Acid-containing Diacylglycerol Species in Response to High Glucose Levels*

    PubMed Central

    Sakai, Hiromichi; Kado, Sayaka; Taketomi, Akinobu; Sakane, Fumio

    2014-01-01

    Decreased expression of diacylglycerol (DG) kinase (DGK) δ in skeletal muscles is closely related to the pathogenesis of type 2 diabetes. To identify DG species that are phosphorylated by DGKδ in response to high glucose stimulation, we investigated high glucose-dependent changes in phosphatidic acid (PA) molecular species in mouse C2C12 myoblasts using a newly established liquid chromatography/MS method. We found that the suppression of DGKδ2 expression by DGKδ-specific siRNAs significantly inhibited glucose-dependent increases in 30:0-, 32:0-, and 34:0-PA and moderately attenuated 30:1-, 32:1-, and 34:1-PA. Moreover, overexpression of DGKδ2 also enhanced the production of these PA species. MS/MS analysis revealed that these PA species commonly contain palmitic acid (16:0). D609, an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), significantly inhibited the glucose-stimulated production of the palmitic acid-containing PA species. Moreover, PC-PLC was co-immunoprecipitated with DGKδ2. These results strongly suggest that DGKδ preferably metabolizes palmitic acid-containing DG species supplied from the PC-PLC pathway, but not arachidonic acid (20:4)-containing DG species derived from the phosphatidylinositol turnover, in response to high glucose levels. PMID:25112873

  16. Berberine treatment attenuates the palmitate-mediated inhibition of glucose uptake and consumption through increased 1,2,3-triacyl-sn-glycerol synthesis and accumulation in H9c2 cardiomyocytes.

    PubMed

    Chang, Wenguang; Chen, Li; Hatch, Grant M

    2016-04-01

    Dysfunction of lipid metabolism and accumulation of 1,2-diacyl-sn-glycerol (DAG) may be a key factor in the development of insulin resistance in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid extract that has shown promise as a hypoglycemic agent in the management of diabetes in animal and human studies. However, its mechanism of action is not well understood. To determine the effect of BBR on lipid synthesis and its relationship to insulin resistance in H9c2 cardiomyocytes, we measured neutral lipid and phospholipid synthesis and their relationship to glucose uptake. Compared with controls, BBR treatment stimulated 2-[1,2-(3)H(N)]deoxy-D-glucose uptake and consumption in palmitate-mediated insulin resistant H9c2 cells. The mechanism was though an increase in protein kinase B (AKT) activity and GLUT-4 glucose transporter expression. DAG accumulated in palmitate-mediated insulin resistant H9c2 cells and treatment with BBR reduced this DAG accumulation and increased accumulation of 1,2,3-triacyl-sn-glycerol (TAG) compared to controls. Treatment of palmitate-mediated insulin resistant H9c2 cells with BBR increased [1,3-(3)H]glycerol and [1-(14)C]glucose incorporation into TAG and reduced their incorporation into DAG compared to control. In addition, BBR treatment of these cells increased [1-(14)C]palmitic acid incorporation into TAG and decreased its incorporation into DAG compared to controls. BBR treatment did not alter phosphatidylcholine or phosphatidylethanolamine synthesis. The mechanism for the BBR-mediated decreased precursor incorporation into DAG and increased incorporation into TAG in palmitate-incubated cells was an increase in DAG acyltransferase-2 activity and its expression and a decrease in TAG hydrolysis. Thus, BBR treatment attenuates palmitate-induced reduction in glucose uptake and consumption, in part, through reduction in cellular DAG levels and accumulation of TAG in H9c2 cells.

  17. Anti-inflammatory and antifibrotic effects of methyl palmitate

    SciTech Connect

    El-Demerdash, Ebtehal

    2011-08-01

    Methyl palmitate (MP) has been shown earlier to inhibit Kupffer cells and rat peritoneal macrophages. To evaluate the potential of MP to inhibit the activation of other macrophages, RAW cells (macrophages of alveolar origin) were treated with varying concentrations of MP (0.25, 0.5, 1 mM). Assessment of cytotoxicity using MTT assay revealed that 0.25 and 0.5 mM are not toxic to RAW cells. MP was able to inhibit the phagocytic function of RAW cells. Treatment of cells with MP 24 hours prior to LPS stimulation significantly decreased nitric oxide release and altered the pattern of cytokines release; there was a significant decrease in TNF-{alpha} and a significant increase in IL-10 compared to the controls. However, there is a non-significant change in IL-6 level. Furthermore, phosphorylation of inhibitory kappa B (I{kappa}B{alpha}) protein was significantly decreased in RAW cells treated with 0.5 mM MP after LPS stimulation. Based upon the in-vitro results, it was examined whether MP treatment will be effective in preventing bleomycin-induced lung inflammation and fibrosis in-vivo. Bleomycin given by itself caused destruction of the lung architecture characterized by pulmonary fibrosis with collapse of air alveoli and emphysematous. Bleomycin induced a significant increase in hydroxyproline level and activated NF-{kappa}B, p65 expression in the lung. MP co-treatment significantly ameliorated bleomycin effects. These results suggest that MP has a potential of inhibiting macrophages in general. The present study demonstrated for the first time that MP has anti-inflammatory and antifibrotic effect that could be through NF-kB inhibition. Thus MP like molecule could be a promising anti-inflammatory and antifibrotic drug. - Research Highlights: >Methyl palmitate is a universal macrophage inhibitor. >It could be a promising nucleus of anti-inflammatory and antifibrotic drugs. >The underlying mechanism of these effects could be through NF-kB inhibition.

  18. One-year mortality after severe COPD exacerbation in Bulgaria.

    PubMed

    Mekov, Evgeni; Slavova, Yanina; Tsakova, Adelina; Genova, Marianka P; Kostadinov, Dimitar T; Minchev, Delcho; Marinova, Dora; Boyanov, Mihail A

    2016-01-01

    One-year mortality in COPD patients is reported to be between 4% and 43%, depending on the group examined. To examine the one-year mortality in COPD patients after severe exacerbation and the correlation between mortality and patients' characteristics and comorbidities. A total of 152 COPD patients hospitalized for severe exacerbation were assessed for vitamin D status, diabetes mellitus (DM), arterial hypertension (AH), and metabolic syndrome (MS). Data were gathered about smoking status and number of exacerbations in previous year. CAT and mMRC questionnaires were completed by all patients. Pre- and post-bronchodilatory spirometry was performed. One-year mortality was established from national death register. One-year mortality is 7.2%. DM, MS, and VD are not predictors for one-year mortality. However there is a trend for increased mortality in patients with AH (9.5% vs. 2.1%, p = 0.107). There is increased mortality in patients with mMRC > 2 (11.1 vs. 0%, p = 0.013). The presence of severe exacerbation in the previous year is a risk factor for mortality (12.5% vs. 1.4%, p = 0.009). There is a trend for increased mortality in the group with FEV1 < 50% (11.5 vs. 4.4%, p = 0.094). Cox regression shows 3.7% increase in mortality rate for 1% decrease in FEV1, 5.2% for 1% decrease in PEF, 7.8% for one year age increase and 8.1% for 1 CAT point increase (all p < 0.05). This study finds relatively low one-year mortality in COPD patients after surviving severe exacerbation. Grade C and FEV1 > 80% may be factors for good prognosis. Risk factors for increased mortality are age, FEV1 value, severe exacerbation in previous year and reduced quality of life.

  19. Myasthenia gravis exacerbation after discontinuing mycophenolate

    PubMed Central

    Rocke, David M.; Dengel, Karsten; Richman, David P.

    2016-01-01

    Objective: To determine whether discontinuation or marked reduction of mycophenolate mofetil (MMF) in patients with myasthenia gravis (MG) causes MG exacerbations. Methods: We identified 88 patients with MG who took MMF during the 5-year period 2007–2011 at our MG clinic. We then performed detailed chart reviews and recorded all MG exacerbations and their relationship to MMF and other treatment changes. We also recorded demographic data and disease characteristics (including antibody status and Myasthenia Gravis Foundation of America status). Results: There were 14 patients who had an MG exacerbation during the study period. Of these, 13 had discontinued MMF therapy, with a median time until exacerbation of 16 weeks after discontinuation (9 patients) or marked dose reduction (4 patients) of MMF therapy (exacerbation in the absence of change in any other component of the immunosuppressive regimen). Using the cluster option in a Cox regression analysis, the MMF coefficient was −5.32, with a standard error of 1.05 and a p value of 0.0002, corresponding to an estimated hazard ratio of 204. Conclusions: This retrospective cohort study suggests that discontinuation/marked reduction of MMF therapy may increase the risk of MG exacerbation many fold, supporting the hypothesis that MMF plays a role in the maintenance of MG remission/minimal manifestation status. Classification of evidence: This study provides Class IV evidence that in patients with MG taking MMF, discontinuation or marked reduction of MMF causes MG exacerbation. PMID:26850977

  20. Serum Telomerase Levels and COPD Exacerbations.

    PubMed

    Bozkus, Fulsen; Guler, Selma; Sımsek, Secıl

    2016-03-01

    To our knowledge, there is no study on the level of telomerase in subjects with COPD during an exacerbation period. The objective of this work was to compare lipid peroxidation, telomerase, zinc (Zn), copper (Cu), and malondialdehyde levels in asymptomatic smokers and subjects with COPD exacerbation. The study included 45 subjects with COPD exacerbation and 42 healthy subjects with tobacco use as a control group. Samples were taken from blood and after the serum levels of telomerase malondialdehyde, Cu, and Zn were measured, the values were compared between the 2 groups. Tests for respiratory function were performed, and sedimentation and C-reactive protein levels were measured. The COPD exacerbation group had a significantly (P < .001) lower Cu/Zn ratio compared with the control group; however, the COPD exacerbation group had significantly (P < .001) higher levels of telomerase malondialdehyde, Cu, and Zn compared with the control group. Malondialdehyde, Cu, Zn, and FEV1 were found negatively correlated in the COPD exacerbation and control groups (P < .001). The COPD exacerbation group had lower FEV1 and FVC compared with the control group. The COPD exacerbation group had significantly (P < .001) higher levels of C-reactive protein and a higher blood cell sedimentation rate compared with the control group. The reason why the subjects had a reduced Cu/Zn ratio and increased levels of telomerase, Cu, and Zn is likely to be oxidative stress, which can be defined as an increased exposure to oxidants and/or decreased antioxidant capacities It is obvious from this study that lung oxidant-antioxidant balance is abnormal in subjects with COPD exacerbation and also that the increased level of telomerase is associated with this imbalance. Copyright © 2016 by Daedalus Enterprises.

  1. Blood Coagulation and Asthma Exacerbation in Children.

    PubMed

    Manuyakorn, Wiparat; Mairiang, Dara; Sirachainan, Nongnuch; Kadegasem, Praguywan; Kamchaisatian, Wasu; Benjaponpitak, Suwat; Chuansumrit, Ampaiwan

    2016-01-01

    Recent studies have demonstrated the activation of coagulation pathways in asthmatic airways. This study aimed to determine systemic blood coagulation during asthma exacerbation compared with the stable state in children. Pediatric patients (aged between 5 and 15 years) suffering from asthma exacerbation were enrolled. von Willebrand factor (vWF), plasminogen activator inhibitor type-1 (PAI-1), protein C, D-dimer, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), and C-reactive protein (CRP) levels were measured during asthma exacerbation and stable state. A total of 22 patients were enrolled. The median vWF, PAI-1, and CRP during asthma exacerbation were significantly higher than those of the stable state: 147.5% (interquartile range, IQR: 111.05-196.57) versus 94% (IQR: 69.72-109.62, p < 0.001), 41.9 ng/ml (IQR: 21.91-48.61) versus 26.17 ng/ml (IQR: 15.89-34.44, p < 0.03), and 4.46 mg/l (IQR: 2.15-16.23) versus 0.87 mg/l (IQR: 0.20-3.89, p < 0.015), respectively. However, the median protein C during asthma exacerbation was significantly lower than that of the stable state: 99.5% (IQR: 86.75-117) versus 113% (IQR: 94-115.25), p = 0.01. No significant difference was found between the levels of D-dimer, F1 + 2, and TAT during asthma exacerbation and stable state. Ultimately, D-dimer was positively correlated with asthma exacerbation score (R = 0.466, p = 0.027). A significant correlation was observed between vWF and CRP (R = 0.527, p = 0.012). Evidence was found of increased endothelial activation and increased PAI-1 during asthma exacerbation. This may emphasize the potential role of blood coagulation in asthma exacerbation. © 2016 S. Karger AG, Basel.

  2. Paliperidone Palmitate Treatment in Outpatient Care Setting: A Naturalistic Study

    PubMed Central

    Di Lorenzo, Rosaria; Cameli, Michela; Bolondi, Marisa; Landi, Giulia; Moretti, Valentina; Piemonte, Chiara; Pollutri, Gabriella

    2016-01-01

    Objectives To evaluate paliperidone palmitate (PP) effectiveness, safety and adherence to treatment. Methods We collected data of all patients (n = 50) affected by Schizophrenia Disorders, treated with PP for a 3 month minimum period in the outpatient setting of Mental Health Department in Modena, from 01/01/2014 to 31/01/2015. We evaluated reasons and modality for PP implementation, improvement in symptom and functioning scales, adverse effects, discontinuations and relapses. We statistically correlated socio-demographic and clinical variables of our sample with PP therapeutic variables. Results We registered an improvement in all scales, with a superior percentage in PANSS positive subscale. The mean PP dose in some patients was lower than official indications, although our sample was clinically severe. Illness relapses affected 60% and dropout 18% of patients. PP was well tolerated and in just a few cases adverse events required treatment interruption. The risk factors for discontinuation were represented by “lack of therapeutic compliance” (HR = 4.11, p < 0.0001) and “inefficacy” (HR = 1.67, p < 0.0001). Conclusions With limitations of observational design, this research highlights that PP was well tolerated and effective in improving both psychotic symptoms and functioning, but moderately effective in preventing relapse, probably due to clinical severity of our patients associated with extremely cautious and flexible PP prescriptions. PMID:27738372

  3. Influence of salt purity on Na+ and palmitic acid interactions.

    PubMed

    Huang, Zishuai; Hua, Wei; Verreault, Dominique; Allen, Heather C

    2013-12-19

    The influence of salt purity on the interactions between Na(+) ions and the carboxylate (COO(-)) head group of palmitic acid (PA) monolayers is studied in the COO(-) and OH stretching regions using broad-band vibrational sum frequency generation (VSFG) spectroscopy. Ultrapure (UP) and ACS grade NaCl salts are used for aqueous solution preparation after proper pretreatment. The time evolution of VSFG spectra of PA monolayers on solutions made from these two grades of salts is different, which reveals that the salt purity has a significant impact on the interactions between Na(+) ions and the COO(-) group of PA. The trace metal impurities in ACS grade salt, which are more abundant than those in UP grade salt, are responsible for this difference due to their stronger affinity for the carboxylate group relative to Na(+) and further affects the interfacial water structure. These results suggest that the alkali salt grade even after pretreatment is critical in the studies of alkali cation-carboxylate interactions and comparison of relative binding affinities of different cations.

  4. Biological and Nutritional Properties of Palm Oil and Palmitic Acid: Effects on Health.

    PubMed

    Mancini, Annamaria; Imperlini, Esther; Nigro, Ersilia; Montagnese, Concetta; Daniele, Aurora; Orrù, Stefania; Buono, Pasqualina

    2015-09-18

    A growing body of evidence highlights the close association between nutrition and human health. Fat is an essential macronutrient, and vegetable oils, such as palm oil, are widely used in the food industry and highly represented in the human diet. Palmitic acid, a saturated fatty acid, is the principal constituent of refined palm oil. In the last few decades, controversial studies have reported potential unhealthy effects of palm oil due to the high palmitic acid content. In this review we provide a concise and comprehensive update on the functional role of palm oil and palmitic acid in the development of obesity, type 2 diabetes mellitus, cardiovascular diseases and cancer. The atherogenic potential of palmitic acid and its stereospecific position in triacylglycerols are also discussed.

  5. Transport of Palmitic Acid Across the Tegument of the Entomophilic Nematode Romanomermis culicivorax

    PubMed Central

    Gordon, Roger; Burford, Ian R.

    1984-01-01

    Romanomermis culicivorax juveniles, dissected out of Aedes aegypti larvae 7 days after infection, were incubated under controlled conditions in isotonic saline containing ¹⁴C-U-palmitic acid to investigate the nature of the transport mechanism(s) used by the nematode for transcuticular uptake of palmitic acid. Net uptake of the isotope by the nematode was of a logarithmic nature with respect to time. Uptake of palmitic acid was accomplished by a combination of diffusion and a mediated process which was substrate saturable and competitively inhibited by myristic and stearic acids. Both 2,4-dinitrophenol and ouabain inhibited uptake of palmitic acid and thus supported the hypothesis that the carrier system is of the active transport variety and is coupled to a Na⁺K⁺ ATPase pump. PMID:19295867

  6. Acute exacerbations of fibrotic interstitial lung disease.

    PubMed

    Churg, Andrew; Wright, Joanne L; Tazelaar, Henry D

    2011-03-01

    An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy. © 2010 Blackwell Publishing Limited.

  7. The lung microbiome and exacerbations of COPD.

    PubMed

    Dy, Rajany; Sethi, Sanjay

    2016-05-01

    Traditional culture methods have identified airway bacterial pathogens that cause acute exacerbations of chronic obstructive pulmonary disease (COPD), and contribute to airway inflammation and COPD progression. However, conventional microbiology is limited by low sensitivity and bias toward predetermined and predominant pathogens. Highly sensitive, unbiased microbiome techniques overcome these limitations. Here, we present recent lung microbiome data, specifically in the context of smoking, COPD, and exacerbations. In contrast to the sterile lung environment found with conventional microbiology, microbiome techniques demonstrate a lower respiratory tract microbiome in health. Alterations in the lung microbiome with smoking and COPD have been clearly demonstrated by culture techniques, however, the findings in microbiome studies are limited and controversial. Increasing COPD disease severity is associated with a reduction in microbial diversity. Though microbial community structure does not change with exacerbation, there are notable changes in its composition. Antibiotic and corticosteroid treatment of acute exacerbations of COPD have significant but opposing effects on microbiome composition. The composition of the lung microbiome changes with smoking, the severity of COPD, during acute exacerbations and with the use of steroids and/or antibiotics. Understanding the role of the microbiome in disease progression and development of exacerbations will lead to novel therapies.

  8. Incidence of pulmonary embolism during COPD exacerbation*, **

    PubMed Central

    Akpinar, Evrim Eylem; Hoşgün, Derya; Akpýnar, Serdar; Ataç, Gökçe Kaan; Doğanay, Beyza; Gülhan, Meral

    2014-01-01

    OBJECTIVE: Because pulmonary embolism (PE) and COPD exacerbation have similar presentations and symptoms, PE can be overlooked in COPD patients. Our objective was to determine the prevalence of PE during COPD exacerbation and to describe the clinical aspects in COPD patients diagnosed with PE. METHODS: This was a prospective study conducted at a university hospital in the city of Ankara, Turkey. We included all COPD patients who were hospitalized due to acute exacerbation of COPD between May of 2011 and May of 2013. All patients underwent clinical risk assessment, arterial blood gas analysis, chest CT angiography, and Doppler ultrasonography of the lower extremities. In addition, we measured D-dimer levels and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. RESULTS: We included 172 patients with COPD. The prevalence of PE was 29.1%. The patients with pleuritic chest pain, lower limb asymmetry, and high NT-pro-BNP levels were more likely to develop PE, as were those who were obese or immobile. Obesity and lower limb asymmetry were independent predictors of PE during COPD exacerbation (OR = 4.97; 95% CI, 1.775-13.931 and OR = 2.329; 95% CI, 1.127-7.105, respectively). CONCLUSIONS: The prevalence of PE in patients with COPD exacerbation was higher than expected. The association between PE and COPD exacerbation should be considered, especially in patients who are immobile or obese. PMID:24626268

  9. Pharmacoeconomic analysis of paliperidone palmitate for treating schizophrenia in Greece

    PubMed Central

    2012-01-01

    Background Patients having chronic schizophrenia with frequent relapses and hospitalizations represent a great challenge, both clinically and financially. Risperidone long-acting injection (RIS-LAI) has been the main LAI atypical antipsychotic treatment in Greece. Paliperidone palmitate (PP-LAI) has recently been approved. It is dosed monthly, as opposed to biweekly for RIS-LAI, but such advantages have not yet been analysed in terms of economic evaluation. Purpose To compare costs and outcomes of PP-LAI versus RIS-LAI in Greece. Methods A cost-utility analysis was performed using a previously validated decision tree to model clinical pathways and costs over 1 year for stable patients started on either medication. Rates were taken from the literature. A local expert panel provided feedback on treatment patterns. All direct costs incurred by the national healthcare system were obtained from the literature and standard price lists; all were inflated to 2011 costs. Patient outcomes analyzed included average days with stable disease, numbers of hospitalizations, emergency room visits, and quality-adjusted life-years (QALYs). Results The total annual healthcare cost with PP-LAI was €3529; patients experienced 325 days in remission and 0.840 QALY; 28% were hospitalized and 15% received emergency room treatment. With RIS-LAI, the cost was €3695, patients experienced 318.6 days in remission and 0.815 QALY; 33% were hospitalized and 17% received emergency room treatment. Thus, PP-LAI dominated RIS-LAI. Results were generally robust in sensitivity analyses with PP-LAI dominating in 74.6% of simulations. Results were sensitive to the price of PP-LAI. Conclusions PP-LAI appears to be a cost-effective option for treating chronic schizophrenia in Greece compared with RIS-LAI since it results in savings to the health care system along with better patient outcomes. PMID:22747533

  10. Metabolomic analyses reveal that anti-aging metabolites are depleted by palmitate but increased by oleate in vivo

    PubMed Central

    Enot, David P.; Niso-Santano, Mireia; Durand, Sylvère; Chery, Alexis; Pietrocola, Federico; Vacchelli, Erika; Madeo, Frank; Galluzzi, Lorenzo; Kroemer, Guido

    2015-01-01

    Recently, we reported that saturated and unsaturated fatty acids trigger autophagy through distinct signal transduction pathways. Saturated fatty acids like palmitate (PA) induce autophagic responses that rely on phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3, best known as VPS34) and beclin 1 (BECN1). Conversely, unsaturated fatty acids like oleate (OL) promote non-canonical, PIK3C3- and BECN1-independent autophagy. Here, we explored the metabolic effects of autophagy-inducing doses of PA and OL in mice. Mass spectrometry coupled to principal component analysis revealed that PA and OL induce well distinguishable changes in circulating metabolites as well as in the metabolic profile of the liver, heart, and skeletal muscle. Importantly, PA (but not OL) causes the depletion of multiple autophagy-inhibitory amino acids in the liver. Conversely, OL (but not PA) increased the hepatic levels of nicotinamide adenine dinucleotide (NAD), an obligate co-factor for autophagy-stimulatory enzymes of the sirtuin family. Moreover, PA (but not OL) raised the concentrations of acyl-carnitines in the heart, a phenomenon that perhaps is linked to its cardiotoxicity. PA also depleted the liver from spermine and spermidine, 2 polyamines have been ascribed with lifespan-extending activity. The metabolic changes imposed by unsaturated and saturated fatty acids may contribute to their health-promoting and health-deteriorating effects, respectively. PMID:26098646

  11. Influenza-associated cystic fibrosis pulmonary exacerbations.

    PubMed

    Ortiz, Justin R; Neuzil, Kathleen M; Victor, John C; Wald, Anna; Aitken, Moira L; Goss, Christopher H

    2010-04-01

    Although cystic fibrosis (CF) is the most common inherited respiratory disease, the burden of influenza among individuals with CF is not well characterized. We used the CF Foundation Patient Registry to determine the relationship between pulmonary exacerbation incidence rate and influenza virus season from July 2003 through June 2007. The outcome of interest, pulmonary exacerbation, was defined as treatment of a respiratory illness with IV antibiotics. Each influenza season was defined as all months during which >/= 15% of laboratory tests for influenza virus were positive in the US influenza virologic surveillance system. We calculated incidence rates of pulmonary exacerbation during the influenza and summertime seasons as well as relative rates with 95% CIs. A multivariate regression model adjusted for demographic and clinical predictors. In 2003, the patient cohort size was 21,506 patients, and 7,727 patients experienced at least one pulmonary exacerbation. The overall pulmonary exacerbation incidence rate in the influenza season was 595.0 per 10,000 person-months compared with a summertime baseline of 549.6 per 10,000 person-months. The incidence rate ratio was 1.08 (95% CI: 1.06, 1.10). Multivariate analysis did not change our estimate of risk (adjusted odds ratio: 1.07; 95% CI: 1.05, 1.10). An estimated annual excess of 147.6 per 10,000 person-months or an excess 2.1% of total exacerbations occur during the influenza season. Our data demonstrate a substantial contribution of the influenza season to CF morbidity. Further studies to determine any causal link between influenza infection and CF pulmonary exacerbations are necessary.

  12. Management and prevention of exacerbations of COPD.

    PubMed

    Aaron, Shawn D

    2014-09-22

    Patients with chronic obstructive pulmonary disease (COPD) are prone to acute respiratory exacerbations, which can develop suddenly or subacutely over the course of several days. Exacerbations have a detrimental effect on patients' health status and increase the burden on the healthcare system. Initial treatment is unsuccessful in 24-27% of patients, who have a relapse or a second exacerbation within 30 days of the initial event. No obvious benefit has been seen in recent clinical trials of anti-tumour necrosis factor therapy, anti-leukotriene therapy, intensive chest physiotherapy, or early inpatient pulmonary rehabilitation for treatment of exacerbations. By contrast, clinical trials of prevention rather than acute treatment have shown promising results. Long acting β agonist (LABA) or long acting anti-muscarinic (LAMA) bronchodilators and inhaled corticosteroid-LABA combinations prevent exacerbations in patients at risk, with relative risk reductions averaging 14-27% for each of these drugs relative to placebo. Triple therapy with inhaled corticosteroid-LABA plus LAMA may provide additional benefit, although study results to date are heterogeneous and more studies are needed. Pneumonia is an important complication of treatment with inhaled corticosteroid-LABA products, and the risk of pneumonia seems to be doubled in patients with COPD who use fluticasone. The addition of azithromycin to usual COPD therapy prevents exacerbations, although it may prolong the Q-T interval and increase the risk of death from cardiovascular disease in patients prone to arrhythmia. New potential drugs--including mitogen activated protein kinase inhibitors, phosphodiesterase 3 inhibitors, and monoclonal antibodies to the interleukin 1 receptor--offer additional hope for treatments that may prevent exacerbations in the future.

  13. Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans123

    PubMed Central

    Kien, C Lawrence; Bunn, Janice Y; Stevens, Robert; Bain, James; Ikayeva, Olga; Crain, Karen; Koves, Timothy R; Muoio, Deborah M

    2014-01-01

    Background: Epidemiologic evidence has suggested that diets with a high ratio of palmitic acid (PA) to oleic acid (OA) increase risk of cardiovascular disease (CVD). Objective: To gain additional insights into the relative effect of dietary fatty acids and their metabolism on CVD risk, we sought to identify a metabolomic signature that tracks with diet-induced changes in blood lipid concentrations and whole-body fat oxidation. Design: We applied comprehensive metabolomic profiling tools to biological specimens collected from 18 healthy adults enrolled in a crossover trial that compared a 3-wk high–palmitic acid (HPA) with a low–palmitic acid and high–oleic acid (HOA) diet. Results: A principal components analysis of the data set including 329 variables measured in 15 subjects in the fasted state identified one factor, the principal components analysis factor in the fasted state (PCF1-Fasted), which was heavily weighted by the PA:OA ratio of serum and muscle lipids, that was affected by diet (P < 0.0001; HPA greater than HOA). One other factor, the additional principal components analysis factor in the fasted state (PCF2-Fasted), reflected a wide range of acylcarnitines and was affected by diet in women only (P = 0.0198; HPA greater than HOA). HOA lowered the ratio of serum low-density lipoprotein to high-density lipoprotein (LDL:HDL) in men and women, and adjustment for the PCF1-Fasted abolished the effect. In women only, adjustment for the PCF2-Fasted eliminated the HOA-diet effect on serum total- and LDL-cholesterol concentrations. The respiratory exchange ratio in the fasted state was lower with the HPA diet (P = 0.04), and the diet effect was eliminated after adjustment for the PCF1-Fasted. The messenger RNA expression of the cholesterol regulatory gene insulin-induced gene-1 was higher with the HOA diet (P = 0.008). Conclusions: These results suggest that replacing dietary PA with OA reduces the blood LDL concentration and whole-body fat oxidation by

  14. Muscle palmitate uptake and binding are saturable and inhibited by antibodies to FABP(PM).

    PubMed

    Turcotte, L P; Swenberger, J R; Tucker, M Z; Yee, A J; Trump, G; Luiken, J J; Bonen, A

    2000-07-01

    Studies show that uptake of long-chain fatty acids (LCFA) across the plasma membranes (PM) may occur partly via a carrier-mediated process and that the plasma membrane fatty acid-binding protein (FABP(PM)) may be a component of this system. To test the hypothesis that FABP(PM) is involved in transsarcolemmal transport of LCFA in muscle, we measured palmitate uptake in giant sarcolemmal vesicles and palmitate binding to PM proteins in rat muscles, (1) in the presence of increasing amounts of unbound palmitate and (2) in the absence or presence of antibody to FABP(PM). Both palmitate uptake and binding were found to be saturable functions of the unbound palmitate concentration with calculated Vmax values of 10.5 +/- 1.2 pmol/mg protein/15 sec and 45.6 +/- 2.9 nmol/mg protein/15 min and Km values of 12.8 +/- 3.8 and 18.4 +/- 1.8 nmol/L, respectively. The Vmax values for both palmitate uptake and binding were significantly decreased by 75-79% in the presence of a polyclonal antibody to the rat hepatic FABP(PM). Antibody inhibition was found to be dose-dependent and specific to LCFA. Glucose uptake was not affected by the presence of the antibody to FABP(PM). Palmitate uptake and binding were also inhibited in the presence of trypsin and phloretin. These results support the hypothesis that transsarcolemmal LCFA transport occurs in part by a carrier-mediated process and that FABP(PM) is a component of this process in muscle.

  15. The Effects of plasticizers and palmitic acid toward the properties of the carrageenan Film

    NASA Astrophysics Data System (ADS)

    Heru Wibowo, Atmanto; Listiyawati, Oktaviana; Purnawan, Candra

    2016-02-01

    Varied plasticizers and palmitic acid additive have been added in the carrageenan film. The film was made by mixing of the carrageenan and plasticizers (glycerol, polyethylene glycol, polyvinyl alcohol) with composition of 92:3, 90:6, 87:9, 84:12, 81:15(%w/w) and in the presence of palmitic acid as additive with 1%, 2%, 3%, 4%, 5% of total weight. Casting method was used for the film molding and drying at 60oC with the oven for 12 hours. To investigate the effects of plasticizers and additive, some mechanical tests on film were performed. The test result concludes that plasticizers in the film decreased the tensile strength and increased the elongation break of the carrageenan film. The additive of palmitic acid decreased the tensile strength of the carrageenan film and also decreased the-the water absorbance of the film. The highest tensile strength of films made was with the formulation of carrageenan: PEG with composition of 92:3 (% w/w). The highest elongation break of the film was for carrageenan:PVA with the composition of 81: 15 (%w/w) and carrageenan:palmitic acid:PEG with the composition of 92: 3: 1 (%w/w). The lowest water absorption of the film was achieved for carrageenan:PVA:palmitic acid with the composition of 87: 3: 5 (%w/w).

  16. Acute Exacerbations of Idiopathic Pulmonary Fibrosis

    PubMed Central

    Collard, Harold R.; Moore, Bethany B.; Flaherty, Kevin R.; Brown, Kevin K.; Kaner, Robert J.; King, Talmadge E.; Lasky, Joseph A.; Loyd, James E.; Noth, Imre; Olman, Mitchell A.; Raghu, Ganesh; Roman, Jesse; Ryu, Jay H.; Zisman, David A.; Hunninghake, Gary W.; Colby, Thomas V.; Egan, Jim J.; Hansell, David M.; Johkoh, Takeshi; Kaminski, Naftali; Kim, Dong Soon; Kondoh, Yasuhiro; Lynch, David A.; Müller-Quernheim, Joachim; Myers, Jeffrey L.; Nicholson, Andrew G.; Selman, Moisés; Toews, Galen B.; Wells, Athol U.; Martinez, Fernando J.

    2007-01-01

    The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed. PMID:17585107

  17. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers

    PubMed Central

    Kwan, Hiu Yee; Niu, Xuyan; Dai, Wenlin; Tong, Tiejun; Chao, Xiaojuan; Su, Tao; Chan, Chi Leung; Lee, Kim Chung; Fu, Xiuqiong; Yi, Hua; Yu, Hua; Li, Ting; Tse, Anfernee Kai Wing; Fong, Wang Fun; Pan, Si-Yuan; Lu, Aiping; Yu, Zhi-Ling

    2015-01-01

    Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism. PMID:25766252

  18. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers.

    PubMed

    Kwan, Hiu Yee; Niu, Xuyan; Dai, Wenlin; Tong, Tiejun; Chao, Xiaojuan; Su, Tao; Chan, Chi Leung; Lee, Kim Chung; Fu, Xiuqiong; Yi, Hua; Yu, Hua; Li, Ting; Tse, Anfernee Kai Wing; Fong, Wang Fun; Pan, Si-Yuan; Lu, Aiping; Yu, Zhi-Ling

    2015-03-13

    Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism.

  19. Premenstrual exacerbation of Meniere's disease revisited.

    PubMed

    Andrews, James C; Honrubia, Vicente

    2010-10-01

    Some women with Meniere disease demonstrate exacerbation of symptoms during the premenstrual period. It is believed that the hormonal stress of the premenstrual period acts on the volatile inner ear with Meniere disease to result in dysfunction. Migraine, Meniere disease, and the premenstrual period may be a complex interaction leading to exacerbation of symptoms. Having patients maintain a daily calendar of symptoms, diet, and menses can be helpful in understanding the disease as well as instigating treatment monitoring. Most patients can be effectively managed with dietary sodium restriction and a loop diuretic.

  20. Azithromycin for prevention of exacerbations of COPD.

    PubMed

    Albert, Richard K; Connett, John; Bailey, William C; Casaburi, Richard; Cooper, J Allen D; Criner, Gerard J; Curtis, Jeffrey L; Dransfield, Mark T; Han, Meilan K; Lazarus, Stephen C; Make, Barry; Marchetti, Nathaniel; Martinez, Fernando J; Madinger, Nancy E; McEvoy, Charlene; Niewoehner, Dennis E; Porsasz, Janos; Price, Connie S; Reilly, John; Scanlon, Paul D; Sciurba, Frank C; Scharf, Steven M; Washko, George R; Woodruff, Prescott G; Anthonisen, Nicholas R

    2011-08-25

    Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment

  1. Azithromycin for Prevention of Exacerbations of COPD

    PubMed Central

    Albert, Richard K.; Connett, John; Bailey, William C.; Casaburi, Richard; Cooper, J. Allen D.; Criner, Gerard J.; Curtis, Jeffrey L.; Dransfield, Mark T.; Han, MeiLan K.; Lazarus, Stephen C.; Make, Barry; Marchetti, Nathaniel; Martinez, Fernando J.; Madinger, Nancy E.; McEvoy, Charlene; Niewoehner, Dennis E.; Porsasz, Janos; Price, Connie S.; Reilly, John; Scanlon, Paul D.; Sciurba, Frank C.; Scharf, Steven M.; Washko, George R.; Woodruff, Prescott G.; Anthonisen, Nicholas R.

    2011-01-01

    BACKGROUND Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. METHODS We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. RESULTS A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04). CONCLUSIONS Among selected subjects with COPD, azithromycin taken daily for

  2. Engineering cytochrome P450 BM3 of Bacillus megaterium for terminal oxidation of palmitic acid.

    PubMed

    Brühlmann, Fredi; Fourage, Laurent; Ullmann, Christophe; Haefliger, Olivier P; Jeckelmann, Nicolas; Dubois, Cédric; Wahler, Denis

    2014-08-20

    Directed evolution via iterative cycles of random and targeted mutagenesis was applied to the P450 domain of the subterminal fatty acid hydroxylase CYP102A1 of Bacillus megaterium to shift its regioselectivity towards the terminal position of palmitic acid. A powerful and versatile high throughput assay based on LC-MS allowed the simultaneous detection of primary and secondary oxidation products, which was instrumental for identifying variants with a strong preference for the terminal oxidation of palmitic acid. The best variants identified acquired up to 11 amino acid alterations. Substitutions at F87, I263, and A328, relatively close to the bound substrate based on available crystallographic information contributed significantly to the altered regioselectivity. However, non-obvious residues much more distant from the bound substrate showed surprising strong contributions to the increased selectivity for the terminal position of palmitic acid.

  3. Structural, electronic, thermodynamical and charge transfer properties of Chloramphenicol Palmitate using vibrational spectroscopy and DFT calculations

    NASA Astrophysics Data System (ADS)

    Mishra, Rashmi; Srivastava, Anubha; Sharma, Anamika; Tandon, Poonam; Baraldi, Cecilia; Gamberini, Maria Christina

    2013-01-01

    The global problem of advancing bacterial resistance to newer drugs has led to renewed interest in the use of Chloramphenicol Palmitate (C27H42Cl2N2O6) [Palmitic acid alpha ester with D-threo-(-),2-dichloro-N-(beta-hydroxy-alpha-(hydroxymethyl)-p-nitrophenethyl)acetamide also known as Detereopal]. The characterization of the three polymorphic forms of Chloramphenicol Palmitate (CPP) was done spectroscopically by employing FT-IR and FT-Raman techniques. The equilibrium geometry, various bonding features, and harmonic wavenumbers have been investigated for most stable form A with the help of DFT calculations and a good correlation was found between experimental data and theoretical values. Electronic properties have been analyzed employing TD-DFT for both gaseous and solvent phase. The theoretical calculation of thermodynamical properties along with NBO analysis has also been performed to have a deep insight into the molecule for further applications.

  4. Tibolone Preserves Mitochondrial Functionality and Cell Morphology in Astrocytic Cells Treated with Palmitic Acid.

    PubMed

    González-Giraldo, Yeimy; Garcia-Segura, Luis Miguel; Echeverria, Valentina; Barreto, George E

    2017-06-30

    Obesity has been associated with increased chronic neuroinflammation and augmented risk of neurodegeneration. This is worsened during the normal aging process when the levels of endogenous gonadal hormones are reduced. In this study, we have assessed the protective actions of tibolone, a synthetic steroid with estrogenic actions, on T98G human astrocytic cells exposed to palmitic acid, a saturated fatty acid used to mimic obesity in vitro. Tibolone improved cell survival, and preserved mitochondrial membrane potential in palmitic acid-treated astrocytic cells. Although we did not find significant actions of tibolone on free radical production, it modulated astrocytic morphology after treatment with palmitic acid. These data suggest that tibolone protects astrocytic cells by preserving both mitochondrial functionality and morphological complexity.

  5. Liquid chromatographic analysis of all-trans-retinyl palmitate, beta-carotene, and vitamin E in fortified foods and the extraction of encapsulated and nonencapsulated retinyl palmitate.

    PubMed

    Ye, L; Landen, W O; Eitenmiller, R R

    2000-09-01

    A liquid chromatographic method is described for the analysis of natural vitamin E homologues, all-rac-alpha-tocopheryl acetate, retinyl palmitate (encapsulated and nonencapsulated), and beta-carotene in various fortified foods. The vitamins are extracted in 2-propanol and hexane without saponification and quantitated by normal phase chromatography with fluorescence and visible detection. The sample components were identified using an on-line three-dimensional photodiode array detector, which permitted profiling of the 190-800 nm absorption spectrum of any chromatographic peak. The method showed linearity for the analytes in their respective calibration ranges. The percent recoveries for retinyl palmitate using starch- and gelatin-encapsulated standards were 101.0 +/- 1.0 and 100.1 +/- 0.9, respectively. The method measures six or more analytes in a single injection and differentiates between natural and synthetic forms of vitamin E.

  6. Lung microbiome dynamics in COPD exacerbations.

    PubMed

    Wang, Zhang; Bafadhel, Mona; Haldar, Koirobi; Spivak, Aaron; Mayhew, David; Miller, Bruce E; Tal-Singer, Ruth; Johnston, Sebastian L; Ramsheh, Mohammadali Yavari; Barer, Michael R; Brightling, Christopher E; Brown, James R

    2016-04-01

    Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics.

  7. MARGINAL IODINE DEFICIENCY EXACERBATES PERCHLORATE THYROID TOXICITY.

    EPA Science Inventory

    The environmental contaminant perchlorate disrupts thyroid homeostasis via inhibition of iodine uptake into the thyroid. This work tested whether iodine deficiency exacerbates the effects of perchlorate. Female 27 day-old LE rats were fed a custom iodine deficient diet with 0, 50...

  8. MARGINAL IODINE DEFICIENCY EXACERBATES PERCHLORATE THYROID TOXICITY.

    EPA Science Inventory

    The environmental contaminant perchlorate disrupts thyroid homeostasis via inhibition of iodine uptake into the thyroid. This work tested whether iodine deficiency exacerbates the effects of perchlorate. Female 27 day-old LE rats were fed a custom iodine deficient diet with 0, 50...

  9. Prevention of Acute Exacerbations of COPD

    PubMed Central

    Bourbeau, Jean; Diekemper, Rebecca L.; Ouellette, Daniel R.; Goodridge, Donna; Hernandez, Paul; Curren, Kristen; Balter, Meyer S.; Bhutani, Mohit; Camp, Pat G.; Celli, Bartolome R.; Dechman, Gail; Dransfield, Mark T.; Fiel, Stanley B.; Foreman, Marilyn G.; Hanania, Nicola A.; Ireland, Belinda K.; Marchetti, Nathaniel; Marciniuk, Darcy D.; Mularski, Richard A.; Ornelas, Joseph; Stickland, Michael K.

    2015-01-01

    BACKGROUND: COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations. METHODS: In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion. RESULTS: The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in

  10. Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction.

    PubMed

    Asahina, Makoto; Shimizu, Fumi; Ohta, Masayuki; Takeyama, Michiyasu; Tozawa, Ryuichi

    2015-01-01

    Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome.

  11. Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction

    PubMed Central

    ASAHINA, Makoto; SHIMIZU, Fumi; OHTA, Masayuki; TAKEYAMA, Michiyasu; TOZAWA, Ryuichi

    2015-01-01

    Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome. PMID:25912321

  12. A hypothesis to phenotype COPD exacerbations by aetiology.

    PubMed

    MacDonald, Martin; Beasley, Richard W; Irving, Louis; Bardin, Philip G

    2011-02-01

    COPD exacerbations have traditionally been defined on the basis of symptoms or health-care utilization without specific reference to the suspected aetiology. Consequently, the term 'exacerbation' has been used to include all patients experiencing an acute deterioration of symptoms associated with COPD. However, exacerbations are known to result from a variety of causes and do not necessarily constitute an equivalent event in the same patient, between different patients or between individual research studies. We therefore hypothesize that phenotyping exacerbations by aetiology may identify exacerbation subgroups, clarify benefits of therapeutic intervention in the subgroups and overall improve clinical care. An acronym is proposed to facilitate phenotyping COPD exacerbations.

  13. Coordinated regulation of esterification and lipolysis by palmitate, H2O2 and the anti-diabetic sulfonylurea drug, glimepiride, in rat adipocytes.

    PubMed

    Müller, Günter; Wied, Susanne; Straub, Julia; Jung, Christian

    2008-11-12

    Inhibition of lipolysis by palmitate, H2O2 and the anti-diabetic sulfonylurea drug, glimepiride, in isolated rat adipocytes has previously been shown to rely on the degradation of cyclic adenosine monophosphate by the phosphodiesterase, Gce1, and the 5'-nucleotidase, CD73. These glycosylphosphatidylinositol (GPI)-anchored proteins are translocated from plasma membrane lipid rafts to intracellular lipid droplets upon H2O2-induced activation of a GPI-specific phospholipase C (GPI-PLC) in response to palmitate and glimepiride in intact adipocytes and, as demonstrated here, in cell-free systems as well. The same agents are also known to stimulate the incorporation of fatty acids into triacylglycerol. Here the involvement of H2O2 production, GPI-PLC activation and translocation of Gce1 and CD73 in the agent-induced esterification and accompanying lipid droplet formation was tested in rat adipocytes using relevant inhibitors. The results demonstrate that upregulation of the esterification and accumulation of triacylglycerol by glimepiride depends on the sequential H2O2-induced GPI-PLC activation and GPI-protein translocation as does inhibition of lipolysis. In contrast, stimulation of the esterification and triacylglycerol accumulation by palmitate relies on insulin-independent tyrosine phosphorylation and thus differs from its anti-lipolytic mechanism. As expected, insulin regulates lipid metabolism via typical insulin signalling independent of H2O2 production, GPI-PLC activation and GPI-protein translocation, albeit these processes are moderately stimulated by insulin. In conclusion, triacylglycerol and lipid droplet formation in response to glimepiride and H2O2 may involve the hydrolysis of cyclic adenosine monophosphate by lipid droplet-associated Gce1 and CD73 which may regulate lipid droplet-associated triacylglycerol-synthesizing and hydrolyzing enzymes in coordinated and inverse fashion.

  14. Synthesis of [11C]palmitic acid for PET imaging using a single molecular sieve 13X cartridge for reagent trapping, radiolabeling and selective purification.

    PubMed

    Amor-Coarasa, Alejandro; Kelly, James M; Babich, John W

    2015-08-01

    Radiolabeled fatty acids are valuable metabolic tracers for PET imaging. Carbon-11 is widely used in clinical PET studies due to the prevalence of facile techniques enabling the incorporation of [(11)C]CO2 and [(11)C]CH3 into molecules and a short half-life (20.4 min) that translates into low patient dose. However, the short half-life considerably limits the time for radiosynthesis. Furthermore, the majority of the syntheses of [(11)C]palmitic acid in common use employ high starting [(11)C]CO2 activities and/or expensive equipment. [(11)C]CO2 was trapped with greater than 99.99% efficiency by a three stage cartridge packed with molecular sieve 13X, 100-120 mesh. The labeling of n-pentadecylmagnesium bromide took place in 5 min in the cartridge, and the [(11)C]palmitic acid product was selectively eluted in ethanol following alkaline and acidic washes of the column. The system reliably produced more than 925 MBq (25 mCi) of [(11)C]palmitic acid suitable for human use from 7.4 GBq (200 mCi) of [(11)C]CO2 in 8 min from end-of-bombardment. We have exploited the properties of the inexpensive molecular sieve 13X to develop a miniature, disposable and leak tight "gas capture" system for the rapid labeling and purification of [(11)C]fatty acids in good yield and >99% radiochemical purity. The rapidity of the synthesis and purification allows small [(11)C]CO2 starting activities to be used, and with no requirement for expensive synthesis equipment or facilities, the system can be implemented in any radiopharmaceutical center. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Fat high in stearic acid favorably affects blood lipids and factor VII coagulant activity in comparison with fats high in palmitic acid or high in myristic and lauric acids.

    PubMed

    Tholstrup, T; Marckmann, P; Jespersen, J; Sandström, B

    1994-02-01

    The effect of fats high in individual, prevalent saturated dietary fatty acids on lipoproteins and hemostatic variables in young healthy subjects was evaluated in a randomized strictly controlled metabolic feeding study. Three experimental diets: shea butter (S; 42% stearic acid), palm oil (P; 43% palmitic palmitic acid), and palm-kernel oil with high-oleic sunflower oil (ML; 10% myristic acid, 30% lauric acid) were served to 15 men for 3 wk each, separated by washout periods. Diet S compared with diet P resulted in significant reduction in plasma cholesterol (22%) LDL cholesterol (26%), apolipoprotein B (18%), HDL cholesterol (12%), apolipoprotein A-I (13%), and a 13% lower factor VII coagulant activity (P = 0.001). Similar differences were observed between diets S and ML. In conclusion, intake of shea butter high in stearic acid favorably affects blood lipids and factor VII coagulant activity in young men, compared with fats high in saturated fatty acids with 12-16 carbons.

  16. Palmitic acid but not palmitoleic acid induces insulin resistance in a human endothelial cell line by decreasing SERCA pump expression.

    PubMed

    Gustavo Vazquez-Jimenez, J; Chavez-Reyes, Jesus; Romero-Garcia, Tatiana; Zarain-Herzberg, Angel; Valdes-Flores, Jesus; Manuel Galindo-Rosales, J; Rueda, Angelica; Guerrero-Hernandez, Agustin; Olivares-Reyes, J Alberto

    2016-01-01

    Palmitic acid is a negative regulator of insulin activity. At the molecular level, palmitic acid reduces insulin stimulated Akt Ser473 phosphorylation. Interestingly, we have found that incubation with palmitic acid of human umbilical vein endothelial cells induced a biphasic effect, an initial transient elevation followed by a sustained reduction of SERCA pump protein levels. However, palmitic acid produced a sustained inhibition of SERCA pump ATPase activity. Insulin resistance state appeared before there was a significant reduction of SERCA2 expression. The mechanism by which palmitic acid impairs insulin signaling may involve endoplasmic reticulum stress, because this fatty acid induced activation of both PERK, an ER stress marker, and JNK, a kinase associated with insulin resistance. None of these effects were observed by incubating HUVEC-CS cells with palmitoleic acid. Importantly, SERCA2 overexpression decreased the palmitic acid-induced insulin resistance state. All these results suggest that SERCA pump might be the target of palmitic acid to induce the insulin resistance state in a human vascular endothelial cell line. Importantly, these data suggest that HUVEC-CS cells respond to palmitic acid-exposure with a compensatory overexpression of SERCA pump within the first hour, which eventually fades out and insulin resistance prevails.

  17. Bacterial exacerbations of chronic obstructive pulmonary disease. The role of lung function in aetiology of exacerbation.

    PubMed

    Kieszko, Robert; Szmygin-Milanowska, Katarzyna; Chudnicka, Alina; Gołebiowska, Izabela; Łagozna, Jolanta; Milanowski, Janusz

    2003-01-01

    The objective of the study was determination of the most frequent bacterial factors, including Haemophilus parainfluenzae, suspected of causing COPD exacerbation, of the relation between bacterial strains and respiratory system functional status as well as of antibiotic sensitivity of sputum isolated bacteria. The examined group comprised 28 patients treated in the Pulmonary Department of Medical University of Lublin. The subjects fulfilled the criteria of type I COPD bacterial exacerbation. Patient's chest x-ray and spirometry tests were performed. Forty-nine bacterial strains were isolated. In the case of nine patients, more than one strain was isolated. Subjects having H. parainfluenzae in sputum had significantly higher (p<0.05) FVC and FEV1 values comparing to patients with H. influenzae or other Gram-negative bacteria. H. parainfluenzae may be an important etiologic factor of COPD exacerbation. Aetiology of bacterial COPD exacerbation depends on the level of respiratory parameter limitation.

  18. Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval.

    PubMed

    Lode, H; Eller, J; Linnhoff, A; Ioanas, M

    2004-12-01

    Antibiotic treatment of bacterial exacerbation of chronic obstructive pulmonary disease (COPD) shows some immediate clinical benefits and may also minimise the frequency of further recurrences. Patients (n=511) were enrolled into a randomised double-blind multicentric study comparing the exacerbation-free interval (EFI), efficacy and safety of 7-day levofloxacin versus 10-day clarithromycin in patients with COPD exacerbation. Patients were monitored over a 1-yr period. A total of 434 patients (per protocol population) received the medication for > or =5 days. The median EFI in the per protocol population was 300 days for levofloxacin and 350 days for clarithromycin. For patients with a new documented exacerbation during follow-up (n=223), the median EFI was 100.5 days in the levofloxacin group and 95 days for clarithromycin. No significant differences in EFI between groups could be observed when stratifying the study population according to microbial aetiology and severity of bronchial obstruction. Levofloxacin and clarithromycin showed similar clinical success rates. The bacteriological success rate was significantly higher in the levofloxacin group. Both antibiotics were well tolerated. In summary, levofloxacin was associated with a significantly higher bacteriological eradication rate but similar exacerbation-free interval in patients with chronic obstructive pulmonary disease exacerbation compared to clarithromycin.

  19. Determining prognosis in acute exacerbation of COPD

    PubMed Central

    Flattet, Yves; Garin, Nicolas; Serratrice, Jacques; Perrier, Arnaud; Stirnemann, Jérome; Carballo, Sebastian

    2017-01-01

    Background Acute exacerbations are the leading causes of hospitalization and mortality in patients with COPD. Prognostic tools for patients with chronic COPD exist, but there are scarce data regarding acute exacerbations. We aimed to identify the prognostic factors of death and readmission after exacerbation of COPD. Methods This was a retrospective study conducted in the Department of Internal Medicine of Geneva University Hospitals. All patients admitted to the hospital with a diagnosis of exacerbation of COPD between 2008 and 2011 were included. The studied variables included comorbidities, Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity classification, and biological and clinical parameters. The main outcome was death or readmission during a 5-year follow-up. The secondary outcome was death. Survival analysis was performed (log-rank and Cox). Results We identified a total of 359 patients (195 men and 164 women, average age 72 years). During 5-year follow-up, 242 patients died or were hospitalized for the exacerbation of COPD. In multivariate analysis, age (hazard ratio [HR] 1.03, 95% CI 1.02–1.05; P<0.0001), severity of airflow obstruction (forced expiratory volume in 1 s <30%; HR 4.65, 95% CI 1.42–15.1; P=0.01), diabetes (HR 1.47, 95% CI 1.003–2.16; P=0.048), cancer (HR 2.79, 95% CI 1.68–4.64; P<0.0001), creatinine (HR 1.003, 95% CI 1.0004–1.006; P=0.02), and respiratory rate (HR 1.03, 95% CI 1.003–1.05; P=0.028) on admission were significantly associated with the primary outcome. Age, cancer, and procalcitonin were significantly associated with the secondary outcome. Conclusion COPD remains of ominous prognosis, especially after exacerbation requiring hospitalization. Baseline pulmonary function remains the strongest predictor of mortality and new admission. Demographic factors, such as age and comorbidities and notably diabetes and cancer, are closely associated with the outcome of the patient. Respiratory rate at admission

  20. [Management of acute exacerbations of COPD].

    PubMed

    Rabbat, A; Guetta, A; Lorut, C; Lefebvre, A; Roche, N; Huchon, G

    2010-10-01

    Exacerbations of COPD are common and cause a considerable burden to the patient and the healthcare system. To optimize the hospital care of patients with exacerbations of COPD, clinicians should be aware of some key points: management of exacerbations is broadly based on clinical features and severity. Initial clinical evaluation is crucial to define those patients requiring hospital admission and those who could be managed as outpatients. In hospitalized patients, the appropriate level of care should be determined by the initial severity and response to initial medical treatment. Medical treatment should follow recent recommendations, including rest, titrated oxygen therapy, inhaled or nebulized short-acting bronchodilators (Beta2-agonists and anticholinergic agents), DVT prevention with LMWH, steroids in most severely ill patients, unless there are contraindications and antibiotics in the case of a clear bacterial infectious aetiology. Severe exacerbations may lead to acute hypercapnic respiratory failure. Unless contraindicated, non-invasive ventilation (NIV) should be the first line ventilatory support for these patients. NIV should be commenced early, before severe acidosis ensues, to avoid the need for endotracheal intubation and to reduce mortality and treatment failures. Several randomised controlled clinical trials support the use of NIV in the management of acute exacerbations of COPD, demonstrating a decreased need for mechanical ventilation and an improved survival. In most severe cases, NIV should be provided in ICU. Although it has been shown that for less severe patients (with pH values>7.30), NIV can be administered safely and effectively on general medical wards, a lead respiratory consultant and trained nurses are mandatory. Mechanical ventilation through an endotracheal tube should be considered when patients have contraindications to the use of NIV or fail to improve on NIV. The duration of mechanical ventilation should be shortened as much as

  1. GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway.

    PubMed

    Ying, Ying; Zhu, Huazhang; Liang, Zhen; Ma, Xiaosong; Li, Shiwei

    2015-12-01

    Activation of apoptosis in cardiomyocytes by saturated palmitic acids contributes to cardiac dysfunction in diabetic cardiomyopathy. Beta-catenin (b-catenin) is a transcriptional regulator of several genes involved in survival/anti-apoptosis. However, its role in palmitate-induced cardiomyocyte apoptosis remains unclear. Glucagon-like peptide 1 (GLP1) has been shown to exhibit potential cardioprotective properties. This study was designed to evaluate the role of b-catenin signalling in palmitate-induced cardiomyocyte apoptosis and the molecular mechanism underlying the protective effects of GLP1 on palmitate-stressed cardiomyocytes. Exposure of neonatal rat cardiomyocytes to palmitate increased the fatty acid transporter CD36-mediated intracellular lipid accumulation and cardiomyocyte apoptosis, decreased accumulation and nuclear translocation of active b-catenin, and reduced expression of b-catenin target protein survivin and BCL2. These detrimental effects of palmitate were significantly attenuated by GLP1 co-treatment. However, the anti-apoptotic effects of GLP1 were markedly abolished when b-catenin was silenced with a specific short hairpin RNA. Furthermore, analysis of the upstream molecules and mechanisms responsible for GLP1-associated cardiac protection revealed that GLP1 restored the decreased phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3b (GSK3b) in palmitate-stimulated cardiomyocytes. In contrast, inhibition of Akt with an Akt-specific inhibitor MK2206 or blockade of GLP1 receptor (GLP1R) with a competitive antagonist exendin-(9-39) significantly abrogated the GLP1-mediated activation of GSK3b/b-catenin signalling, leading to increased apoptosis in palmitate-stressed cardiomyocytes. Collectively, our results demonstrated for the first time that the attenuated b-catenin signalling may contribute to palmitate-induced cardiomyocyte apoptosis, while GLP1 can protect cardiomyocytes from palmitate-induced apoptosis through

  2. Palmitate Antagonizes Wnt/Beta-catenin Signaling in 3T3-L1 Pre-adipocytes

    USDA-ARS?s Scientific Manuscript database

    Long chain saturated free fatty acids such as palmitate (PA) produce insulin resistance, endoplasmic reticulum stress, and apoptosis in mature adipocytes and pre-adipocytes. In pre-adipocytes, saturated free fatty acids also promote adipogenic induction in the presence of adipogenic hormones. Wnt/be...

  3. Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro

    PubMed Central

    Jiang, Xu-shun; Chen, Xue-mei; Wan, Jiang-min; Gui, Hai-bo; Ruan, Xiong-zhong; Du, Xiao-gang

    2017-01-01

    Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis. PMID:28225005

  4. Induction of micronuclei by palmitic acid and its unique radiolytic product 2-dodecylcyclobutanone

    USDA-ARS?s Scientific Manuscript database

    Palmitic acid (PA), one of the most abundant fatty acids in the human diet, can cause oxidative stress, DNA strand breakage, cellular necrosis and apoptosis in human and rodent cells in vitro. Radiolysis of PA leads to the formation of 2-dodecylcyclobutanone (2-DCB), a unique radiolytic product for...

  5. Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro.

    PubMed

    Jiang, Xu-Shun; Chen, Xue-Mei; Wan, Jiang-Min; Gui, Hai-Bo; Ruan, Xiong-Zhong; Du, Xiao-Gang

    2017-02-22

    Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis.

  6. Acylation of keratinocyte transglutaminase by palmitic and myristic acids in the membrane anchorage region

    SciTech Connect

    Chakravarty, R.; Rice, R.H.

    1989-01-05

    The membrane-bound form of keratinocyte transglutaminase was found to be labeled by addition of (/sup 3/H) acetic, (/sup 3/H)myristic, or (/sup 3/H)palmitic acids to the culture medium of human epidermal cells. Acid methanolysis and high performance liquid chromatography analysis of palmitate-labeled transglutaminase yielded only methyl palmitate. In contrast, analysis of the myristate-labeled protein yielded approximately 40% methyl myristate and 60% methyl palmitate. Incorporation of neither label was significantly affected by cycloheximide inhibition of protein synthesis. The importance of the fatty acid moiety for membrane anchorage was demonstrated in three ways. First, the enzyme was solubilized from the particulate fraction of cell extracts by treatment with neutral 1 M hydroxylamine, which was sufficient to release the fatty acid label. Second, solubilization of active enzyme from the particulate fraction upon mild trypsin treatment resulted in a reduction in size by approximately 10 kDa and removal of the fatty acid radiolabels. Third, the small fraction of soluble transglutaminase in cell extracts was found almost completely to lack fatty acid labeling. Keratinocyte transglutaminase translated from poly(A+) RNA in a reticulocyte cell-free system was indistinguishable in size from the native enzyme, suggesting anchorage requires only minor post-translational processing. Thus, the data are highly compatible with membrane anchorage by means of fatty acid acylation within 10 kDa of the NH/sub 2/ or COOH terminus.

  7. Preparation of starch-stabilized silver nanoparticles from amylose-sodium palmitate inclusion complexes.

    PubMed

    Fanta, George F; Kenar, James A; Felker, Frederick C; Byars, Jeffrey A

    2013-01-30

    Starch-stabilized silver nanoparticles (AgNP) were prepared from amylose-sodium palmitate helical inclusion complexes by first converting sodium palmitate within the amylose helix to silver palmitate by an ion-exchange reaction with silver nitrate, and then reducing the complexed silver palmitate salt with NaBH(4). This process yielded stable aqueous solutions that could be dried and then re-dispersed in water for end-use applications. Reaction products were characterized by inductively coupled plasma-atomic emission spectroscopy (ICP-AES), UV-VIS spectroscopy, X-ray diffraction, TEM, SEM and light microscopy. Addition of acid to reduce the pH of aqueous starch-AgNP solutions produced an increase in viscosity, and nearly quantitative precipitation of starch-AgNP was observed at low pH. Smaller AgNP and higher conversions of silver nitrate to water-soluble starch-AgNP were obtained in this process, as compared with a process carried out under similar conditions using a commercial soluble starch as a stabilizer.

  8. 21 CFR 178.3450 - Esters of stearic and palmitic acids.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Esters of stearic and palmitic acids. 178.3450 Section 178.3450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND...

  9. 21 CFR 178.3450 - Esters of stearic and palmitic acids.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Esters of stearic and palmitic acids. 178.3450 Section 178.3450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND SANITIZERS Certain Adjuvants and...

  10. 21 CFR 178.3450 - Esters of stearic and palmitic acids.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Esters of stearic and palmitic acids. 178.3450 Section 178.3450 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: ADJUVANTS, PRODUCTION AIDS, AND...

  11. Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts.

    PubMed

    Keene, Jason D; Jacobson, Sean; Kechris, Katerina; Kinney, Gregory L; Foreman, Marilyn G; Doerschuk, Claire M; Make, Barry J; Curtis, Jeffrey L; Rennard, Stephen I; Barr, R Graham; Bleecker, Eugene R; Kanner, Richard E; Kleerup, Eric C; Hansel, Nadia N; Woodruff, Prescott G; Han, MeiLan K; Paine, Robert; Martinez, Fernando J; Bowler, Russell P; O'Neal, Wanda K

    2017-02-15

    Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux. To determine the value of adding blood biomarkers to clinical variables to predict exacerbations. Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis. Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations. Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the

  12. [Diagnosis and therapy of COPD exacerbation].

    PubMed

    Bauer, T T; Nilius, G; Grüning, W; Rasche, K

    2012-04-01

    The acute exacerbation of COPD (AECOPD) is a life-threatening clinical situation. This review summarizes the definition of AECOPD, the severity assessment, typical clinical signs and symptoms, and refers to clinical pitfalls of diagnosis and therapy. Important aspects of clinical history and physical examination in severe exacerbations are reported. The necessary accompanying examinations like chest X-ray, blood gas analysis, ECG and echocardiography and their differential diagnosis as well as therapeutic significance are described. The most important lab examinations are summarized and controversial parameters, e.g., procalcitonin, are commented upon. The differentiated need for a microbiological sputum screening is emphasized. The authors place special weight on the essential components of the therapeutic management of severe AECOPD. Practical aspects of uncontrolled oxygen therapy, drug selection, and application form of inhalative acute therapy, dose, and duration of glucocorticoids, the indication for antibiotics, mechanical ventilation, and also opiates are summarized.

  13. Menstrual cycle-related exacerbation of disease

    PubMed Central

    Pinkerton, JoAnn V.; Guico-Pabia, Christine J.; Taylor, Hugh S.

    2011-01-01

    Exacerbation of common medical and mental health disorders at specific phases of the menstrual cycle is a prevalent phenomenon. Although the precise cause is unclear, studies implicate complex interactions between the immune and neuroendocrine systems. The menstrual cycle also is a trigger for the onset of depressive disorders, including premenstrual dysphoric disorder, a disorder specific to the luteal phase of the menstrual cycle, and depression associated with the transition to menopause. This article discusses common mental health problems exacerbated by the menstrual cycle, with a particular focus on premenstrual dysphoric disorder and perimenopausal depression. Throughout the reproductive lifespan, routine screening and assessment for the presence of common psychiatric disorders are critical for accurate diagnosis and provision of effective treatment. Management options include referral or consultation with a primary care provider or psychiatrist; treatment options for premenstrual dysphoric disorder and perimenopausal depression include pharmacotherapy with antidepressant agents and/or psychotherapy. Hormones may be helpful. PMID:20207238

  14. [Treatment of patients with acute asthma exacerbation].

    PubMed

    Ostojić, Jelena; Mose, Jakov

    2009-01-01

    Asthma is a chronic inflammatory disease of the airways. The global prevalence of asthma ranges from 1% to 18% of the population, so it remains a common problem with enormous medical and economic impacts. In majority of patients, asthma can be well controlled with simple regimens of inhaled anti-inflammatory and bronchodilating medications. However, some patients tend to suffer from poorly controlled disease in terms of chronic symptoms with episodic severe exacerbations. Major factors that may be related to the emergency department visits and hospitalisation include prior severe attacks, nonadherence to therapeutic regimens, inadequate use of inhaled corticosteroids, poor self-management skills, frequent use of inhaled short-acting beta-agonists, cigarette smoking, poor socioeconomic status and age over 40 years. Severe exacerbations of asthma are life-threatening medical emergencies and require careful brief assesment, treatment according to current GINA (Global Initiative for Asthma) guidelines with periodic reassesment of patient's response to therapy usually in an emergency department.

  15. Activation of PPAR{delta} up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic {beta}-cells

    SciTech Connect

    Wan, Jun; Jiang, Li; Lue, Qingguo; Ke, Linqiu; Li, Xiaoyu; Tong, Nanwei

    2010-01-15

    Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic {beta}-cells. After HIT-T15 cells (a {beta}-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR{delta}), we found that administration of GW increased the expression of PPAR{delta} mRNA. GW-induced activation of PPAR{delta} up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR{delta} plays an important role in protecting pancreatic {beta}-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

  16. Reduction of immunosuppression in UV-irradiated mice by dietary retinyl palmitate plus canthaxanthin.

    PubMed

    Gensler, H L

    1989-01-01

    The ability of dietary retinyl palmitate, canthaxanthin or the combination of both, to prevent induction of immunosuppression by UVB irradiation was tested by passive transfer of splenocytes. The basal diet was the American Institute of Nutrition diet 76A, containing 4 IU retinyl palmitate/g diet. Groups of 55 mice were fed this basal diet alone, or supplemented with 120 IU retinyl palmitate/g diet, 1% canthaxanthin or the combination of both. After 18 weeks of these diets, UVB radiation treatments began. The UVB radiation source was a bank of six unfiltered Westinghouse FS40 lamps which delivered an average dose of 4.6 J/m2/s over the wavelength range of 280-340 nm. After 27.5 weeks of UV treatments, and approximately 1.14 X 10(6) J/m2, spleens were removed from mice and used as sources of splenocytes for passive transfer into naive recipients. These recipients were then challenged with an immunogenic, syngeneic UV-induced tumor (UV20). Approximately twice as many tumor challenges grew in recipients of splenocytes from UV-irradiated (19/20), as compared with unirradiated (11/20) donors fed the basal diet. Transfer of splenocytes from UV-irradiated donors fed the basal diet admixed with 1% canthaxanthin, 120 IU retinyl palmitate/g diet or the combination, resulted in 16/20, 13/20 and 10/20 growing tumors, respectively. These values were insignificantly (P = 0.25), marginally (P = 0.054) or significantly (P less than 0.02) different from the positive control value, respectively. Thus, dietary supplementation with retinyl palmitate plus canthaxanthin prevented the transfer of UV-induced immunosuppression with splenocytes from UV-irradiated mice.

  17. Antimicrobial activity of gentamicin palmitate against high concentrations of Staphylococcus aureus.

    PubMed

    Kittinger, Clemens; Marth, Egon; Windhager, Reinhard; Weinberg, Annelie M; Zarfel, Gernot; Baumert, Rita; Felisch, Susanne; Kuehn, Klaus-Dieter

    2011-06-01

    The reduction of implant related infections plays a pivotal role in orthopaedic surgery as an increasing number of people require implants (up to 200,000 per year in the United States (source: Joint Implant Surgery & Research Foundation 2010)). The aim of the current study is to prevent and thus decrease the number of bacterial infections. Both pre and post operative systemic antibiotic treatment and gentamicin containing bone cements (polymethylmethacrylate, PMMA) are commonly used strategies to overcome infections. In this study, the antimicrobial efficacy of gentamicin sulfate loaded bone cement was compared with titan discs coated with a new form of gentamicin, gentamicin palmitate. Adherence prevention, killing rates and killing kinetics were compared in an in vitro model, using Staphylococcus aureus (S. aureus), which together with Staphylococcus epidermidis (S. epidermidis) represents 60% of bacteria found responsible for hip implant infections (An and Friedman, 1996, J Hosp Infect 33(2):93-108). In our experiments gentamicin, which was applied as gentamicin palmitate on the surface of the implants, showed a high efficacy in eliminating bacteria. In contrast to gentamicin sulfate containing bone cements, gentamicin palmitate is released over a shorter period of time thus not inducing antibiotic resistance. Another benefit for clinical application is that it achieves high local levels of active ingredient which fight early infections and minimize toxic side effects. Furthermore, the short term hydrophobic effect of gentamicin palmitate can successfully impede biofilm formation. Thus, the use of self-adhesive antibiotic fatty acid complexes like gentamicin palmitate represents a new option for the anti-infective coating of cementless titan implants.

  18. Tetramethylpyrazine protects palmitate-induced oxidative damage and mitochondrial dysfunction in C2C12 myotubes.

    PubMed

    Gao, Xin; Zhao, Xiao-long; Zhu, Yan-hui; Li, Xiao-mu; Xu, Qiong; Lin, Huan-dong; Wang, Ming-wei

    2011-04-25

    Tetramethylpyrazine (TMP), one of the active ingredients isolated from a Chinese herbal prescription, possesses protective effects against oxidative stress caused by high glucose in endothelial cells. In this study, the role of TMP in preventing muscle cells from palmitate-induced oxidative damage was investigated and the possible mechanisms of action elucidated. Mitochondrial reactive oxygen species (ROS) were measured in C2C12 myotubes, a palmitate-induced oxidative stress cell model, with or without TMP. Both mitochondrial membrane potential (MMP) and oxygen consumption were assessed in conjunction with quantification of mitochondrial DNA and mitochondrial biogenesis-related factors, such as peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (Tfam), by real-time polymerase chain reaction. Expression of mitochondrial respiratory chain complex III as an index of mitochondrial function was evaluated by immunoblotting, and glucose transport into the C2C12 myotube examined by analyzing 2-deoxy-[(3)H]glucose uptake. TMP significantly alleviated palmitate-induced mitochondrial ROS production, mitigated mitochondrial dysfunction and increased D-loop mRNA expression as compared with the control. This was accompanied by a marked reversal of palmitate-induced down-regulation in the expression of mitochondrial biogenesis-related factors (PGC1α, NRF1 and Tfam) and decreased glucose uptake in C2C12 myotubes. As a result, cell respiration, as reflected by the elevated expression of mitochondrial respiratory chain complex III and oxygen consumption, was enhanced. TMP is capable of protecting C2C12 myotubes against palmitate-induced oxidative damage and mitochondrial dysfunction, and improving glucose uptake in muscle cells partially through the up-regulation of mitochondrial biogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Palmitic and linoleic acids induce ER stress and apoptosis in hepatoma cells

    PubMed Central

    2012-01-01

    Objectives Hepatic inflammation and degeneration induced by lipid depositions may be the major cause of nonalcoholic fatty liver disease. In this study, we tried to investigate the effects of saturated and unsaturated fatty acids on hepatoma cell apoptosis. Methods H4IIE liver cells were treated with palmitic acid, linoleic acid, or both with or without the calcium-specific chelator BAPTA-AM after which the expression of proteins associated with endoplasmic reticulum (ER) stress, apoptosis, caspase-3 levels, and calcium flux were measured. Results Palmitic or linoleic acid (250 μM) induced H4IIE cell apoptosis, which required calcium flux but not caspase-3. Apoptosis was not observed when cells were co-treated with linoleic acid (125 μM) and palmitic acid (250 μM). Importantly, the release of cytochrome C from mitochondria into cytoplasm during cell apoptosis was specifically detected only when linoleic acid (125 μM), but not palmitic acid (250 μM), was added to the cells. Depletion of intracellular calcium flux by the calcium-specific chelator, BAPTA-AM, abolished linoleic acid-induced apoptosis. Moreover, in the presence of BAPTA-AM, expression of the unfolded protein response (UPR)-associated genes, CHOP, GRP78, and GRP94, was induced by linoleic acid, but not palmitic acid. Conclusions The results suggest that linoleic acid promotes cell apoptosis through the release of cytochrome C, only if the intracellular calcium flux is unperturbed and intact. These results confirm that ER stress contributes to fatty acid-induced liver cell apoptosis. PMID:22221411

  20. Calcium Uptake via Mitochondrial Uniporter Contributes to Palmitic Acid-induced Apoptosis in Mouse Podocytes.

    PubMed

    Yuan, Zeting; Cao, Aili; Liu, Hua; Guo, Henjiang; Zang, Yingjun; Wang, Yi; Wang, Yunman; Wang, Hao; Yin, Peihao; Peng, Wen

    2017-02-09

    Podocytes are component cells of the glomerular filtration barrier, and their loss by apoptosis is the main cause of proteinuria that leads to diabetic nephropathy (DN). Therefore, insights into podocyte apoptosis mechanism would allow a better understanding of DN pathogenesis and thus help develop adequate therapeutic strategies. Here, we investigated the molecular mechanism of palmitic acid-inhibited cell death in mouse podocytes, and found that palmitic acid increased cell death in a dose- and time-dependent manner. Palmitic acid induces apoptosis in podocytes through up-regulation of cytosolic and mitochondrial Ca(2+) , mitochondrial membrane potential (MMP), cytochrome c release and depletion of endoplasmic reticulum (ER) Ca(2+) , The intracellular calcium chelator, 1,2-bis (2-aminophenoxy) ethane-N,N,N, N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM), partially prevented this up-regulation whereas 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-triphosphate receptor (IP3R) inhibitor; dantrolene, a ryanodine receptor (RyR) inhibitor; and 4,4'-diisothiocyanatostibene-2,2'-disulfonic acid (DIDS), an anion exchange inhibitor, had no effect. Interestingly, ruthenium red and Ru360, both inhibitors of the mitochondrial Ca(2+) uniporter (MCU), blocked palmitic acid-induced mitochondrial Ca(2+) elevation, cytochrome c release from mitochondria to cytosol, and apoptosis. siRNA to MCU markedly reduced curcumin-induced apoptosis. These data indicate that Ca(2+) uptake via mitochondrial uniporter contributes to palmitic acid-induced apoptosis in mouse podocytes. This article is protected by copyright. All rights reserved.

  1. Subcutaneous adipocytes promote melanoma cell growth by activating the Akt signaling pathway: role of palmitic acid.

    PubMed

    Kwan, Hiu Yee; Fu, Xiuqiong; Liu, Bin; Chao, Xiaojuan; Chan, Chi Leung; Cao, Huihui; Su, Tao; Tse, Anfernee Kai Wing; Fong, Wang Fun; Yu, Zhi-Ling

    2014-10-31

    Tumorigenesis involves constant communication between tumor cells and neighboring normal cells such as adipocytes. The canonical function of adipocytes is to store triglyceride and release fatty acids for other tissues. This study was aimed to find out if adipocytes promoted melanoma cell growth and to investigate the underlying mechanism. Here we isolated adipocytes from inguinal adipose tissue in mice and co-cultured with melanoma cells. We found that the co-cultured melanoma had higher lipid accumulation compared with mono-cultured melanoma. In addition, fluorescently labeled fatty acid BODIPY® FLC16 signal was detected in melanoma co-cultured with the adipocytes that had been loaded with the fluorescent dye, suggesting that the adipocytes provide fatty acids to melanoma cells. Compared with mono-cultured melanoma, co-cultured melanoma cells had a higher proliferation and phospho-Akt (Ser-473 and Thr-450) expression. Overexpression of Akt mutants in melanoma cells reduced the co-culture-enhanced proliferation. A lipidomic study showed that the co-cultured melanoma had an elevated palmitic acid level. Interestingly, we found that palmitic acid stimulated melanoma cell proliferation, changed the cell cycle distribution, and increased phospho-Akt (Ser-473 and Thr-450) and PI3K but not phospho-PTEN (phosphophosphatase and tensin homolog) expressions. More importantly, the palmitic acid-stimulated proliferation was further enhanced in the Akt-overexpressed melanoma cells and was reduced by LY294002 or knockdown of endogenous Akt or overexpression of Akt mutants. We also found that palmitic acid-pretreated B16F10 cells were grown to a significantly larger tumor in mice compared with control cells. Taken together, we suggest that adipocytes may serve as an exogenous source of palmitic acid that promotes melanoma cell growth by activating Akt.

  2. GDF11 does not improve the palmitate induced insulin resistance in C2C12.

    PubMed

    Jing, Y-Y; Li, D; Wu, F; Gong, L-L; Li, R

    2017-04-01

    GDF11 (Growth Differentiation factor 11) has been reported to rejuvenate skeletal muscle, heart and brain in aged mice, and the aged skeletal muscle is closely related to insulin resistance. We wondered whether GDF11 has an effect on skeletal muscle insulin resistance. High fat diet induced obese mice with insulin resistance were established in vivo. Palmitate-induced insulin resistance in C2C12 myotubes was established in vitro. The mRNA expression of GDF11, GLUT4, IRS-1 (insulin receptor substrate-1) and PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator 1) were tested by reverse transcriptase-polymerase chain reaction (RT-PCR). The protein level of GDF11 and PGC-1α were detected by Western blot. The glucose uptake was measured by 2NBDG uptake assay. In high fat diet induced obese mice, both serum level of GDF11 and the expression of GDF11 in skeletal muscle decreased. Similarly, the expression of GDF11 also reduced in palmitate-treated C2C12 myotubes. In vitro, the glucose uptake and the expression of GLUT4, IRS-1 and PGC-1α significantly decreased after palmitate intervention, but GDF11 treatment did not reverse the reduction of glucose uptake and the expression of GLUT4, IRS-1 and PGC-1α in C2C12 myotubes. We firstly confirmed that the expression of GDF11 decreased both in the skeletal muscle of obese mice and palmitate-treated myotubes, but supplementation GDF11 does not ameliorate the palmitate-induced insulin resistance in C2C12 myotubes.

  3. Zinc Supplementation in Children with Asthma Exacerbation

    PubMed Central

    Rerksuppaphol, Sanguansak

    2016-01-01

    Zinc deficiency has demonstrated an association with the risk of asthma. This study aimed to evaluate the efficacy of zinc supplementation in reducing the severity of childhood asthma exacerbation. A number of 42 children with asthma exacerbation admitted to the hospital were randomized to receive either zinc bis-glycinate (30 mg elemental zinc/day) or a placebo in adjuvant to the standard treatment. The pediatric respiratory assessment measure (PRAM) was used to measure the asthma severity. The primary outcome was a change in asthma severity from the baseline to the end of study. The study found that PRAM score in the zinc group showed a more rapid decrease compared to the control group at the 24-hour (2.2±1.3 vs. 1.2±1.3; P = 0.015) and 48-hour (3.4±2.0 vs. 2.2±1.8; P = 0.042) intervals. At admission, overall mean serum zinc level was 63.8 mg/dL and 57.1% of children had zinc deficiency with no difference in prevalence between groups. PRAM scores did not differ between children with low and normal zinc status. In conclusion, zinc supplementation as the adjuvant therapy to the standard treatment during asthma exacerbation resulted in rapid lessening of severity. PMID:28058103

  4. The exacerbation component of impairment and risk in pediatric asthma.

    PubMed

    Bloomberg, Gordon R

    2010-04-01

    The new guidelines for assessment of asthma control emphasize two domains: impairment and risk. Exacerbations of asthma are an important component of risk but have not received as much attention as the day-to-day symptoms that make up impairment. The purpose of this review is to report what has recently been learned about exacerbations. Exacerbations occur in the context of both controlled and uncontrolled asthma. Exacerbations are a strong independent risk factor of further exacerbations. This suggests that unrecognized factors may be involved in susceptibility to exacerbations in addition to more commonly recognized triggers such as viruses, allergens, and poorly controlled asthma. Such factors may be the result of genetic variation. Recent evidence now shows a residual effect on lung function from an exacerbation event. There are no current specific intervention measures to prevent exacerbations but attention to management practices continues to look at the role of the emergency department in improving care. The presence of exacerbations is considered a risk factor of the likelihood of further exacerbations and requires assessment of the triggers identified with history of exacerbations, host factors, atopic disposition, exposure to allergens, adherence to prescribed medications, and preventive measures to reduce future risk of such an event.

  5. Palmitic acid increased yields of milk and milk fat and nutrient digestibility across production level of lactating cows.

    PubMed

    Piantoni, P; Lock, A L; Allen, M S

    2013-01-01

    The effects of palmitic acid supplementation on feed intake, digestibility, and metabolic and production responses were evaluated in dairy cows with a wide range of milk production (34.5 to 66.2 kg/d) in a crossover design experiment with a covariate period. Thirty-two multiparous Holstein cows (151 ± 66 d in milk) were randomly assigned to treatment sequence within level of milk production. Treatments were diets supplemented (2% of diet DM) with palmitic acid (PA; 99% C16:0) or control (SH; soyhulls). Treatment periods were 21 d, with the final 4 d used for data and sample collection. Immediately before the first treatment period, cows were fed the control diet for 21 d and baseline values were obtained for all variables (covariate period). Milk production measured during the covariate period (preliminary milk yield) was used as covariate. In general, no interactions were detected between treatment and preliminary milk yield for the response variables measured. The PA treatment increased milk fat percentage (3.40 vs. 3.29%) and yields of milk (46.0 vs. 44.9 kg/d), milk fat (1.53 vs. 1.45 kg/d), and 3.5% fat-corrected milk (44.6 vs. 42.9 kg/d), compared with SH. Concentrations and yields of protein and lactose were not affected by treatment. The PA treatment did not affect dry matter (DM) intake or body weight, tended to decrease body condition score (2.93 vs. 2.99), and increased feed efficiency (3.5% fat-corrected milk/DM intake; 1.60 vs. 1.54), compared with SH. The PA treatment increased total-tract digestibility of neutral detergent fiber (39.0 vs.35.7%) and organic matter (67.9 vs. 66.2%), but decreased fatty acid (FA) digestibility (61.2 vs. 71.3%). As total FA intake increased, total FA digestibility decreased (R(2) = 0.51) and total FA absorbed increased (quadratic R(2) = 0.82). Fatty acid yield response, calculated as the additional FA yield secreted in milk per unit of additional FA intake, was 11.7% for total FA and 16.5% for C16:0 plus cis-9 C16:1 FA

  6. Brucellosis in spondyloarthritis mimicking an exacerbation.

    PubMed

    Garip, Y; Eser, F; Erten, S; Yilmaz, O; Yildirim, P

    2014-01-01

    Spondyloarthritis are a group of chronic inflammatory diseases that affect the axial skeleton, entheses and peripheral joints and may have extraarticular manifestations such as uveitis, psoriasis and inflammatory bowel disease. Brucellosis is a systemic infectious disease, endemic in Middle East, Latin America, and Mediterranean countries, which may present manifestations that resemble other diseases posing serious problems of differential diagnosis. Some hallmarks of Brucellosis may mimic a spondyloarthritis flare. In this paper, authors present a clinical case of brucellosis occurring in a patient with spondyloarthritis. Clinical symptoms initially mimicked exacerbation of spondyloarthritis.

  7. Palmitic Acid Reduces Circulating Bone Formation Markers in Obese Animals and Impairs Osteoblast Activity via C16-Ceramide Accumulation.

    PubMed

    Alsahli, Ahmad; Kiefhaber, Kathryn; Gold, Tziporah; Muluke, Munira; Jiang, Hongfeng; Cremers, Serge; Schulze-Späte, Ulrike

    2016-05-01

    Obesity and impaired lipid metabolism increase circulating and local fatty acid (FA) levels. Our previous studies showed that a high high-saturated -fat diet induced greater bone loss in mice than a high high-unsaturated-fat diet due to increased osteoclast numbers and activity. The impact of elevated FA levels on osteoblasts is not yet clear. We induced obesity in 4 week old male mice using a palmitic acid (PA)- or oleic acid (OA)-enriched high fat high-fat diet (HFD) (20 % of calories from FA), and compared them to mice on a normal (R) caloric diet (10 % of calories from FA). We collected serum to determine FA and bone metabolism marker levels. Primary osteoblasts were isolated; cultured in PA, OA, or control (C) medium; and assessed for mineralization activity, gene expression, and ceramide levels. Obese animals in the PA and OA groups had significantly lower serum levels of bone formation markers P1NP and OC compared to normal weight animals (*p < 0.001), with the lowest marker levels in animals on an PA-enriched HFD (*p < 0.001). Accordingly, elevated levels of PA significantly reduced osteoblast mineralization activity in vitro (*p < 0.05). Elevated PA intake significantly increased C16 ceramide accumulation. This accumulation was preventable through inhibition of SPT2 (serine palmitoyl transferase 2) using myriocin. Elevated levels of PA reduce osteoblast function in vitro and bone formation markers in vivo. Our findings suggest that saturated PA can compromise bone health by affecting osteoblasts, and identify a potential mechanism through which obesity promotes bone loss.

  8. Preparation and characterization of a new lipid nano-emulsion containing two cosurfactants, sodium palmitate for droplet size reduction and sucrose palmitate for stability enhancement.

    PubMed

    Takegami, Shigehiko; Kitamura, Keisuke; Kawada, Hiroto; Matsumoto, Yu; Kitade, Tatsuya; Ishida, Hiroharu; Nagata, Chieyo

    2008-08-01

    A new lipid nano-emulsion (LNE) was prepared from soybean oil and phosphatidylcholine (PC) employing two cosurfactants, sodium palmitate (PA) for reduced droplet size and sucrose palmitate (SP) for stability enhancement. The mean droplet size of LNEs prepared at a PA/PC (w/w) ratio of larger than 1/10 was found to be ca. 50 nm by dynamic light scattering and atomic force microscopy. However, during the 12-month storage, the PA/PC (1/10)-LNE showed an increase in mean droplet size and broadening of the droplet size distribution due to coalescence of the LNE particles. In a saline solution, the coalescence proceeded very rapidly, i.e., the mean droplet size increased to more than 150 nm within 0.5 h. To suppress the coalescence of LNE particles, four sucrose fatty acid esters of different chain lengths were examined as candidate cosurfactants. The results showed that PA/SP/PC (1/4/10)-LNE could maintain a mean droplet size around 50 nm for 12 months. In a saline solution, the mean droplet size could be maintained within 100 nm even after 24 h. Slight formation of flocculation in the LNEs depending on the storage period was suggested by measurement of the 31P nuclear magnetic resonance line width of the LNEs.

  9. Apolipoprotein E isoforms 3/3 and 3/4 differentially interact with circulating stearic, palmitic, and oleic fatty acids and lipid levels in Alaskan Natives.

    PubMed

    Castellanos-Tapia, Lyssia; López-Alvarenga, Juan Carlos; Ebbesson, Sven O E; Ebbesson, Lars O E; Tejero, M Elizabeth

    2015-04-01

    Lifestyle changes in Alaskan Natives have been related to the increase of cardiovascular disease and metabolic syndrome in the last decades. Variation of the apolipoprotein E (Apo E) genotype may contribute to the diverse response to diet in lipid metabolism and influence the association between fatty acids in plasma and risk factors for cardiovascular disease. The aim of this investigation was to analyze the interaction between Apo E isoforms and plasma fatty acids, influencing phenotypes related to metabolic diseases in Alaskan Natives. A sample of 427 adult Siberian Yupik Alaskan Natives was included. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, Apo A1, and Apo B plasma concentrations were measured using reference methods. Concentrations of 13 fatty acids in fasting plasma were analyzed by gas chromatography, and Apo E variants were identified. Analyses of covariance were conducted to identify Apo E isoform and fatty acid main effects and multiplicative interactions. The means for body mass index and age were 26 ± 5.2 and 47 ± 1.5, respectively. Significant main effects were observed for variation in Apo E and different fatty acids influencing Apo B levels, triglycerides, and total cholesterol. Significant interactions were found between Apo E isoform and selected fatty acids influencing total cholesterol, triglycerides, and Apo B concentrations. In summary, Apo E3/3 and 3/4 isoforms had significant interactions with circulating levels of stearic, palmitic, oleic fatty acids, and phenotypes of lipid metabolism in Alaskan Natives.

  10. Palm oil and palmitic acid: a review on cardiovascular effects and carcinogenicity.

    PubMed

    Fattore, Elena; Fanelli, Roberto

    2013-08-01

    We reviewed the scientific literature on the evidence of the relationship between palm oil and adverse effects on human health. Few studies have investigated the effects of palm oil per se, and the main reason why it has been associated with negative health effects is the relatively high content of saturated fatty acids (SFAs), particularly palmitic acid, which in turn have been associated with increased risk of coronary heart disease and some tumours. However, more recent investigations on the topic seem to have reconsidered the negative role of the dietary SFAs as a risk factor for cardiovascular diseases and show that not only the type of fat, but also that the triglyceride structure plays a role in cholesterolaemia. As regards to a role in cancer, specific studies on dietary palmitic acid or palm oil and the risk of cancer development are scanty, and the evidence is not convincing.

  11. Enzymatic synthesis of cocoa butter equivalent from olive oil and palmitic-stearic fatty acid mixture.

    PubMed

    Mohamed, Ibrahim O

    2015-01-01

    The main goal of the present research is to restructure olive oil triacylglycerol (TAG) using enzymatic acidolysis reaction to produce structured lipids that is close to cocoa butter in terms of TAG structure and melting characteristics. Lipase-catalyzed acidolysis of refined olive oil with a mixture of palmitic-stearic acids at different substrate ratios was performed in an agitated batch reactor maintained at constant temperature and agitation speed. The reaction attained steady-state conversion in about 5 h with an overall conversion of 92.6 % for the olive oil major triacylglycerol 1-palmitoy-2,3-dioleoyl glycerol (POO). The five major TAGs of the structured lipids produced with substrate mass ratio of 1:3 (olive oil/palmitic-stearic fatty acid mixture) were close to that of the cocoa butter with melting temperature between 32.6 and 37.7 °C. The proposed kinetics model used fits the experimental data very well.

  12. Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity.

    PubMed

    Zhao, Linjing; Ni, Yan; Yu, Haoyong; Zhang, Pin; Zhao, Aihua; Bao, Yuqian; Liu, Jiajian; Chen, Tianlu; Xie, Guoxiang; Panee, Jun; Chen, Wenlian; Rajani, Cynthia; Wei, Runmin; Su, Mingming; Jia, Weiping; Jia, Wei

    2017-04-01

    Endogenous fatty acid metabolism that results in elongation and desaturation lipid products is thought to play a role in the development of type 2 diabetes mellitus (T2DM). In this study, we evaluated the potential of estimated elongase and desaturase activities for use as predictive markers for T2DM remission after Roux-en-Y gastric bypass (RYGB). The results of a targeted metabolomics approach from 2 independent studies were used to calculate 24 serum FA concentration ratios (product/precursor). Gene expression data from an open public data set was also analyzed. In a longitudinal study of 38 obese diabetic patients with RYGB, we found higher baseline stearic acid/palmitic acid (S/P) ratio. This ratio reflects an elovl6-encoded elongase enzyme activity that has been found to be associated with greater possibility for diabetes remission after RYGB [odds ratio, 2.16 (95% CI 1.10-4.26)], after adjustment for age, gender, body mass index, diabetes duration, glycosylated hemoglobin A1c, and fasting C-peptide. Our results were validated by examination of postsurgical elovl6 gene expression in morbidly obese patients. The association of S/P with the metabolic status of obese individuals was further validated in a cross-sectional cohort of 381 participants. In summary, higher baseline S/P was associated with greater probability of diabetes remission after RYGB and may serve as a diagnostic marker in preoperative patient assessment. - Zhao, L., Ni, Y., Yu, H., Zhang, P., Zhao, A., Bao, Y., Liu, J., Chen, T., Xie, G., Panee, J., Chen, W., Rajani, C., Wei, R., Su, M., Jia, W., Jia, W. Serum stearic acid/palmitic acid ratio as a potential predictor of diabetes remission after Roux-en-Y gastric bypass in obesity. © FASEB.

  13. Moisturizing potentials of ascorbyl palmitate and calcium ascorbate in various topical formulations.

    PubMed

    Gönüllü, U; Yener, G; Uner, M; Incegül, T

    2004-02-01

    The aim of this study was to use two of Vitamin C derivatives, lipophilic ascorbyl palmitate and hydrophilic calcium ascorbate to determine their skin-hydrating effects for the first time. For this purpose, anhydrous cream, gel and w/o emulsion were prepared and applied to the volunteers' inner forearms. A commercial topical preparation containing a known moisturizer, Vitamin E, was also chosen and used for comparison. Moisture contents of the skin were measured by using corneometer.

  14. Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance.

    PubMed

    Talukder, M A Hassan; Preda, Marilena; Ryzhova, Larisa; Prudovsky, Igor; Pinz, Ilka M

    2016-03-01

    Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  15. Apolipoprotein E polymorphism influences postprandial retinyl palmitate but not triglyceride concentrations

    SciTech Connect

    Boerwinkle, E. ); Brown, S.; Patsch, W. ); Sharrett, A.R. ); Heiss, G. )

    1994-02-01

    To quantify the effect of the apolipoprotein (apo) E polymorphism on the magnitude of postprandial lipemia, the authors have defined its role in determining the response to a single high-fat meal in a large sample of (N = 474) individuals taking part in the biethnic Atherosclerosis Risk in Communities Study. The profile of postprandial response in plasma was monitored over 8 h by triglyceride, triglyceride-rich lipoprotein (TGRL)-triglyceride, apo B-48/apo B-100 ratio, and retinyl palmitate concentrations, and the apo E polymorphism was determined by DNA amplification and digestion. The frequency of the apo E alleles and their effects on fasting lipid levels in this sample with vitamin A was significantly different among apo E genotypes, with delayed clearance in individuals with an [var epsilon]2 allele, compared with [var epsilon]3/3 and [var epsilon]3/4 individuals. In the sample of 397 Caucasians, average retinyl palmitate response was 1,489 [mu]g/dl in [var epsilon]2/3 individuals, compared with 1,037 [mu]g/dl in [var epsilon]3/3 individuals and 1,108 [mu]g/dl in [var epsilon]3/4 individuals. The apo E polymorphism accounted for 7.1% of the interindividual variation in postprandial retinyl palmitate response, a contribution proportionally greater than its well-known effect on fasting LDL-cholesterol. However, despite this effect on postprandial retinyl palmitate, the profile of postprandial triglyceride response was not significantly different among apo E genotypes. The profile of postprandial response was consistent between the sample of Caucasians and a smaller sample of black subjects. While these data indicate that the removal of remnant particles from circulation is delayed in subjects with the [var epsilon]2/3 genotype, there is no reported evidence that the [var epsilon]2 allele predisposes to coronary artery disease (CAD). 82 refs., 6 figs., 4 tabs.

  16. A Case of Ileus in a Patient with Schizophrenia Under Paliperidone Palmitate Treatment

    PubMed Central

    Kabadayı, Esra

    2016-01-01

    Constipation is a side effect of antipsychotic drugs that have high affinity for muscarinic cholinergic receptors. In addition, ileus is an important side effect of antipsychotic treatment, with potentially morbid and mortal consequences if early detection fails. In this report, a colonic ileus case is described in a patient with schizophrenia under the treatment of paliperidone palmitate. Consequently, complete physical examination and close screening of side effects are recommended when antipsychotics are prescribed. PMID:27909459

  17. A Case of Ileus in a Patient with Schizophrenia Under Paliperidone Palmitate Treatment.

    PubMed

    Can, Serdar Süleyman; Kabadayı, Esra

    2016-11-01

    Constipation is a side effect of antipsychotic drugs that have high affinity for muscarinic cholinergic receptors. In addition, ileus is an important side effect of antipsychotic treatment, with potentially morbid and mortal consequences if early detection fails. In this report, a colonic ileus case is described in a patient with schizophrenia under the treatment of paliperidone palmitate. Consequently, complete physical examination and close screening of side effects are recommended when antipsychotics are prescribed.

  18. Efficient dermal delivery of retinyl palmitate: Progressive polarimetry and Raman spectroscopy to evaluate the structure and efficacy.

    PubMed

    Lee, Jun Bae; Lee, Dong Ryeol; Choi, Nak Cho; Jang, Jihui; Park, Chun Ho; Yoon, Moung Seok; Lee, Miyoung; Won, Kyoungae; Hwang, Jae Sung; Kim, B Moon

    2015-10-12

    Over the past decades, there has been a growing interest in dermal drug delivery. Although various novel delivery devices and methods have been developed, dermal delivery is still challenging because of problems such as poor drug permeation, instability of vesicles and drug leakage from vesicles induced by fusion of vesicles. To solve the vesicle instability problems in current dermal delivery systems, we developed materials comprised of liquid crystals as a new delivery vehicle of retinyl palmitate and report the characterization of the liquid crystals using a Mueller matrix polarimetry. The stability of the liquid-crystal materials was evaluated using the polarimeter as a novel evaluation tool along with other conventional methods. The dermal delivery of retinyl palmitate was investigated through the use of confocal Raman spectroscopy. The results indicate that the permeation of retinyl palmitate was enhanced by up to 106% compared to that using an ordinary emulsion with retinyl palmitate. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Paliperidone Palmitate Long-Acting Injectable Given Intramuscularly in the Deltoid Versus the Gluteal Muscle: Are They Therapeutically Equivalent?

    PubMed

    Yin, John; Collier, Abby C; Barr, Alasdair M; Honer, William G; Procyshyn, Ric M

    2015-08-01

    Paliperidone palmitate long-acting injectable is a second-generation antipsychotic indicated for the treatment of schizophrenia. According to the product monograph, the monthly maintenance dose of paliperidone palmitate can be given in either the deltoid or gluteal muscle. Unfortunately, many clinicians may misinterpret these directions to mean that these intramuscular sites are interchangeable, and thus therapeutically equivalent. Currently, the literature on this topic is sparse, but the published pharmacokinetic studies and Food and Drug Administration submission data on paliperidone palmitate show discrepancies in the elimination half-life, peak plasma concentration, and absorption rate that are dependent on the site of injection. The degree of shifts in pharmacokinetic parameters suggests that paliperidone palmitate injections via the deltoid and gluteal muscle are not bioequivalent and therefore are not therapeutically equivalent. Thus, using the same maintenance dosing regimen at both sites or switching between sites of injection may result in unforeseen consequences in patient outcomes.

  20. Daily exhaled nitric oxide measurements and asthma exacerbations in children.

    PubMed

    van der Valk, R J P; Baraldi, E; Stern, G; Frey, U; de Jongste, J C

    2012-02-01

    Fractional exhaled Nitric Oxide (FeNO) is a biomarker for eosinophilic airway inflammation and can be measured at home on a daily basis. A short-term increase in FeNO may indicate a higher risk of future asthma exacerbations. To assess changes in FeNO before and after asthma exacerbations compared to a stable control period. A post hoc analysis was performed on daily FeNO measurements over 30 weeks in children with asthma (n = 77). Moderate exacerbations were defined by an increase in symptom scores and severe exacerbations by prescription of prednisone. Individual mean and maximum FeNO, the variability of FeNO assessed by the coefficient of variation (CV), and slopes of FeNO in time were all quantified in 3-week blocks. Cross-correlation of FeNO with symptoms and autocorrelation of FeNO were assessed in relation to exacerbations and examined as predictors for exacerbations compared to reference periods using logistic regression. Fractional exhaled nitric oxide could be assessed in relation to 25 moderate and 12 severe exacerbations. The CV, slope, cross-correlation, and autocorrelation of daily FeNO increased before moderate exacerbations. Increases in slope were also randomly seen in 19% of 2-week blocks of children without exacerbations. At least 3-5 FeNO measurements in the 3 weeks before an exacerbation were needed to calculate a slope that could predict moderate exacerbations. No specific pattern of FeNO was seen before severe exacerbations. Fractional exhaled nitric oxide monitoring revealed changes in FeNO prior to moderate exacerbations. Whether this can be used to prevent loss of asthma control should be further explored. © 2011 John Wiley & Sons A/S.

  1. Seasonal Risk Factors for Asthma Exacerbations among Inner City Children

    PubMed Central

    Teach, Stephen J.; Gergen, Peter J.; Szefler, Stanley J.; Mitchell, Herman E.; Calatroni, Agustin; Wildfire, Jeremy; Bloomberg, Gordon; Kercsmar, Carolyn; Liu, Andrew H.; Makhija, Melanie; Matsui, Elizabeth; Morgan, Wayne; O'Connor, George; Busse, William W.

    2015-01-01

    Background Exacerbations of asthma remain common even in children and adolescents despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly for seasonal episodes. Objective Define host risk factors for asthma exacerbations unique to their season of occurrence. Methods This is a retrospective analysis of patients aged 6-20 years who comprised the control groups of the Asthma Control Evaluation trial and the Inner City Anti-IgE Therapy for Asthma trial. Univariate and multivariate models were constructed to determine if patient demographic and historical factors, allergic sensitization, fractional exhaled nitric oxide, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations. Results The analysis included 400 patients (54.5% male; 59.0% African American; median age 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis, impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis, exacerbation in the previous season was the strongest predictor in fall and winter while a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed). Conclusions Among a large cohort of inner city children with asthma, patient risk factors for exacerbations vary by season. Thus, individual patient information may be beneficial in strategies to prevent these seasonal events. Clinical Implications Inner city children remain at risk for asthma exacerbations despite appropriate therapy. Because their risk factors vary by season, strategies to prevent them may need to differ as

  2. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  3. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.

    PubMed

    An, Lin; Hu, Xiao-Wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-02-22

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.

  4. Golimumab-exacerbated subacute cutaneous lupus erythematosus.

    PubMed

    Wilkerson, Eric; Hazey, Matthew A; Bahrami, Soon; Callen, Jeffrey P

    2012-10-01

    Subacute cutaneous lupus erythematosus (SCLE) is characterized by annular, nonscarring, photodistributed, or papulosquamous lesions. The disease may be idiopathic, drug induced, or drug exacerbated. A 66-year-old woman with a history of hypertension, parkinsonism, rheumatoid arthritis, anxiety and depression, and symptoms of Sjögren syndrome was seen with a 1-month history of an eruption on her upper extremities and upper trunk. The eruption had begun 2 to 3 weeks after subcutaneous injection of golimumab for rheumatoid arthritis. She had developed SCLE 2 years previously due to furosemide use and 10 years previously due to hydrochlorothiazide use. Physical examination revealed scaly, annular, erythematous plaques photodistributed on the arms, legs, and upper trunk. A punch biopsy specimen demonstrated vacuolar interface dermatitis and lymphohistiocytic perivascular inflammation. Serological abnormalities included a positive antinuclear antibody, an elevated anti-La/SS-B antibody level, and an elevated anti-Ro/SS-A antibody level. She was diagnosed as having SCLE and was initially treated with desonide lotion, photoprotection, prednisone (40 mg/d) tapered over 6 weeks, and hydroxychloroquine sulfate (200 mg twice daily). Because of persistent disease, methotrexate sodium (12.5 mg/wk) was subsequently added to the regimen, and her eruption cleared completely. Golimumab should be added to the list of medications capable of inducing or exacerbating SCLE. Our patient demonstrated variable times to the resolution of SCLE, possibly attributable in part to the different half-lives of the agents administered.

  5. Th17 profile in COPD exacerbations

    PubMed Central

    Ponce-Gallegos, Marco Antonio; Ramírez-Venegas, Alejandra; Falfán-Valencia, Ramcés

    2017-01-01

    COPD is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow. It is mainly associated with exposure to cigarette smoke. In addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide. Many cells participate in the pathophysiology of COPD, the most important are neutrophils, macrophages and CD4+ and CD8+ T cells. Neutrophil migration to the inflammation area could be mediated largely by cytokines related to CD4+ Th17 lymphocytes, because it has been shown that IL-17A, IL-17F and IL-22 act as inducers for CXCL8, CXCL1, CXCL5, G-CSF, and GM-CSF secretion by epithelial cells of the airways. The aims of these molecules are differentiation, proliferation and recruitment of neutrophils. Furthermore, it is believed that CD4+ lymphocytes Th17 may be involved in protection against pathogens for which Th1 and Th2 are not prepared to fight. In COPD exacerbations, there is an increased cellularity in the lung region and respiratory tract. Therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of Th17 profile in this entity. PMID:28694696

  6. Antitumor activity of Corynebacterium parvum and retinyl palmitate used in combination on the Lewis lung carcinoma.

    PubMed

    Pavelic, Z P; Dave, S; Bialkowski, S; Priore, R L; Greco, W R

    1980-12-01

    The effects of Corynebacterium parvum and retinyl palmitate given at various levels, schedules, and routes of administration on primary Lewis lung carcinoma and its metastases have been evaluated in C57BL/6J mice given s.c. inoculations of 5 X 10(5) tumor cells. Single i.v., but not i.p., s.c., or i.m., administration of C. parvum (0.35 mg/mouse given on Days 0, 1, or 3) reduced growth of tumor and prolonged survival time. Retinyl palmitate (3000 IU/mouse/day) given alone i.p. either before, after, or both before and after tumor inoculation showed no effect on tumor growth, survival of mice, or lung metastases. The combination of retinyl palmitate i.p. (6 daily injections of 1500 IU/mouse after tumor implantation) and C. parvum (0.175 mg/mouse) given i.v. resulted in an increase in life span over control of 146% and appeared to be therapeutically synergistic. This combination produced 90-day cures in about 20% of the treated animals, all of which were found to be tumor free. Two nonparametric statistical procedures, the Kruskal-Wallis and the Dunn test, were used to assess the effects of treatments on survival time and tumor growth and may be generally applicable to animal tumor studies. They provide multiple comparisons of different treatments and allow the inclusion of long-term survivors into the analysis.

  7. Chronic effects of palmitate overload on nutrient-induced insulin secretion and autocrine signalling in pancreatic MIN6 beta cells.

    PubMed

    Watson, Maria L; Macrae, Katherine; Marley, Anna E; Hundal, Harinder S

    2011-01-01

    Sustained exposure of pancreatic β cells to an increase in saturated fatty acids induces pleiotropic effects on β-cell function, including a reduction in stimulus-induced insulin secretion. The objective of this study was to investigate the effects of chronic over supply of palmitate upon glucose- and amino acid-stimulated insulin secretion (GSIS and AASIS, respectively) and autocrine-dependent insulin signalling with particular focus on the importance of ceramide, ERK and CaMKII signalling. GSIS and AASIS were both stimulated by >7-fold resulting in autocrine-dependent activation of protein kinase B (PKB, also known as Akt). Insulin release was dependent upon nutrient-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) as their pharmacological inhibition suppressed GSIS/AASIS significantly. Chronic (48 h, 0.4 mM) palmitate treatment blunted glucose/AA-induced activation of CaMKII and ERK and caused a concomitant reduction (~75%) in GSIS/AASIS and autocrine-dependent activation of PKB. This inhibition could not be attributed to enhanced mitochondrial fatty acid uptake/oxidation or ceramide synthesis, which were unaffected by palmitate. In contrast, diacylglycerol synthesis was elevated suggesting increased palmitate esterification rather than oxidation may contribute to impaired stimulus-secretion coupling. Consistent with this, 2-bromopalmitate, a non-oxidisable palmitate analogue, inhibited GSIS as effectively as palmitate. Our results exclude changes in ceramide content or mitochondrial fatty acid handling as factors initiating palmitate-induced defects in insulin release from MIN6 β cells, but suggest that reduced CaMKII and ERK activation associated with palmitate overload may contribute to impaired stimulus-induced insulin secretion.

  8. Chronic Effects of Palmitate Overload on Nutrient-Induced Insulin Secretion and Autocrine Signalling in Pancreatic MIN6 Beta Cells

    PubMed Central

    Watson, Maria L.; Macrae, Katherine; Marley, Anna E.; Hundal, Harinder S.

    2011-01-01

    Background Sustained exposure of pancreatic β cells to an increase in saturated fatty acids induces pleiotropic effects on β-cell function, including a reduction in stimulus-induced insulin secretion. The objective of this study was to investigate the effects of chronic over supply of palmitate upon glucose- and amino acid-stimulated insulin secretion (GSIS and AASIS, respectively) and autocrine-dependent insulin signalling with particular focus on the importance of ceramide, ERK and CaMKII signalling. Principal Findings GSIS and AASIS were both stimulated by >7-fold resulting in autocrine-dependent activation of protein kinase B (PKB, also known as Akt). Insulin release was dependent upon nutrient-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) as their pharmacological inhibition suppressed GSIS/AASIS significantly. Chronic (48 h, 0.4 mM) palmitate treatment blunted glucose/AA-induced activation of CaMKII and ERK and caused a concomitant reduction (∼75%) in GSIS/AASIS and autocrine-dependent activation of PKB. This inhibition could not be attributed to enhanced mitochondrial fatty acid uptake/oxidation or ceramide synthesis, which were unaffected by palmitate. In contrast, diacylglycerol synthesis was elevated suggesting increased palmitate esterification rather than oxidation may contribute to impaired stimulus-secretion coupling. Consistent with this, 2-bromopalmitate, a non-oxidisable palmitate analogue, inhibited GSIS as effectively as palmitate. Conclusions Our results exclude changes in ceramide content or mitochondrial fatty acid handling as factors initiating palmitate-induced defects in insulin release from MIN6 β cells, but suggest that reduced CaMKII and ERK activation associated with palmitate overload may contribute to impaired stimulus-induced insulin secretion. PMID:21998735

  9. Dietary palmitic acid influences LDL-mediated lymphocyte proliferation differently to other mono- and polyunsaturated fatty acids in rats.

    PubMed

    Tinahones, F J; Gómez-Zumaquero, J M; Monzón, A; Rojo-Martínez, G; Pareja, A; Morcillo, S; Cardona, F; Olveira, G; Soriguer, F

    2004-10-01

    Recent studies suggest that the biological effects of saturated fatty acids depend on the length of their chain. We compared the effect of diets containing different fatty acids on plasma lipids and lymphocyte proliferation in the presence of lovastatin and with increasing amounts of LDL. Lymphocytes from rats fed with a diet rich in palmitic acid had a greater lymphocyte proliferation capacity than those from rats fed with diets rich in oleic acid, linoleic acid, or fish oil. This effect was maintained when small amounts of polyunsaturatwed fatty acids (PUFA; sunflower oil) were added to the palmitic acid diet. LDL receptor activity, measured by the capacity of lovastatin to revert the inhibition of lymphocyte proliferation with increasing amounts of LDL in the medium, was greater in the rats fed with palmitic acid, and was similar to the other groups when small amounts of PUFA were added. All the groups had similar levels of plasma cholesterol, but the LDL levels were significantly lower in the group fed with palmitic acid plus PUFA. The highest HDL-cholesterol (HDLc) levels were found in the palmitic acid group and the lowest LDL-cholesterol (LDLc)/HDLc ratio in the palmitic acid plus PUFA group. These results suggest that diets rich in palmitic acid do not raise total cholesterol, but reduce LDLc or keep it normal, and raise HDLc levels. This effect may be partly due to an increase in LDL receptor activity. The inclusion of small amounts of PUFA in the diet rich in palmitic acid substantially modified the LDL receptor response in the lymphocytes, suggesting that the proportion of different families of dietary fatty acids may be more important than the individual amount of each in absolute terms to explain their effects on plasma lipids and lipoproteins.

  10. Pharmacological properties of beta-amyrin palmitate, a novel centrally acting compound, isolated from Lobelia inflata leaves.

    PubMed

    Subarnas, A; Tadano, T; Oshima, Y; Kisara, K; Ohizumi, Y

    1993-06-01

    Effects of beta-amyrin palmitate isolated from the leaves of Lobelia inflata were studied on the central nervous system of mice and were compared with those of antidepressant drugs, mianserin and imipramine. In the forced swimming test, beta-amyrin palmitate, like mianserin and imipramine, reduced the duration of immobility of mice significantly in a dose-dependent manner (5, 10 and 20 mg kg-1). beta-Amyrin palmitate (5, 10 and 20 mg kg-1) or mianserin (5, 10 and 20 mg kg-1) elicited a dose-related reduction in locomotor activity of mice and antagonized locomotor stimulation induced by methamphetamine. In contrast, imipramine (5, 10 and 20 mg kg-1) increased locomotor activity and potentiated methamphetamine-induced hyperactivity. beta-Amyrin palmitate showed no effect on reserpine-induced hypothermia, whilst mianserin (10 mg kg-1) and imipramine (10 and 20 mg kg-1) antagonized the reserpine-induced effect. Unlike imipramine, beta-amyrin palmitate and mianserin did not affect haloperidol-induced catalepsy, tetrabenazine-induced ptosis and apomorphine-induced stereotypy. beta-Amyrin palmitate and imipramine had no effects on the head-twitch response induced by 5-hydroxytryptophan, whereas mianserin (5, 10 and 20 mg kg-1) decreased it in a dose-dependent manner. A potentiating effect of beta-amyrin palmitate (5, 10 and 20 mg kg-1) on narcosis induced by sodium pentobarbitone was stronger than that of imipramine (10, 20 and 40 mg kg-1) but weaker than that of mianserin (2.5, 5 and 10 mg kg-1). These results suggest that beta-amyrin palmitate has similar properties in some respects to mianserin and might possess a sedative action.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Metabolic imaging of patients with cardiomyopathy

    SciTech Connect

    Geltman, E.M. )

    1991-09-01

    The cardiomyopathies comprise a diverse group of illnesses that can be characterized functionally by several techniques. However, the delineation of derangements of regional perfusion and metabolism have been accomplished only relatively recently with positron emission tomography (PET). Regional myocardial accumulation and clearance of 11C-palmitate, the primary myocardial substrate under most conditions, demonstrate marked spatial heterogeneity when studied under fasting conditions or with glucose loading. PET with 11C-palmitate permits the noninvasive differentiation of patients with nonischemic from ischemic dilated cardiomyopathy, since patients with ischemic cardiomyopathy demonstrate large zones of intensely depressed accumulation of 11C-palmitate, probably reflecting prior infarction. Patients with hypertrophic cardiomyopathy and Duchenne's muscular dystrophy demonstrate relatively unique patterns of myocardial abnormalities of perfusion and metabolism. The availability of new tracers and techniques for the evaluation of myocardial metabolism (11C-acetate), perfusion (H2(15)O), and autonomic tone (11-C-hydroxyephedrine) should facilitate further understanding of the pathogenesis of the cardiomyopathies.

  12. Increased incorporation of /sup 14/C-palmitate into tissue lipids by isolated heart myocytes in endotoxic shock

    SciTech Connect

    Liu, M.S.

    1982-01-01

    The incorporation of /sup 14/C-palmitate into various classes of tissue lipids by isolated adult dog heart myocytes was studied in an attempt to understand the pathophysiology of myocardial dysfunction during endotoxic shock. The results showed that the incorporation of /sup 14/C-palmitate into phospholipids was increased by 85.3% and 108.8% at 0.5 hours and two hours, respectively, following endotoxin (0.5 mg Escherichia coli lipopolysaccharide B per kg body weight) administration. Incorporation of radioactive palmitate into triglycerides was increased by 50.9% and 107.2% at 0.5 and two hours, respectively, postendotoxin. Incorporation of /sup 14/C-palmitate into diglycerides was stimulated by 51.9% and 64.5% at 0.5 and two hours, respectively, after endotoxin injection. The incorporation of /sup 14/C-palmitate into tissue-free fatty acids and unaltered at 0.5 hours but it was increased by 211.7% at two hours postendotoxin. These data demonstrated that myocardial membrane lipid profile was greatly altered by increased incorporation of /sup 14/C-palmitate into phospholipids and neutral lipids after endotoxin administration. An alteration in myocardial lipid profile, as reported in this study, may contribute to the development of myocardial dysfunction during shock.

  13. The Presence of Cysteine in the Cytoplasmic Domain of the Vesicular Stomatitis Virus Glycoprotein is Required for Palmitate Addition

    NASA Astrophysics Data System (ADS)

    Rose, John K.; Adams, Gregg A.; Gallione, Carol J.

    1984-04-01

    The transmembrane glycoprotein (G protein) of vesicular stomatitis virus (VSV) is known to contain 1-2 mol of covalently linked fatty acid (palmitate) per mol of protein. G protein is oriented in cellular membranes such that the carboxyl-terminal 29 amino acids protrude into the cytoplasm. We have obtained expression in eukaryotic cells of mutagenized cDNA clones that encode VSV G proteins lacking portions of this cytoplasmic domain. Labeling of these truncated proteins with [3H]palmitate indicated that the palmitate might be linked to an amino acid residue within the first 14 residues on the carboxyl-terminal side of the transmembrane domain. Using oligonucleotide directed mutagenesis, we changed the single codon specifying cysteine in this domain to a codon specifying serine. Expression of this mutant gene results in synthesis of a G protein lacking palmitate. We suggest that linkage of palmitate to G protein is through the cysteine in the cytoplasmic domain and that such a linkage may occur in many viral and cellular glycoproteins. The G protein lacking palmitate is glycosylated and is transported normally to the cell surface.

  14. Molecular characterization of two high-palmitic-acid mutant loci induced by X-ray irradiation in soybean.

    PubMed

    Anai, Toyoaki; Hoshino, Tomoki; Imai, Naoko; Takagi, Yutaka

    2012-01-01

    Palmitic acid is the most abundant (approx. 11% of total fatty acids) saturated fatty acid in conventional soybean seed oil. Increasing the saturated acid content of soybean oil improves its oxidative stability and plasticity. We have developed three soybean mutants with high palmitic acid content by X-ray irradiation. In this study, we successfully identified the mutated sites of two of these high-palmitic-acid mutants, J10 and M22. PCR-based mutant analysis revealed that J10 has a 206,203-bp-long deletion that includes the GmKASIIA gene and 16 other predicted genes, and M22 has a 26-bp-long deletion in the sixth intron of GmKASIIB. The small deletion in M22 causes mis-splicing of GmKASIIB transcripts, which should result in nonfunctional products. In addition, we designed co-dominant marker sets for these mutant alleles and confirmed the association of genotypes and palmitic acid contents in F(2) seeds of J10 X M22. This information will be useful in breeding programs to develop novel soybean cultivars with improved palmitic acid content. However, in the third mutant, KK7, we found no polymorphism in either GmKASIIA or GmKASIIB, which suggests that several unknown genes in addition to GmKASIIA and GmKASIIB may be involved in elevating the palmitic acid content of soybean seed oil.

  15. Fatty Acid Chain Elongation in Palmitate-perfused Working Rat Heart

    PubMed Central

    Kerner, Janos; Minkler, Paul E.; Lesnefsky, Edward J.; Hoppel, Charles L.

    2014-01-01

    Rat hearts were perfused with [1,2,3,4-13C4]palmitic acid (M+4), and the isotopic patterns of myocardial acylcarnitines and acyl-CoAs were analyzed using ultra-HPLC-MS/MS. The 91.2% 13C enrichment in palmitoylcarnitine shows that little endogenous (M+0) palmitate contributed to its formation. The presence of M+2 myristoylcarnitine (95.7%) and M+2 acetylcarnitine (19.4%) is evidence for β-oxidation of perfused M+4 palmitic acid. Identical enrichment data were obtained in the respective acyl-CoAs. The relative 13C enrichment in M+4 (84.7%, 69.9%) and M+6 (16.2%, 17.8%) stearoyl- and arachidylcarnitine, respectively, clearly shows that the perfused palmitate is chain-elongated. The observed enrichment of 13C in acetylcarnitine (19%), M+6 stearoylcarnitine (16.2%), and M+6 arachidylcarnitine (17.8%) suggests that the majority of two-carbon units for chain elongation are derived from β-oxidation of [1,2,3,4-13C4]palmitic acid. These data are explained by conversion of the M+2 acetyl-CoA to M+2 malonyl-CoA, which serves as the acceptor for M+4 palmitoyl-CoA in chain elongation. Indeed, the 13C enrichment in mitochondrial acetyl-CoA (18.9%) and malonyl-CoA (19.9%) are identical. No 13C enrichment was found in acylcarnitine species with carbon chain lengths between 4 and 12, arguing against the simple reversal of fatty acid β-oxidation. Furthermore, isolated, intact rat heart mitochondria 1) synthesize malonyl-CoA with simultaneous inhibition of carnitine palmitoyltransferase 1b and 2) catalyze the palmitoyl-CoA-dependent incorporation of 14C from [2-14C]malonyl-CoA into lipid-soluble products. In conclusion, rat heart has the capability to chain-elongate fatty acids using mitochondria-derived two-carbon chain extenders. The data suggest that the chain elongation process is localized on the outer surface of the mitochondrial outer membrane. PMID:24558043

  16. Take my breath away: a case of lactic acidosis in an asthma exacerbation.

    PubMed

    McGonigle, Reid; Woods, Robert A

    2011-07-01

    A 36-year-old male with a history of chronic asthma presented to an emergency department with shortness of breath consistent with an asthma exacerbation. He had persistent tachypnea following inhaled bronchodilator treatment; thus, the workup and differential diagnosis were expanded. He was found to have a mixed respiratory alkalosis and metabolic acidosis with elevated serum lactate without an obvious cause and was admitted to hospital. His case was reviewed, and the lactic acidosis was thought to be caused by inhaled β2-agonist use. Emergency physicians should be aware of the potential side effects of inhaled β2-agonists as lactic acidosis may complicate clinical assessment and management of asthma exacerbations and lead to unnecessary and potentially dangerous escalations in therapy.

  17. Airways inflammation and treatment during acute exacerbations of COPD

    PubMed Central

    Bathoorn, Erik; Kerstjens, Huib; Postma, Dirkje; Timens, Wim; MacNee, William

    2008-01-01

    Introduction Inflammation is a core feature of acute chronic obstructive pulmonary disease (COPD) exacerbations. It is important to focus on inflammation since it gives insight into the pathological changes causing an exacerbation, thereby possibly providing directions for future therapies which modify inflammation. Objectives To provide a cell-by-cell overview of the inflammatory processes during COPD exacerbations. To evaluate cell activation, and cytokine production, cellular interactions, damaging effects of inflammatory mediators to tissue, and the relation to symptoms at the onset of COPD exacerbations. To speculate on future therapeutic options to modify inflammation during COPD exacerbations. Results During COPD exacerbations, there is increased airway wall inflammation, with pathophysiological influx of eosinophils, neutrophils, and lymphocytes. Although links have been suggested between the increase in eosinophils and lymphocytes and a viral etiology of the exacerbation, and between the increase in neutrophils and a bacterial aetiology, these increases in both inflammatory cell types are not limited to the respective aetiologies and the underlying mechanisms remain elusive. Conclusion Further research is required to fully understand the inflammatory mechanisms in the onset and development of COPD exacerbations. This might make inflammatory pathway-specific intervention possible, resulting in a more effective treatment of COPD exacerbations with fewer side effects. PMID:18686731

  18. [Treatment of multiple sclerosis symptoms and exacerbations].

    PubMed

    Prieto González, José María

    2014-12-01

    In the last few years, there has been an explosion of new drugs acting on the clinical course of multiple sclerosis (MS) but less attention has been paid to better knowledge of the symptoms of this disease and their pathogenesis and treatment, which is essential to improve patients' quality of life. Because many patients have numerous concurrent symptoms during their clinical course, their management is complex and consequently it is important to know which symptoms are a direct result of the degenerative lesions of MS. The present article describes all the therapeutic options available for spasticity and its associated pain, paroxystic symptoms, fatigue, genitourinary disorders and sexual dysfunction, tremor, ataxia, gait disorder and cognitive impairment, with special emphasis on novel treatments. The article also defines exacerbations, how to recognize them and the available treatments, mainly oral administration of high-dose methylprednisolone and plasmapheresis. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  19. SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.

    PubMed

    Lu, Zhongping; Bourdi, Mohammed; Li, Jian H; Aponte, Angel M; Chen, Yong; Lombard, David B; Gucek, Marjan; Pohl, Lance R; Sack, Michael N

    2011-07-01

    Acetaminophen/paracetamol-induced liver failure--which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption--is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice to toxic metabolite-mediated disruption of mitochondrial proteins. We show that mitochondrial deacetylase SIRT3(-/-) mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. Thus, protein deacetylation enhances xenobiotic liver injury by modulating the binding of a toxic metabolite to mitochondrial proteins.

  20. Exacerbating factors of itch in atopic dermatitis.

    PubMed

    Murota, Hiroyuki; Katayama, Ichiro

    2017-01-01

    Atopic dermatitis (AD) displays different clinical symptoms, progress, and response to treatment during early infancy and after childhood. After the childhood period, itch appears first, followed by formation of well-circumscribed plaque or polymorphous dermatoses at the same site. When accompanied with dermatitis and dry skin, treatment of skin lesions should be prioritized. When itch appears first, disease history, such as causes and time of appearance of itch should be obtained by history taking. In many cases, itch increases in the evening when the sympathetic nerve activity decreased. Treatment is provided considering that hypersensitivity to various external stimulations can cause itch. Heat and sweating are thought to especially exacerbate itch. Factors causing itch, such as cytokines and chemical messengers, also induce itch mainly by stimulating the nerve. Scratching further aggravates dermatitis. Skin hypersensibility, where other non-itch senses, such as pain and heat, are felt as itch, sometimes occurs in AD. Abnormal elongation of the sensory nerve into the epidermis, as well as sensitizing of the peripheral/central nerve, are possible causes of hypersensitivity, leading to itch. To control itch induced by environmental factors such as heat, treatment for dermatitis is given priority. In the background of itch exacerbated by sweating, attention should be given to the negative impact of sweat on skin homeostasis due to 1) leaving excess sweat on the skin, and 2) heat retention due to insufficient sweating. Excess sweat on the skin should be properly wiped off, and dermatitis should be controlled so that appropriate amount of sweat can be produced. Not only stimulation from the skin surface, but also visual and auditory stimulation can induce new itch. This "contagious itch" can be notably observed in patients with AD. This article reviews and introduces causes of aggravation of itch and information regarding how to cope with such causes.

  1. Clinical presentation of metabolic alkalosis in an adult patient with cystic fibrosis.

    PubMed

    Sweetser, Lisel J; Douglas, James A; Riha, Renata L; Bell, Scott C

    2005-03-01

    In subtropical and tropical climates, dehydration is common in cystic fibrosis patients with respiratory exacerbations. This may lead to a clinical presentation of metabolic alkalosis with associated hyponatraemia and hypochloraemia. An adult cystic fibrosis patient who presented with a severe respiratory exacerbation accompanied by metabolic alkalosis is presented and the effects of volume correction are reported.

  2. Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol.

    PubMed

    Favre, Julie; Yildirim, Cansu; Leyen, Thomas A; Chen, Weena J Y; van Genugten, Renate E; van Golen, Larissa W; Garcia-Vallejo, Juan-Jesus; Musters, Rene; Baggen, Josefien; Fontijn, Ruud; van der Pouw Kraan, Tineke; Serné, Erik; Koolwijk, Pieter; Diamant, Michaela; Horrevoets, Anton J G

    2015-12-01

    A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.

  3. Susceptibility to exacerbation in chronic obstructive pulmonary disease.

    PubMed

    Hurst, John R; Vestbo, Jørgen; Anzueto, Antonio; Locantore, Nicholas; Müllerova, Hana; Tal-Singer, Ruth; Miller, Bruce; Lomas, David A; Agusti, Alvar; Macnee, William; Calverley, Peter; Rennard, Stephen; Wouters, Emiel F M; Wedzicha, Jadwiga A

    2010-09-16

    Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the

  4. Fate of the naphthenic acid, U-{sup 14}C-palmitic acid, in constructed wetlands; A microcosm study

    SciTech Connect

    Wood, A.; Barjaktarovic, L.; Moore, M.; Kennedy, C.; Farrell, A.P.; Bendell-Young, L.I.

    1995-12-31

    This study represents part of an overall initiative to assess the ecological viability of constructed wetlands for the treatment of oil sands wastewater. To determine the fate of naphthenic acids (C{sub n}H{sub 2n+z}O{sub 2}), the most toxic component of oil sands wastewater, in constructed wetlands, a representative naphthenic acid (NA), U-{sup 14}C-palmitic acid was added to microcosms placed within three control and three treatment wetlands. Treatment wetlands receive wastewater typical of effluent resulting from the oil sands extraction process. In each of the 6 microcosms, biotic compartments measured for {sup 14}C at t = 0, 1, 3, 5, 7, 14 and 21 days were: mineralized palmitic acid (evolved {sup 14}C-CO{sub 2}), water, suspended sediments, bottom sediments, cattail, chironomid larvae, and sticklebacks (liver, muscle and skin). The fate of the {sup 14}C-palmitic acid was similar between the control versus treatment microcosms. Exceptions were greater amounts of {sup 14}C-palmitic acid detected in water and suspended sediments of treatment versus control microcosms. Of the biotic compartments, at t = 21 days, the majority of the {sup 14}C-palmitic acid was found in chironomids and fish tissues. Mineralization and partitioning of {sup 14}C-palmitic acid onto sediments also represented important fates. From the initial addition of the labelled compound, with the exception of bottom sediments, by t = 1 day {sup 14}C was detected in ail biotic compartments. {sup 14}C was detected in bottom sediments by t = 7 days. These results indicate that in addition to mineralization being an important process influencing the fate palmitic acid within the wetlands, partitioning into biotic compartments such as chironomids and fish are also important fates. Hence, when considering the use of constructed wetlands for the treatment of oil sands effluent, the adverse effects of naphthenic acids on the biota needs to be fully addressed.

  5. Vitamin A palmitate and α-lipoic acid stability in o/w emulsions for cosmetic application.

    PubMed

    Moyano, M A; Segall, A

    2011-01-01

    Skin becomes thin, dry, pale, and finely wrinkled with age. Retinoids are a large class of compounds that are important in modern therapy for dermatological treatment of wrinkled skin. Of the retinoids, retinol and vitamin A palmitate are thought to induce thickening of the epidermis and to be effective for treatment of skin diseases. Accordingly, α-lipoic acid or the reduced form, dihydrolipoate, are potent scavengers of hydroxyl radicals, superoxide radicals, peroxyl radicals, singlet oxygen, and nitric oxide with anti-inflammatory properties (1). Cosmetic ingredient stability prediction relies on kinetic quantitative chemical analysis of active components at different temperatures. Vitamin A palmitate and α-lipoic acid, are known to be unstable to light or heat (2). The aims of this study were to evaluate the stability of α-lipoic acid and vitamin A palmitate in the presence of vitamin E (acetate) and other antioxidants in lipophilic/hydrophilic medium (O/W emulsions) at pH 3.0, 5.0, and 7.0. The formulations that were investigated contained 0.12% (w/w) vitamin A palmitate, 0.4% (w/w) vitamin E acetate, and 0.5 % α-lipoic acid (formulation A), supplemented with ascorbyl palmitate, magnesium ascorbyl phosphate, and vitamin C (formulation B) or with butylhydroxytoluene (BHT, formulation C) or ascorbyl palmitate (formulation D). The chemical analyses of α-lipoic acid and vitamin A palmitate were carried out by HPLC. Formulations C and D at pH 7.0 were selected as the most stable for these components. The purpose of this paper is the selection of the most stable formulations for their application in in vivo studies.

  6. Palmitate increases musclin gene expression through activation of PERK signaling pathway in C2C12 myotubes.

    PubMed

    Gu, Ning; Guo, Qian; Mao, Ke; Hu, Hailong; Jin, Sanli; Zhou, Ying; He, Hongjuan; Oh, Yuri; Liu, Chuanpeng; Wu, Qiong

    2015-11-20

    Musclin is a type of muscle-secreted cytokine and its increased gene expression induces insulin resistance in type 2 diabetes. However, the mechanism underlying increased musclin gene expression is currently unclear. Excessive saturated fatty acids (SFA) can activate the secretion of several muscle-secreted cytokines as well as endoplasmic reticulum (ER) stress pathway, thereby contributing to the development of type 2 diabetes. The purpose of this study was to investigate the mechanisms responsible for the effect of palmitate, the most abundant SFA in the plasma, on the gene expression of musclin in C2C12 myotubes. Treatment of C2C12 myotubes with palmitate or tunicamycin significantly increased the expression of musclin as well as ER stress-related genes, but treatment with oleate did not. Pre-treatment of C2C12 myotubes with 4-phenyl butyrate suppressed the expression of ER stress-related genes, simultaneously, resulting in decreased expression of the musclin gene induced by palmitate or tunicamycin. These results indicate that ER stress is related to palmitate-induced musclin gene expression. Moreover, palmitate-induced musclin gene expression was significantly inhibited in C2C12 myotubes when PERK pathway signaling was suppressed by knockdown of the PERK gene or treatment with GSK2656157, a PERK autophosphorylation inhibitor. However, there was no difference in the palmitate-induced musclin gene expression when IRE1 and ATF6 signaling pathways were suppressed by knockdown of the IRE1 and ATF6 genes. These findings suggest that palmitate increases musclin gene expression via the activation of the PERK signaling pathway in C2C12 myotubes.

  7. Cytotoxicity, oxidative stress and inflammation induced by ZnO nanoparticles in endothelial cells: interaction with palmitate or lipopolysaccharide.

    PubMed

    Gong, Yu; Ji, Yuejia; Liu, Fang; Li, Juan; Cao, Yi

    2016-11-15

    Recent studies showed that ZnO nanoparticles (NPs) might induce the toxicity to human endothelial cells. However, little is known about the interaction between ZnO NPs and circulatory components, which is likely to occur when NPs enter the blood. In this study, we evaluated ZnO NP-induced cytotoxicity, oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs), with the emphasis on the interaction with palmitate (PA) or lipopolysaccharide (LPS), because PA and LPS are normal components in human blood that increase in metabolic diseases. Overall, ZnO NPs induced cytotoxicity and intracellular reactive oxygen species (ROS) at a concentration of 32 μg ml(-1) , but did not significantly affect the release of inflammatory cytokines or adhesion of THP-1 monocytes to HUVECs. In addition, exposure to ZnO NPs dose-dependently promoted intracellular Zn ions in HUVECs. PA and LPS have different effects. Two hundred μm PA significantly induced cytotoxicity and THP-1 monocyte adhesion, but did not affect ROS or release of inflammatory cytokines. In contrast, 1 μg ml(-1) LPS significantly induced ROS, release of inflammatory cytokines and THP-1 monocyte adhesion, but not cytotoxicity. The presence of ZnO NPs did not significantly affect the toxicity induced by PA or LPS. In addition, the accumulation of Zn ions after ZnO NP exposure was not significantly affected by the presence of PA or LPS. We concluded that there was no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro. Copyright © 2016 John Wiley & Sons, Ltd.

  8. Preparation and properties of films cast from mixtures of poly(vinyl alcohol) and submicron particles prepared from amylose-palmitic acid inclusion complexes.

    PubMed

    Fanta, George F; Selling, Gordon W; Felker, Frederick C; Kenar, James A

    2015-05-05

    The use of starch in polymer composites for film production has been studied for increasing biodegradability, improving film properties and reducing cost. In this study, submicron particles were prepared from amylose-sodium palmitate complexes both by rapidly cooling jet-cooked starch-palmitic acid mixtures and by acidifying solutions of starch-sodium palmitate complexes. Films were cast containing poly(vinyl alcohol) (PVOH) with up to 50% starch particles. Tensile strength decreased and Young's modulus increased with starch concentration, but percent elongations remained similar to controls regardless of preparation method or starch content. Microscopy showed particulate starch distribution in films made with rapidly cooled starch-palmitic acid particles but smooth, diffuse starch staining with acidified sodium palmitate complexes. The mild effects on tensile properties suggest that submicron starch particles prepared from amylose-palmitic acid complexes provide a useful, commercially viable approach for PVOH film modification.

  9. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis

    PubMed Central

    Lee, J.S.; Song, J.W.; Wolters, P.J.; Elicker, B.M.; King, T.E.; Kim, D.S.; Collard, H.R.

    2017-01-01

    Some patients with idiopathic pulmonary fibrosis experience acute exacerbations in their respiratory status leading to substantial morbidity and mortality. Occult aspiration of gastric contents has been proposed as one possible mechanism leading to these acute exacerbations. We sought to determine whether pepsin, amarker of gastric aspiration, is elevated in bronchoalveolar lavage fluid obtained from patients during acute exacerbation of idiopathic pulmonary fibrosis, compared with that obtained in stable disease. Lavage samples were obtained in a case–control study of well-characterised patients. Acute exacerbation was defined using standard criteria. Levels of lavage pepsin were compared in cases and controls, and were correlated with clinical features and disease course. 24 cases with acute exacerbations and 30 stable controls were identified. There were no significant differences in baseline demographics between the two groups. Pepsin level was an indicator of acute exacerbation status (p=0.04). On average, pepsin appeared higher in patients with acute exacerbations compared with stable controls. This difference was driven by a subgroup of eight patients (33%) with pepsin levels ≥70 ng·mL−1. Pepsin level was not an independent predictor of survival time. These results suggest occult aspiration may play a role in some cases of acute exacerbation of idiopathic pulmonary fibrosis. PMID:22183478

  10. Skin phototoxicity of cosmetic formulations containing photounstable and photostable UV-filters and vitamin A palmitate.

    PubMed

    Gaspar, Lorena R; Tharmann, Julian; Maia Campos, Patricia M B G; Liebsch, Manfred

    2013-02-01

    The aim of this study was to evaluate the in vitro skin phototoxicity of cosmetic formulations containing photounstable and photostable UV-filters and vitamin A palmitate, assessed by two in vitro techniques: 3T3 Neutral Red Uptake Phototoxicity Test and Human 3-D Skin Model In Vitro Phototoxicity Test. For this, four different formulations containing vitamin A palmitate and different UV-filters combinations, two of them considered photostable and two of them considered photounstable, were prepared. Solutions of each UV-filter and vitamin under study and solutions of four different combinations under study were also prepared. The phototoxicity was assessed in vitro by the 3T3 NRU phototoxicity test (3T3-NRU-PT) and subsequently in a phototoxicity test on reconstructed human skin model (H3D-PT). Avobenzone presented a pronounced phototoxicity and vitamin A presented a tendency to a weak phototoxic potential. A synergistic effect of vitamin A palmitate on the phototoxicity of combinations containing avobenzone was observed. H3D-PT results did not confirm the positive 3T3-NRU-PT results. However, despite the four formulations studied did not present any acute phototoxicity potential, the combination 2 containing octyl methoxycinnamate (OMC), avobenzone (AVB) and 4-methylbenzilidene camphor (MBC) presented an indication of phototoxicity that should be better investigated in terms of the frequency of photoallergic or chronic phototoxicity in humans, once these tests are scientifically validated only to detect phototoxic potential with the aim of preventing phototoxic reactions in the general population, and positive results cannot predict the exact incidence of phototoxic reactions in humans.

  11. Anti-Angiogenic Properties of Cafestol and Kahweol Palmitate Diterpene Esters.

    PubMed

    Moeenfard, Marzieh; Cortez, Alice; Machado, Vera; Costa, Raquel; Luís, Carla; Coelho, Pedro; Soares, Raquel; Alves, Arminda; Borges, Nuno; Santos, Alejandro

    2016-12-01

    Epidemiological studies support the association of coffee-specific diterpenes, with various beneficial health effects. Although anti-antiangiogenic properties of free cafestol and kahweol have been recently described, available data regarding their esterified form, in particular palmitate esters as the main diterpene esters present in coffee, are still rare. Given that angiogenesis plays an important role in many pathological conditions, including cancer growth and metastasis, this study aimed to assess and compare the potential anti-angiogenic effects of cafestol palmitate (CP) and kahweol palmitate (KP) in an in vitro angiogenesis model. According to our findings, both compounds inhibited angiogenesis steps on human microvascular endothelial cells (HMVECs), although a more significant effect was observed for KP. Compared to control, HMVECs viability decreased in a dose-dependent manner upon incubation either with CP or KP. Concentrations of 75 and 100 μM of each compound were cytotoxic. Cell proliferation was also dramatically reduced by both diterpene esters at 50 μM, although KP had a stronger inhibitory effect. However, CP and KP did not induce apoptosis on HMVECs. Both compounds reduced cell migration, but this effect was only statistically significant after KP incubation. Inhibition of VEGFR2 expression and its downstream effector Akt, but not Erk, was also observed in CP- and KP-treated HMVECs. These findings were confirmed using ELISA assay for phosphorylated (active) VEGFR-2. Taken together, these data indicate that both CP and KP can be considered potent compounds against angiogenesis-dependent disorders. Our findings further indicate that KP exerts more potent anti-angiogenic effects than CP, in most of assays. J. Cell. Biochem. 117: 2748-2756, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Prevention of COPD exacerbations: medications and other controversies.

    PubMed

    Vestbo, Jørgen; Lange, Peter

    2015-05-01

    Exacerbations have significant impact on the morbidity and mortality of patients with chronic obstructive pulmonary disease. Most guidelines emphasise prevention of exacerbations by treatment with long-acting bronchodilators and/or anti-inflammatory drugs. Whereas most of this treatment is evidence-based, it is clear that patients differ regarding the nature of exacerbations and are likely to benefit differently from different types of treatment. In this short review, we wish to highlight this, suggest a first step in differentiating pharmacological exacerbation prevention and call for more studies in this area. Finally, we wish to highlight that there are perhaps easier ways of achieving similar success in exacerbation prevention using nonpharmacological tools.

  13. [Management of an acute exacerbation of asthma and COPD].

    PubMed

    Leuppi, Jörg D; Ott, Sebastian R

    2014-05-01

    Asthma and chronic obstructive airways disease are chronic pulmonary diseases which have a high prevalence world-wide. Both conditions can deteriorate acutely and potentially put patients into life-threatening situations. Management of an acute exacerbation starts in the emergency consultation-setting and ends only once the longterm management has been thoroughly assessed and optimised in order to prevent future exacerbations. Exacerbation frequency is strongly associated with long-term morbidity and mortality in both diseases. Recent data have shown that short-course systemic steroids (5 days) for the treatment of an acute exacerbation of COPD are as successful as long-course treatments (14 days) in preventing exacerbations during the subsequent 6 months. Similarly the targeted use of antibiotics is discussed in this review.

  14. Immune Responses in Rhinovirus-Induced Asthma Exacerbations.

    PubMed

    Steinke, John W; Borish, Larry

    2016-11-01

    Acute asthma exacerbations are responsible for urgent care visits and hospitalizations; they interfere with school and work productivity, thereby driving much of the morbidity and mortality associated with asthma. Approximately 80 to 85 % of asthma exacerbations in children, adolescents, and less frequently adults are associated with viral upper respiratory tract viral infections, and rhinovirus (RV) accounts for ∼60-70 % of these virus-associated exacerbations. Evidence suggests that it is not the virus itself but the nature of the immune response to RV that drives this untoward response. In particular, evidence supports the concept that RV acts to exacerbate an ongoing allergic inflammatory response to environmental allergens present at the time of the infection. The interaction of the ongoing IgE- and T cell-mediated response to allergen superimposed on the innate and adaptive immune responses to the virus and how this leads to triggering of an asthma exacerbation is discussed.

  15. The causes and consequences of seasonal variation in COPD exacerbations

    PubMed Central

    Donaldson, Gavin C; Wedzicha, Jadwiga A

    2014-01-01

    The time of year when patients experience exacerbations of chronic obstructive pulmonary disease is a much-overlooked feature of the disease. The higher incidence of exacerbations in winter has important consequences for patients in terms of increased morbidity and mortality. The seasonality also imposes a considerable burden on already-overloaded health care services, with both primary care consultations and hospital admissions increasing in number. The seasonality of exacerbations varies with latitude, and is greater in more temperate climates, where there may be less protection from outdoor and indoor cold exposure. The precise causes of the seasonality are unknown, but thought to be partly due to the increased prevalence of respiratory viral infections circulating in cold, damp conditions. Increased susceptibility to viral infection may also be a mechanism mediated through increased airway inflammation or possibly reduced vitamin D levels. The seasonality of exacerbations informs us about the triggers of exacerbations and suggests possible strategies to reduce their number. PMID:25336941

  16. Effect of Fatty Acids on Human Bone Marrow Mesenchymal Stem Cell Energy Metabolism and Survival

    PubMed Central

    Fillmore, Natasha; Huqi, Alda; Jaswal, Jagdip S.; Mori, Jun; Paulin, Roxane; Haromy, Alois; Onay-Besikci, Arzu; Ionescu, Lavinia; Thébaud, Bernard; Michelakis, Evangelos; Lopaschuk, Gary D.

    2015-01-01

    Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation. We report here the first direct evidence that human bone marrow mesenchymal stem cell (BMMSC) energy metabolism is highly glycolytic with low rates of mitochondrial oxidative metabolism. The contribution of glycolysis to ATP production is greater than 97% in undifferentiated BMMSCs, while glucose and fatty acid oxidation combined only contribute 3% of ATP production. We also assessed the effect of physiological levels of fatty acids on human BMMSC survival and energy metabolism. We found that the saturated fatty acid palmitate induces BMMSC apoptosis and decreases proliferation, an effect prevented by the unsaturated fatty acid oleate. Interestingly, chronic exposure of human BMMSCs to physiological levels of palmitate (for 24 hr) reduces palmitate oxidation rates. This decrease in palmitate oxidation is prevented by chronic exposure of the BMMSCs to oleate. These results suggest that reducing saturated fatty acid oxidation can decrease human BMMSC proliferation and cause cell death. These results also suggest that saturated fatty acids may be involved in the long-term impairment of BMMSC survival in vivo. PMID:25768019

  17. Normal mode analyses of methyl palmitate all-trans and disordered forms in wagging progressive region.

    PubMed

    Ishioka, Tsutomu; Yan, Wenhong; Strauss, Herbert L; Snyder, Robert G

    2003-03-01

    Normal mode analyses are made for methyl palmitate molecule having all-trans or conformational disorders around the ester head group, in order to explain characteristic observed frequency shifts in the wagging progressive region between all-trans and disorder chains in triglyceride molecules. It was found that one gauche conformation at C(alpha)-C(beta) position and 90 degrees rotation of the ester head group in an alkyl chain produce frequency shifts for twisting mode as observed. For wagging modes, contamination of the disorders around the head group makes assignments change and apparent frequency shifts occur.

  18. Ascorbyl palmitate-loaded chitosan nanoparticles: characteristic and polyphenol oxidase inhibitory activity.

    PubMed

    Kim, Mi Kyung; Lee, Ji-Soo; Kim, Kwang Yup; Lee, Hyeon Gyu

    2013-03-01

    The aim of this study was to produce ascorbyl palmitate (AP)-loaded nanoparticles in order to inhibit polyphenol oxidase (PPO) in bananas. AP-loaded chitosan nanoparticles were prepared using acetic acid and citric acid (denoted as CS/AA and CS/CA nanoparticles, respectively). As the initial AP concentration increases, the particle size significantly decreases, and the zeta potential, entrapment and loading efficiency significantly increases. The PPO inhibitory activity of AP was effectively improved when AP was nano-encapsulated by chitosan compared to no encapsulation. These results suggest that chitosan nano-encapsulation can be used to enhance the PPO inhibitory activity of AP.

  19. Five Month-Persistent Extrapyramidal Symptoms following a Single Injection of Paliperidone Palmitate: A Case Report.

    PubMed

    Jang, Seoyoung; Woo, Jungmin

    2017-08-31

    Long-acting injectable (LAI) antipsychotics are useful in the treatments for schizophrenic patients with poor adherence due to their maintaining feature of therapeutic plasma level without daily administrations. However, their long-lasting property can cause complicated problems such as a long-lasting side effect. We report a patient who experienced LAI-induced extrapyramidal symptoms (EPSs) for 5 months after a single injection. During that period, every trial to ameliorate this condition turned out to be a failure. The 3-month formulation of paliperidone palmitate is now close at hand. We have to be aware of possible long-lasting adverse events and confirm the tolerability to LAI before use.

  20. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia.

    PubMed

    Hough, David; Lindenmayer, Jean-Pierre; Gopal, Srihari; Melkote, Rama; Lim, Pilar; Herben, Virginie; Yuen, Eric; Eerdekens, Marielle

    2009-08-31

    Paliperidone palmitate is an investigational, injectable atypical antipsychotic. The safety and tolerability of initiating treatment with paliperidone palmitate via deltoid versus gluteal injections given once monthly, and of switching injection sites, in adults with stable schizophrenia were assessed. In this crossover trial, stable outpatients (N=252) were randomly assigned 1:1:1 to 3 dose groups (paliperidone palmitate 50, 75, or 100 mg eq.) and 2 treatment sequences (blinded to dose): deltoid muscle (period 1 [13 weeks]) followed by gluteal muscle (period 2 [12 weeks]) or the reverse. The intent-to-treat analysis set had 249 patients: mean age=43 (SD: 12.8) years; 57% men, 81% white, baseline mean Positive and Negative Syndrome Scale (PANSS) total score=56 (SD: 11.5). A total of 170 (68%) patients completed the study, with a similar proportion completing each treatment sequence. The incidence of systemic treatment-emergent adverse events (TEAEs) was similar between the 2 injection sites across doses during period 1 (deltoid [D]: 61% to 67%; gluteus [G]: 58% to 65%), and during the last 8 weeks of the 2 study periods (DG: 32% to 45% [period 1], 29% to 42% [period 2]; GD: 31% to 40% [period 1], 30% to 41% [period 2]). During the first treatment week, median plasma paliperidone concentrations were higher with treatment initiation in the deltoid muscle compared with the gluteal muscle. At apparent steady state, there was little difference in plasma paliperidone concentrations between the deltoid and gluteus sites for a given dose. Local tolerability was slightly better with gluteal injections. Patient preference for injection sites differed between geographical regions, e.g. patients from the US preferred deltoid to gluteal sites. The most common (>or=5% overall) TEAEs were: (period 1) insomnia, anxiety, headache, and agitation; and (period 2) insomnia, psychotic disorder, weight increased, and tachycardia. Paliperidone palmitate treatment was tolerated

  1. Metabolic precursors of surfactant disaturated-phosphatidylcholine in preterms with respiratory distress

    PubMed Central

    Cogo, Paola E.; Ori, Carlo; Simonato, Manuela; Verlato, Giovanna; Isak, Ilena; Hamvas, Aaron; Carnielli, Virgilio P.

    2009-01-01

    Our objective was to study the metabolic precursors of surfactant disaturated-phosphatidylcholine (DSPC) in preterm infants with respiratory distress syndrome (RDS) on mechanical ventilation. We performed 46 DSPC kinetic studies in 23 preterms on fat-free parenteral nutrition and mechanical ventilation (birth weight = 1167 ± 451 g, gestational age = 28.5 ± 2.0 weeks). Eight infants received a simultaneous intravenous infusion of U13C-glucose and [16,16,16]2H-palmitate, eight infants received U13C-glucose and 2H2O, and seven received U13C-palmitate and 2H2O. Surfactant DSPC kinetics were calculated from the isotopic enrichments of DSPC-palmitate from sequential tracheal aspirates and its metabolic precursors in plasma or urine. DSPC fractional synthesis rate (FSR) was 17 ± 11, 21 ± 16, and 15 ± 6%/day from glucose, palmitate, and body water, respectively (P = 0.36). DSPC-FSR from U13C-glucose and 2H2O were significantly correlated and yielded similar estimates (difference of –0.1 ± 3%) (P = 0.91). The difference in the 15 infants receiving palmitate versus 2H2O or palmitate versus glucose was +6.0 ± 12%/day (P = 0.21). There was a significant correlation between DSPC-FSRs from plasma glucose and plasma FFA. The contribution of glucose versus palmitate to DSPC-FSR was 49 ± 20% versus 51 ± 20%, respectively. Plasma glucose and FFA showed similar contributions to DSPC-FSR in infants with RDS and fat-free parenteral nutrition. FSRs from 2H2O or glucose were highly correlated. PMID:19474458

  2. Frequent exacerbators--a distinct phenotype of severe asthma.

    PubMed

    Kupczyk, M; ten Brinke, A; Sterk, P J; Bel, E H; Papi, A; Chanez, P; Nizankowska-Mogilnicka, E; Gjomarkaj, M; Gaga, M; Brusselle, G; Dahlén, B; Dahlén, S-E

    2014-02-01

    Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 μg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice. © 2013 John Wiley & Sons Ltd.

  3. The effect of cetyl palmitate crystallinity on physical properties of gamma-oryzanol encapsulated in solid lipid nanoparticles

    NASA Astrophysics Data System (ADS)

    Ruktanonchai, Uracha; Limpakdee, Surachai; Meejoo, Siwaporn; Sakulkhu, Usawadee; Bunyapraphatsara, Nuntavan; Junyaprasert, Varaporn; Puttipipatkhachorn, Satit

    2008-03-01

    This present study was aimed at investigating the effect of the crystallinity of cetyl palmitate based solid lipid nanoparticles (SLNs) on the physical properties of γ-oryzanol-loaded SLNs. SLNs consisting of varying ratios of cetyl palmitate and γ-oryzanol were prepared. Their hydrodynamic diameters were in the range 210-280 nm and the zeta potentials were in the range -27 to -35 mV. The size of SLNs increased as the amount of cetyl palmitate decreased whereas no significant change of zeta potentials was found. Atomic force microscopy pictures indicated the presence of disc-like particles. The crystallinity of SLNs, determined by differential scanning calorimetry and powder x-ray diffraction, was directly dependent on the ratio of cetyl palmitate to γ-oryzanol and decreased with decreasing cetyl palmitate content in the lipid matrix. Varying this ratio in the lipid mix resulted in a shift in the melting temperature and enthalpy, although the SLN structure remained unchanged as an orthorhombic lamellar lattice. This has been attributed to a potential inhibition by γ-oryzanol during lipid crystal growth as well as a less ordered structure of the SLNs. The results revealed that the crystallinity of the SLNs was mainly dependent on the solid lipid, and that the crystallinity has an important impact on the physical characteristics of active-loaded SLNs.

  4. Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis

    PubMed Central

    Zhang, Zili; Wu, Xiumei; Duan, Jie; Hinrichs, David; Wegmann, Keith; Zhang, Gary L.; Hall, Mark; Rosenbaum, James T.

    2012-01-01

    Background Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis. Design and Methods B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining. Results Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response. Conclusion These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response. PMID:22574188

  5. Early life persistent vitamin D deficiency exacerbates ...

    EPA Pesticide Factsheets

    Epidemiological and animal data have conclusively linked adverse cardiovascular outcomes to air pollution exposure. As such, cardiovascular function is maintained by adequate levels of certain essential micronutrients like vitamin D. Unfortunately, vitamin D deficiency (VDD) has become highly prevalent in the United States, as well as in the world, even affecting otherwise healthy individuals. My initial studies showed that VDD alters cardiac function, increases cardiac arrhythmia and HRV (i.e. indirect measure of autonomic tone) in mice; this response is further exacerbated after smog exposure. VDD has been shown to alter the responsiveness of transient receptor potential A1 (TRPA1) channels, which we have previously shown to be involved in cardiopulmonary dysfunction to acrolein, which is a ubiquitous air pollutant and potent TRPA1 agonist. The effect of VDD on TRPA1-induced air pollution responses is not known and is the purpose of this study. 3-week old mice were placed on a VDD or normal diet (ND) for 19 weeks and then implanted with radiotelemeters for the measurement of heart rate, electrocardiogram and HRV. Mice were exposed to filtered air then acrolein for 3 hours each on separate days. During exposure, ventilatory function and ECG were simultaneously recorded. Acrolein increased parasympathetic tone in ND mice, but not VDD mice during exposure. However, acrolein caused cardiac arrhythmias only in VDD mice during exposure. Similar to previous studies,

  6. Predicting asthma exacerbations using artificial intelligence.

    PubMed

    Finkelstein, Joseph; Wood, Jeffrey

    2013-01-01

    Modern telemonitoring systems identify a serious patient deterioration when it already occurred. It would be much more beneficial if the upcoming clinical deterioration were identified ahead of time even before a patient actually experiences it. The goal of this study was to assess artificial intelligence approaches which potentially can be used in telemonitoring systems for advance prediction of changes in disease severity before they actually occur. The study dataset was based on daily self-reports submitted by 26 adult asthma patients during home telemonitoring consisting of 7001 records. Two classification algorithms were employed for building predictive models: naïve Bayesian classifier and support vector machines. Using a 7-day window, a support vector machine was able to predict asthma exacerbation to occur on the day 8 with the accuracy of 0.80, sensitivity of 0.84 and specificity of 0.80. Our study showed that methods of artificial intelligence have significant potential in developing individualized decision support for chronic disease telemonitoring systems.

  7. Does self-management prevent severe exacerbations?

    PubMed

    Pinnock, Hilary; Thomas, Mike

    2015-01-01

    Despite effective therapies, asthma outcomes remain suboptimal. Education in self-management is crucial to maintaining control in a variable condition such as asthma and reducing the risk of severe asthma exacerbations, hospitalizations and deaths. This review considers the evidence for supported self-management. Recent systematic reviews have clarified and confirmed the major benefits from effective self-management education, but have also shown that implementation is rare in routine practice, with consequent avoidable morbidity and mortality. Recent research has focused on the most effective ways of delivering and supporting self-management in different patient groups and has clarified the relative effectiveness of the different components. Self-management support using new digital technologies has been investigated. All clinicians treating patients with asthma should be supporting their patients to understand and manage their own condition. Optimal self-management incorporates education, provision of a personalized asthma action plan and is supported by regular professional review. Action plans in a written or digital format should advise on recognizing deterioration and the actions to take, including when to seek professional help, appropriate changes in medication dose or commencing rescue oral steroids. Action plans should be personalized and agreed by the patient, and provided in a culturally tailored form.

  8. Exposure to lead exacerbates dental fluorosis.

    PubMed

    Leite, G A S; Sawan, R M M; Teófilo, J M; Porto, I M; Sousa, F B; Gerlach, R F

    2011-07-01

    Our aim was to test the hypothesis that co-exposure to lead and fluoride alter the severity of enamel fluorosis. Wistar rats were allocated in four groups: control, and 3 groups that received water containing 100 ppm of fluoride (F), 30 ppm of lead (Pb), or 100 ppm of F and 30 ppm of Pb (F+Pb) from the beginning of gestation. Enamel analysis and F and Pb determinations in enamel, dentine, and bone were performed in 81-day-old animals. Fluorosis was quantified using a new fluorosis index based on the identification of incisor enamel defects (white bands and white islets, representing hypomineralization, and cavities) weighted according to their severity and quantity. Hypomineralization was validated histopathologically by polarizing microscopy and microradiography. Scores were given by two blinded calibrated examiners (intra and interexaminer kappa values were 0.8 and 0.86, respectively). The control and the Pb groups presented normal enamel. The F+Pb group presented more severe enamel defects compared with the F group (P<0.0001). This study shows that lead exacerbates dental fluorosis in rodents, suggesting that co-exposure to lead may affect the degree of fluorosis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. IRON HOMEOSTASIS DURING CYSTIC FIBROSIS PULMONARY EXACERBATION

    PubMed Central

    Gifford, Alex H.; Moulton, Lisa A.; Dorman, Dana B.; Olbina, Gordana; Westerman, Mark; Parker, H. Worth; Stanton, Bruce A.; O’Toole, George A.

    2012-01-01

    Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease. Methods: Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percent-predicted forced expiratory volume in one second (FEV1%) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic antibiotics. Results: After treatment, subjects showed median FEV1% and body weight improvements of 4.5% and 2.0 kg, respectively (p <0.05). Median serum iron rose by 2.4 μmol/l (p <0.05), but 75% of patients remained hypoferremic. Median serum IL-6 and hepcidin-25 levels fell by 12.1 pg/ml and 37.5 ng/ml, respectively (p <0.05). Median serum erythropoietin (EPO) and hemoglobin levels were unaffected by treatment. We observed a trend toward lower sputum iron content after treatment. Conclusions: Hypoferremia is a salient characteristic of CFPE that improves with waning inflammation. Despite antibiotic treatment, many patients remain hypoferremic and anemic due to ineffective erythropoiesis. PMID:22883617

  10. Intermediary metabolism during brief and prolonged low tissue temperature. [mammalian thermoregulation during hibernation and hypothermia

    NASA Technical Reports Server (NTRS)

    Enteman, C.

    1973-01-01

    The intermediary metabolism of the depressed metabolic state in the hypothermic hamster and the hibernating ground squirrel was studied by observing acetate and palmitic acid metabolisms in their tissues. The oxidative metabolism seemed to be dominant in the depressed state although synthetic reactions such as fat synthesis proceeded in some cases at a faster rate than normothermic metabolism for the same tissues. Fat syntheses proceeded in all tissues with brown fat and liver especially active. Enzymes for the synthesis of cholesterol seemed to be more temperature sensitive than enzymes for fatty acid synthesis. It was concluded that there are no great differences between metabolisms in hypothermic and hibernating animals.

  11. Intermediary metabolism during brief and prolonged low tissue temperature. [mammalian thermoregulation during hibernation and hypothermia

    NASA Technical Reports Server (NTRS)

    Enteman, C.

    1973-01-01

    The intermediary metabolism of the depressed metabolic state in the hypothermic hamster and the hibernating ground squirrel was studied by observing acetate and palmitic acid metabolisms in their tissues. The oxidative metabolism seemed to be dominant in the depressed state although synthetic reactions such as fat synthesis proceeded in some cases at a faster rate than normothermic metabolism for the same tissues. Fat syntheses proceeded in all tissues with brown fat and liver especially active. Enzymes for the synthesis of cholesterol seemed to be more temperature sensitive than enzymes for fatty acid synthesis. It was concluded that there are no great differences between metabolisms in hypothermic and hibernating animals.

  12. Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling.

    PubMed

    Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Hida, Shigeaki; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Nakamoto, Nobuhiro; Saito, Hidetsugu; Hibi, Toshifumi; Miura, Soichiro; Hokari, Ryota; Kanai, Takanori

    2017-10-01

    Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA. C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9(-/-)) mice and their Tlr9(+/+) littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses. The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs. HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism

  13. Cumulative reduction of primary skin tumor growth in UV-irradiated mice by the combination of retinyl palmitate and canthaxanthin.

    PubMed

    Gensler, H L; Aickin, M; Peng, Y M

    1990-08-01

    The effects of dietary supplementation with retinyl palmitate, canthaxanthin, or the combination of both, on photocarcinogenesis was determined in pigmented C3H/HeN mice. The basal diet was the American Institute of Nutrition Diet 76A, to which was added 120 IU of retinyl palmitate per g diet, 1% canthaxanthin, or the combination of both. Administration of the diets began 18 weeks before the first UVB radiation (280-320 nm) treatment and continued throughout the study. The UV source was a bank of 6 Westinghouse FS40 lamps which delivered to the mice a total dose of 9.9 x 10(5) J/m2, delivered over 24 weeks. These diets significantly reduced the tumor burden per mouse induced by UV irradiation, however they did not influence tumor incidence. The combination of retinyl palmitate plus canthaxanthin was more effective than either agent alone at reducing autochthonous tumor growth, a result which has not been previously reported.

  14. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4)

    NASA Technical Reports Server (NTRS)

    Hardy, R. W.; Ladenson, J. H.; Henriksen, E. J.; Holloszy, J. O.; McDonald, J. M.

    1991-01-01

    In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.

  15. Formation, stability, and pH sensitivity of free-floating, giant unilamellar vesicles using palmitic acid-cholesterol mixtures.

    PubMed

    Cottenye, Nicolas; Carbajal, Gustavo; Cui, Zhong-Kai; Ducharme, Philippe Dauphin; Mauzeroll, Janine; Lafleur, Michel

    2014-09-14

    Despite the fact that palmitic acid (PA) and cholesterol (Chol) do not form fluid bilayers once hydrated individually, giant unilamellar vesicles (GUVs) were formed from a mixture of palmitic acid and cholesterol, 30/70 mol/mol. These free-floating GUVs were stable over weeks, did not aggregate and were shown to be highly stable in alkaline pH compared to conventional phospholipid-based GUVs. Acidic pH-triggered payload release from the GUVs was associated with the protonation state of palmitic acid that dictated the mixing lipid properties, thus affecting the stability of the fluid lamellar phase. The successful formation of PA-Chol GUVs reveals the possibility to create monoalkylated amphiphile-based GUVs with distinct pH stability/sensitivity.

  16. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4)

    NASA Technical Reports Server (NTRS)

    Hardy, R. W.; Ladenson, J. H.; Henriksen, E. J.; Holloszy, J. O.; McDonald, J. M.

    1991-01-01

    In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.

  17. Virus-induced exacerbations in asthma and COPD

    PubMed Central

    Kurai, Daisuke; Saraya, Takeshi; Ishii, Haruyuki; Takizawa, Hajime

    2013-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses. COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage. In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections. PMID:24098299

  18. EAACI position statement on asthma exacerbations and severe asthma.

    PubMed

    Custovic, A; Johnston, S L; Pavord, I; Gaga, M; Fabbri, L; Bel, E H; Le Souëf, P; Lötvall, J; Demoly, P; Akdis, C A; Ryan, D; Mäkelä, M J; Martinez, F; Holloway, J W; Saglani, S; O'Byrne, P; Papi, A; Sergejeva, S; Magnan, A; Del Giacco, S; Kalayci, O; Hamelmann, E; Papadopoulos, N G

    2013-12-01

    Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. High Beta-palmitate formula and bone strength in term infants: a randomized, double-blind, controlled trial.

    PubMed

    Litmanovitz, Ita; Davidson, Keren; Eliakim, Alon; Regev, Rivka H; Dolfin, Tzipora; Arnon, Shmuel; Bar-Yoseph, Fabiana; Goren, Amit; Lifshitz, Yael; Nemet, Dan

    2013-01-01

    We aimed to compare the effect of 12-week feeding of commercially available infant formulas with different percentages of palmitic acid at sn-2 (beta-palmitate) on anthropometric measures and bone strength of term infants. It was hypothesized that feeding infants with high beta-palmitate (HBP) formula will enhance their bone speed of sound (SOS). Eighty-three infants appropriate for gestational age participated in the study; of these, 58 were formula-fed and 25 breast-fed infants, serving as a reference group. The formula-fed infants were randomly assigned to receive HBP formula (43 % of the palmitic acid is esterified to the middle position of the glycerol backbone, study group; n = 30) or regular formula with low-beta palmitate (LBP, 14 % of the palmitic acid is esterified to the middle position of the glycerol backbone, n = 28). Sixty-six infants completed the 12-week study. Anthropometric and quantitative ultrasound measurements of bone SOS for assessment of bone strength were performed at randomization and at 6 and 12 weeks postnatal age. At randomization, gestational age, birth weight, and bone SOS were comparable between the three groups. At 12 weeks postnatal age, the mean bone SOS of the HBP group was significantly higher than that of the LBP group (2,896 ± 133 vs. 2,825 ± 79 m/s respectively, P = 0.049) and comparable with that of the breast-fed group (2,875 ± 85 m/s). We concluded that infants consuming HBP formula had changes in bone SOS that were comparable to those of infants consuming breast milk and favorable compared to infants consuming LBP formula.

  20. Effect of high β-palmitate content in infant formula on the intestinal microbiota of term infants.

    PubMed

    Yaron, Sima; Shachar, Dina; Abramas, Lee; Riskin, Arik; Bader, David; Litmanovitz, Ita; Bar-Yoseph, Fabiana; Cohen, Tzafra; Levi, Liora; Lifshitz, Yael; Shamir, Raanan; Shaoul, Ron

    2013-04-01

    Palmitic acid (PA) constitutes 17% to 25% of the human milk fatty acids, and ~70% is esterified in the sn-2 position of triglycerides (β-palmitate). In the sn-2 position, PA is not hydrolyzed and thus is efficiently absorbed. The PA in palm oils, commonly used in infant formulas, is esterified in the sn-1 and sn-3 positions. In these positions, PA is hydrolyzed and forms poorly absorbed calcium complexes. The present study assessed whether high β-palmitate in infant formulas affects the intestinal flora. Thirty-six term infants were enrolled: 14 breast-fed (BF group) and 22 formula-fed infants who were randomly assigned to receive formula containing high β-palmitate (HBP group, n=14), or low β-palmitate (LBP group, n=8), where 44% and 14% of the PA was β-palmitate, respectively. The total amount of PA in the formulas was 19% and 22% in the LBP and HBP groups, respectively. Neither formula contained pre- or probiotics. Stool samples were collected at enrollment and at 6 weeks for the quantification of bacteria. At 6 weeks, the HBP and BF groups had higher Lactobacillus and bifidobacteria counts than the LBP group (P<0.01). The Lactobacillus counts at 6 weeks were not significantly different between the HBP and BF groups. Lactobacillus counts were 1.2×10¹⁰, 1.2×10¹¹, and 5.6×10¹⁰ CFU/g for LBP, HBP, and BF groups, respectively. Bifidobacteria counts were 5.1×10⁹, 1.2×10¹¹, and 3.9×10¹⁰ CFU/g for LBP, HBP, and BF groups, respectively. HBP formula beneficially affected infant gut microbiota by increasing the Lactobacillus and bifidobacteria counts in fecal stools.

  1. Palmitate Diet-induced Loss of Cardiac Caveolin-3: A Novel Mechanism for Lipid-induced Contractile Dysfunction

    PubMed Central

    Knowles, Catherine J.; Cebova, Martina; Pinz, Ilka M.

    2013-01-01

    Obesity is associated with an increased risk of cardiomyopathy, and mechanisms linking the underlying risk and dietary factors are not well understood. We tested the hypothesis that dietary intake of saturated fat increases the levels of sphingolipids, namely ceramide and sphingomyelin in cardiac cell membranes that disrupt caveolae, specialized membrane micro-domains and important for cellular signaling. C57BL/6 mice were fed two high-fat diets: palmitate diet (21% total fat, 47% is palmitate), and MCT diet (21% medium-chain triglycerides, no palmitate). We established that high-palmitate feeding for 12 weeks leads to 40% and 50% increases in ceramide and sphingomyelin, respectively, in cellular membranes. Concomitant with sphingolipid accumulation, we observed a 40% reduction in systolic contractile performance. To explore the relationship of increased sphingolipids with caveolins, we analyzed caveolin protein levels and intracellular localization in isolated cardiomyocytes. In normal cardiomyocytes, caveolin-1 and caveolin-3 co-localize at the plasma membrane and the T-tubule system. However, mice maintained on palmitate lost 80% of caveolin-3, mainly from the T-tubule system. Mice maintained on MCT diet had a 90% reduction in caveolin-1. These data show that caveolin isoforms are sensitive to the lipid environment. These data are further supported by similar findings in human cardiac tissue samples from non-obese, obese, non-obese cardiomyopathic, and obese cardiomyopathic patients. To further elucidate the contractile dysfunction associated with the loss of caveolin-3, we determined the localization of the ryanodine receptor and found lower expression and loss of the striated appearance of this protein. We suggest that palmitate-induced loss of caveolin-3 results in cardiac contractile dysfunction via a defect in calcium-induced calcium release. PMID:23585895

  2. alpha-Linolenic acid protects renal cells against palmitic acid lipotoxicity via inhibition of endoplasmic reticulum stress.

    PubMed

    Katsoulieris, Elias; Mabley, Jon G; Samai, Mohamed; Green, Irene C; Chatterjee, Prabal K

    2009-11-25

    Unsaturated fatty acids may counteract the lipotoxicity associated with saturated fatty acids. Palmitic acid induced endoplasmic reticulum (ER) stress and caused apoptotic and necrotic cell death in the renal proximal tubular cell line, NRK-52E. We investigated whether alpha-linolenic acid, an unsaturated fatty acid, protected against ER stress and cell death induced by palmitic acid or by other non-nutrient ER stress generators. Incubation of NRK-52E cells for 24h with palmitic acid produced a significant increase in apoptosis and necrosis. Palmitic acid also increased levels of three indicators of ER stress - the phosphorylated form of the eukaryotic initiation factor 2alpha (eIF2alpha), C/EBP homologous protein (CHOP), and glucose regulated protein 78 (GRP78). alpha-Linolenic acid dramatically reduced cell death and levels of all three indicators of ER stress brought about by palmitic acid. Tunicamycin, which induces ER stress by glycosylation of proteins, produced similar effects to those obtained using palmitic acid; its effects were partially reversed by alpha-linolenic acid. Salubrinal (a phosphatase inhibitor) causes increased levels of the phosphorylated form of eIF2alpha - this effect was partially reversed by alpha-linolenic acid. Palmitoleate, a monosaturated fatty acid, had similar effects to those of alpha-linolenic acid. These results suggest that part of the mechanism of protection of the kidney by unsaturated fatty acids is through inhibition of ER stress, eIF2alpha phosphorylation and consequential reduction of CHOP protein expression and apoptotic renal cell death.

  3. D-isoascorbyl palmitate: lipase-catalyzed synthesis, structural characterization and process optimization using response surface methodology

    PubMed Central

    2013-01-01

    Background Isoascorbic acid is a stereoisomer of L-ascorbic acid, and widely used as a food antioxidant. However, its highly hydrophilic behavior prevents its application in cosmetics or fats and oils-based foods. To overcome this problem, D-isoascorbyl palmitate was synthesized in the present study for improving the isoascorbic acid’s oil solubility with an immobilized lipase in organic media. The structural information of synthesized product was clarified using LC-ESI-MS, FT-IR, 1H and 13C NMR analysis, and process parameters for high yield of D-isoascorbyl palmitate were optimized by using One–factor-at-a-time experiments and response surface methodology (RSM). Results The synthesized product had the purity of 95% and its structural characteristics were confirmed as isoascorbyl palmitate by LC-ESI-MS, FT-IR, 1H, and 13C NMR analysis. Results from “one–factor-at-a-time” experiments indicated that the enzyme load, reaction temperature and D-isoascorbic-to-palmitic acid molar ratio had a significant effect on the D-isoascorbyl palmitate conversion rate. 95.32% of conversion rate was obtained by using response surface methodology (RSM) under the the optimized condition: enzyme load of 20% (w/w), reaction temperature of 53°C and D- isoascorbic-to-palmitic acid molar ratio of 1:4 when the reaction parameters were set as: acetone 20 mL, 40 g/L of molecular sieves content, 200 rpm speed for 24-h reaction time. Conclusion The findings of this study can become a reference for developing industrial processes for the preparation of isoascorbic acid ester, which might be used in food additives, cosmetic formulations and for the synthesis of other isoascorbic acid derivatives. PMID:23835418

  4. No effect of menstrual cycle phase on glycerol or palmitate kinetics during 90 min of moderate exercise.

    PubMed

    Horton, Tracy J; Miller, Emily K; Bourret, Kristen

    2006-03-01

    The systemic flux of glycerol and palmitate [a representative nonesterified free fatty acid (NEFA)] was assessed in three different phases of the menstrual cycle at rest and during moderate-intensity exercise. It was hypothesized that circulating glycerol and NEFA turnover would be greatest in the midfollicular (MF) phase of the menstrual cycle, when estrogen is elevated but progesterone low, followed by the midluteal phase (ML; high estrogen and progesterone), and lowest in the early follicular (EF) phase of the menstrual cycle (low estrogen and progesterone). Subjects included moderately active, eumenorrheic, healthy women. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting and exercise (50% maximal oxygen uptake, 90 min) measurements of tracer-determined glycerol and palmitate kinetics were made. There was a significant increase in both glycerol and palmitate turnover from rest to exercise in all phases of the menstrual cycle (P<0.0001). No significant differences, however, were observed between cycle phases in the systemic flux of glycerol or palmitate, at rest or during exercise. Maximal peripheral lipolysis during exercise, as represented by glycerol rate of appearance at 90 min, equaled 8.45+/-0.96, 8.35+/-1.12, and 7.71+/-0.96 micromol.kg-1.min-1 in the EF, MF, and ML phases, respectively. Circulating free fatty acid utilization also peaked at 90 min of exercise, as indicated by the palmitate rate of disappearance (3.31+/-0.35, 3.17+/-0.39, and 3.47+/-0.26 micromol.kg-1.min-1) in the EF, MF, and ML phases, respectively. In conclusion, systemic rates of glycerol and NEFA turnover (as represented by palmitate flux) were not significantly affected by the cyclic fluctuations in estrogen and progesterone that occur throughout the normal menstrual cycle, either at rest or during 90 min of moderate exercise.

  5. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    PubMed Central

    Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-01-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole. PMID

  6. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    PubMed

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  7. Chronic obstructive pulmonary disease exacerbations: latest evidence and clinical implications

    PubMed Central

    Qureshi, Hammad; Sharafkhaneh, Amir

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. The natural history of COPD is punctuated by exacerbations which have major short- and long-term implications on the patient and healthcare system. Evidence-based guidelines stipulate that early detection and prompt treatment of exacerbations are essential to ensure optimal outcomes and to reduce the burden of COPD. Several factors can identify populations at risk of exacerbations. Implementing prevention measures in patients at risk is a major goal in the management of COPD. PMID:25177479

  8. The recent advances of phenotypes in acute exacerbations of COPD

    PubMed Central

    Zhou, Aiyuan; Zhou, Zijing; Zhao, Yiyang; Chen, Ping

    2017-01-01

    Exacerbations of COPD are clinically relevant events with therapeutic and prognostic implications. Yet, significant heterogeneity of clinical presentation and disease progression exists within acute exacerbations of COPD (AECOPD). Currently, different phenotypes have been widely used to describe the characteristics among patients with AECOPD. This has proved to be significant in the treatment and prediction of the outcomes of the disease. In this review of published literature, the phenotypes of AECOPD were classified according to etiology, inflammatory biomarkers, clinical manifestation, comorbidity, the frequency of exacerbations, and so on. This review concentrates on advancements in the use of phenotypes of AECOPD. PMID:28392685

  9. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.

    PubMed

    Flume, Patrick A; Mogayzel, Peter J; Robinson, Karen A; Goss, Christopher H; Rosenblatt, Randall L; Kuhn, Robert J; Marshall, Bruce C

    2009-11-01

    The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

  10. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets

    USDA-ARS?s Scientific Manuscript database

    The aim of this study was to assess multifactorial Beta-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of ...

  11. AMPKα, C/EBPβ, CPT1β, GPR43, PPARγ, and SCD Gene Expression in Single- and Co-cultured Bovine Satellite Cells and Intramuscular Preadipocytes Treated with Palmitic, Stearic, Oleic, and Linoleic Acid

    PubMed Central

    Choi, S. H.; Park, S. K.; Johnson, B. J.; Chung, K. Y.; Choi, C. W.; Kim, K. H.; Kim, W. Y.; Smith, B.

    2015-01-01

    We previously demonstrated that bovine subcutaneous preadipocytes promote adipogenic gene expression in muscle satellite cells in a co-culture system. Herein we hypothesize that saturated fatty acids would promote adipogenic/lipogenic gene expression, whereas mono- and polyunsaturated fatty acids would have the opposite effect. Bovine semimembranosus satellite cells (BSC) and intramuscular preadipocytes (IPA) were isolated from crossbred steers and cultured with 10% fetal bovine serum (FBS)/Dulbecco’s Modified Eagle Medium (DMEM) and 1% antibiotics during the 3-d proliferation period. After proliferation, cells were treated for 3 d with 3% horse serum/DMEM (BSC) or 5% FBS/DMEM (IPA) with antibiotics. Media also contained 10 μg/mL insulin and 10 μg/mL pioglitazone. Subsequently, differentiating BSC and IPA were cultured in their respective media with 40 μM palmitic, stearic, oleic, or linoleic acid for 4 d. Finally, BSC and IPA were single- or co-cultured for an additional 2 h. All fatty acid treatments increased (p = 0.001) carnitine palmitoyltransferase-1 beta (CPT1β) gene expression, but the increase in CPT1β gene expression was especially pronounced in IPA incubated with palmitic and stearic acid (6- to 17- fold increases). Oleic and linoleic acid decreased (p = 0.001) stearoyl-CoA desaturase (SCD) gene expression over 80% in both BSC and IPA. Conversely, palmitic and stearic acid increased SCD gene expression three fold in co-cultured in IPA, and stearic acid increased AMPKα gene expression in single- and co-cultured BSC and IPA. Consistent with our hypothesis, saturated fatty acids, especially stearic acid, promoted adipogenic and lipogenic gene expression, whereas unsaturated fatty acids decreased expression of those genes associated with fatty acid metabolism. PMID:25656188

  12. AMPKα, C/EBPβ, CPT1β, GPR43, PPARγ, and SCD Gene Expression in Single- and Co-cultured Bovine Satellite Cells and Intramuscular Preadipocytes Treated with Palmitic, Stearic, Oleic, and Linoleic Acid.

    PubMed

    Choi, S H; Park, S K; Johnson, B J; Chung, K Y; Choi, C W; Kim, K H; Kim, W Y; Smith, B

    2015-03-01

    We previously demonstrated that bovine subcutaneous preadipocytes promote adipogenic gene expression in muscle satellite cells in a co-culture system. Herein we hypothesize that saturated fatty acids would promote adipogenic/lipogenic gene expression, whereas mono- and polyunsaturated fatty acids would have the opposite effect. Bovine semimembranosus satellite cells (BSC) and intramuscular preadipocytes (IPA) were isolated from crossbred steers and cultured with 10% fetal bovine serum (FBS)/Dulbecco's Modified Eagle Medium (DMEM) and 1% antibiotics during the 3-d proliferation period. After proliferation, cells were treated for 3 d with 3% horse serum/DMEM (BSC) or 5% FBS/DMEM (IPA) with antibiotics. Media also contained 10 μg/mL insulin and 10 μg/mL pioglitazone. Subsequently, differentiating BSC and IPA were cultured in their respective media with 40 μM palmitic, stearic, oleic, or linoleic acid for 4 d. Finally, BSC and IPA were single- or co-cultured for an additional 2 h. All fatty acid treatments increased (p = 0.001) carnitine palmitoyltransferase-1 beta (CPT1β) gene expression, but the increase in CPT1β gene expression was especially pronounced in IPA incubated with palmitic and stearic acid (6- to 17- fold increases). Oleic and linoleic acid decreased (p = 0.001) stearoyl-CoA desaturase (SCD) gene expression over 80% in both BSC and IPA. Conversely, palmitic and stearic acid increased SCD gene expression three fold in co-cultured in IPA, and stearic acid increased AMPKα gene expression in single- and co-cultured BSC and IPA. Consistent with our hypothesis, saturated fatty acids, especially stearic acid, promoted adipogenic and lipogenic gene expression, whereas unsaturated fatty acids decreased expression of those genes associated with fatty acid metabolism.

  13. Mapping the low palmitate fap1 mutation and validation of its effects on soybean oil and agronomic traits in three soybean populations

    USDA-ARS?s Scientific Manuscript database

    Soybean oil with reduced palmitic acid content is desirable to reduce the risks of coronary diseases and; breast, colon, and prostate cancer incidence associated with consumption of this fatty acid. The objectives of this study were: to identify the genomic location of the reduced palmitate fap1 mut...

  14. Phenytoin induced Stevens-Johnson syndrome exacerbated by cefepime.

    PubMed

    Prabhu, Varsha A; Doddapaneni, Sahiti; Thunga, Girish; Thiyagu, Rajakannan; Prabhu, M Mukyaprana; Naha, Kushal

    2013-10-01

    Steven Johnson syndrome (SJS) is a rare drug induced mucocutaneous reaction. Here, we present an elaborate report of a 28-year-old female patient who developed Phenytoin induced SJS, which was exacerbated by cefepime.

  15. The Sputum Microbiome in Chronic Obstructive Pulmonary Disease Exacerbations.

    PubMed

    Huang, Yvonne J; Boushey, Homer A

    2015-11-01

    Acute exacerbations of chronic obstructive pulmonary disease (COPD) are thought to be associated with--and perhaps to mediate--accelerated loss of lung function in COPD. Although the application of culture-independent methods for detection of bacteria have shown COPD to be associated with marked differences in the burden, diversity, and composition of the bronchial bacterial microbiome, few studies have examined the changes associated with community-acquired exacerbations of the disease. In a longitudinal cohort study of COPD, the availability of sputum samples from subjects obtained at the onset of an exacerbation and during periods of clinical stability before and after the event enabled us to recently address this gap in knowledge, using culture-independent, 16S rRNA-based analysis methods combined with in silico inference of metagenomic functions. We observed sputum bacterial composition to be generally stable over the preexacerbation period of clinical stability, but to change at the time of exacerbation, with specific enrichment in not only typical COPD-associated bacterial species (e.g., Haemophilus influenzae) but also other phylogenetically related species with pathogenic potential. Concurrently, we observed depleted abundance of other bacteria whose predicted metagenomes suggest functional capacities to produce a variety of antiinflammatory compounds. Most strikingly, we found that resolution of these exacerbation-related changes in sputum microbiota composition differed significantly, depending on the exacerbation treatments prescribed. Treatment with corticosteroids resulted in microbiome enrichment for a number of bacterial communities, mostly members of the Proteobacteria phylum, whereas prolonged suppression of microbiota was seen in those treated with antibiotics alone. Taken together, our findings suggest that exacerbations of COPD are associated with heterogeneous changes in the bronchial microbiome, with increases in the abundance of species

  16. Can resistive breathing injure the lung? Implications for COPD exacerbations

    PubMed Central

    Vassilakopoulos, Theodoros; Toumpanakis, Dimitrios

    2016-01-01

    In obstructive lung diseases, airway inflammation leads to bronchospasm and thus resistive breathing, especially during exacerbations. This commentary discusses experimental evidence that resistive breathing per se (the mechanical stimulus) in the absence of underlying airway inflammation leads to lung injury and inflammation (mechanotransduction). The potential implications of resistive breathing-induced mechanotrasduction in COPD exacerbations are presented along with the available clinical evidence. PMID:27713628

  17. Exacerbation of symptoms in agricultural pesticide applicators with asthma

    PubMed Central

    Liang, Xiaoming; London, Stephanie J.; Umbach, David M.; Sandler, Dale P.; Hoppin, Jane A.

    2014-01-01

    Purpose Exacerbation is a critical event in asthma management. We investigated whether exacerbation of symptoms is associated with farming exposures among agricultural pesticide applicators with asthma. Methods Participants were pesticide applicators with active asthma (wheezing and breathing problems in past 12 months) who completed enrollment questionnaires for the Agricultural Health Study (AHS). Exacerbation of asthma was defined as having visited a hospital emergency room or doctor for an episode of wheezing or whistling in the past 12 months. Exposures of interest were using 36 specific pesticides in the past 12 months and conducting various agricultural activities. Adjusted odds ratios (ORs) were estimated by logistic regression while controlling for potential confounders. Results The 926 AHS adult pesticide applicators with active asthma included 202 (22%) with exacerbation. Inverse associations with exacerbation were observed for two herbicides (glyphosate, odds ratio (OR) = 0.5, 95% confidence interval (CI) 0.3–0.8, and paraquat, OR=0.3, 95% CI 0.1–0.9) and several agricultural activities (repairing engines, grinding metal, driving diesel tractors, and performing veterinary procedures). Only asthma cases with allergies (i.e., doctor-diagnosed hay fever or eczema, 46%) had positive exacerbation-pesticide associations, with OR=2.1 (95% CI 1.1–4.1) for the herbicide pendimethalin and OR=10.2 (95% CI 1.9–55) for the insecticide aldicarb. Conclusions The inverse associations with two pesticides and specific farm activities are consistent with the possibility that asthma cases prone to exacerbation may avoid exposures that trigger symptoms. Although limited by small sample size and a cross-sectional design, our study suggests that use of specific pesticides may contribute to exacerbation of asthma among individuals with allergies. PMID:23670403

  18. Severe exacerbations and decline in lung function in asthma.

    PubMed

    O'Byrne, Paul M; Pedersen, Søren; Lamm, Carl Johan; Tan, Wan C; Busse, William W

    2009-01-01

    To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.

  19. Exacerbation of symptoms in agricultural pesticide applicators with asthma.

    PubMed

    Henneberger, Paul K; Liang, Xiaoming; London, Stephanie J; Umbach, David M; Sandler, Dale P; Hoppin, Jane A

    2014-05-01

    Exacerbation is a critical event in asthma management. We investigated whether exacerbation of symptoms is associated with farming exposures among agricultural pesticide applicators with asthma. Participants were pesticide applicators with active asthma (wheezing and breathing problems in past 12 months) who completed enrollment questionnaires for the Agricultural Health Study (AHS). Exacerbation of asthma was defined as having visited a hospital emergency room or doctor for an episode of wheezing or whistling in the past 12 months. Exposures of interest were using 36 specific pesticides in the past 12 months and conducting various agricultural activities. Adjusted odds ratios (ORs) were estimated by logistic regression while controlling for potential confounders. The 926 AHS adult pesticide applicators with active asthma included 202 (22%) with exacerbation. Inverse associations with exacerbation were observed for two herbicides [glyphosate, odds ratio (OR) = 0.5, 95% confidence interval (CI) 0.3, 0.8, and paraquat, OR = 0.3, 95% CI 0.1, 0.9] and several agricultural activities (repairing engines, grinding metal, driving diesel tractors, and performing veterinary procedures). Only asthma cases with allergies (i.e., doctor-diagnosed hay fever or eczema, 46%) had positive exacerbation-pesticide associations, with OR = 2.1 (95% CI 1.1, 4.1) for the herbicide pendimethalin and OR = 10.2 (95% CI 1.9, 55) for the insecticide aldicarb. The inverse associations with two pesticides and specific farm activities are consistent with the possibility that asthma cases prone to exacerbation may avoid exposures that trigger symptoms. Although limited by small sample size and a cross-sectional design, our study suggests that use of specific pesticides may contribute to exacerbation of asthma among individuals with allergies.

  20. Pulmonary Strongyloidiasis Masquerading as Exacerbation of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Pradhan, Gourahari; Behera, Priyadarshini; Bhuniya, Sourin; Mohapatra, Prasanta Raghab; Turuk, Jyotirmayee; Mohanty, Srujana

    2016-01-01

    Pulmonary strongyloidiasis is an uncommon presentation of Strongyloides infection, usually seen in immunocompromised hosts. The manifestations are similar to that of acute exacerbation of chronic obstructive pulmonary disease (COPD). Therefore, the diagnosis of pulmonary strongyloidiasis could be challenging in a COPD patient, unless a high index of suspicion is maintained. Here, we present a case of Strongyloides hyperinfection in a COPD patient mimicking acute exacerbation, who was on chronic steroid therapy. PMID:27790284

  1. Airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease.

    PubMed

    Huang, Yvonne J; Sethi, Sanjay; Murphy, Timothy; Nariya, Snehal; Boushey, Homer A; Lynch, Susan V

    2014-08-01

    Specific bacterial species are implicated in the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD). However, recent studies of clinically stable COPD patients have demonstrated a greater diversity of airway microbiota, whose role in acute exacerbations is unclear. In this study, temporal changes in the airway microbiome before, at the onset of, and after an acute exacerbation were examined in 60 sputum samples collected from subjects enrolled in a longitudinal study of bacterial infection in COPD. Microbiome composition and predicted functions were examined using 16S rRNA-based culture-independent profiling methods. Shifts in the abundance (≥ 2-fold, P < 0.05) of many taxa at exacerbation and after treatment were observed. Microbiota members that were increased at exacerbation were primarily of the Proteobacteria phylum, including nontypical COPD pathogens. Changes in the bacterial composition after treatment for an exacerbation differed significantly among the therapy regimens clinically prescribed (antibiotics only, oral corticosteroids only, or both). Treatment with antibiotics alone primarily decreased the abundance of Proteobacteria, with the prolonged suppression of some microbiota members being observed. In contrast, treatment with corticosteroids alone led to enrichment for Proteobacteria and members of other phyla. Predicted metagenomes of particular microbiota members involved in these compositional shifts indicated exacerbation-associated loss of functions involved in the synthesis of antimicrobial and anti-inflammatory products, alongside enrichment in functions related to pathogen-elicited inflammation. These trends reversed upon clinical recovery. Further larger studies will be necessary to determine whether specific compositional or functional changes detected in the airway microbiome could be useful indicators of exacerbation development or outcome. Copyright © 2014, American Society for Microbiology. All Rights

  2. Intracerebroventricular streptozotocin exacerbates Alzheimer-like changes of 3xTg-AD mice.

    PubMed

    Chen, Yanxing; Liang, Zhihou; Tian, Zhu; Blanchard, Julie; Dai, Chun-Ling; Chalbot, Sonia; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2014-02-01

    Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3-6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase in tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease in synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

  3. Machine learning approaches to personalize early prediction of asthma exacerbations.

    PubMed

    Finkelstein, Joseph; Jeong, In Cheol

    2017-01-01

    Patient telemonitoring results in an aggregation of significant amounts of information about patient disease trajectory. However, the potential use of this information for early prediction of exacerbations in adult asthma patients has not been systematically evaluated. The aim of this study was to explore the utility of telemonitoring data for building machine learning algorithms that predict asthma exacerbations before they occur. The study dataset comprised daily self-monitoring reports consisting of 7001 records submitted by adult asthma patients during home telemonitoring. Predictive modeling included preparation of stratified training datasets, predictive feature selection, and evaluation of resulting classifiers. Using a 7-day window, a naive Bayesian classifier, adaptive Bayesian network, and support vector machines were able to predict asthma exacerbation occurring on day 8, with sensitivity of 0.80, 1.00, and 0.84; specificity of 0.77, 1.00, and 0.80; and accuracy of 0.77, 1.00, and 0.80, respectively. Our study demonstrated that machine learning techniques have significant potential in developing personalized decision support for chronic disease telemonitoring systems. Future studies may benefit from a comprehensive predictive framework that combines telemonitoring data with other factors affecting the likelihood of developing acute exacerbation. Approaches implemented for advanced asthma exacerbation prediction may be extended to prediction of exacerbations in patients with other chronic health conditions. © 2016 New York Academy of Sciences.

  4. Minimal clinically important difference--exacerbations of COPD.

    PubMed

    Calverley, Peter M A

    2005-03-01

    Exacerbations of COPD are now recognised as being important events in the natural history of the condition and become more frequent as the disease worsens. Defining a minimum clinically important difference in exacerbation rate is fraught with difficulty. There is substantial between and within subject differences in the occurrence of these events that makes an individual evaluation of their importance problematic. At present, the most widely used definition of an exacerbation identifies an episode where the patient seeks medical help rather than a predefined change in one or more symptoms. Despite these problems, intervention studies with bronchodilator drugs, inhaled corticosteroids, and pulmonary rehabilitation appear to reduce the frequency of exacerbation events. In patients with an FEV1 below 50% predicted there is reasonable consistency about the magnitude of change and a 4-unit improvement in the St George's Respiratory Questionnaire is commonly associated with a 20-25% reduction in the reported number of exacerbations. Individual studies vary depending upon the recruitment protocol. Patients who experience symptomatic benefit may be those in whom a clinically important change in exacerbations occurs but this concept requires testing prospectively. Existing methodologies for estimating clinically important differences are hard to apply with a binary outcome like this, and more work will be needed to develop a robust approach for dealing with this important clinical variable.

  5. Palmitic acid induces interleukin-1β secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells.

    PubMed

    Shirasuna, Koumei; Takano, Hiroki; Seno, Kotomi; Ohtsu, Ayaka; Karasawa, Tadayoshi; Takahashi, Masafumi; Ohkuchi, Akihide; Suzuki, Hirotada; Matsubara, Shigeki; Iwata, Hisataka; Kuwayama, Takehito

    2016-08-01

    Maternal obesity, a major risk factor for adverse pregnancy complications, results in inflammatory cytokine release in the placenta. Levels of free fatty acids are elevated in the plasma of obese human. These fatty acids include obesity-related palmitic acids, which is a major saturated fatty acid, that promotes inflammatory responses. Increasing evidence indicates that nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasomes mediate inflammatory responses induced by endogenous danger signals. We hypothesized that inflammatory responses associated with gestational obesity cause inflammation. To test this hypothesis, we investigated the effect of palmitic acid on the activation of NLRP3 inflammasomes and inflammatory responses in a human Sw.71 trophoblast cell line. Palmitic acid stimulated caspase-1 activation and markedly increased interleukin (IL)-1β secretion in Sw.71 cells. Treatment with a caspase-1 inhibitor diminished palmitic acid-induced IL-1β release. In addition, NLRP3 and caspase-1 genome editing using a CRISPR/Cas9 system in Sw.71 cells suppressed IL-1β secretion, which was stimulated by palmitic acid. Moreover, palmitic acid stimulated caspase-3 activation and inflammatory cytokine secretion (e.g., IL-6 and IL-8). Palmitic acid-induced cytokine secretion were dependent on caspase-3 activation. In addition, palmitic acid-induced IL-1β, IL-6, and IL-8 secretion was depended on reactive oxygen species (ROS) generation. In conclusion, palmitic acid caused activation of NLRP3 inflammasomes and inflammatory responses, inducing IL-1β, IL-6, and IL-8 secretion, which is associated with ROS generation, in human Sw.71 placental cells. We suggest that obesity-related palmitic acid induces placental inflammation, resulting in association with pregnancy complications.

  6. Thermal properties of silica-filled high density polyethylene composites compatibilized with glut palmitate

    NASA Astrophysics Data System (ADS)

    Samsudin, Dalina; Ismail, Hanafi; Othman, Nadras; Hamid, Zuratul Ain Abdul

    2017-07-01

    A study of thermal properties resulting from the utilization of Glut Palmitate (GP) on the silica filled high density polyethylene (HDPE) composites was carried out. The composites with the incorporation of GP at 0.5, 1.0, 2.0 and 3.0 phr were prepared by using an internal mixer at the temperature 180 °C and the rotor speed of 50 rpm. The thermal behaviours of the composites were then investigated using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). It was found that the crystallinity and the thermal stability of the composites increased with the incorporation of GP. The highest crystallinity contents and decomposition temperatures were observed at the 1 phr GP loading.

  7. Incorporation of Palmitic Acid or Stearic Acid into Soybean Oils Using Enzymatic Interesterification.

    PubMed

    Teh, Soek Sin; Voon, Phooi Tee; Hock Ong, Augustine Soon; Choo, Yuen May

    2016-09-01

    Incorporations of nature fatty acids which were palmitic acid and stearic acid into the end positions of soybean oils were done using sn-1,3 specific immobilised lipase from Rhizomucor miehei at different ratios in order to produce symmetrical triglycerides without changing the fatty acids at sn-2 position. The optimum ratio for the process was 25:75 w/w. There were 19.2% increase of SFA for P25 and 16% increase for S25 at the sn-1,3 positions. The research findings indicated that the structured lipids produced from enzymatic interesterification possessed a higher oxidative stability than soybean oil. The newly formed structured lipids (SUS type) could be good sources for various applications in food industry.

  8. Investigation on microstructure and thermal properties of graphene-nanoplatelet/palmitic acid composites

    NASA Astrophysics Data System (ADS)

    Wang, Jifen; Xie, Huaqing; Xin, Zhong

    2012-07-01

    Graphene-nanoplatelets (GNPs) were added into melting palmitic acid (PA) to prepare GNP/PA composites. Experimental results revealed that the temperature has little effect on the thermal conductivity of GNP/PA in either solid state or liquid state. Generally, thermal conductivity of GNP/PA increases with the addition of GNPs. There are two sudden increases in thermal conductivity for GNP/PA. One is at 0.5 wt% where GNPs begin to congregate and the thermal conductivity of GNP/PA increases suddenly. The other is at 5.0 wt% where the GNP aggregates are large enough to contact each other and the thermal conductivity of GNP/PA spurts with more GNP loadings.

  9. Encapsulation of Vitamin A palmitate for animal supplementation: Formulation, manufacturing and stability implications.

    PubMed

    Albertini, Beatrice; Di Sabatino, Marcello; Calogerà, Giacomo; Passerini, Nadia; Rodriguez, Lorenzo

    2010-01-01

    Two manufacturing methods and numerous formulative approaches have been evaluated to obtain a stable oral pharmaceutical form of Vitamin A palmitate (VAP), a substance very sensitive to light, temperature, humidity and metal ions. The best results were obtained by formulating VAP, stabilized with butylated hydroxytoluene (BHT), in double layer microcapsules constituted by a core of chitosan, Tween 20, CaCl(2) and EDTA surrounded by a first chitosan-alginate membrane and an outer membrane of calcium-alginate. This formulation design enabled the production of beads with high drug loading (42% w/w) and high encapsulation efficiency (94%). The stability of VAP-loaded microcapsules was assessed according to EMEA guidelines. This formulation design showed the best performance in terms of VAP recovery (t(50%) > 360 days) after 1 year of storage at room conditions. This is a very important result considering the poor shelf-life (45 days) of pure VAP stabilized with BHT stored at the same conditions.

  10. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

    PubMed

    Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

    2016-10-21

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH.

  11. Influence of pH and temperature on the rheological properties of aqueous dispersions of starch-sodium palmitate complexes

    USDA-ARS?s Scientific Manuscript database

    Aqueous dispersions of high-amylose corn starch were steam jet cooked and blended with aqueous solutions of sodium palmitate to form amylose inclusion complexes. The rheology of dispersions of these complexes was examined. Acetic acid was added to reduce the pH, converting complexed sodium palmita...

  12. Gastrointestinal handling of [1-13C]palmitic acid in healthy controls and patients with cystic fibrosis

    PubMed Central

    Murphy, J.; Jones, A.; Stolinski, M.; Wootton, S.

    1997-01-01

    Accepted 2 January 1997
 AIM—To examine the gastrointestinal handling of [1-13C]palmitic acid given as the free acid by measuring the excretion of 13C label in stool in 16 healthy children and 11 patients with cystic fibrosis on their habitual enzyme replacement treatment.
METHODS—After an overnight fast, each child ingested 10 mg/kg body weight [1-13C]palmitic acid with a standardised test meal of low natural 13C abundance. A stool sample was collected before the test and all stools were collected thereafter for a period of up to five days. The total enrichment of 13C in stool and the species bearing the 13C label was measured using isotope ratio mass spectrometry.
RESULTS—The proportion of administered 13C label excreted in stool was 24.0% (range 10.7-64.9%) in healthy children and only 4.4% (range 1.2-11.6%) in cystic fibrosis patients. The enrichment of 13C in stool was primarily restricted to the species consumed by the subjects (that is as palmitic acid).
CONCLUSION—There does not appear to be a specific defect in the absorption of [1-13C]palmitic acid in patients with cystic fibrosis. The reasons why cystic fibrosis patients appear to absorb more of this saturated fatty acid than healthy children is not clear and requires further investigation.

 PMID:9196358

  13. Comparison of microwave processing and excess steam jet cooking for spherulite production of from starch:palmitic acid inclusion complexes

    USDA-ARS?s Scientific Manuscript database

    It was previously shown that toroid and spherical/lobed spherulites were formed upon slow cooling of aqueous dispersions of corn starch and palmitic acid after passing through an excess steam jet cooker. Spherulite yield was 86% based on amylose. In order to determine whether excess steam jet cookin...

  14. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPARβ/δ in HepG2 cells.

    PubMed

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua; Berggren-Söderlund, Maria; Nilsson-Ehle, Peter; Zhang, Xiaoying; Xu, Ning

    2014-02-28

    It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPARβ/δ pathway.

  15. Colfosceril palmitate. A pharmacoeconomic evaluation of a synthetic surfactant preparation (Exosurf Neonatal) in infants with respiratory distress syndrome.

    PubMed

    Bryson, H M; Whittington, R

    1994-12-01

    Comprehensive clinical data provide strong evidence of the efficacy of the synthetic lung surfactant colfosceril palmitate (Exosurf Neonatal) administered as prophylaxis or rescue therapy in infants with respiratory distress syndrome (RDS). The use of rescue therapy with colfosceril palmitate is further supported by cost-effectiveness analyses which report a 9 to 48% reduction in the cost per survivor compared with placebo or historical controls, despite divergent study methodology and location. Importantly, the savings were evident in both larger (> or = 1250g) and smaller (700 to 1350g) infants. All studies considered costs or charges accrued during initial hospitalisation through to 1 year; measurement of long term resource use data and all resulting costs are required for a more complete pharmacoeconomic evaluation. The optimal timing of surfactant administration is likely to be an important economic issue given that efficacy data from a large international trial support earlier administration of colfosceril palmitate versus delayed therapy in high risk patients. Further economic benefits may be realised by the sequential use of antenatal corticosteroids and surfactant therapy, although this has yet to be prospectively investigated. In conclusion, clinical and pharmacoeconomic data strongly support the use of rescue therapy with colfosceril palmitate. Additionally, recent clinical data indicating that even better results may be achieved with earlier administration and/or combined use with antenatal corticosteroids should be assessed from an economic standpoint to determine the optimal prescribing strategy for this agent.

  16. Evidence for the involvement of GPR40 and NADPH oxidase in palmitic acid-induced superoxide production and insulin secretion.

    PubMed

    Graciano, Maria Fernanda; Valle, Maíra Mello; Curi, Rui; Carpinelli, Angelo Rafael

    2013-01-01

    G protein coupled receptor 40 (GPR40) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex have been shown to be involved in the fatty acid amplification of glucose-stimulated insulin secretion (GSIS). The effect of palmitic acid on superoxide production and insulin secretion by INS-1E cells and the possible involvement of GPR40 and NADPH oxidase in these processes were examined in this study. Cells were incubated during 1 h with palmitic acid in low and high glucose concentrations, a GPR40 agonist (GW9508) and inhibitors of NADPH oxidase (diphenyleneiodonium, DPI) and PKC (calphostin C). GW9508 induced superoxide production at 2.8 and 5.6 mM glucose concentrations and stimulated insulin secretion at 16.7 mM glucose concentration involving both PKC and NADPH oxidase activation. Palmitic acid induced superoxide production through NADPH oxidase and GPR40-dependent pathways and the stimulation of insulin secretion in the presence of a high glucose concentration was reduced by knockdown of GPR40 using siRNA. Our results suggest that palmitic acid induces superoxide production and potentiates GSIS through NADPH oxidase and GPR40 pathways in pancreatic ? cells.

  17. [PPARα attenuates palmitate-induced endoplasmic reticulum stress in human cardiac cells by enhancing AMPK activity].

    PubMed

    Palomer, Xavier; Capdevila-Busquets, Eva; Garreta, Gerard; Davidson, Mercy M; Vázquez-Carrera, Manuel

    2014-01-01

    Endoplasmic reticulum (ER) stress has been linked to several cardiovascular diseases, such as atherosclerosis, heart failure and cardiac hypertrophy. ER stress impairs insulin signalling, thus contributing to the development of insulin resistance and diabetes. Since several studies have reported that PPARα may inhibit ER stress, the main aim of this study consisted in investigating whether activation of this nuclear receptor is able to prevent lipid-induced ER stress in cardiac cells, as well as studying the mechanisms involved. A cardiomyocyte cell line of human origin, AC16, was treated with palmitate in the presence or absence of several AMPK and PPARα pharmacological agonists and antagonists. For the in vivo studies, wild-type male mice were fed a standard diet, or a high-fat diet (HFD), for two months. At the end of the experiments, several ER stress markers were assessed in cardiac cells or in the mice hearts, using real-time RT-PCR and Western-blot analyses. The results demonstrate that both palmitate and the HFD induced ER stress in cardiac cells, since they upregulated the expression (ATF3, BiP/GRP78 and CHOP), splicing (sXBP1), and phosphorylation (IRE-1α and eIF2α) of several ER stress markers. Interestingly, treatment with the PPARα agonist Wy-14,643 prevented an increase in the majority of these ER stress markers in human cardiac cells by means of AMPK activation. These data indicate that PPARα activation by Wy-14,643 might be useful to prevent the harmful effects of ER stress and associated cardiovascular diseases in obese patients, and even during diabetic cardiomyopathy, by enhancing AMPK activity. Copyright © 2013 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  18. Palmitic acid-labeled lipids selectively incorporated into platelet cytoskeleton during aggregation

    SciTech Connect

    Packham, M.A.; Guccione, M.A.; Bryant, N.L.; Livne, A. )

    1990-07-01

    Previous experiments showed that during the early stages (20-30 seconds) of aggregation induced by adenosine diphosphate (ADP, 2 microM) or thrombin (0.1 U/mL) of rabbit or human platelets prelabeled with (3H)palmitic acid, labeled lipid became associated with the cytoskeleton isolated after lysis with 1% Triton X-100, 5 mM EGTA (ethylene glycol-bis-(beta-aminoethyl ether))-N,N,N',N'-tetra-acetic acid. The association appeared to be related to the number of sites of contact and was independent of the release of granule contents. We have now investigated the nature of the labeled lipids by thin-layer and column chromatography and found differences between the distribution of the label in intact platelets (both stimulated and unstimulated) and the isolated cytoskeletons. In both species, and with either ADP or thrombin as aggregating agent, 70-85% of the label in both intact platelets and in the cytoskeletons was in phospholipids. The distribution of label among the phospholipids in the cytoskeletons was similar to that in intact platelets except that the percentage of label in phosphatidylcholine was significantly higher in the cytoskeletons of human platelets than in the intact platelets, and the percentage of label in phosphatidylserine/phosphatidylinositol was significantly lower in the cytoskeletons of rabbit platelets and thrombin-aggregated human platelets than in intact platelets. The cytoskeletons contained a lower percentage of label in triacylglycerol, diacylglycerol, and cholesterol ester than the intact platelets. Contrary to a report in the literature, we found no evidence for the incorporation of diacylglycerol and palmitic acid into the cytoskeleton.

  19. A Palmitic Acid Elongase Affects Eicosapentaenoic Acid and Plastidial Monogalactosyldiacylglycerol Levels in Nannochloropsis.

    PubMed

    Dolch, Lina-Juana; Rak, Camille; Perin, Giorgio; Tourcier, Guillaume; Broughton, Richard; Leterrier, Marina; Morosinotto, Tomas; Tellier, Frédérique; Faure, Jean-Denis; Falconet, Denis; Jouhet, Juliette; Sayanova, Olga; Beaudoin, Frédéric; Maréchal, Eric

    2017-01-01

    Nannochloropsis species are oleaginous eukaryotes containing a plastid limited by four membranes, deriving from a secondary endosymbiosis. In Nannochloropsis, thylakoid lipids, including monogalactosyldiacylglycerol (MGDG), are enriched in eicosapentaenoic acid (EPA). The need for EPA in MGDG is not understood. Fatty acids are de novo synthesized in the stroma, then converted into very-long-chain polyunsaturated fatty acids (FAs) at the endoplasmic reticulum (ER). The production of MGDG relies therefore on an EPA supply from the ER to the plastid, following an unknown process. We identified seven elongases and five desaturases possibly involved in EPA production in Nannochloropsis gaditana Among the six heterokont-specific saturated FA elongases possibly acting upstream in this pathway, we characterized the highly expressed isoform Δ0-ELO1 Heterologous expression in yeast (Saccharomyces cerevisiae) showed that NgΔ0-ELO1 could elongate palmitic acid. Nannochloropsis Δ0-elo1 mutants exhibited a reduced EPA level and a specific decrease in MGDG In NgΔ0-elo1 lines, the impairment of photosynthesis is consistent with a role of EPA-rich MGDG in nonphotochemical quenching control, possibly providing an appropriate MGDG platform for the xanthophyll cycle. Concomitantly with MGDG decrease, the level of triacylglycerol (TAG) containing medium chain FAs increased. In Nannochloropsis, part of EPA used for MGDG production is therefore biosynthesized by a channeled process initiated at the elongation step of palmitic acid by Δ0-ELO1, thus acting as a committing enzyme for galactolipid production. Based on the MGDG/TAG balance controlled by Δ0-ELO1, this study also provides novel prospects for the engineering of oleaginous microalgae for biotechnological applications.

  20. Ca(2+)-dependent permeabilization of mitochondria and liposomes by palmitic and oleic acids: a comparative study.

    PubMed

    Belosludtsev, Konstantin N; Belosludtseva, Natalia V; Agafonov, Alexey V; Astashev, Maxim E; Kazakov, Alexey S; Saris, Nils-Erik L; Mironova, Galina D

    2014-10-01

    In the present work, we examine and compare the effects of saturated (palmitic) and unsaturated (oleic) fatty acids in relation to their ability to cause the Ca(2+)-dependent membrane permeabilization. The results obtained can be summarized as follows. (1) Oleic acid (OA) permeabilizes liposomal membranes at much higher concentrations of Ca(2+) than palmitic acid (PA): 1mM versus 100μM respectively. (2) The OA/Ca(2+)-induced permeabilization of liposomes is not accompanied by changes in the phase state of lipid bilayer, in contrast to what is observed with PA and Ca(2+). (3) The addition of Ca(2+) to the PA-containing vesicles does not change their size; in the case of OA, it leads to the appearance of larger and smaller vesicles, with larger vesicles dominating. This can be interpreted as a result of fusion and fission of liposomes. (4) Like PA, OA is able to induce a Ca(2+)-dependent high-amplitude swelling of mitochondria, yet it requires higher concentrations of Ca(2+) (30 and 100μM for PA and OA respectively). (5) In contrast to PA, OA is unable to cause the Ca(2+)-dependent high-amplitude swelling of mitoplasts, suggesting that the cause of OA/Ca(2+)-induced permeability transition in mitochondria may be the fusion of the inner and outer mitochondrial membranes. (6) The presence of OA enhances PA/Ca(2+)-induced permeabilization of liposomes and mitochondria. The paper discusses possible mechanisms of PA/Ca(2+)- and OA/Ca(2+)-induced membrane permeabilization, the probability of these mechanisms to be realized in the cell, and their possible physiological role.

  1. Post-traumatic stress symptoms and exacerbations in COPD patients.

    PubMed

    Teixeira, Paulo Josè Zimermann; Porto, Lucia; Kristensen, Christian Haag; Santos, Alvaro Huber; Menna-Barreto, Sergio Saldanha; Do Prado-Lima, Pedro AntÙnio Schmidt

    2015-02-01

    Post-Traumatic Stress Disorder (PTSD) is a common psychological consequence of exposure to traumatic stressful life events. During COPD exacerbations dyspnea can be considered a near-death experience that may induce post-traumatic stress symptoms. The aim of this study was to evaluate the relationship between COPD exacerbations and PTSD- related symptoms. Thirty-three in-patients with COPD exacerbations were screened for the following: PTSS (Screen for Posttraumatic Stress Symptoms), anxiety (Beck Anxiety Inventory) and depression (Beck Depression Inventory). Patients had a median age of 72 years and 72.7% were female. Mean FEV1 and FVC were 0.8 ± 0.3 (37.7 ± 14.9% of predicted) and 1.7 ± 0.6 (60 ± 18.8% of predicted), respectively with a mean exacerbation of 2.9 episodes over the past year. Post-traumatic stress symptoms related to PTSD were found in 11 (33.3%) patients (SPTSS mean score 4.13 ± 2.54); moderate to severe depression in 16 (48.5%) (BDI mean score 21.2 ± 12.1) and moderate to severe anxiety in 23 (69.7%) (BAI mean score 23.5 ± 12.4). In a linear regression model, exacerbations significantly predicted post-traumatic stress symptoms scores: SPTSS scores increased 0.9 points with each exacerbation (p = 0.001). Significant correlations were detected between PTSD-related symptoms and anxiety (rs = 0.57; p = 0.001) and PTSD symptoms and depression (rs = 0.62; p = 0.0001). In a multivariable analysis model, two or more exacerbation episodes led to a near twofold increase in the prevalence ratio of post-traumatic stress symptoms related to PTSD(PR1.71; p = 0.015) specially those requiring hospitalization (PR 1.13; p = 0.030) CONCLUSION: PTSD symptoms increase as the patient's exacerbations increase. Two or more exacerbation episodes lead to a near twofold increase in the prevalence ratio of post-traumatic symptomatology. Overall, these findings suggest that psychological domains should be addressed along with respiratory function and exacerbations in

  2. Targeted metabolomic analysis reveals the association between the postprandial change in palmitic acid, branched-chain amino acids and insulin resistance in young obese subjects.

    PubMed

    Liu, Liyan; Feng, Rennan; Guo, Fuchuan; Li, Ying; Jiao, Jundong; Sun, Changhao

    2015-04-01

    Obesity is the result of a positive energy balance and often leads to difficulties in maintaining normal postprandial metabolism. The changes in postprandial metabolites after an oral glucose tolerance test (OGTT) in young obese Chinese men are unclear. In this work, the aim is to investigate the complex metabolic alterations in obesity provoked by an OGTT using targeted metabolomics. We used gas chromatography-mass spectrometry and ultra high performance liquid chromatography-triple quadrupole mass spectrometry to analyze serum fatty acids, amino acids and biogenic amines profiles from 15 control and 15 obese subjects at 0, 30, 60, 90 and 120 min during an OGTT. Metabolite profiles from 30 obese subjects as independent samples were detected in order to validate the change of metabolites. There were the decreased levels of fatty acid, amino acids and biogenic amines after OGTT in obesity. At 120 min, percent change of 20 metabolites in obesity has statistical significance when comparing with the controls. The obese parameters was positively associated with changes in arginine and histidine (P<0.05) and the postprandial change in palmitic acid (PA), branched-chain amino acids (BCAAs) and phenylalanine between 1 and 120 min were positively associated with fasting insulin and HOMA-IR (all P<0.05) in the obese group. The postprandial metabolite of PA and BCAAs may play important role in the development and onset of insulin resistance in obesity. Our findings offer new insights in the complex physiological regulation of the metabolism during an OGTT in obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. SHIP2 on pI3K/Akt pathway in palmitic acid stimulated islet β cell.

    PubMed

    Liu, Qingjuan; Wang, Ruiying; Zhou, Hong; Zhang, Lihui; Cao, Yanping; Wang, Xianjuan; Hao, Yongmei

    2015-01-01

    This study is to investigate the influence of SHIP2 on palmitic acid stimulated islet β cell and insulin secretion, as well as its role in pI3K/Akt pathway. We defined four groups: control, acid group, acid + NC siRNA group and acid + siRNA transfection group. The control was neither treated by palmitic acid nor transfection. The acid group was subjected to palmitic acid incubation. The acid + NC siRNA group was transiently transfected by NC siRNA, then was stimulated by palmitic acid. The acid + siRNA group was transiently transfected by siRNA, then was stimulated by palmitic acid. Cell proliferation and apoptosis were measured by MTT and flow cytometry. Immunocytochemistry, Western Blot and QPCR were designed to detect the expression of SHIP2, Akt, p-Akt protein and mRNA. Insulin secretion was tested by radioimmunoassay. The apoptosis rate in the acid + siRNA group was non-significantly lower than the acid group and the acid + NC siRNA group (P > 0.05). The expression levels of Akt phosphorylation in the acid + siRNA group was significantly higher than in the acid + NC siRNA group and the acid group (P < 0.05). And under 22.4 mmol/L glucose KRB, insulin secretion in the acid + siRNA group was significantly more than the acid + NC siRNA group and the acid group (P < 0.05). SHIP2 silencing probably stimulates insulin secretion, which may be associated with the enhanced proliferation in the pI3K/Akt pathway.

  4. Celastrol attenuates mitochondrial dysfunction and inflammation in palmitate-mediated insulin resistance in C3A hepatocytes.

    PubMed

    Abu Bakar, Mohamad Hafizi; Sarmidi, Mohamad Roji; Tan, Joo Shun; Mohamad Rosdi, Mohamad Norisham

    2017-03-15

    Accumulating evidence indicates that mitochondrial dysfunction-induced inflammation is among the convergence points for the greatest hallmarks of hepatic insulin resistance. Celastrol, an anti-inflammatory compound from the root of Tripterygium Wilfordii has been reported to mitigate insulin resistance and inflammation in animal disease models. Nevertheless, the specific mechanistic actions of celastrol in modulating such improvements at the cellular level remain obscure. The present study sought to explore the mechanistic roles of celastrol upon insulin resistance induced by palmitate in C3A human hepatocytes. The hepatocytes exposed to palmitate (0.75mM) for 48h exhibited reduced both basal and insulin-stimulated glucose uptake, mitochondrial dysfunction, leading to increased mitochondrial oxidative stress with diminished fatty acid oxidation. Elevated expressions of nuclear factor-kappa B p65 (NF-κB p65), c-Jun NH(2)-terminal kinase (JNK) signaling pathways and the amplified release of pro-inflammatory cytokines including IL-8, IL-6, TNF-α and CRP were observed following palmitate treatment. Consistently, palmitate reduced and augmented phosphorylated Tyrosine-612 and Serine-307 of insulin receptor substrate-1 (IRS-1) proteins, respectively in hepatocytes. However, celastrol at the optimum concentration of 30nM was able to reverse these deleterious occasions and protected the cells from mitochondrial dysfunction and insulin resistance. Importantly, we presented evidence for the first time that celastrol efficiently prevented palmitate-induced insulin resistance in hepatocytes at least, via improved mitochondrial functions and insulin signaling pathways. In summary, the present investigation underlines a conceivable mechanism to elucidate the cytoprotective potential of celastrol in attenuating mitochondrial dysfunction and inflammation against the development of hepatic insulin resistance. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Cost effectiveness of paliperidone palmitate versus oral antipsychotics in patients with schizophrenia and a history of criminal justice involvement.

    PubMed

    Muser, Erik; Kozma, Chris M; Benson, Carmela J; Mao, Lian; Starr, H Lynn; Alphs, Larry; Fastenau, John

    2015-01-01

    Conduct a cost effectiveness analysis for the Paliperidone palmitate Research In Demonstrating Effectiveness (PRIDE) trial. PRIDE was a 15 month, prospective, randomized, open-label study in which once monthly paliperidone palmitate significantly delayed the time to first treatment failure (healthcare or criminal justice system [HC/CJS] events) versus oral antipsychotics in recently incarcerated adults with schizophrenia. The present analysis used a state government perspective and HC/CJS event data that were collected on a resource use questionnaire (RUQ) every 3 months. Since cost information was not collected in the trial, cost estimates from published literature and an analysis of multistate Medicaid data for CJS and HC events, respectively, were applied to RUQ event data. Effectiveness and costs were adjusted to 456 days (trial duration). Incremental cost effectiveness was calculated as the adjusted cost difference divided by the adjusted effectiveness difference. Adjusted costs (in US dollars) in the paliperidone palmitate group (n = 198) and the oral antipsychotic group (n = 193), respectively, were: non-drug costs $22,331 and $25,027; drug costs $18,592 and $7833; and total costs $40,923 and $32,860. Adjusted effectiveness differences and corresponding incremental cost effectiveness per event avoided (in parentheses) for paliperidone palmitate versus oral antipsychotics were as follows: 0.33 fewer CJS events ($24,409), 0.13 fewer psychiatric hospitalizations ($60,484), 0.46 fewer psychiatric hospitalizations or CJS events combined ($17,391), and 0.30 fewer incarcerations ($26,754). Costs for HC/CJS events avoided offset 25% of the greater drug cost for the paliperidone palmitate versus oral antipsychotic treatment group in this vulnerable population. Use of a recall-dependent RUQ for event rates and cost estimates instead of actual costs are potential limitations and may make the results conservative from a state government perspective. Indirect

  6. Measuring the cost of poor asthma control and exacerbations.

    PubMed

    Sullivan, Patrick W; Ghushchyan, Vahram H; Campbell, Jonathan D; Globe, Gary; Bender, Bruce; Magid, David J

    2017-01-02

    Previous studies have shown an association between cost and poor asthma control. However, longitudinal studies of general populations are lacking. To examine the cost of poor asthma control and exacerbations across a broad spectrum of asthma patients. The Observational Study of Asthma Control and Outcomes (OSACO) was a prospective survey of persistent asthma patients in Kaiser Colorado in 2011-2012. Patients received a survey 3 times in one year, which included the Asthma Control Questionnaire (ACQ) and questions on exacerbations. Self-reported exacerbations were compared to actual oral corticosteroid (OCS) use. Regression analyses examined the association of control (ACQ-5 scores) and exacerbations with healthcare expenditures, controlling for sociodemographics and smoking. Analyses of expenditures used Generalized Linear Models (GLM) with log-link. 2681 individuals completed at least one survey; 1799 completed all three. ACQ-5 scores were associated with higher all-cause and asthma-specific expenditures across all categories of costs (medical, outpatient, ER, pharmacy) except for inpatient expenditures. Each 1-point increase in the ACQ-5 score (i.e., worse control) was associated with a corresponding increase in all-cause annual healthcare and asthma-specific expenditures of $1443 and $927 ($US 2013). Asthma exacerbations with documented OCS use were associated with an increase of $3014 and $1626 over 4 months, while self-reported exacerbations were $713 and $506. Results demonstrate that poor asthma control and exacerbations are strongly associated with higher healthcare expenditures. Results also confirm that collection of validated measures of control such as the ACQ-5 may provide valuable information toward improving clinical and economic outcomes.

  7. Inappropriate home albuterol use during an acute asthma exacerbation.

    PubMed

    Clayton, Kelly; Monroe, Kathy; Magruder, Teresa; King, William; Harrington, Kathy

    2012-12-01

    Increased asthma morbidity and mortality is associated with inappropriate home self-management skills. To examine the proportion of children presenting to the emergency department (ED) with an acute asthma exacerbation with incorrect home use of their albuterol inhaler and to identify factors associated with improper treatment. Caregivers of children with asthma aged 4 to 14 years, presenting to the ED with an asthma exacerbation, participated in the study. Interviewers collected caregiver's perceived severity of the asthma exacerbation and home albuterol use before the ED visit. National Asthma Education and Prevention Program guidelines were used to classify home albuterol use as appropriate or inappropriate. Home albuterol use for the current asthma exacerbation was categorized as inappropriate (56 [68%]) and appropriate (26 [32%]) for 84 participants. Thirty-nine of the inappropriate group undertreated, with 24 not giving albuterol frequently enough and 15 without albuterol at home. Other reasons for incorrect home albuterol use included: no spacer, overtreating, overreacting, and using a controller medicine for quick relief. Those with appropriate albuterol use were more likely to have their child hospitalized for asthma in the past 48 months (P=.004). Caregivers with inappropriate use perceived their child's asthma exacerbation as more severe (P<.001) compared with physician rating. Physicians rated asthma severity higher in the appropriate group than the inappropriate group (P<.001). A significant proportion of caregivers incorrectly treat children's asthma exacerbation with albuterol. Despite perceiving their children's asthma exacerbations as more severe, most undertreat with albuterol. Correctly assessing asthma symptom severity and appropriate home albuterol use may be linked to disease experience. Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  8. Norepinephrine inhibits islet lipid metabolism, sup 45 Ca sup 2+ uptake, and insulin secretion

    SciTech Connect

    Vara, E.; Tamarit-Rodriguez, J. )

    1989-12-01

    We have previously shown that palmitate potentiates, in isolated islets, glucose-induced stimulation of insulin release, de novo lipid synthesis, and {sup 45}Ca{sup 2+} turnover in a correlative manner. Norepinephrine, a known inhibitor of the secretory response, has now been used to further investigate the relationships among the three phenomena. The amine decreased insulin secretion dose dependently in response to glucose and palmitate with alpha 2-adrenergic specificity. It also reduced similarly the oxidation of 1 mmol/l (U-{sup 14}C)palmitate as well as the incorporation of 20 mmol/l D-(U-{sup 14}C)glucose into islet phospholipids and neutral lipids through an alpha 2-adrenergic mechanism. These results indirectly suggest that alpha 2-adrenoceptor stimulation inhibits in islets both palmitate oxidation and esterification through an inactivation of long-chain acyl-CoA synthetase and other enzymes of glycerolipid synthesis. Islet uptake of {sup 45}Ca{sup 2+} was also decreased by norepinephrine with a similar sensitivity to that shown by insulin release and de novo lipid synthesis. Therefore, it is suggested that alpha 2-adrenoceptor-mediated reduction of the potentiation by palmitate of the secretory response to glucose depends on the inhibition of fatty acid metabolism and the resulting impairment of de novo lipid synthesis and {sup 45}Ca{sup 2+} turnover.

  9. Short-term cigarette smoke exposure leads to metabolic alterations in lung alveolar cells.

    PubMed

    Agarwal, Amit R; Yin, Fei; Cadenas, Enrique

    2014-08-01

    Cigarette smoke (CS)-induced alveolar destruction and energy metabolism changes are known contributors to the pathophysiology of chronic obstructive pulmonary disease (COPD). This study examines the effect of CS exposure on metabolism in alveolar type II cells. Male A/J mice (8 wk old) were exposed to CS generated from a smoking machine for 4 or 8 weeks, and a recovery group was exposed to CS for 8 weeks and allowed to recover for 2 weeks. Alveolar type II cells were isolated from air- or CS- exposed mice. Acute CS exposure led to a reversible airspace enlargement in A/J mice as measured by the increase in mean linear intercept, indicative of alveolar destruction. The effect of CS exposure on cellular respiration was studied using the XF Extracellular Flux Analyzer. A decrease in respiration while metabolizing glucose was observed in the CS-exposed group, indicating altered glycolysis that was compensated by an increase in palmitate utilization; palmitate utilization was accompanied by an increase in the expression of CD36 and carnitine-palmitoyl transferase 1 in type II alveolar cells for the transport of palmitate into the cells and into mitochondria, respectively. The increase in palmitate use for energy production likely affects the surfactant biosynthesis pathway, as evidenced by the decrease in phosphatidylcholine levels and the increase in phospholipase A2 activity after CS exposure. These findings help our understanding of the mechanism underlying the surfactant deficiency observed in smokers and provide a target to delay the onset of COPD.

  10. Epidemiological relationships between the common cold and exacerbation frequency in COPD.

    PubMed

    Hurst, J R; Donaldson, G C; Wilkinson, T M A; Perera, W R; Wedzicha, J A

    2005-11-01

    Higher exacerbation incidence rates in chronic obstructive pulmonary disease (COPD) are associated with more rapid decline in lung function and poorer quality of life, yet the mechanisms determining susceptibility to exacerbation remain ill-defined. The same viruses responsible for common colds are frequently isolated during exacerbations. The current authors hypothesised that exacerbation frequency may be associated with an increased frequency of colds, and investigated whether increased exacerbation frequency was associated with increased acquisition of colds, or a greater likelihood of exacerbation once a cold has been acquired. A total of 150 patients with COPD completed diary cards recording peak expiratory flow, and respiratory and coryzal symptoms for a median 1,047 days. Annual cold and exacerbation incidence rates (cold and exacerbation frequency) were calculated, and the relationships between these variables were investigated. This analysis is based on 1,005 colds and 1,493 exacerbations. Frequent exacerbators (i.e. those whose exacerbation frequency was greater than the median) experienced significantly more colds than infrequent exacerbators (1.73 versus 0.94.yr(-1)). The likelihood of exacerbation during a cold was unaffected by exacerbation frequency. Patients experiencing frequent colds had a significantly higher exposure to cigarette smoke (46 versus 33 pack-yrs). Exacerbation frequency in chronic obstructive pulmonary disease is associated with an increased frequency of acquiring the common cold, rather than an increased propensity to exacerbation once a cold has been acquired.

  11. Tiotropium versus salmeterol for the prevention of exacerbations of COPD.

    PubMed

    Vogelmeier, Claus; Hederer, Bettina; Glaab, Thomas; Schmidt, Hendrik; Rutten-van Mölken, Maureen P M H; Beeh, Kai M; Rabe, Klaus F; Fabbri, Leonardo M

    2011-03-24

    Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD. In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

  12. Pulmonary Arterial Enlargement and Acute Exacerbations of COPD

    PubMed Central

    Wells, J. Michael; Washko, George R.; Han, MeiLan K.; Abbas, Naseer; Nath, Hrudaya; Mamary, A. James; Regan, Elizabeth; Bailey, William C.; Martinez, Fernando J.; Westfall, Elizabeth; Beaty, Terri H.; Curran-Everett, Douglas; Curtis, Jeffrey L.; Hokanson, John E.; Lynch, David A.; Make, Barry J.; Crapo, James D.; Silverman, Edwin K.; Bowler, Russell P.; Dransfield, Mark T.

    2013-01-01

    BACKGROUND Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. METHODS We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. RESULTS Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. CONCLUSIONS

  13. Pulmonary arterial enlargement and acute exacerbations of COPD.

    PubMed

    Wells, J Michael; Washko, George R; Han, MeiLan K; Abbas, Naseer; Nath, Hrudaya; Mamary, A James; Regan, Elizabeth; Bailey, William C; Martinez, Fernando J; Westfall, Elizabeth; Beaty, Terri H; Curran-Everett, Douglas; Curtis, Jeffrey L; Hokanson, John E; Lynch, David A; Make, Barry J; Crapo, James D; Silverman, Edwin K; Bowler, Russell P; Dransfield, Mark T

    2012-09-06

    Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. Pulmonary artery enlargement (a PA:A ratio of

  14. Evidence-based approach to acute exacerbations of COPD.

    PubMed

    Soto, Francisco J; Varkey, Basil

    2003-03-01

    Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and it accounts for approximately 500,000 hospitalizations for exacerbations each year. New definitions of acute COPD exacerbation have been suggested, but the one used by Anthonisen et al. is still widely accepted. It requires the presence of one or more of the following findings: increase in sputum purulence, increase in sputum volume, and worsening of dyspnea. Patients with COPD typically present with acute decompensation of their disease one to three times a year, and 3% to 16% of these will require hospital admission. Hospital mortality of these admissions ranges from 3% to 10% in severe COPD patients, and it is much higher for patients requiring ICU admission. The etiology of the exacerbations is mainly infectious (up to 80%). Other conditions such as heart failure, pulmonary embolism, nonpulmonary infections, and pneumothorax can mimic an acute exacerbation or possibly act as "triggers." Baseline chest radiography and arterial blood gas analysis during an exacerbation are recommended. Oxygen administration through a venturi mask seems to be appropriate and safe, and the oxygen saturation should be kept just above 90%. Either a short acting beta 2-agonist or an anticholinergic is the preferred bronchodilator agent. The choice between the two depends largely on potential undesirable side effects and the patient's coexistent conditions. Adding a second bronchodilator to the first one does not seem to offer much benefit. The evidence suggests similar benefit of MDIs when compared with nebulized treatment for bronchodilator delivery. If MDIs are to be used, spacer devices are recommended. Steroids do improve several outcomes during an acute COPD exacerbation, and a 10- to 14-day course seems appropriate. Antibiotic use has been shown to be beneficial, especially for patients with severe exacerbation. Changes in bacteria strains have been documented during

  15. Impact of exacerbations of cystic fibrosis on muscle strength

    PubMed Central

    2013-01-01

    Background Adult patients with cystic fibrosis have peripheral muscle weakness, which is related to exercise intolerance and poor prognosis. The influence of acute exacerbations on muscle strength has been poorly studied. This study aimed to investigate whether quadriceps force (QF), as assessed with an involuntary technique, changes during intravenous antibiotics therapy (IVAT) for an exacerbation. Methods QF was measured in 20 patients using twitch stimulation of the femoral nerve at the day of hospitalization (day 1) and at termination (day 14) of the IVAT. Physical activity was monitored during IVAT using a SenseWear armband. Ten stable patients served as control subjects. Results QF did not change during exacerbation (potentiated twitch force at day 1: 140 ± 42 N, at day 14: 140 ± 47 N), but a decrease was observed in individual patients. Changes in twitch force during exacerbation were correlated with time spent in activities of at least moderate intensity (r = 0.61, p = 0.007). Conclusions QF does not systematically decrease during exacerbations of cystic fibrosis. Individual changes in QF are well correlated with daily time spent in activities of at least moderate intensity. PMID:23601143

  16. The profile of psychiatric symptoms exacerbated by methamphetamine use.

    PubMed

    McKetin, Rebecca; Dawe, Sharon; Burns, Richard A; Hides, Leanne; Kavanagh, David J; Teesson, Maree; McD Young, Ross; Voce, Alexandra; Saunders, John B

    2016-04-01

    Methamphetamine use can produce symptoms almost indistinguishable from schizophrenia. Distinguishing between the two conditions has been hampered by the lack of a validated symptom profile for methamphetamine-induced psychiatric symptoms. We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Exacerbation of psychiatric symptoms with methamphetamine use was quantified using random coefficient models. The dimensions of symptom exacerbation were examined using principal axis factoring and a latent profile analysis. Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms (suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity). Methamphetamine use did not significantly increase negative symptoms. Vulnerability to positive psychotic and affective symptom exacerbation was shared by 28% of participants, and this vulnerability aligned with a past year DSM-IV diagnosis of substance-induced psychosis (38% vs. 22%, χ(2)(df1)=3.66, p=0.056). Methamphetamine use produced a symptom profile comprised of positive psychotic and affective symptoms, which aligned with a diagnosis of substance-induced psychosis, with no evidence of a negative syndrome. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Prevalence of eosinophilia in hospitalized patients with asthma exacerbation.

    PubMed

    Hasegawa, Kohei; Stoll, Samantha J; Ahn, Jason; Bittner, Jane C; Camargo, Carlos A

    2015-09-01

    Recent studies have identified the "eosinophilic phenotype" of asthma that is characterized by persistent eosinophilic inflammation and frequent exacerbations. However, the prevalence of eosinophilia in patients hospitalized for asthma exacerbation is not known. We performed a pilot study in two sites participating in a multicenter chart review project of children and adults hospitalized for asthma exacerbation during 2012-2013. The pilot study investigated the prevalence of blood eosinophilia in this patient population. Eosinophilia was defined as a count of ≥300 cells/microliter at some time during the hospitalization. Among 80 patients hospitalized for asthma exacerbation, 47 (59%) underwent CBC with differential and had data on blood eosinophil count. These 47 comprised the analytic cohort. The median patient age was 32 years (IQR, 24-44 years), and 51% were female. Overall, 40% (95% CI, 26%-56%) of patients had eosinophilia. Although statistical power was limited, there were no statistically significant differences in patient characteristics or hospital course between patients with eosinophilia and those without (all P > 0.05). Our pilot study showed that 40% of patients hospitalized for asthma exacerbation had eosinophilia. The clinical meaning of this biomarker in the emergency department/inpatient setting requires further study in much larger samples with long-term follow-up; such studies appear feasible. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Proteomic analysis of the palmitate-induced myotube secretome reveals involvement of the annexin A1-formyl peptide receptor 2 (FPR2) pathway in insulin resistance.

    PubMed

    Yoon, Jong Hyuk; Kim, Dayea; Jang, Jin-Hyeok; Ghim, Jaewang; Park, Soyeon; Song, Parkyong; Kwon, Yonghoon; Kim, Jaeyoon; Hwang, Daehee; Bae, Yoe-Sik; Suh, Pann-Ghill; Berggren, Per-Olof; Ryu, Sung Ho

    2015-04-01

    Elevated levels of the free fatty acid palmitate are found in the plasma of obese patients and induce insulin resistance. Skeletal muscle secretes myokines as extracellular signaling mediators in response to pathophysiological conditions. Here, we identified and characterized the skeletal muscle secretome in response to palmitate-induced insulin resistance. Using a quantitative proteomic approach, we identified 36 secretory proteins modulated by palmitate-induced insulin resistance. Bioinformatics analysis revealed that palmitate-induced insulin resistance induced cellular stress and modulated secretory events. We found that the decrease in the level of annexin A1, a secretory protein, depended on palmitate, and that annexin A1 and its receptor, formyl peptide receptor 2 agonist, played a protective role in the palmitate-induced insulin resistance of L6 myotubes through PKC-θ modulation. In mice fed with a high-fat diet, treatment with the formyl peptide receptor 2 agonist improved systemic insulin sensitivity. Thus, we identified myokine candidates modulated by palmitate-induced insulin resistance and found that the annexin A1- formyl peptide receptor 2 pathway mediated the insulin resistance of skeletal muscle, as well as systemic insulin sensitivity.

  19. Proteomic Analysis of the Palmitate-induced Myotube Secretome Reveals Involvement of the Annexin A1-Formyl Peptide Receptor 2 (FPR2) Pathway in Insulin Resistance*

    PubMed Central

    Yoon, Jong Hyuk; Kim, Dayea; Jang, Jin-Hyeok; Ghim, Jaewang; Park, Soyeon; Song, Parkyong; Kwon, Yonghoon; Kim, Jaeyoon; Hwang, Daehee; Bae, Yoe-Sik; Suh, Pann-Ghill; Berggren, Per-Olof; Ryu, Sung Ho

    2015-01-01

    Elevated levels of the free fatty acid palmitate are found in the plasma of obese patients and induce insulin resistance. Skeletal muscle secretes myokines as extracellular signaling mediators in response to pathophysiological conditions. Here, we identified and characterized the skeletal muscle secretome in response to palmitate-induced insulin resistance. Using a quantitative proteomic approach, we identified 36 secretory proteins modulated by palmitate-induced insulin resistance. Bioinformatics analysis revealed that palmitate-induced insulin resistance induced cellular stress and modulated secretory events. We found that the decrease in the level of annexin A1, a secretory protein, depended on palmitate, and that annexin A1 and its receptor, formyl peptide receptor 2 agonist, played a protective role in the palmitate-induced insulin resistance of L6 myotubes through PKC-θ modulation. In mice fed with a high-fat diet, treatment with the formyl peptide receptor 2 agonist improved systemic insulin sensitivity. Thus, we identified myokine candidates modulated by palmitate-induced insulin resistance and found that the annexin A1- formyl peptide receptor 2 pathway mediated the insulin resistance of skeletal muscle, as well as systemic insulin sensitivity. PMID:25616869

  20. Fasting increases palmitic acid incorporation into rat hind-limb intramuscular acylglycerols while short-term cold exposure has no effect.

    PubMed

    Synak, M; Zarzeczny, R; Górecka, M; Langfort, J; Kaciuba-Uściłko, H; Zernicka, Ewa

    2011-09-01

    The aim of the study was to investigate the palmitic acid incorporation into intramuscular acylglycerols in perfused hind-limb skeletal muscles of different fibre types in rats either fasted for 48 h or exposed to cold (6 °C) for 12 h. Hind-limb preparations of fasted and cold exposed rats were perfused with buffers containing tritium labelled and cold palmitic acid. Palmitic acid incorporation into intracellular lipid pools in the soleus, plantaris, red and white gastrocnemius and red and white quadriceps was measured. It was found that fasting increased approximately 2-fold palmitic acid incorporation in all muscles examined regardless of the fibre type composition of the muscle. On the other hand, exposure to cold had no effect on the palmitic acid incorporation into intramuscular acylglycerols regardless the muscle fibre type. The increased incorporation of palmitic acid into acylglycerols in fasted animals is in line with data showing that 48 h fasting stimulates the expression of plasma membrane proteins putatively facilitating fatty acid uptake. It appears that although 12 h cold exposure increases the use of fatty acids as energy substrates it does not alter the incorporation of palmitic acid into intramuscular acylglycerols in the perfused rat hind-limb.

  1. Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection.

    PubMed

    Pardo, Virginia; González-Rodríguez, Águeda; Muntané, Jordi; Kozma, Sara C; Valverde, Ángela M

    2015-06-01

    The excess of saturated free fatty acids, such as palmitic acid, that induces lipotoxicity in hepatocytes, has been implicated in the development of non-alcoholic fatty liver disease also associated with insulin resistance. By contrast, oleic acid, a monounsaturated fatty acid, attenuates the effects of palmitic acid. We evaluated whether palmitic acid is directly associated with both insulin resistance and lipoapoptosis in mouse and human hepatocytes and the impact of oleic acid in the molecular mechanisms that mediate both processes. In human and mouse hepatocytes palmitic acid at a lipotoxic concentration triggered early activation of endoplasmic reticulum (ER) stress-related kinases, induced the apoptotic transcription factor CHOP, activated caspase 3 and increased the percentage of apoptotic cells. These effects concurred with decreased IR/IRS1/Akt insulin pathway. Oleic acid suppressed the toxic effects of palmitic acid on ER stress activation, lipoapoptosis and insulin resistance. Besides, oleic acid suppressed palmitic acid-induced activation of S6K1. This protection was mimicked by pharmacological or genetic inhibition of S6K1 in hepatocytes. In conclusion, this is the first study highlighting the activation of S6K1 by palmitic acid as a common and novel mechanism by which its inhibition by oleic acid prevents ER stress, lipoapoptosis and insulin resistance in hepatocytes.

  2. Egr2 enhances insulin resistance via JAK2/STAT3/SOCS-1 pathway in HepG2 cells treated with palmitate.

    PubMed

    Lu, Lin; Ye, Xinhua; Yao, Qing; Lu, Aijiao; Zhao, Zhen; Ding, Yang; Meng, Chuchen; Yu, Wenlong; Du, Yunfeng; Cheng, JinLuo

    2017-08-22

    Insulin resistance is generally responsible for the pathogenesis of type 2 diabetes mellitus (T2DM). Early growth response proteins-2 (Egr2) has been reported to be able to increase the expression of the suppressors of cytokine signaling-1 (SOCS-1), and impair insulin signaling pathway through suppression of insulin receptor substrates (IRS), including IRS-1 and IRS-2. However, whether Egr2 is directly involved in the development of insulin resistance, and how its potential contributions to insulin resistance still remain unknown. Here, our present investigation found that the expression levels of Egr2 were up-regulated when insulin resistance occurs, and knockdown of Egr2 abolished the effect of insulin resistance in HepG2 cells induced with palmitate (PA). Importantly, inhibition of Egr2 decreased the expression of SOCS-1 as well as reduced phosphorylation of JAK2 and STAT3. And, our data indicated that silencing of Egr2 accelerated hepatic glucose uptake and reversed the impaired lipid metabolism upon insulin resistance. In summary, the present study confirms that Egr2 could deteriorate insulin resistance via the pathway of JAK2/STAT3/SOCS-1 and may shed light on resolving insulin resistance and further the pathogenesis of T2DM. Copyright © 2017. Published by Elsevier Inc.

  3. CPT1{alpha} over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells

    SciTech Connect

    Jambor de Sousa, Ulrike L.; Koss, Michael D.; Fillies, Marion; Gahl, Anja; Scheeder, Martin R.L.; Cardoso, M. Cristina; Leonhardt, Heinrich; Geary, Nori; Langhans, Wolfgang; Leonhardt, Monika . E-mail: monika.leonhardt@inw.agrl.ethz.ch

    2005-12-16

    To test the cellular response to an increased fatty acid oxidation, we generated a vector for an inducible expression of the rate-limiting enzyme carnitine palmitoyl-transferase 1{alpha} (CPT1{alpha}). Human embryonic 293T kidney cells were transiently transfected and expression of the CPT1{alpha} transgene in the tet-on vector was activated with doxycycline. Fatty acid oxidation was measured by determining the conversion of supplemented, synthetic cis-10-heptadecenoic acid (C17:1n-7) to C15:ln-7. CPT1{alpha} over-expression increased mitochondrial long-chain fatty acid oxidation about 6-fold. Addition of palmitic acid (PA) decreased viability of CPT1{alpha} over-expressing cells in a concentration-dependent manner. Both, PA and CPT1{alpha} over-expression increased cell death. Interestingly, PA reduced total cell number only in cells over-expressing CPT1{alpha}, suggesting an effect on cell proliferation that requires PA translocation across the mitochondrial inner membrane. This inducible expression system should be well suited to study the roles of CPT1 and fatty acid oxidation in lipotoxicity and metabolism in vivo.

  4. Adipose Weight Gain during Chronic Insulin Treatment of Mice Results from Changes in Lipid Storage without Affecting De Novo Synthesis of Palmitate

    PubMed Central

    Frikke-Schmidt, Henriette; Pedersen, Thomas Åskov; Fledelius, Christian; Olsen, Grith Skytte; Hellerstein, Marc

    2013-01-01

    Insulin treatment is associated with increased adipose mass in both humans and mice. However, the underlying dynamic basis of insulin induced lipid accumulation in adipose tissue remains elusive. To assess this, young female C57BL6/J mice were fed a low fat diet for 3 weeks, treated subsequently with 7 days of constant subcutaneous insulin infusion by osmotic minipumps and compared to mice with only buffer infused. To track changes in lipid deposition during insulin treatment, metabolic labeling was conducted with heavy water for the final 4 days. Blood glucose was significantly lowered within one hour after implantation of insulin loaded mini pumps and remained lower throughout the study. Insulin treated animals gained significantly more weight during treatment and the mean weight of the subcutaneous adipose depots was significantly higher with the highest dose of insulin. Surprisingly, de novo palmitate synthesis within the subcutaneous and the gonadal depots was not affected significantly by insulin treatment. In contrast insulin treatment caused accumulation of triglycerides in both depots due to either deposition of newly synthesised triglycerides (subcutaneous depot) or inhibition of lipolysis (gonadal depot). PMID:24069458

  5. Adipose weight gain during chronic insulin treatment of mice results from changes in lipid storage without affecting de novo synthesis of palmitate.

    PubMed

    Frikke-Schmidt, Henriette; Pedersen, Thomas Åskov; Fledelius, Christian; Olsen, Grith Skytte; Hellerstein, Marc

    2013-01-01

    Insulin treatment is associated with increased adipose mass in both humans and mice. However, the underlying dynamic basis of insulin induced lipid accumulation in adipose tissue remains elusive. To assess this, young female C57BL6/J mice were fed a low fat diet for 3 weeks, treated subsequently with 7 days of constant subcutaneous insulin infusion by osmotic minipumps and compared to mice with only buffer infused. To track changes in lipid deposition during insulin treatment, metabolic labeling was conducted with heavy water for the final 4 days. Blood glucose was significantly lowered within one hour after implantation of insulin loaded mini pumps and remained lower throughout the study. Insulin treated animals gained significantly more weight during treatment and the mean weight of the subcutaneous adipose depots was significantly higher with the highest dose of insulin. Surprisingly, de novo palmitate synthesis within the subcutaneous and the gonadal depots was not affected significantly by insulin treatment. In contrast insulin treatment caused accumulation of triglycerides in both depots due to either deposition of newly synthesised triglycerides (subcutaneous depot) or inhibition of lipolysis (gonadal depot).

  6. GPR40/FFA1 and Neutral Sphingomyelinase Are Involved in Palmitate-Boosted Inflammatory Response of Microvascular Endothelial Cells to LPS

    PubMed Central

    Lu, Zhongyang; Li, Yanchun; Jin, Junfei; Zhang, Xiaoming; Hannun, Yusuf A.; Huang, Yan

    2015-01-01

    Objectives Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms. Methods Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated. Results G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post-transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation. Conclusion PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase. PMID:25795558

  7. Topical Application of Trisodium Ascorbyl 6-Palmitate 2-Phosphate Actively Supplies Ascorbate to Skin Cells in an Ascorbate Transporter-Independent Manner

    PubMed Central

    Shibuya, Shuichi; Sakaguchi, Ikuyo; Ito, Shintaro; Kato, Eiko; Watanabe, Kenji; Izuo, Naotaka; Shimizu, Takahiko

    2017-01-01

    Ascorbic acid (AA) possesses multiple beneficial functions, such as regulating collagen biosynthesis and redox balance in the skin. AA derivatives have been developed to overcome this compound’s high fragility and to assist with AA supplementation to the skin. However, how AA derivatives are transferred into cells and converted to AA in the skin remains unclear. In the present study, we showed that AA treatment failed to increase the cellular AA level in the presence of AA transporter inhibitors, indicating an AA transporter-dependent action. In contrast, torisodium ascorbyl 6-palmitate 2-phosphate (APPS) treatment significantly enhanced the cellular AA level in skin cells despite the presence of inhibitors. In ex vivo experiments, APPS treatment also increased the AA content in a human epidermis model. Interestingly, APPS was readily metabolized and converted to AA in keratinocyte lysates via an intrinsic mechanism. Furthermore, APPS markedly repressed the intracellular superoxide generation and promoted viability associated with an enhanced AA level in Sod1-deficient skin cells. These findings indicate that APPS effectively restores the AA level and normalizes the redox balance in skin cells in an AA transporter-independent manner. Topical treatment of APPS is a beneficial strategy for supplying AA and improving the physiology of damaged skin. PMID:28640219

  8. Topical Application of Trisodium Ascorbyl 6-Palmitate 2-Phosphate Actively Supplies Ascorbate to Skin Cells in an Ascorbate Transporter-Independent Manner.

    PubMed

    Shibuya, Shuichi; Sakaguchi, Ikuyo; Ito, Shintaro; Kato, Eiko; Watanabe, Kenji; Izuo, Naotaka; Shimizu, Takahiko

    2017-06-22

    Ascorbic acid (AA) possesses multiple beneficial functions, such as regulating collagen biosynthesis and redox balance in the skin. AA derivatives have been developed to overcome this compound's high fragility and to assist with AA supplementation to the skin. However, how AA derivatives are transferred into cells and converted to AA in the skin remains unclear. In the present study, we showed that AA treatment failed to increase the cellular AA level in the presence of AA transporter inhibitors, indicating an AA transporter-dependent action. In contrast, torisodium ascorbyl 6-palmitate 2-phosphate (APPS) treatment significantly enhanced the cellular AA level in skin cells despite the presence of inhibitors. In ex vivo experiments, APPS treatment also increased the AA content in a human epidermis model. Interestingly, APPS was readily metabolized and converted to AA in keratinocyte lysates via an intrinsic mechanism. Furthermore, APPS markedly repressed the intracellular superoxide generation and promoted viability associated with an enhanced AA level in Sod1-deficient skin cells. These findings indicate that APPS effectively restores the AA level and normalizes the redox balance in skin cells in an AA transporter-independent manner. Topical treatment of APPS is a beneficial strategy for supplying AA and improving the physiology of damaged skin.

  9. Resveratrol Ameliorates Palmitate-Induced Inflammation in Skeletal Muscle Cells by Attenuating Oxidative Stress and JNK/NF-κB Pathway in a SIRT1-Independent Mechanism.

    PubMed

    Sadeghi, Asie; Seyyed Ebrahimi, Shadi Sadat; Golestani, Abolfazl; Meshkani, Reza

    2017-09-01

    Resveratrol has been shown to exert anti-inflammatory and anti-oxidant effects in a variety of cell types, however, its role in prevention of inflammatory responses mediated by palmitate in skeletal muscle cells remains unexplored. In the present study, we investigated the effects of resveratrol on palmitate-induced inflammation and elucidated the underlying mechanisms in skeletal muscle cells. The results showed that palmitate significantly enhanced TNF-α and IL-6 mRNA expression and protein secretion from C2C12 cells at 12, 24, and 36 h treatments. Increased expression of cytokines was accompanied by an enhanced phosphorylation of JNK, P38, ERK1/2, and IKKα/IKKβ. In addition, JNK and P38 inhibitors could significantly attenuate palmitate-induced mRNA expression of TNF-α and IL-6, respectively, whereas NF-κB inhibitor reduced the expression of both cytokines in palmitate-treated cells. Resveratrol pretreatment significantly prevented palmitate-induced TNF-α and IL-6 mRNA expression and protein secretion in C2C12 cells. Importantly, pre-treatment of the cells with resveratrol completely abrogated the phosphorylation of ERK1/2, JNK, and IKKα/IKKβ in palmitate treated cells. The protection from palmitate-induced inflammation by resveratrol was accompanied by a decrease in the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), a known scavenger of ROS, could protect palmitate-induced expression of TNF-α and IL-6. Furthermore, inhibition of SIRT1 by shRNA or sirtinol demonstrated that the anti-inflammatory effect of resveratrol in muscle cells is mediated through a SIRT1-independent mechanism. Taken together, these findings suggest that resveratrol may represent a promising therapy for prevention of inflammation in skeletal muscle cells. J. Cell. Biochem. 118: 2654-2663, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  10. Genome-wide identification of palmitate-regulated immediate early genes and target genes in pancreatic beta-cells reveals a central role of NF-κB.

    PubMed

    Choi, Hyung Jin; Hwang, Seungwoo; Lee, Se-Hee; Lee, You Ri; Shin, Jiyon; Park, Kyong Soo; Cho, Young Min

    2012-06-01

    Free fatty acid-induced pancreatic β-cell dysfunction plays a key role in the pathogenesis of type 2 diabetes. We conducted gene expression microarray analysis to comprehensively investigate the transcription machinery of palmitate-regulated genes in pancreatic β-cells in vitro. In particular, mouse pancreatic βTC3 cells were treated with palmitate in the presence or absence of cycloheximide (CHX), which blocks protein synthesis and thereby allows us to distinguish immediate early genes (IEGs) from their target genes. The microarray experiments identified 34 palmitate-regulated IEGs and 74 palmitate-regulated target genes. In silico promoter analysis revealed that transcription factor binding sites for NF-κB were over-represented, regulating approximately one-third of the palmitate-regulated target genes. In cells treated with CHX, nfkb1 showed an up-regulation by palmitate, suggesting that NF-κB could be an IEG. Functional enrichment analysis of 27 palmitate-regulated genes with NF-κB binding sites showed an over-representation of genes involved in immune response, inflammatory response, defense response, taxis, regulation of cell proliferation, and regulation of cell death pathways. Electrophoretic mobility shift assay showed that palmitate stimulates NF-κB activity both in the presence and absence of CHX. In conclusion, by identifying IEGs and target genes, the present study depicted a comprehensive view of transcription machinery underlying palmitate-induced inflammation and cell proliferation/death in pancreatic β-cells and our data demonstrated the central role of NF-κB.

  11. Perturbation of N-linked oligosaccharide structure results in an altered incorporation of (/sup 3/H)palmitate into specific proteins in Chinese hamster ovary cells

    SciTech Connect

    Wellner, R.B.; Ghosh, P.C.; Roecklein, B.; Wu, H.C.

    1987-09-25

    Increased (/sup 3/H)palmitate incorporation into specific cellular proteins has been reported to occur in Chinese hamster ovary and yeast mutant cells. In this paper we report studies concerning the relationship between N-linked oligosaccharide structure and (/sup 3/H)palmitate incorporation into proteins of Chinese hamster ovary (CHO) cells. We have compared the incorporation of (/sup 3/H)palmitate into proteins of wild-type and four different mutant CHO cell lines defective in various steps of N-linked protein glycosylation. Sodium dodecyl sulfate-gel electrophoretic analysis showed that three of the mutants exhibited increased (/sup 3/H)palmitate incorporation into several CHO cellular proteins (approximately 30,000-38,000 molecular weight) as compared to the wild-type cells. One of the affected mutants which accumulates the Man5Gn2Asn intermediate structure was examined in detail. In agreement with earlier reports, virtually all of the (/sup 3/H) palmitate-labeled proteins of both wild-type and mutant cell lines are membrane-bound. Pretreatment of the mutant cell line with tunicamycin blocked the increased (/sup 3/H)palmitate incorporation into the two specific proteins (both of approximately 30,000 molecular weight) observed in untreated cells; the decreased incorporation of (/sup 3/H)palmitate into the 30,000 molecular weight species was accompanied by a concomitant increase in the incorporation of (/sup 3/H)palmitate into two proteins of approximately 20,000 molecular weight. Pretreatment of wild-type cells with tunicamycin also caused increased (/sup 3/H)palmitate incorporation into the 20,000 molecular weight species.

  12. Influence of high carbohydrate versus high fat diet in ozone induced pulmonary injury and systemic metabolic impairment in a Brown Norway (BN) rat model of healthy aging

    EPA Science Inventory

    Rationale: Air pollution has been recently linked to the increased prevalence of metabolic syndrome. It has been postulated that dietary risk factors might exacerbate air pollution-induced metabolic impairment. We have recently reported that ozone exposure induces acute systemic ...

  13. Influence of high carbohydrate versus high fat diet in ozone induced pulmonary injury and systemic metabolic impairment in a Brown Norway (BN) rat model of healthy aging

    EPA Science Inventory

    Rationale: Air pollution has been recently linked to the increased prevalence of metabolic syndrome. It has been postulated that dietary risk factors might exacerbate air pollution-induced metabolic impairment. We have recently reported that ozone exposure induces acute systemic ...

  14. Inhibitory effects of fatty acids on glucose-regulated B-cell function: association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism.

    PubMed

    Zhou, Y P; Ling, Z C; Grill, V E

    1996-08-01

    Long-term exposure to fatty acids (FA) inhibits B-cell function. We tested whether the inhibitory effects are associated with increased islet triglycerides (TG). Rat pancreatic islets were cultured for 48 hours in RPMI 1640 medium with 10% fetal calf serum (FCS) and 11 mmol/L glucose in the presence or absence of the long-chain FA, palmitate. Palmitate (0.125 mmol/L) exposure successively increased islet TG 70% after 6 hours and 200% after 48 hours of culture. The dose-response for palmitate was similar for the increase in TG and inhibition of glucose-induced insulin secretion. Reversal of elevated islet TG in RPMI medium (after 48 hours of palmitate) was 29% after 6 hours and 84% after 24 hours. A more rapid decline of TG was observed in Krebs-Ringer bicarbonate (KRB) medium in the absence of nutrients. This decline was totally prevented by 1 mumol/L of the carnitine palmitoyl transferase-I (CPT-I) inhibitor, etomoxir. Etomoxir enhanced glucose-induced insulin secretion from palmitate-cultured islets; however, this effect was lost when TG were normalized. Under conditions when oxidation of FA from islet TG stores was blocked with etomoxir, we tested the effects of octanoate, the oxidation of which is not blocked by etomoxir. Oxidation of [1-14C]octanoate from islets precultured with palmitate (48 hours) did not differ from that in control islets. Conversely, after palmitate, octanoate inhibited glucose oxidation (14CO2 production from [U-14C]glucose, 613 +/- 41 pmol/10 islets/90 min v 1,129 +/- 87 after control conditions, P < .01). In conclusion, (1) palmitate induces increases in islet TG that are associated with inhibition of B-cell function, and (2) long-term exposure to palmitate also induces an inhibitory effect of FA oxidation on glucose metabolism that is independent of TG.

  15. Newer fluoroquinolones in the treatment of acute exacerbations of COPD.

    PubMed

    Patel, Amit; Wilson, Robert

    2006-01-01

    Acute exacerbations of COPD are a major cause of morbidity and mortality. Bacteria are implicated in about half of all cases. The frequency of exacerbations is related to decline in lung function and poorer quality of life. 25% of patients with COPD have bacterial colonization of the lower airways in stable state whereas non-smokers without COPD have airways that are sterile. The significance of the colonization is unclear, but there is emerging evidence that it may be detrimental. Much of the data recommending antibiotic treatment are based on findings more than 10 years old and do not take into account emerging bacterial resistance. This article reviews these data and that from newer antibiotic trials. It also reviews current antibiotic prescribing guidelines from major respiratory societies around the world. Recent antibiotic trials have compared fluoroquinolones with "standard" antibiotics and found, in the main, longer exacerbation-free intervals and better bacterial eradication rates in those treated with fluoroquinolones.

  16. Newer fluoroquinolones in the treatment of acute exacerbations of COPD

    PubMed Central

    Patel, Amit; Wilson, Robert

    2006-01-01

    Acute exacerbations of COPD are a major cause of morbidity and mortality. Bacteria are implicated in about half of all cases. The frequency of exacerbations is related to decline in lung function and poorer quality of life. 25% of patients with COPD have bacterial colonization of the lower airways in stable state whereas non-smokers without COPD have airways that are sterile. The significance of the colonization is unclear, but there is emerging evidence that it may be detrimental. Much of the data recommending antibiotic treatment are based on findings more than 10 years old and do not take into account emerging bacterial resistance. This article reviews these data and that from newer antibiotic trials. It also reviews current antibiotic prescribing guidelines from major respiratory societies around the world. Recent antibiotic trials have compared fluoroquinolones with “standard” antibiotics and found, in the main, longer exacerbation-free intervals and better bacterial eradication rates in those treated with fluoroquinolones. PMID:18046861

  17. Premenstrual Exacerbations: Achieving Stability All Month, Every Month.

    PubMed

    Leahy, Laura G

    2017-04-01

    Premenstrual syndrome, premenstrual dysphoric disorder, or premenstrual exacerbation of a psychiatric condition may disrupt 10 years of a woman's life over the course of her reproductive lifespan. As health care practitioners, nurses see women who experience these premenstrual symptom exacerbations in all treatment settings. Premenstrual exacerbation of psychiatric illness is a common phenomenon, and it is treatable; however, research is limited and evidence-based guidelines for treatment are sparse. The current article offers insights and an algorithm, extrapolated from the existing literature, into a lesser-known treatment strategy, semi-intermittent dosing, which will provide symptom stability all month, every month. [Journal of Psychosocial Nursing and Mental Health Services, 55(4), 9-13.].

  18. Predicting frequent COPD exacerbations using primary care data.

    PubMed

    Kerkhof, Marjan; Freeman, Daryl; Jones, Rupert; Chisholm, Alison; Price, David B

    2015-01-01

    Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio <0.7 were included in this historical follow-up study if they were ≥40 years old and had data encompassing the year before (predictor year) and year after (outcome year) study index date. The data set contained potential risk factors including demographic, clinical, and comorbid variables. Following univariable analysis, predictors of two or more exacerbations were fed into a stepwise multivariable logistic regression. Sensitivity analyses were conducted for subpopulations of patients without any asthma diagnosis ever and those with questionnaire data on symptoms and smoking pack-years. The full predictive model was validated against 1 year of prospective OPCRD data. The full data set contained 16,565 patients (53% male, median age 70 years), including 9,393 patients without any recorded asthma and 3,713 patients with questionnaire data. The full model retained eleven variables that significantly predicted two or more exacerbations, of which the number of exacerbations in the preceding year had the strongest association; others included height, age, forced expiratory volume in 1 second, and several comorbid conditions. Significant predictors not previously identified included eosinophilia and COPD Assessment Test score. The predictive ability of the full model (C statistic 0.751) changed little when applied to the validation data set (n=2,713; C statistic 0.735). Results of the sensitivity analyses supported the main findings. Patients at risk of exacerbation can be identified from routinely available, computerized primary care

  19. Predicting frequent COPD exacerbations using primary care data

    PubMed Central

    Kerkhof, Marjan; Freeman, Daryl; Jones, Rupert; Chisholm, Alison; Price, David B

    2015-01-01

    Purpose Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. Patients and methods Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio <0.7 were included in this historical follow-up study if they were ≥40 years old and had data encompassing the year before (predictor year) and year after (outcome year) study index date. The data set contained potential risk factors including demographic, clinical, and comorbid variables. Following univariable analysis, predictors of two or more exacerbations were fed into a stepwise multivariable logistic regression. Sensitivity analyses were conducted for subpopulations of patients without any asthma diagnosis ever and those with questionnaire data on symptoms and smoking pack-years. The full predictive model was validated against 1 year of prospective OPCRD data. Results The full data set contained 16,565 patients (53% male, median age 70 years), including 9,393 patients without any recorded asthma and 3,713 patients with questionnaire data. The full model retained eleven variables that significantly predicted two or more exacerbations, of which the number of exacerbations in the preceding year had the strongest association; others included height, age, forced expiratory volume in 1 second, and several comorbid conditions. Significant predictors not previously identified included eosinophilia and COPD Assessment Test score. The predictive ability of the full model (C statistic 0.751) changed little when applied to the validation data set (n=2,713; C statistic 0.735). Results of the sensitivity analyses supported the main findings. Conclusion Patients at risk of exacerbation can be identified

  20. Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Cardiovascular Links

    PubMed Central

    Laratta, Cheryl R.; van Eeden, Stephan

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is a chronic, progressive lung disease resulting from exposure to cigarette smoke, noxious gases, particulate matter, and air pollutants. COPD is exacerbated by acute inflammatory insults such as lung infections (viral and bacterial) and air pollutants which further accelerate the steady decline in lung function. The chronic inflammatory process in the lung contributes to the extrapulmonary manifestations of COPD which are predominantly cardiovascular in nature. Here we review the significant burden of cardiovascular disease in COPD and discuss the clinical and pathological links between acute exacerbations of COPD and cardiovascular disease. PMID:24724085

  1. Cervical and mediastinal emphysema associated with an asthma exacerbation.

    PubMed

    Khan, Waseem Asrar; Abbas, Shoneen; Bright, John

    2013-02-18

    Surgical emphysema associated with an acute asthma exacerbation is very rare. This report presents the case of a 19- year-old male patient with a background of asthma who presented with palpable cervical surgical emphysema and CT evidence of mediastinal emphysema. There are only a limited number of case reports associated with surgical emphysema in the absence of pneumothorax in patients with an asthma exacerbation. Evidence with regard to the management of such cases is limited and is largely consensus based. Below we discuss the case in a greater detail.

  2. Complex formation in alkyldimethylamine oxide/sodium palmitate/water mixtures.

    PubMed

    Tanaka, Shimon; Kawasaki, Hideya; Maeda, Hiroshi

    2005-03-01

    The complex formation between nonionic alkyldimethylamine oxide (CnDMAO, n=14, 16, and 18) and sodium palmitate (NaPa) in the solid phase of CnDMAO/NaPa mixtures and the dependence of the interaction parameter beta of the regular solution theory (RST) on the mixed micelle composition of C16DMAO/NaPa mixtures were investigated. The dissolution temperature showed a maximum at a NaPa mole fraction X(Pa)(*) of 0.3-0.4 for C16DMAO/NaPa and 0.2 for C18DMAO/NaPa. The compositions of the complexes suggested by X(Pa)(*) are C16DMAO: NaPa=3:2 or 2:1 and C18DMAO:NaPa=4:1. The composition X(Pa)(*) depended on the chain length of the amine oxides. The maximum was not observed in the case of the C14DMAO/NaPa/water system. In the range 0.7< or =X(Pa)< or =1.0, dissolution temperature depression was observed with decreasing X(Pa). The dissolution temperature depression was analyzed by taking into account the nonideal behavior in the mixed micelles and the counterion binding on the mixed micelle surface. The negative beta values were obtained for all three mixed systems. It was shown that the counterion activity remained practically constant in the range of 0.7< or =X(Pa)< or =1.0. The cmc values of C16DMAO/NaPa mixtures were determined by pyrene fluorescence measurement. For C16DMAO/NaPa mixtures, the dependence of the RST interaction parameter beta on the mixed micelle composition X(Pa) was determined for a wide range (0.2< or =X(Pa) < or =0.9). In the range 0.2< or =X(Pa)< or =0.5, the beta values were obtained from an analysis of cmc based on the RST. In the range 0.7< or=X(Pa)< or=0.9, the beta values were obtained from an analysis of the dissolution temperature depression. From the analysis of the micelle composition dependence of the beta values, a short-range attractive interaction between the headgroup of C16DMAO and palmitate anion is suggested.

  3. Effectiveness of Paliperidone Palmitate vs. Haloperidol Decanoate for Maintenance Treatment of Schizophrenia: A Randomized Clinical Trial

    PubMed Central

    McEvoy, Joseph P.; Byerly, Matthew; Hamer, Robert M.; Dominik, Rosalie; Swartz, Marvin S.; Rosenheck, Robert A.; Ray, Neepa; Lamberti, J. Steven; Buckley, Peter F.; Wilkins, Tania M.; Stroup, T. Scott

    2014-01-01

    Importance Long-acting injectable (LAI) antipsychotics are used to reduce medication non-adherence and subsequent relapse in schizophrenia-spectrum disorders. The relative effectiveness of LAI versions of second-generation (atypical) and older antipsychotics has not been assessed. Objective To compare the effectiveness of the second-generation LAI antipsychotic paliperidone palmitate (PP) to the older LAI antipsychotic haloperidol decanoate (HD). Design, Setting, and Participants Multisite, double-blind, randomized clinical trial conducted at 22 clinical research sites in the U.S. The 311 randomized patients (PP=157, HD=154) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a LAI antipsychotic. Interventions Intramuscular injections of HD 25–200 mg or PP 39–234 mg every month for up to 24 months. Main Outcome Measures Efficacy failure, which reflected inadequate control of psychopathology by the study medication, as determined by a blinded adjudication committee. Key secondary outcomes were common adverse effects of antipsychotic medications. Results There was no statistically significant difference in the rate of efficacy failure for PP compared to HD (adjusted hazard ratio 0.98, 95% confidence interval [CI] 0.65–1.47). On average, patients on PP gained and those on HD lost weight; after six months the least squares mean weight change on PP was +2.17 kg (1.25 to 3.09) and on HD was −0.96 kg (−1.88 to −0.04). Patients taking PP had significantly greater increases in serum prolactin (men 34.56 µg/L (29.75 to 39.37) vs. 15.41 (10.73 to 20.08), p<0.001; women 75.19 (63.03 to 87.36) vs. 26.84 (13.29 to 40.40), p<0.001). Patients taking HD had significantly larger increases in global ratings of akathisia (0.73 [0.59 to 0.87] vs. 0.45 [0.31 to 0.59], p=0.006). Conclusions and Relevance Among adults with schizophrenia or schizoaffective disorder, treatment with

  4. PPARα-dependent exacerbation of experimental colitis by the hypolipidemic drug fenofibrate

    PubMed Central

    Qi, Yunpeng; Jiang, Changtao; Tanaka, Naoki; Krausz, Kristopher W.; Brocker, Chad N.; Fang, Zhong-Ze; Bredell, Bryce X.; Shah, Yatrik M.

    2014-01-01

    Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor-α (PPARα) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPARα in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPARα target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPARα activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNFα found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid β-oxidation, which were possibly related to the exacerbated colitis. PMID:25035112

  5. CTRP5 ameliorates palmitate-induced apoptosis and insulin resistance through activation of AMPK and fatty acid oxidation.

    PubMed

    Yang, Won-Mo; Lee, Wan

    2014-09-26

    Lipotoxicity resulting from a high concentration of saturated fatty acids is closely linked to development of insulin resistance, as well as apoptosis in skeletal muscle. CTRP5, an adiponectin paralog, is known to activate AMPK and fatty acid oxidation; however, the effects of CTRP5 on palmitate-induced lipotoxicity in myocytes have not been investigated. We found that globular domain of CTRP5 (gCTRP5) prevented palmitate-induced apoptosis and insulin resistance in myocytes by inhibiting the activation of caspase-3, reactive oxygen species accumulation, and IRS-1 reduction. These beneficial effects of gCTRP5 are mainly attributed to an increase in fatty acid oxidation through phosphorylation of AMPK. These results provide a novel function of CTRP5, which may have preventive and therapeutic potential in management of obesity, insulin resistance, and type 2 diabetes mellitus.

  6. Enhancement in electrical conductivity of pastes containing submicron Ag-coated Cu filler with palmitic acid surface modification

    NASA Astrophysics Data System (ADS)

    Choi, Eun Byeol; Lee, Jong-Hyun

    2017-09-01

    The fabrication and applied use of submicron Ag-coated Cu (Cu@Ag) particles as a filler material for epoxy-based conductive pastes having the advantages of a lower material cost and antioxidation behavior were studied. Submicron Cu@Ag particles were successfully prepared and surface-modified using palmitic acid. Diffuse reflectance infrared Fourier transform spectroscopy and thermogravimetric differential scanning calorimetry results indicated the formation of an organic layer by the chemical interaction between the Cu@Ag surface and palmitic acid and the survival of the organic layer after treatment at 160 °C for 3 h in air. The printed pastes containing both commercial micron Cu@Ag flakes and the fabricated submicron Cu@Ag particles showed a greatly reduced electrical resistivity (4.68 × 10-4 Ω cm) after surface modification compared to an initial value of 1.85 × 10-3 Ω cm when cured.

  7. Chemometric approach to develop frying stable sunflower oil blends stabilized with oleoresin rosemary and ascorbyl palmitate.

    PubMed

    Upadhyay, Rohit; Sehwag, Sneha; Niwas Mishra, Hari

    2017-03-01

    The frying performance of sunflower oil blends (SOBs) stabilized with oleoresin rosemary (Rosmarinus officinalis L.) (ROSM) (200-1500mg/kg) and ascorbyl palmitate (AP) (100-300mg/kg) were tested for 18hopen pan-frying. Sunflower oil with TBHQ (SOTBHQ) (200mg/kg) and without additives (SOcontrol) served as positive and negative controls, respectively. The frying stability was monitored over time by estimating the levels of conjugated dienes, total polar compounds, polymeric compounds viz., triglyceride polymers, dimers, oxidized triglyceride monomers, diglycerides and free fatty acids, and induction period based on Rancimat. Chemometric tools were used to classify the oil samples based on frying stability. Thermo-oxidative changes were reduced significantly for blends stabilized with ROSM and AP (p<0.05). Principal component analysis (PCA) and hierarchical cluster analysis (HCA) distinguished SOBs from positive controls. A formulation consisting of 1309.62 and 129.29mg/kg of ROSM and AP, respectively, was optimized using a hybrid PCA-RSM approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Liraglutide ameliorates palmitate-induced endothelial dysfunction through activating AMPK and reversing leptin resistance.

    PubMed

    Li, Nana; Zhao, Yihe; Yue, Yingying; Chen, Liming; Yao, Zhi; Niu, Wenyan

    2016-09-09

    Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, is an antidiabetic drug. It has been shown to improve endothelial dysfunction, but the mechanism remains somewhat unclear. Leptin can also improve endothelial function. Cardiovascular disease (CVD) is linked to hyperleptinemia, and leptin resistance, how liraglutide influences the effect of leptin on endothelial function, is never reported. We used palmitic acid (PA) to mimic hyperlipidemia in endothelial cells to explore the cardio-protective mechanism of liraglutide and its impact on the role of leptin. Human umbilical vein endothelial cells (HUVECs) were incubated with PA for 16 h and then were treated with liraglutide for 30 min. PA elevated not only phosphorylation of JNK and IKKα/β, but also the expression of IL-6 in HUVECs. These effects of PA were reversed by liraglutide. In addition, liraglutide increased phosphorylation of eNOS, AMPK, and the release of NO but had no effect on PKC phosphorylation. In addition, leptin elevated eNOS phosphorylation but was abrogated by PA. However, in the presence of liraglutide, leptin regained its function of elevating eNOS phosphorylation. Last, we found that liraglutide inhibited PA-elevated SOCS3, which is a marker of leptin resistance. GLP-1 impairs endothelial inflammatory signals, improves endothelial function, and reverses leptin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Preparation and evaluation of ofloxacin-loaded palmitic acid solid lipid nanoparticles

    PubMed Central

    Xie, Shuyu; Zhu, Luyan; Dong, Zhao; Wang, Yan; Wang, Xiaofang; Zhou, WenZhong

    2011-01-01

    The purpose of this study was to use solid lipid nanoparticles (SLN) to improve the pharmacological activity of ofloxacin. Ofloxacin-loaded SLN were prepared using palmitic acid as lipid matrix and poly vinyl alcohol (PVA) as emulsifier by a hot homogenization and ultrasonication method. The physicochemical characteristics of SLN were investigated by optical microscope, scanning electron microscopy, and photon correlation spectroscopy. Pharmacokinetics was studied after oral administration in mice. In vitro antibacterial activity and in vivo antibacterial efficacy of the SLN were investigated using minimal inhibitory concentrations (MIC) and a mouse protection model. The results demonstrated that the encapsulation efficiency, loading capacity, diameter, polydispersivity index, and zeta potential of the nanoparticles were 41.36% ± 1.50%, 4.40% ± 0.16%, 156.33 ± 7.51 nm, 0.26 ± 0.04, and −22.70 ± 1.40 mv, respectively. The SLN showed sustained release and enhanced antibacterial activity in vitro. Pharmacokinetic results demonstrated that SLN increased the bioavailability of ofloxacin by 2.27-fold, and extended the mean residence time of the drug from 10.50 to 43.44 hours. Single oral administrations of ofloxacin-loaded nanoparticles at 3 drug doses, 5 mg/kg, 10 mg/kg, and 20 mg/kg, all produced higher survival rates of lethal infected mice compared with native ofloxacin. These results indicate that SLN might be a promising delivery system to enhance the pharmacological activity of ofloxacin. PMID:21468357

  10. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for application of ascorbyl palmitate.

    PubMed

    Uner, M; Wissing, S A; Yener, G; Müller, R H

    2005-08-01

    The aim of this study was to improve the chemical stability of ascorbyl palmitate (AP) in a colloidal lipid carrier for its topical use. For this purpose, AP-loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and for comparison, a nanoemulsion (NE) were prepared employing the high pressure homogenization technique and stored at room temperature (RT), 4 degrees C and 40 degrees C. During 3 months, physical stability of these formulations compared to placebo formulations which were prepared by the same production method, was studied including recrystallization behaviour of the lipid with differential scanning calorimetry (DSC), particle size distribution and storage stability with photon correlation spectroscopy (PCS) and laser diffractometry (LD). After evaluating data indicating excellent physical stability, AP-loaded SLN, NLC and NE were incorporated into a hydrogel by the same production method as the next step. Degradation of AP by HPLC and physical stability in the same manner were investigated at the same storage temperatures during 3 months. As a result, AP was found most stable in both the NLC and SLN stored at 4 degrees C (p > 0.05) indicating the importance of storage temperature. Nondegraded AP content in NLC, SLN and NE was found to be 71.1% +/- 1.4, 67.6% +/- 2.9 and 55.2% +/- 0.3 after 3 months, respectively. Highest degradation was observed with NE at all the storage temperatures indicating even importance of the carrier structure.

  11. Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion.

    PubMed

    Lin, Hung Wen; Liu, Chao-Zong; Cao, Deshou; Chen, Po-Yi; Chen, Mei-Fang; Lin, Shinn-Zong; Mozayan, Mansoor; Chen, Alex F; Premkumar, Louis S; Torry, Donald S; Lee, Tony J-F

    2008-12-09

    Nitric oxide (NO) is identified as the endothelium-derived relaxing factor and a neurotransmitter with a superfusion bioassay cascade technique. By using a similar technique with rat superior cervical ganglion (SCG) as donor tissue and rabbit endothelium-denuded aortic ring as detector tissue, we report here that a vasodilator, which is more potent than NO, is released in the SCG upon field electrical stimulation (FES) or addition of nicotine. Release of this vasodilator was enhanced by arginine analogs, including N(omega)-nitro-l-arginine (a NO synthase inhibitor), suggesting that it is not NO. Analysis by gas chromatography/mass spectrometry identified 2 saturated fatty acids, palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME), being released from the SCG upon FES in the presence of arginine analogs. Exogenous PAME but not SAME induced significant aortic dilation (EC(50) = 0.19 nM), indicating that PAME is the potent vasodilator. Release of PAME and SAME was significantly diminished in chronically decentralized SCG but not denervated SCG, suggesting the preganglionic origin. Furthermore, release of both fatty acids was calcium- and myosin light chain kinase-dependent, suggesting that both were released from axoplasmic vesicular stores. Electrophysiological studies further demonstrated that PAME but not SAME inhibited nicotine-induced inward currents in cultured SCG and the alpha7-nicotinic acetylcholine receptor-expressing Xenopus oocytes. Endogenous PAME appears to play a role in modulation of the autonomic ganglionic transmission and to complement the vasodilator effect of NO.

  12. Attenuation of palmitate induced insulin resistance in muscle cells by harmala, clove and river red gum.

    PubMed

    Ghaffar, Safina; Afridi, Shabbir Khan; Aftab, Meha Fatima; Murtaza, Munazza; Syed, Saqib Ali; Begum, Sabira; Waraich, Rizwana Sanaullah

    2016-09-01

    The present study aimed to decipher the mechanism of action of selected anti-diabetic plants extracts on palmitic acid mediated insulin resistance in muscle cells. Our results showed that extract from Peganum harmala seeds, Eucalyptus camaldulensis and Syzygium aromaticum leaves, showed significant antioxidant activity. We found that these extracts were able to affect stress signalling by reducing p-38 MAP kinase phosphorylation. They also reduced phosphorylation of substrate for insulin receptor (IRS) at serine residues and increased its phosphorylation at tyrosine residues and also enhanced PKB phosphorylation. Glucose uptake was also enhanced in muscle cells after treatment with these extracts. Extracts from Lantana camara, Psidium gujava fruit and different parts of Cassia alata did not affect FFA mediated down-regulation of insulin signalling. The study conclude that seeds of Peganum harmala and leaves of Eucalyptus camaldulensis and Syzygium aromaticum enhanced insulin signal transduction and glucose uptake in muscle cells via reducing oxidative stress. As a result, these herbal extracts may be considered useful to protect from insulin resistance.

  13. Inhibition of Receptor Interacting Protein Kinases Attenuates Cardiomyocyte Hypertrophy Induced by Palmitic Acid

    PubMed Central

    Zhao, Mingyue; Lu, Lihui; Lei, Song; Chai, Hua; Wu, Siyuan; Tang, Xiaoju; Bao, Qinxue; Chen, Li; Wu, Wenchao; Liu, Xiaojing

    2016-01-01

    Palmitic acid (PA) is known to cause cardiomyocyte dysfunction. Cardiac hypertrophy is one of the important pathological features of PA-induced lipotoxicity, but the mechanism by which PA induces cardiomyocyte hypertrophy is still unclear. Therefore, our study was to test whether necroptosis, a receptor interacting protein kinase 1 and 3 (RIPK1 and RIPK3-) dependent programmed necrosis, was involved in the PA-induced cardiomyocyte hypertrophy. We used the PA-treated primary neonatal rat cardiac myocytes (NCMs) or H9c2 cells to study lipotoxicity. Our results demonstrated that cardiomyocyte hypertrophy was induced by PA treatment, determined by upregulation of hypertrophic marker genes and cell surface area enlargement. Upon PA treatment, the expression of RIPK1 and RIPK3 was increased. Pretreatment with the RIPK1 inhibitor necrostatin-1 (Nec-1), the PA-induced cardiomyocyte hypertrophy, was attenuated. Knockdown of RIPK1 or RIPK3 by siRNA suppressed the PA-induced myocardial hypertrophy. Moreover, a crosstalk between necroptosis and endoplasmic reticulum (ER) stress was observed in PA-treated cardiomyocytes. Inhibition of RIPK1 with Nec-1, phosphorylation level of AKT (Ser473), and mTOR (Ser2481) was significantly reduced in PA-treated cardiomyocytes. In conclusion, RIPKs-dependent necroptosis might be crucial in PA-induced myocardial hypertrophy. Activation of mTOR may mediate the effect of necroptosis in cardiomyocyte hypertrophy induced by PA. PMID:27057269

  14. A mutant of Arabidopsis deficient in desaturation of palmitic acid in leaf lipids

    SciTech Connect

    Kunst, L.; Somerville, C. ); Browse, J. )

    1989-07-01

    The overall fatty acid composition of leaf lipids in a mutant of Arabidopsis thaliana was characterized by elevated amounts of palmitic acid and a decreased amount of unsaturated 16-carbon fatty acids as a consequence of a single nuclear mutation. Quantitative analysis of the fatty acid composition of individual lipids suggested that the mutant is deficient in the activity of a chloroplast {omega}9 fatty acid desaturase which normally introduces a double bond in 16-carbon acyl chains esterified to monogalactosyldiacylglycerol (MGD). The mutant exhibited an increased ratio of 18- to 16-carbon fatty acids in MGD due to a change in the relative contribution of the prokaryotic and eukaryotic pathways of lipid biosynthesis. This appears to be a regulated response to the loss of chloroplast {omega}9 desaturase and presumably reflects a requirement for polyunsaturated fatty acids for the normal assembly of chloroplast membranes. The reduction in mass of prokaryotic MGD species involved both a reduction in synthesis of MGD by the prokaryotic pathway and increased turnover of MGD molecular species which contain 16:0.

  15. Coating of peanuts with edible whey protein film containing alpha-tocopherol and ascorbyl palmitate.

    PubMed

    Han, J H; Hwang, H-M; Min, S; Krochta, J M

    2008-10-01

    Physical properties of whey protein isolate (WPI) coating solution incorporating ascorbic palmitate (AP) and alpha-tocopherol (tocopherol) were characterized, and the antioxidant activity of dried WPI coatings against lipid oxidation in roasted peanuts were investigated. The AP and tocopherol were mixed into a 10% (w/w) WPI solution containing 6.7% glycerol. Process 1 (P1) blended an AP and tocopherol mixture directly into the WPI solution using a high-speed homogenizer. Process 2 (P2) used ethanol as a solvent for dissolving AP and tocopherol into the WPI solution. The viscosity and turbidity of the WPI coating solution showed the Newtonian fluid behavior, and 0.25% of critical concentration of AP in WPI solution rheology. After peanuts were coated with WPI solutions, color changes of peanuts were measured during 16 wk of storage at 25 degrees C, and the oxidation of peanuts was determined by hexanal analysis using solid-phase micro-extraction samplers and GC-MS. Regardless of the presence of antioxidants in the coating layer, the formation of hexanal from the oxidation of peanut lipids was reduced by WPI coatings, which indicates WPI coatings protected the peanuts from oxygen permeation and oxidation. However, the incorporation of antioxidants in the WPI coating layer did not show a significant difference in hexanal production from that of WPI coating treatment without incorporation of antioxidants.

  16. Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of β-oxidation1[S

    PubMed Central

    Kien, C. Lawrence; Matthews, Dwight E.; Poynter, Matthew E.; Bunn, Janice Y.; Fukagawa, Naomi K.; Crain, Karen I.; Ebenstein, David B.; Tarleton, Emily K.; Stevens, Robert D.; Koves, Timothy R.; Muoio, Deborah M.

    2015-01-01

    Palmitic acid (PA) is associated with higher blood concentrations of medium-chain acylcarnitines (MCACs), and we hypothesized that PA may inhibit progression of FA β-oxidation. Using a cross-over design, 17 adults were fed high PA (HPA) and low PA/high oleic acid (HOA) diets, each for 3 weeks. The [1-13C]PA and [13-13C]PA tracers were administered with food in random order with each diet, and we assessed PA oxidation (PA OX) and serum AC concentration to determine whether a higher PA intake promoted incomplete PA OX. Dietary PA was completely oxidized during the HOA diet, but only about 40% was oxidized during the HPA diet. The [13-13C]PA/[1-13C]PA ratio of PA OX had an approximate value of 1.0 for either diet, but the ratio of the serum concentrations of MCACs to long-chain ACs (LCACs) was significantly higher during the HPA diet. Thus, direct measurement of PA OX did not confirm that the HPA diet caused incomplete PA OX, despite the modest, but statistically significant, increase in the ratio of MCACs to LCACs in blood. PMID:26156077

  17. Lecithin based lamellar liquid crystals as a physiologically acceptable dermal delivery system for ascorbyl palmitate.

    PubMed

    Gosenca, Mirjam; Bešter-Rogač, Marija; Gašperlin, Mirjana

    2013-09-27

    Liquid crystalline systems with a lamellar structure have been extensively studied as dermal delivery systems. Ascorbyl palmitate (AP) is one of the most studied and used ascorbic acid derivatives and is employed as an antioxidant to prevent skin aging. The aim of this study was to develop and characterize skin-compliant dermal delivery systems with a liquid crystalline structure for AP. First, a pseudoternary phase diagram was constructed using Tween 80/lecithin/isopropyl myristate/water at a Tween 80/lecithin mass ratio of 1/1, and the region of lamellar liquid crystals was identified. Second, selected unloaded and AP-loaded lamellar liquid crystal systems were physicochemically characterized with polarizing optical microscopy, small-angle X-ray scattering, differential scanning calorimetry, and rheology techniques. The interlayer spacing and rheological parameters differ regarding quantitative composition, whereas the microstructure of the lamellar phase was affected by the AP incorporation, resulting either in additional micellar structures (at 25 and 32 °C) or being completely destroyed at higher temperature (37°C). After this, the study was oriented towards in vitro cytotoxicity evaluation of lamellar liquid crystal systems on a keratinocyte cell line. The results suggest that the lamellar liquid crystals that were developed could be used as a physiologically acceptable dermal delivery system. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. 3-MCPD 1-Palmitate Induced Tubular Cell Apoptosis In Vivo via JNK/p53 Pathways.

    PubMed

    Liu, Man; Huang, Guoren; Wang, Thomas T Y; Sun, Xiangjun; Yu, Liangli Lucy

    2016-05-01

    Fatty acid esters of 3-chloro-1, 2-propanediol (3-MCPD esters) are a group of processing induced food contaminants with nephrotoxicity but the molecular mechanism(s) remains unclear. This study investigated whether and how the JNK/p53 pathway may play a role in the nephrotoxic effect of 3-MCPD esters using 3-MCPD 1-palmitate (