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Sample records for acyl-coa metabolism induces

  1. Disruption of the acyl-coa binding protein gene delays hepatic adaptation to metabolic changes at weaning

    DEFF Research Database (Denmark)

    Neess, Ditte; Bloksgaard, Maria; Sørensen, Signe Bek;

    2011-01-01

    , little is known about the in vivo function in mammalian cells. We have generated mice with targeted disruption of ACBP (ACBP-/-). These mice are viable and fertile and develop normally. However, around weaning the ACBP-/- mice go through a crisis with overall weakness, and a slightly decreased growth...... rate. Using microarray analysis we show that the liver of ACBP-/- mice display a significantly delayed adaptation to weaning with late induction of target genes of the sterol regulatory element binding protein (SREBP) family. As a result, hepatic de novo cholesterogenesis is decreased at weaning....... The delayed induction of SREBP target genes around weaning is caused by a compromised processing and decreased expression of SREBP precursors leading to reduced binding of SREBP to target sites in chromatin. In conclusion, lack of ACBP interferes with the normal metabolic adaptation to weaning and leads...

  2. Cold-induced metabolism

    NARCIS (Netherlands)

    Lichtenbelt, W. van Marken; Daanen, H.A.M.

    2003-01-01

    Purpose of review Cold response can be insulative (drop in peripheral temperature) or metabolic (increase in energy expenditure). Nonshivering thermogenesis by sympathetic, norepinephrine-induced mitochondrial heat production in brown adipose tissue is a well known component of this metabolic respon

  3. Cerebral energy metabolism during induced mitochondrial dysfunction

    DEFF Research Database (Denmark)

    Nielsen, T H; Bindslev, TT; Pedersen, S M;

    2013-01-01

    In patients with traumatic brain injury as well as stroke, impaired cerebral oxidative energy metabolism may be an important factor contributing to the ultimate degree of tissue damage. We hypothesize that mitochondrial dysfunction can be diagnosed bedside by comparing the simultaneous changes...... in brain tissue oxygen tension (PbtO(2)) and cerebral cytoplasmatic redox state. The study describes cerebral energy metabolism during mitochondrial dysfunction induced by sevoflurane in piglets....

  4. Gene expression in plant lipid metabolism in Arabidopsis seedlings.

    Directory of Open Access Journals (Sweden)

    An-Shan Hsiao

    Full Text Available Events in plant lipid metabolism are important during seedling establishment. As it has not been experimentally verified whether lipid metabolism in 2- and 5-day-old Arabidopsis thaliana seedlings is diurnally-controlled, quantitative real-time PCR analysis was used to investigate the expression of target genes in acyl-lipid transfer, β-oxidation and triacylglycerol (TAG synthesis and hydrolysis in wild-type Arabidopsis WS and Col-0. In both WS and Col-0, ACYL-COA-BINDING PROTEIN3 (ACBP3, DIACYLGLYCEROL ACYLTRANSFERASE1 (DGAT1 and DGAT3 showed diurnal control in 2- and 5-day-old seedlings. Also, COMATOSE (CTS was diurnally regulated in 2-day-old seedlings and LONG-CHAIN ACYL-COA SYNTHETASE6 (LACS6 in 5-day-old seedlings in both WS and Col-0. Subsequently, the effect of CIRCADIAN CLOCK ASSOCIATED1 (CCA1 and LATE ELONGATED HYPOCOTYL (LHY from the core clock system was examined using the cca1lhy mutant and CCA1-overexpressing (CCA1-OX lines versus wild-type WS and Col-0, respectively. Results revealed differential gene expression in lipid metabolism between 2- and 5-day-old mutant and wild-type WS seedlings, as well as between CCA1-OX and wild-type Col-0. Of the ACBPs, ACBP3 displayed the most significant changes between cca1lhy and WS and between CCA1-OX and Col-0, consistent with previous reports that ACBP3 is greatly affected by light/dark cycling. Evidence of oil body retention in 4- and 5-day-old seedlings of the cca1lhy mutant in comparison to WS indicated the effect of cca1lhy on storage lipid reserve mobilization. Lipid profiling revealed differences in primary lipid metabolism, namely in TAG, fatty acid methyl ester and acyl-CoA contents amongst cca1lhy, CCA1-OX, and wild-type seedlings. Taken together, this study demonstrates that lipid metabolism is subject to diurnal regulation in the early stages of seedling development in Arabidopsis.

  5. Drug-Induced Metabolic Acidosis [version 1; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Amy Quynh Trang Pham

    2015-12-01

    Full Text Available Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics.

  6. Enzyme clustering can induce metabolic channeling

    Science.gov (United States)

    Castellana, Michele

    2015-03-01

    Direct channeling of intermediates via a physical tunnel between enzyme active sites is an established mechanism to improve metabolic efficiency. In this talk, I will present a theoretical model that demonstrates that coclustering multiple enzymes into proximity can yield the full efficiency benefits of direct channeling. The model predicts the separation and size of coclusters that maximize metabolic efficiency, and this prediction is in agreement with the spacing between coclusters in yeast and mammalian cells. The model also predicts that enzyme agglomerates can regulate steady-state flux division at metabolic branch points: we experimentally test this prediction for a fundamental branch point in Escherichia coli, and the results confirm that enzyme colocalization within an agglomerate can accelerate the processing of a shared intermediate by one branch. Our studies establish a quantitative framework to understand coclustering-mediated metabolic channeling and its application to both efficiency improvement and metabolic regulation.

  7. Liver fatty acid binding protein (LFABP) transfers fatty acids and fatty acyl coas to membranes

    OpenAIRE

    De Gerónimo, Eduardo; Hagan, Robert M; Wilton, David C.; Córsico, Betina

    2010-01-01

    The objective of this work was to analyze LFABP´s capacity to transfer acyl CoAs to artificial membranes and compare it to LCFA transfer employing natural ligands, in order to better understand the specific physiological role of LFABP in the cell.

  8. Moduretic-induced metabolic acidosis and hyperkalaemia.

    OpenAIRE

    Wan, H. H.; Lye, M. D.

    1980-01-01

    A patient who developed significant metabolic acidosis and severe hyperkalaemia while taking Moduretic (amiloride and hydrochlorothiazide) is reported. During the period of hyperkalaemia (maximum potassium 7-6 mmol/l) the patient's whole body potassium content was normal. His acid-base balance and serum potassium returned to normal some 10 days after stopping the drug. The possible mechanism of acidosis and hyperkalaemia in this patient is discussed.

  9. Perinatal programming of metabolic dysfunction and obesity-induced inflammation

    DEFF Research Database (Denmark)

    Ingvorsen, Camilla; Hellgren, Lars; Pedersen, Susanne Brix

    The number of obese women in the childbearing age is drastically increasing globally. As a consequence, more children are born by obese mothers. Unfortunately, maternal obesity and/ or high fat intake during pregnancy increase the risk of developing obesity, type-2 diabetes, cardiovascular disease...... associated with chronic low grade inflammation. Nobody have yet investigated the role of this inflammatory phenotype, but here we demonst rate that obesity induced inflammation is reversed during pregnancy in mice, and is therefore less likely to affect the fetal programming of metabolic dysfunction. Instead...... and non-alcoholic fatty liver disease in the children, which passes obesity and metabolic dysfunction on from generation to generation. Several studies try to elucidate causative effects of maternal metabolic markers on the metabolic imprinting in the children; however diet induced obesity is also...

  10. AMPKα in Exercise-Induced Substrate Metabolism and Exercise Training-Induced Metabolic and Mitochondrial Adaptations

    DEFF Research Database (Denmark)

    Fentz, Joachim

    metabolic capacity through several mechanisms. Some of the most important are increases in muscle capillarization and in expression of metabolic and mitochondrial proteins that transport and metabolize glucose and fatty acids. The protein AMPK is a trimeric protein composed of an  α-, β- and a y...

  11. Secondary psychosis induced by metabolic disorders

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    Olivier eBonnot

    2015-05-01

    Full Text Available Metabolic disorders are not well recognized by psychiatrists as a possible source of secondary psychoses. Inborn errors of metabolism (IEMs are not frequent. Although, their prompt diagnosis may lead to suitable treatments. IEMs are well known to paediatricians, in particular for their most serious forms, having an early expression most of the time. Recent years discoveries have unveiled later expression forms, and sometimes, very discreet first physical signs. There is a growing body of evidence that supports the hypothesis that IEMs can manifest as atypical psychiatric symptoms, even in the absence of clear neurological symptoms. In the present review, we propose a detailed overview at schizophrenia-like and autism-like symptoms that can lead practitioners to bear in mind an IEM. Other psychiatric manifestations are also found, as behavioral., cognitive, learning and mood disorders. However, they are less frequent. Ensuring an accurate IEM diagnosis, in front of these psychiatric symptoms should be a priority, in order to grant suitable and valuable treatment for these pathologies.

  12. Implication of snail in metabolic stress-induced necrosis.

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    Cho Hee Kim

    Full Text Available BACKGROUND: Necrosis, a type of cell death accompanied by the rupture of the plasma membrane, promotes tumor progression and aggressiveness by releasing the pro-inflammatory and angiogenic cytokine high mobility group box 1. It is commonly found in the core region of solid tumors due to hypoxia and glucose depletion (GD resulting from insufficient vascularization. Thus, metabolic stress-induced necrosis has important clinical implications for tumor development; however, its regulatory mechanisms have been poorly investigated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that the transcription factor Snail, a key regulator of epithelial-mesenchymal transition, is induced in a reactive oxygen species (ROS-dependent manner in both two-dimensional culture of cancer cells, including A549, HepG2, and MDA-MB-231, in response to GD and the inner regions of a multicellular tumor spheroid system, an in vitro model of solid tumors and of human tumors. Snail short hairpin (sh RNA inhibited metabolic stress-induced necrosis in two-dimensional cell culture and in multicellular tumor spheroid system. Snail shRNA-mediated necrosis inhibition appeared to be linked to its ability to suppress metabolic stress-induced mitochondrial ROS production, loss of mitochondrial membrane potential, and mitochondrial permeability transition, which are the primary events that trigger necrosis. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings demonstrate that Snail is implicated in metabolic stress-induced necrosis, providing a new function for Snail in tumor progression.

  13. Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

    KAUST Repository

    Papsdorf, Katharina

    2015-09-03

    Background Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. Conclusion These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.

  14. Sleep deprivation induces abnormal bone metabolism in temporomandibular joint

    OpenAIRE

    Geng, Wei; Wu, Gaoyi; Huang, Fei; Zhu, Yong; Nie, Jia; He, Yuhong; Chen, Lei

    2015-01-01

    Background: The purpose of this study was to explore the effect of experimental sleep deprivation (SD) on the temporomandibular joint (TMJ) of rats and the possible mechanism related to abnormal bone metabolism. Material and methods: SD was induced by a modified multiple platform method and assessed by serum adrenocorticotropic hormone (ACTH) level. TMJs were detached and stained with hematoxylin and eosin (H&E). Expression of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), osteo...

  15. Base substitution mutations induced by metabolically activated aflatoxin B1.

    Science.gov (United States)

    Foster, P L; Eisenstadt, E; Miller, J H

    1983-05-01

    We have determined the base substitutions generated by metabolically activated aflatoxin B1 in the lacI gene of a uvrB- strain of Escherichia coli. By monitoring over 70 different nonsense mutation sites, we show that activated aflatoxin B1 specifically induced GxC leads to TxA transversions. One possible pathway leading to this base change involves depurination at guanine residues. We consider this mechanism of mutagenesis in the light of our other findings that the carcinogens benzo[a]pyrene diol epoxide and N-acetoxyacetylaminofluorene also specifically induce GxC leads to TxA transversions. PMID:6405385

  16. Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes

    Institute of Scientific and Technical Information of China (English)

    Xin Li; Su Zeng

    2000-01-01

    AIM To study the influence of inducers BNF and PB on the stereoselective metabolism of propranolol in rat hepatic microsomes.METHODS Phase Ⅰ metabolism of propranolol was studied by using the microsomes induced by BNF and PB and the non-induced microsome as the control. The enzymatic kinetic parameters of propranolol enantiomers were calculated by regression analysis of Lineweaver-Burk plots.Propranolol concentrations were assayed by HPLC.RESULTS A RP-HPLC method was developed to determine propranolol concentration in rat hepatic microsomes. The linearity equations for R( + )-propranolol and S ( - )-propranolol were A=705.7C+ 311.2C (R =0.9987) and A=697.2C +311.4C (R = 0.9970) respectively. Recoveries of each enantiomer were 98.9%, 99.5%, 101.0% at 60 μmol/L, 120 μmol/L, 240 μmol/L respectively. At the concentration level of 120 μmol/L, propranolol enantiomers were metabolized at different rates in different microsomes. The concentration ratio R (+)/S (-) of control and PB induced microsomes increased with time, whereas that of microsome induced by BNF decreased. The assayed enzyme parameters were: 1. Km. Control group: R( + )30±8, S( - )18 ± 5; BNF group: R( + )34 ± 3, S (-)39±7; PB group: R(+)38±17, S(-)36± 10.2. Vmax. Control group: R(+ )1.5 ±0.2, S( - )2.9±0.3; BNF group: R(+)3.8±0.3, S(-)3.3±0.5; PB group: R( + )0.07±0.03, S( - )1.94±0.07.3.Clint. Control group: R( + )60±3, S(- )170±30; BNF group: R( + )111.0 ±1, S(- ) 84±5; PB group: R(+)2.0 ± 2, S(- )56.0 ± 1. The enzyme parameters compared with unpaired t tests showed that no stereoselectivity was observed in enzymatic affinity of three microsomes to enantiomers and their catalytic abilitieswere quite different and had stereoselectivities. Compared with the control,microsome induced by BNF enhanced enzyme activity to propranolol R ( + )-enantiomer, and microsome induced by PB showed less enzyme activity to propranolol S(- )-enantiomer which remains the same stereoselectivities as

  17. Elicitor-induced transcription factors for metabolic reprogramming of secondary metabolism in Medicago truncatula

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    Dixon Richard A

    2008-12-01

    Full Text Available Abstract Background Exposure of Medicago truncatula cell suspension cultures to pathogen or wound signals leads to accumulation of various classes of flavonoid and/or triterpene defense molecules, orchestrated via a complex signalling network in which transcription factors (TFs are essential components. Results In this study, we analyzed TFs responding to yeast elicitor (YE or methyl jasmonate (MJ. From 502 differentially expressed TFs, WRKY and AP2/EREBP gene families were over-represented among YE-induced genes whereas Basic Helix-Loop-Helix (bHLH family members were more over-represented among the MJ-induced genes. Jasmonate ZIM-domain (JAZ transcriptional regulators were highly induced by MJ treatment. To investigate potential involvement of WRKY TFs in signalling, we expressed four Medicago WRKY genes in tobacco. Levels of soluble and wall bound phenolic compounds and lignin were increased in all cases. WRKY W109669 also induced tobacco endo-1,3-β-glucanase (NtPR2 and enhanced the systemic defense response to tobacco mosaic virus in transgenic tobacco plants. Conclusion These results confirm that Medicago WRKY TFs have broad roles in orchestrating metabolic responses to biotic stress, and that they also represent potentially valuable reagents for engineering metabolic changes that impact pathogen resistance.

  18. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements.

    Science.gov (United States)

    Swithers, Susan E

    2013-09-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements. PMID:23850261

  19. Base substitution mutations induced by metabolically activated aflatoxin B1.

    OpenAIRE

    Foster, P. L.; Eisenstadt, E; Miller, J H

    1983-01-01

    We have determined the base substitutions generated by metabolically activated aflatoxin B1 in the lacI gene of a uvrB- strain of Escherichia coli. By monitoring over 70 different nonsense mutation sites, we show that activated aflatoxin B1 specifically induced GxC leads to TxA transversions. One possible pathway leading to this base change involves depurination at guanine residues. We consider this mechanism of mutagenesis in the light of our other findings that the carcinogens benzo[a]pyren...

  20. Local auxin metabolism regulates environment-induced hypocotyl elongation.

    Science.gov (United States)

    Zheng, Zuyu; Guo, Yongxia; Novák, Ondřej; Chen, William; Ljung, Karin; Noel, Joseph P; Chory, Joanne

    2016-01-01

    A hallmark of plants is their adaptability of size and form in response to widely fluctuating environments. The metabolism and redistribution of the phytohormone auxin play pivotal roles in establishing active auxin gradients and resulting cellular differentiation. In Arabidopsis thaliana, cotyledons and leaves synthesize indole-3-acetic acid (IAA) from tryptophan through indole-3-pyruvic acid (3-IPA) in response to vegetational shade. This newly synthesized auxin moves to the hypocotyl where it induces elongation of hypocotyl cells. Here we show that loss of function of VAS2 (IAA-amido synthetase Gretchen Hagen 3 (GH3).17) leads to increases in free IAA at the expense of IAA-Glu (IAA-glutamate) in the hypocotyl epidermis. This active IAA elicits shade- and high temperature-induced hypocotyl elongation largely independently of 3-IPA-mediated IAA biosynthesis in cotyledons. Our results reveal an unexpected capacity of local auxin metabolism to modulate the homeostasis and spatial distribution of free auxin in specialized organs such as hypocotyls in response to shade and high temperature. PMID:27249562

  1. Role of retinal metabolism in methanol-induced retinal toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Garner, C.D. [General Motors Corp., Warren, MI (United States)]|[Wayne State Univ., Detroit, MI (United States); Lee, E.W.; Terzo, T.S. [General Motors Corp., Warren, MI (United States); Louis-Ferdinand, R.T. [Wayne State Univ., Detroit, MI (United States)

    1995-08-01

    Methanol is a toxicant that causes systemic and ocular toxicity after acute exposure. The folate-reduced (FR) rat is an excellent animal model that mimics characteristic human methanol toxic responses. The present study examines the role of the methanol metabolites formaldehyde and formate in the initiation of methanol-induced retinal toxicity. After a single oral dose of 3.0 g/kg methanol, blood methanol concentrations were not significantly different in FR rats compared with folate-sufficient (FS) (control) rats. However, FR rats treated with 3.0 g/kg methanol displayed elevated blood (14.6 mM) and vitreous humor (19.5 mM) formate levels and abnormal electroretinograms (loss of b-wave) 48 h postdose. FR rats pretreated with disulfiram (DSF) prior to 3.0 g/kg methanol treatment failed to display these symptoms. Formaldehyde was not detected in blood or vitreous humor with or without DSF treatment, suggesting that formate is the toxic metabolite in methanol-induced retinal toxicity. Additionally, creating a blood formate profile (14.2 mM at 48 h) similar to that observed in methanol-treated rats by iv infusion of pH-buffered formate does not alter the electroretinogram as is observed with methanol treatment. These data suggest that intraretinal metabolism of methanol is necessary for the formate-mediated initiation of methanol-induced retinal toxicity. 31 refs., 5 figs., 2 tabs.

  2. Copper and zinc metabolism in aminonucleoside-induced nephrotic syndrome.

    Science.gov (United States)

    Pedraza-Chaverrí, J; Torres-Rodríguez, G A; Cruz, C; Mainero, A; Tapia, E; Ibarra-Rubio, M E; Silencio, J L

    1994-01-01

    Copper (Cu) and zinc (Zn) were measured in urine, serum and tissues from rats with nephrotic syndrome (NS) induced with a single subcutaneous dose of puromycin aminonucleoside (PAN; 15 mg/100 g BW). Control animals were pair-fed. Urine was collected daily, and the rats were sacrificed on day 10. PAN-nephrotic rats had proteinuria (days 3-10), high urinary Cu (days 1, 2, 4-10) and Zn (days 3-10) excretion. On day 10, nephrotic rats had: (a) albuminuria, hypoalbuminemia, hypoproteinemia, high urine and low serum levels of ceruloplasmin; (b) low Cu and Zn serum levels; (c) high clearance and fractional excretion of Cu and Zn, and (d) low kidney and liver Cu content and essentially normal tissue Zn levels. The alterations in Cu metabolism were more intense than those in Zn metabolism. Urine Cu and Zn showed a positive correlation with urine total protein on days 3-10 which suggests that high urinary excretion of Cu and Zn may be due to the excretion of its carrier proteins. In conclusion, these rats did not show a typical Zn deficiency but a clear decrease in Cu in the liver and kidney.

  3. REPEATED ACUTE STRESS INDUCED ALTERATIONS IN CARBOHYDRATE METABOLISM IN RAT

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    Nirupama R.

    2010-09-01

    Full Text Available Acute stress induced alterations in the activity levels of rate limiting enzymes and concentration of intermediates of different pathways of carbohydrate metabolism have been studied. Adult male Wistar rats were restrained (RS for 1 h and after an interval of 4 h they were subjected to forced swimming (FS exercise and appropriate controls were maintained. Five rats were killed before the commencement of the experiment (initial controls, 5 control and equal number of stressed rats were killed 2 h after RS and remaining 5 rats in each group were killed 4 h after FS. There was a significant increase in the adrenal 3β- hydroxy steroid dehydrogenase activity following RS, which showed further increase after FS compared to controls and thereby indicated stress response of rats. There was a significant increase in the blood glucose levels following RS which showed further increase and reached hyperglycemic condition after FS. The hyperglycemic condition due to stress was accompanied by significant increases in the activities of glutamate- pyruvate transaminase, glutamate- oxaloacetate transaminase, glucose -6- phosphatase and lactate dehydrogenase and significant decrease in the glucose -6- phosphate dehydrogenase and pyruvate dehydrogenase activities, whereas pyruvate kinase activity did not show any alteration compared to controls. Further, the glycogen and total protein contents of the liver were decreased whereas those of pyruvate and lactate showed significant increase compared to controls after RS as well as FS.The results put together indicate that acute stress induced hyperglycemia results due to increased gluconeogenesis and glycogenolysis without alteration in glycolysis. The study first time reveals that after first acute stress exposure, the subsequent stressful experience augments metabolic stress response leading to hyperglycemia. The results have relevance to human health as human beings are exposed to several stressors in a day and

  4. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice

    OpenAIRE

    Ishimoto, Takuji; Lanaspa, Miguel A.; MyPhuong T Le; Garcia, Gabriela E.; Diggle, Christine P; MacLean, Paul S.; Jackman, Matthew R.; Asipu, Aruna; Roncal-Jimenez, Carlos A.; Kosugi, Tomoki; Rivard, Christopher J.; Maruyama, Shoichi; Rodriguez-Iturbe, Bernardo; Sánchez-Lozada, Laura G.; Bonthron, David T.

    2012-01-01

    Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expr...

  5. Exercise-induced albuminuria is related to metabolic syndrome.

    Science.gov (United States)

    Greenberg, Sharon; Shenhar-Tsarfaty, Shani; Rogowski, Ori; Shapira, Itzhak; Zeltser, David; Weinstein, Talia; Lahav, Dror; Vered, Jaffa; Tovia-Brodie, Oholi; Arbel, Yaron; Berliner, Shlomo; Milwidsky, Assi

    2016-06-01

    Microalbuminuria (MA) is a known marker for endothelial dysfunction and future cardiovascular events. Exercise-induced albuminuria (EiA) may precede the appearance of MA. Associations between EiA and metabolic syndrome (MS) have not been assessed so far. Our aim was to investigate this association in a large sample of apparently healthy individuals with no baseline albuminuria. This was a cross-sectional study of 2,027 adults with no overt cardiovascular diseases who took part in a health survey program and had no baseline MA. Diagnosis of MS was based on harmonized criteria. All patients underwent an exercise test (Bruce protocol), and urinary albumin was measured before and after the examination. Urinary albumin-to-creatinine ratio (ACR) values before and after exercise were 0.40 (0.21-0.89) and 1.06 (0.43-2.69) mg/g for median (interquartile range) respectively. A total of 394 (20%) subjects had EiA; ACR rose from normal rest values (0.79 mg/g) to 52.28 mg/g after exercise (P metabolic equivalents (P < 0.001), higher baseline blood pressure (P < 0.001), and higher levels of fasting plasma glucose, triglycerides, and body mass index (P < 0.001). Multivariate binary logistic regression model showed that subjects with MS were 98% more likely to have EiA (95% confidence interval: 1.13-3.46, P = 0.016). In conclusion, EiA in the absence of baseline MA is independently related to MS.

  6. Induced phenylpropanoid metabolism during suberization and lignification: a comparative analysis

    Science.gov (United States)

    Bernards, M. A.; Susag, L. M.; Bedgar, D. L.; Anterola, A. M.; Lewis, N. G.

    2000-01-01

    Induction of the biosynthesis of phenylpropanoids was monitored at the enzyme level through measurement of the temporal change in the activity of two marker enzymes of phenylpropanoid metabolism, phenylalanine ammonia-lyase, (PAL, E.C. 4.1.3.5) and 4-coumaryl-CoA ligase (4-CL, E.C. 6.2.1.12) and two marker enzymes for hydroxycinnamyl alcohol biosynthesis, cinnamoyl-CoA:NADP+ oxidoreductase (CCR, E.C. 1.2.1.44) and cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195) in both suberizing potato (Solanum tuberosum) tubers and lignifying loblolly pine (Pinus taeda) cell cultures. While measurable activities of PAL, 4-CL and CAD increased upon initiation of suberization in potato tubers, that of CCR did not. By contrast, all four enzymes were induced upon initiation of lignification in pine cell cultures. The lack of CCR induction in potato by wound treatment is consistent with the channelling of hydroxycinnamoyl-CoA derivatives away from monolignol formation and toward other hydroxycinnamoyl derivatives such as those that accumulate during suberization.

  7. Colonization-Induced Host-Gut Microbial Metabolic Interaction

    NARCIS (Netherlands)

    Claus, S.P.; Ellero, S.L.; Berger, B.; Krause, L.; Bruttin, A.; Molina, J.; Paris, A.; Want, E.J.; Waziers, de I.; Cloarec, O.; Richards, S.E.; Wang, Y.; Dumas, M.E.; Ross, A.; Rezzi, S.; Kochhar, S.; Bladeren, van P.J.; LindOn, J.C.; Holmes, E.; Nicholson, J.K.

    2011-01-01

    The gut microbiota enhances the host’s metabolic capacity for processing nutrients and drugs and modulate the activities of multiple pathways in a variety of organ systems. We have probed the systemic metabolic adaptation to gut colonization for 20 days following exposure of axenic mice (n = 35) to

  8. Targeting one carbon metabolism with an antimetabolite disrupts pyrimidine homeostasis and induces nucleotide overflow

    OpenAIRE

    Ser, Zheng; GAO, XIA; Johnson, Christelle; Mehrmohamadi, Mahya; Liu, Xiaojing; Li, SiQi; Locasale, Jason W.

    2016-01-01

    Anti-metabolite agents that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used anti-metabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of ...

  9. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

    DEFF Research Database (Denmark)

    Catoire, Milène; Alex, Sheril; Paraskevopulos, Nicolas;

    2014-01-01

    Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise...

  10. Islet transplantation in diabetic rats normalizes basal and exercise-induced energy metabolism

    NARCIS (Netherlands)

    Houwing, Harmina; Benthem, L.; Suylichem, P.T.R. van; Leest, J. van der; Strubbe, J.H.; Steffens, A.B.

    1995-01-01

    Transplantation of islets of Langerhans in diabetic rats normalizes resting glucose and insulin levels, but it remains unclear whether islet transplantation restores resting and exercise-induced energy metabolism. Therefore, we compared energy metabolism in islet transplanted rats with energy metabo

  11. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise.

    NARCIS (Netherlands)

    Catoire, M.; Alex, S.; Paraskevopulos, N.; Mattijssen, F.; Evers-van Gogh, I.; Schaart, G.; Jeppesen, J.; Kneppers, A.; Mensink, M.; Voshol, P.J.; Olivecrona, G.; Tan, N.S.; Hesselink, M.K.; Berbee, J.F.; Rensen, P.C.; Kalkhoven, E.; Schrauwen, P.; Kersten, S.

    2014-01-01

    Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise e

  12. Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats

    OpenAIRE

    Ji Hun Park; Min Chul Kho; Hye Yoom Kim; You Mee Ahn; Yun Jung Lee; Dae Gill Kang; Ho Sub Lee

    2015-01-01

    Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC) is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks) significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP), total bilirubin, leptin, and insulin in rats with induced...

  13. Exercise ameliorates chronic kidney disease–induced defects in muscle protein metabolism and progenitor cell function

    OpenAIRE

    Wang, Xiaonan H.; Du, Jie; Klein, Janet D.; Bailey, James L; Mitch, William E.

    2009-01-01

    Chronic kidney disease (CKD) impairs muscle protein metabolism leading to muscle atrophy, and exercise can counteract this muscle wasting. Here we evaluated how resistance exercise (muscle overload) and endurance training (treadmill running) affect CKD-induced abnormalities in muscle protein metabolism and progenitor cell function using mouse plantaris muscle. Both exercise models blunted the increase in disease-induced muscle proteolysis and improved phosphorylation of Akt and the forkhead t...

  14. Tidal switch on metabolic activity: Salinity induced responses on bacterioplankton metabolic capabilities in a tropical estuary

    Digital Repository Service at National Institute of Oceanography (India)

    Thottathil, S.D.; Balachandran, K.K.; Jayalakshmy, K.V.; Gupta, G.V.M.; Nair, S.

    Biolog plates were used to study the changes in the metabolic capabilities of bacterioplankton over a complete tidal cycle in a tropical ecosystem (Cochin Estuary, Kerala, India) along southwest coast of India. The pattern of utilization of carbon...

  15. Metabolism

    Science.gov (United States)

    ... also influenced by body composition — people with more muscle and less fat generally have higher BMRs. previous continue Things That Can Go Wrong With Metabolism Most of the time your metabolism works effectively ...

  16. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism.

    Science.gov (United States)

    Abruzzese, Giselle Adriana; Heber, Maria Florencia; Ferreira, Silvana Rocio; Velez, Leandro Martin; Reynoso, Roxana; Pignataro, Omar Pedro; Motta, Alicia Beatriz

    2016-07-01

    Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. PMID:27179108

  17. Metabolism

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008255 Serum adiponectin level declines in the elderly with metabolic syndrome.WU Xiaoyan(吴晓琰),et al.Dept Geriatr,Huashan Hosp,Fudan UnivShanghai200040.Chin J Geriatr2008;27(3):164-167.Objective To investigate the correlation between ser-um adiponectin level and metabolic syndrome in the elderly·Methods Sixty-one subjects with metabolic syndrome and140age matched subjects without metabolic

  18. Proteomics Analysis Reveals Post-Translational Mechanisms for Cold-Induced Metabolic Changes in Arabidopsis

    Institute of Scientific and Technical Information of China (English)

    Tian Li; Alma L.Burlingame; Zhi-Ping Deng; Zhi Yong Wang; Shou-Ling Xu; Juan A.Oses-Prieto; Sunita Putil; Peng Xu; Rui-Ju Wang; Kathy H.Li; David A.Malty; Liz-He An

    2011-01-01

    Cold-induced changes of gene expression and metabolism are critical for plants to survive freezing. Largely by changing gene expression, exposure to a period of non-freezing low temperatures increases plant tolerance to freezing-a phenomenon known as cold acclimation. Cold also induces rapid metabolic changes, which provide instant protection before temperature drops below freezing point. The molecular mechanisms for such rapid metabolic responses to cold remain largely unknown. Here, we use two-dimensional difference gel electrophoresis (2-D DIGE) analysis of sub-cellular fractions of Arabidopsis thaliana proteome coupled with spot identification by tandem mass spectrometry to identify early cold-responsive proteins in Arabidopsis. These proteins include four enzymes involved in starch degradation, three HSP100 proteins, several proteins in the tricarboxylic acid cycle, and sucrose metabolism. Upon cold treatment, the Disproportionating Enzyme 2 (DPE2), a cytosolic transglucosidase metabolizing maltose to glucose, increased rapidly in the centrifugation pellet fraction and decreased in the soluble fraction. Consistent with cold-induced inactivation of DPE2 enzymatic activity, the dpe2 mutant showed increased freezing tolerance without affecting the C-repeat binding transcription factor (CBF) transcriptional pathway. These results support a model that cold-induced inactivation of DPE2 leads to rapid accumulation of maltose, which is a cold-induced compatible solute that protects cells from freezing damage. This study provides evidence for a key role of rapid post-translational regulation of carbohydrate metabolic enzymes in plant protection against sudden temperature drop.

  19. Changes in brain oxidative metabolism induced by water maze training.

    Science.gov (United States)

    Conejo, N M; González-Pardo, H; Vallejo, G; Arias, J L

    2007-03-16

    Although the hippocampus has been shown to be essential for spatial memory, the contribution of associated brain regions is not well established. Wistar rats were trained to find a hidden escape platform in the water maze during eight days. Following training, the oxidative metabolism in different brain regions was evaluated using cytochrome oxidase histochemistry. Metabolic activations were found in the prelimbic cortex, cornu ammonis (CA) 1 subfield of the dorsal hippocampus and the anterior thalamic nuclei, relative to yoked swim controls and naïve rats. In addition, many cross-correlations in brain metabolism were observed among the latter regions. These results support the implication of a hippocampal-prefrontal-thalamic system to spatial memory in rats. PMID:17222984

  20. Hypoxia Induced Tumor Metabolic Switch Contributes to Pancreatic Cancer Aggressiveness

    International Nuclear Information System (INIS)

    Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3–5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. The disease is characterized by the presence of a dense stroma of fibroblasts and inflammatory cells, termed desmoplasia, which limits the oxygen diffusion in the organ, creating a strong hypoxic environment within the tumor. In this review, we argue that hypoxia is responsible for the highly aggressive and metastatic characteristics of this tumor and drives pancreatic cancer cells to oncogenic and metabolic changes facilitating their proliferation. However, the molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. Cachexia is a hallmark of this disease and illustrates that this cancer is a real metabolic disease. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialog during the development of this cancer. Such a hypothesis would better explain how under fuel source limitation, pancreatic cancer cells are maintained, show a growth advantage, and develop metastasis

  1. Quantitative evaluation of respiration induced metabolic oscillations in erythrocytes

    DEFF Research Database (Denmark)

    Hald, Bjørn; Madsen, Mads F; Danø, Sune;

    2009-01-01

    The changes in the partial pressures of oxygen and carbon dioxide (P(O(2)) and P(CO(2))) during blood circulation alter erythrocyte metabolism, hereby causing flux changes between oxygenated and deoxygenated blood. In the study we have modeled this effect by extending the comprehensive kinetic mo...

  2. Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Aibin; Liu, Jingyi [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China); Institute of Cardiovascular Disease, General Hospital of Beijing Command, PLA, Beijing (China); Liu, Peilin; Jia, Min; Wang, Han [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China); Tao, Ling, E-mail: lingtao2006@gmail.com [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China)

    2014-04-18

    Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H{sub 2}O{sub 2} led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H{sub 2}O{sub 2} and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the

  3. Role of Metabolism by Intestinal Bacteria in Arbutin-Induced Suppression of Lymphoproliferative Response in vitro

    Science.gov (United States)

    Kang, Mi Jeong; Ha, Hyun Woo; Kim, Ghee Hwan; Lee, Sang Kyu; Ahn, Young Tae; Kim, Dong Hyun; Jeong, Hye Gwang; Jeong, Tae Cheon

    2012-01-01

    Role of metabolism by intestinal bacteria in arbutin-induced immunotoxicity was investigated in splenocyte cultures. Following an incubation of arbutin with 5 different intestinal bacteria for 24 hr, its aglycone hydroquinone could be produced and detected in the bacterial culture media with different amounts. Toxic effects of activated arbutin by intestinal bacteria on lymphoproliferative response were tested in splenocyte cultures from normal mice. Lipopolysaccharide and concanavalin A were used as mitogens for B- and T-cells, respectively. When bacteria cultured medium with arbutin was treated into the splenocytes for 3 days, the medium cultured with bacteria producing large amounts of hydroquinone induced suppression of lymphoproliferative responses, indicating that metabolic activation by intestinal bacteria might be required in arbutin-induced toxicity. The results indicated that the present testing system might be applied for determining the possible role of metabolism by intestinal bacteria in certain chemical-induced immunotoxicity in animal cell cultures. PMID:24116295

  4. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements

    OpenAIRE

    Swithers, Susan E.

    2013-01-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. ...

  5. Formaldehyde Metabolism and Formaldehyde-induced Alterations in Glucose and Glutathione Metabolism of Cultured Brain Cells

    OpenAIRE

    Tulpule, Ketki

    2013-01-01

    Formaldehyde is an environmental pollutant that is also generated in the body during normal metabolic processes. Interestingly, several pathological conditions are associated with an increase in formaldehyde-generating enzymes in the body. The level of formaldehyde in the brain is elevated with increasing age and in neurodegenerative conditions which may contribute to lowered cognitive functions. Although the neurotoxic potential of formaldehyde is well established, the molecular mechanisms i...

  6. Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes

    Directory of Open Access Journals (Sweden)

    Paula Wesendonck Caponi

    2013-07-01

    Full Text Available OBJECTIVES: We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome. METHODS: Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome, MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks, H (sedentary spontaneously hypertensive rats and H-T (trained spontaneously hypertensive rats. The Lee index, blood pressure (tail-cuff system, insulin sensitivity (insulin tolerance test and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA (p<0.05. RESULTS: At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS, but not of the H rats (H-T vs. H. There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups. CONCLUSION: In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity.

  7. Strategies for reversing the effects of metabolic disorders induced as a consequence of developmental programming

    Directory of Open Access Journals (Sweden)

    Mark H Vickers

    2012-07-01

    Full Text Available Obesity and the metabolic syndrome have reached epidemic proportions worldwide with far-reaching health care and economic implications. The rapid increase in the prevalence of these disorders suggests that environmental and behavioural influences, rather than genetic causes, are fuelling the epidemic. The developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal and early infant phases of life and the subsequent development of metabolic disorders in later life. In particular, the impact of poor maternal nutrition on susceptibility to later life metabolic disease in offspring is now well documented. Several studies have now shown, at least in experimental animal models, that some components of the metabolic syndrome, induced as a consequence of developmental programming, are potentially reversible by nutritional or targeted therapeutic interventions during windows of developmental plasticity. This review will focus on critical windows of development and possible therapeutic avenues that may reduce metabolic and obesogenic risk following an adverse early life environment.

  8. Antituberculosis Drug-Induced Hepatotoxicity in IranianTuberculosis Patients: Role of Isoniazid Metabolic Polymorphism

    OpenAIRE

    Sistanizad, Mohammad; Azizi, Ebrahim; KHALILI, Hosein; Hajiabdolbaghi, Mahboobeh; Gholami, Kheirollah; Mahjub, Reza

    2011-01-01

    The aim of this study was to determine the association of n-acetyltransferase-2 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Iranian pulmonary tuberculosis patients. Acetylating phenotypes was studied in 50 Iranian pulmonary tuberculosis patients using metabolic ratio of plasma acetyl-Isoniazid to Isoniazid. The association between hepatotoxicity and the n-acetyltransferase-2 phenotype was evaluated by using the chi-square (x2) test. The metabolic ratio had a bimodal dis...

  9. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

    International Nuclear Information System (INIS)

    Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic–pituitary–adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, and blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglyceride levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2. - Highlights: • Caffeine-induced neuroendocrine metabolic programming of HPA has hereditary effect. • Caffeine-induced

  10. Prenatal caffeine ingestion induces transgenerational neuroendocrine metabolic programming alteration in second generation rats

    Energy Technology Data Exchange (ETDEWEB)

    Luo, Hanwen [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Deng, Zixin; Liu, Lian; Shen, Lang; Kou, Hao; He, Zheng [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Ping, Jie; Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Ma, Lu [Department of Epidemiology and Health Statistics, Public Health School of Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: lbchen@whu.edu.cn [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2014-02-01

    Our previous studies have demonstrated that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes in adult first generation (F1) of intrauterine growth retardation (IUGR) rats, and the underlying mechanism is originated from a hypothalamic–pituitary–adrenal (HPA) axis-associated neuroendocrine metabolic programming alteration in utero. This study aims to investigate the transgenerational effects of this programming alteration in adult second generation (F2). Pregnant Wistar rats were administered with caffeine (120 mg/kg·d) from gestational day 11 until delivery. Four groups in F2 were set according to the cross-mating between control and caffeine-induced IUGR rats. F2 were subjected to a fortnight ice water swimming stimulus on postnatal month 4, and blood samples were collected before and after stress. Results showed that the majority of the activities of HPA axis and phenotypes of glucose and lipid metabolism were altered in F2. Particularly, comparing with the control group, caffeine groups had an enhanced corticosterone levels after chronic stress. Compared with before stress, the serum glucose levels were increased in some groups whereas the triglyceride levels were decreased. Furthermore, total cholesterol gain rates were enhanced but the high-density lipoprotein-cholesterol gain rates were decreased in most caffeine groups after stress. These transgenerational effects were characterized partially with gender and parental differences. Taken together, these results indicate that the reproductive and developmental toxicities and the neuroendocrine metabolic programming mechanism by prenatal caffeine ingestion have transgenerational effects in rats, which may help to explain the susceptibility to metabolic syndrome and associated diseases in F2. - Highlights: • Caffeine-induced neuroendocrine metabolic programming of HPA has hereditary effect. • Caffeine-induced

  11. Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats.

    Science.gov (United States)

    Park, Ji Hun; Kho, Min Chul; Kim, Hye Yoom; Ahn, You Mee; Lee, Yun Jung; Kang, Dae Gill; Lee, Ho Sub

    2015-01-01

    Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC) is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks) significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP), total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1) and phosphorylated AMP-activated protein kinase (p-AMPK) in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo. PMID:26504474

  12. Blackcurrant Suppresses Metabolic Syndrome Induced by High-Fructose Diet in Rats

    Directory of Open Access Journals (Sweden)

    Ji Hun Park

    2015-01-01

    Full Text Available Increased fructose ingestion has been linked to obesity, hyperglycemia, dyslipidemia, and hypertension associated with metabolic syndrome. Blackcurrant (Ribes nigrum; BC is a horticultural crop in Europe. To induce metabolic syndrome, Sprague-Dawley rats were fed 60% high-fructose diet. Treatment with BC (100 or 300 mg/kg/day for 8 weeks significantly suppressed increased liver weight, epididymal fat weight, C-reactive protein (CRP, total bilirubin, leptin, and insulin in rats with induced metabolic syndrome. BC markedly prevented increased adipocyte size and hepatic triglyceride accumulation in rats with induced metabolic syndrome. BC suppressed oral glucose tolerance and protein expression of insulin receptor substrate-1 (IRS-1 and phosphorylated AMP-activated protein kinase (p-AMPK in muscle. BC significantly suppressed plasma total cholesterol, triglyceride, and LDL content. BC suppressed endothelial dysfunction by inducing downregulation of endothelin-1 and adhesion molecules in the aorta. Vascular relaxation of thoracic aortic rings by sodium nitroprusside and acetylcholine was improved by BC. The present study provides evidence of the potential protective effect of BC against metabolic syndrome by demonstrating improvements in dyslipidemia, hypertension, insulin resistance, and obesity in vivo.

  13. Metabolism

    Science.gov (United States)

    ... a particular food provides to the body. A chocolate bar has more calories than an apple, so ... More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood ...

  14. Exercise Induced Adipokine Changes and the Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Saeid Golbidi

    2014-01-01

    Full Text Available The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is characterized by the deposition of adipose tissue in various parts of the body; it is now evident that adipose tissue also acts as an endocrine organ capable of secreting many cytokines that are though to be involved in the pathophysiology of obesity, insulin resistance, and metabolic syndrome. Adipokines, or adipose tissue-derived proteins, play a pivotal role in this scenario. Increased secretion of proinflammatory adipokines leads to a chronic inflammatory state that is accompanied by insulin resistance and glucose intolerance. Lifestyle change in terms of increased physical activity and exercise is the best nonpharmacological treatment for obesity since these can reduce insulin resistance, counteract the inflammatory state, and improve the lipid profile. There is growing evidence that exercise exerts its beneficial effects partly through alterations in the adipokine profile; that is, exercise increases secretion of anti-inflammatory adipokines and reduces proinflammatory cytokines. In this paper we briefly describe the pathophysiologic role of four important adipokines (adiponectin, leptin, TNF-α, and IL-6 in the metabolic syndrome and review some of the clinical trials that monitored these adipokines as a clinical outcome before and after exercise.

  15. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    Science.gov (United States)

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC. PMID:27206315

  16. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer.

    Science.gov (United States)

    Matassa, D S; Amoroso, M R; Lu, H; Avolio, R; Arzeni, D; Procaccini, C; Faicchia, D; Maddalena, F; Simeon, V; Agliarulo, I; Zanini, E; Mazzoccoli, C; Recchi, C; Stronach, E; Marone, G; Gabra, H; Matarese, G; Landriscina, M; Esposito, F

    2016-09-01

    Tumour cells have long been considered defective in mitochondrial respiration and mostly dependent on glycolytic metabolism. However, this assumption is currently challenged by several lines of evidence in a growing number of tumours. Ovarian cancer (OC) is one of the most lethal cancers worldwide, but it continues to be a poorly understood disease and its metabolic features are far to be elucidated. In this context, we investigated the role of tumour necrosis factor receptor-associated protein 1 (TRAP1), which is found upregulated in several cancer types and is a key modulator of tumour cell metabolism. Surprisingly, we found that TRAP1 expression inversely correlated with grade, stage and lower survival in a large cohort of OC patients. Accordingly, TRAP1 silencing induced resistance to cisplatin, resistant cells showed increased oxidative metabolism compared with their sensitive counterpart, and the bioenergetics cellular index of higher grade tumours indicated increased mitochondrial respiration. Strikingly, cisplatin resistance was reversible upon pharmacological inhibition of mitochondrial oxidative phosphorylation by metformin/oligomycin. At molecular level, increased oxidative metabolism in low TRAP1-expressing OC cells and tissues enhanced production of inflammatory mediators such as interleukin (IL)-6 and IL-8. Mechanistically, we identified members of the multidrug resistance complex (MDR) as key mediators of such metabolism-driven, inflammation-induced process. Indeed, treatment of OC cell lines with TNFα and IL6 induced a selective increase in the expression of TAP1 and multidrug resistance protein 1, whereas TAP1 silencing sensitized cells to cisplatin-induced apoptosis. Our results unveil a novel role for TRAP1 and oxidative metabolism in cancer progression and suggest the targeting of mitochondrial bioenergetics to increase cisplatin efficacy in human OC.

  17. Kaposi's sarcoma herpesvirus microRNAs induce metabolic transformation of infected cells.

    Directory of Open Access Journals (Sweden)

    Ohad Yogev

    2014-09-01

    Full Text Available Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV is the etiological agent of Kaposi's sarcoma (KS. KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are latently infected with KSHV, while a small number are lytically infected, producing virions. Latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, the metabolic properties of KSHV-infected cells closely resemble the metabolic hallmarks of cancer cells. However, how and why KSHV alters host cell metabolism remains poorly understood. Here, we investigated the effect of KSHV infection on the metabolic profile of primary dermal microvascular lymphatic endothelial cells (LEC and the functional relevance of this effect. We found that the KSHV microRNAs within the oncogenic cluster collaborate to decrease mitochondria biogenesis and to induce aerobic glycolysis in infected cells. KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1α and decreases mitochondria copy number. Importantly this metabolic shift is important for latency maintenance and provides a growth advantage. Mechanistically we show that KSHV alters host cell energy metabolism through microRNA-mediated down regulation of EGLN2 and HSPA9. Our data suggest that the KSHV microRNAs induce a metabolic transformation by concurrent regulation of two independent pathways; transcriptional reprograming via HIF1 activation and reduction of mitochondria biogenesis through down regulation of the mitochondrial import machinery. These findings implicate viral microRNAs in the regulation of the cellular metabolism and highlight new potential avenues to inhibit viral latency.

  18. Lactose-Inducible System for Metabolic Engineering of Clostridium ljungdahlii

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, A; Leang, C; Ueki, T; Nevin, KP; Lovley, DR

    2014-03-25

    The development of tools for genetic manipulation of Clostridium ljungdahlii has increased its attractiveness as a chassis for autotrophic production of organic commodities and biofuels from syngas and microbial electrosynthesis and established it as a model organism for the study of the basic physiology of acetogenesis. In an attempt to expand the genetic toolbox for C. ljungdahlii, the possibility of adapting a lactose-inducible system for gene expression, previously reported for Clostridium perfringens, was investigated. The plasmid pAH2, originally developed for C. perfringens with a gusA reporter gene, functioned as an effective lactose-inducible system in C. ljungdahlii. Lactose induction of C. ljungdahlii containing pB1, in which the gene for the aldehyde/alcohol dehydrogenase AdhE1 was downstream of the lactose-inducible promoter, increased expression of adhE1 30-fold over the wild-type level, increasing ethanol production 1.5-fold, with a corresponding decrease in acetate production. Lactose-inducible expression of adhE1 in a strain in which adhE1 and the adhE1 homolog adhE2 had been deleted from the chromosome restored ethanol production to levels comparable to those in the wild-type strain. Inducing expression of adhE2 similarly failed to restore ethanol production, suggesting that adhE1 is the homolog responsible for ethanol production. Lactose-inducible expression of the four heterologous genes necessary to convert acetyl coenzyme A (acetyl-CoA) to acetone diverted ca. 60% of carbon flow to acetone production during growth on fructose, and 25% of carbon flow went to acetone when carbon monoxide was the electron donor. These studies demonstrate that the lactose-inducible system described here will be useful for redirecting carbon and electron flow for the biosynthesis of products more valuable than acetate. Furthermore, this tool should aid in optimizing microbial electrosynthesis and for basic studies on the physiology of acetogenesis.

  19. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.

    Science.gov (United States)

    Panchal, Sunil K; Poudyal, Hemant; Brown, Lindsay

    2012-06-01

    Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-κB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-κB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

  20. Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism

    OpenAIRE

    AOI, WATARU; Ogaya, Yumi; Takami, Maki; Konishi, Toru; Sauchi, Yusuke; Park, Eun Young; Wada, Sayori; Sato, Kenji; Higashi, Akane

    2015-01-01

    Backgrounds Glutathione is an endogenous redox couple in animal cells and plays important roles in antioxidant defense and detoxification, although it is unknown if oral glutathione supplementation affects exercise-induced physiological changes. The present study investigated the effect of glutathione intake on exercise-induced muscle metabolism and fatigue in mice and humans. Methods ICR mice were divided into 4 groups: sedentary control, sedentary supplemented with glutathione (2.0%, 5 μL/g...

  1. Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism

    OpenAIRE

    AOI, WATARU; Ogaya, Yumi; Takami, Maki; Konishi, Toru; Sauchi, Yusuke; Park, Young Y.; Wada, Sayori; Sato, Kenji; Higashi, Akane

    2015-01-01

    Backgrounds: Glutathione is an endogenous redox couple in animal cells and plays important roles in antioxidant defense and detoxification, although it is unknown if oral glutathione supplementation affects exercise-induced physiological changes. The present study investigated the effect of glutathione intake on exercise-induced muscle metabolism and fatigue in mice and humans. Methods: ICR mice were divided into 4 groups: sedentary control, sedentary supplemented with glutathione (2.0%, 5μL/...

  2. Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

    OpenAIRE

    Papsdorf, Katharina; Kaiser, Christoph J. O.; Drazic, Adrian; Grötzinger, Stefan W.; Haeßner, Carmen; Eisenreich, Wolfgang; Richter, Klaus

    2015-01-01

    Background Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast...

  3. Rhinacanthus nasutus leaf improves metabolic abnormalities in high-fat diet-induced obese mice

    Directory of Open Access Journals (Sweden)

    Supaporn Wannasiri

    2016-01-01

    Conclusions: To the best of our knowledge, the present study is the first report on the impact of R. nasutus extract in improving the impaired glucose and lipid metabolism in high-fat diet-induced obesity in mice via stimulating the insulin sensitivity in the liver and adipose tissues.

  4. Loxapine for Reversal of Antipsychotic-Induced Metabolic Disturbances: A Chart Review

    Science.gov (United States)

    Jain, Seema; Andridge, Rebecca; Hellings, Jessica A.

    2016-01-01

    Loxapine substitution is a promising option for patients with autism spectrum disorder (ASD) who develop antipsychotic-induced metabolic illness. We performed a chart review of 15 adolescents and adults meeting DSM-IV-TR criteria for ASD, all with antipsychotic-associated weight gain, who received low dose loxapine in an attempt to taper or…

  5. Effect of opium on glucose metabolism and lipid profiles in rats with streptozotocin-induced diabetes

    NARCIS (Netherlands)

    Sadeghian, Saeed; Boroumand, Mohammad Ali; Sotoudeh-Anvari, Maryam; Rahbani, Shahram; Sheikhfathollahi, Mahmood; Abbasi, Ali

    2009-01-01

    Background: This experimental study was performed to determine the impact of opium use on serum lipid profile and glucose metabolism in rats with streptozotocin-induced diabetes. Material and methods: To determine the effect of opium, 20 male rats were divided into control (n = 10) and opium-treated

  6. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease

    OpenAIRE

    Finck, Brian N; Kelly, Daniel P.

    2006-01-01

    Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.

  7. The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress

    NARCIS (Netherlands)

    van der Harg, J. M.; Nolle, A.; Zwart, R.; Boerema, A. S.; van Haastert, E. S.; Strijkstra, A. M.; Hoozemans, J. J. M.; Scheper, W.

    2014-01-01

    The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstra

  8. Diabetes and hyperlipidemia induce dysfunction of VSMCs: contribution of the metabolic inflammation/miRNA pathway.

    Science.gov (United States)

    Li, Tao; Yang, Guang-ming; Zhu, Yu; Wu, Yue; Chen, Xiang-yun; Lan, Dan; Tian, Kun-lun; Liu, Liang-ming

    2015-02-15

    Vascular endothelial cell injury is considered to be the major factor inducing vascular complications in metabolic diseases and plays an important role in other organ damage. With diabetic and hyperlipidemic rats and cultured VSMCs, the present study was aimed at investigating whether the early damage of VSMCs during metabolic diseases plays a critical role in vascular dysfunction and the underlying mechanisms and would be a promising treatment target. With diabetic and hyperlipidemic rats and cultured VSMCs, the changes and relationships of vascular relaxation and contractile function to the vital organ damage and the underlying mechanisms were investigated; meanwhile, the protective and preventive effects of lowering blood lipid and glucose and inhibition of diabetes and hyperlipidemia-induced vascular hyperreactivity were observed. Diabetic and hyperlipidemic rats presented hyperreactivity in vascular contractile response in the early stages. Hyperglycemia and hyperlipidemia directly affected the contractile function of VSMCs. Early application of fasudil, a specific antagonist of Rho kinase, significantly alleviated diabetes and hyperlipidemia-induced organ damage by inhibiting vascular hyperreactivity. Diabetes and hyperlipidemia-induced inflammatory response could upregulate the expression of connexins and Rho kinase by selective downregulation of the expression of miR-10a, miR-139b, miR-206, and miR-222. These findings suggest that hyperglucose and lipid may directly impair VSMCs and induce vascular hyperreactivity in the early stages. Metabolic inflammation-induced changes in the miRNA-connexin/Rho kinase regulatory pathway are the main mechanism for vascular hyperreactivity and organ damage. Measures inhibiting vascular hyperreactivity are promising for the prevention of organ damage induced by metabolic diseases.

  9. Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

    Directory of Open Access Journals (Sweden)

    Peter Belenky

    2015-11-01

    Full Text Available Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (β-lactams, aminoglycosides, quinolones. These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products.

  10. Pharmacological inhibition of soluble epoxide hydrolase ameliorates diet-induced metabolic syndrome in rats.

    Science.gov (United States)

    Iyer, Abishek; Kauter, Kathleen; Alam, Md Ashraful; Hwang, Sung Hee; Morisseau, Christophe; Hammock, Bruce D; Brown, Lindsay

    2012-01-01

    The signs of metabolic syndrome following chronic excessive macronutrient intake include body weight gain, excess visceral adipose deposition, hyperglycaemia, glucose and insulin intolerances, hypertension, dyslipidaemia, endothelial damage, cardiovascular hypertrophy, inflammation, ventricular contractile dysfunction, fibrosis, and fatty liver disease. Recent studies show increased activity of soluble epoxide hydrolase (sEH) during obesity and metabolic dysfunction. We have tested whether sEH inhibition has therapeutic potential in a rat model of diet-induced metabolic syndrome. In these high-carbohydrate, high-fat-fed rats, chronic oral treatment with trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a potent sEH inhibitor, alleviated the signs of metabolic syndrome in vivo including glucose, insulin, and lipid abnormalities, changes in pancreatic structure, increased systolic blood pressure, cardiovascular structural and functional abnormalities, and structural and functional changes in the liver. The present study describes the pharmacological responses to this selective sEH inhibitor in rats with the signs of diet-induced metabolic syndrome.

  11. Regulation of exercise-induced lipid metabolism in skeletal muscle

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting; Kiens, Bente

    2014-01-01

    Exercise increases the utilization of lipids in muscle. The sources of lipids are long-chain fatty acids taken up from the plasma and fatty acids released from stores of intramuscular triacylglycerol by the action of intramuscular lipases. In the present review, we focus on the role of fatty acid...... binding proteins, particularly fatty acid translocase/cluster of differentiation 36 (FAT/CD36), in the exercise- and contraction-induced increase in uptake of long-chain fatty acids in muscle. The FAT/CD36 translocates from intracellular depots to the surface membrane upon initiation of exercise...... triglyceride lipase in regulation of muscle lipolysis. Although the molecular regulation of the lipases in muscle is not understood, it is speculated that intramuscular lipolysis may be regulated in part by the availability of the plasma concentration of long-chain fatty acids....

  12. Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity.

    Science.gov (United States)

    Griffin, C; Lanzetta, N; Eter, L; Singer, K

    2016-08-01

    It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses. PMID:27252473

  13. Exercise training prevents diastolic dysfunction induced by metabolic syndrome in rats

    Directory of Open Access Journals (Sweden)

    Cristiano Mostarda

    2012-07-01

    Full Text Available OBJECTIVE: High fructose consumption contributes to the incidence of metabolic syndrome and, consequently, to cardiovascular outcomes. We investigated whether exercise training prevents high fructose diet-induced metabolic and cardiac morphofunctional alterations. METHODS: Wistar rats receiving fructose overload (F in drinking water (100 g/l were concomitantly trained on a treadmill (FT for 10 weeks or kept sedentary. These rats were compared with a control group (C. Obesity was evaluated by the Lee index, and glycemia and insulin tolerance tests constituted the metabolic evaluation. Blood pressure was measured directly (Windaq, 2 kHz, and echocardiography was performed to determine left ventricular morphology and function. Statistical significance was determined by one-way ANOVA, with significance set at p<0.05. RESULTS: Fructose overload induced a metabolic syndrome state, as confirmed by insulin resistance (F: 3.6 ± 0.2 vs. C: 4.5 ± 0.2 mg/dl/min, hypertension (mean blood pressure, F: 118 ± 3 vs. C: 104 ± 4 mmHg and obesity (F: 0.31±0.001 vs. C: 0.29 ± 0.001 g/mm. Interestingly, fructose overload rats also exhibited diastolic dysfunction. Exercise training performed during the period of high fructose intake eliminated all of these derangements. The improvements in metabolic parameters were correlated with the maintenance of diastolic function. CONCLUSION: The role of exercise training in the prevention of metabolic and hemodynamic parameter alterations is of great importance in decreasing the cardiac morbidity and mortality related to metabolic syndrome.

  14. Superovulation Induced Changes of Lipid Metabolism in Ovaries and Embryos and Its Probable Mechanism.

    Directory of Open Access Journals (Sweden)

    Li-Ya Wang

    Full Text Available This research was intended to investigate the fetal origins of changed birth weight of the offspring born through assisted reproductive technology (ART. The association between hormone and lipid metabolism or body weight has been generally accepted, and as the basic and specific treatment in ART procedure, gonadotropin stimulation might have potential effects on intrauterine lipid metabolism. In our studies, the mice were superovulated with two doses of gonadotropin. The cholesterol metabolism in ovaries and the triglyceride metabolism in embryos were analyzed. The results showed gonadotropin probably accelerated luteinization and induced a longer time follicle development and ovulation, which resulted in histological and morphological alteration of ovary, and increased the cholesterol content and the expressions of steroidogenesis-related genes. In embryos, gonadotropin increased lipid accumulation and decreased fatty acid synthesis in a dose-dependent manner. Moreover, the changes of fatty acid composition were also shown in superovulation groups. Our studies firstly provided the evidence that the superovulation might affect the maternal and fetal lipid metabolism. These variations of lipid metabolism in our results may be associated with birth weight of ART infants.

  15. Permethrin-induced oxidative stress and toxicity and metabolism. A review.

    Science.gov (United States)

    Wang, Xu; Martínez, María-Aránzazu; Dai, Menghong; Chen, Dongmei; Ares, Irma; Romero, Alejandro; Castellano, Victor; Martínez, Marta; Rodríguez, José Luis; Martínez-Larrañaga, María-Rosa; Anadón, Arturo; Yuan, Zonghui

    2016-08-01

    Permethrin (PER), the most frequently used synthetic Type I pyrethroid insecticide, is widely used in the world because of its high activity as an insecticide and its low mammalian toxicity. It was originally believed that PER exhibited low toxicity on untargeted animals. However, as its use became more extensive worldwide, increasing evidence suggested that PER might have a variety of toxic effects on animals and humans alike, such as neurotoxicity, immunotoxicity, cardiotoxicity, hepatotoxicity, reproductive, genotoxic, and haematotoxic effects, digestive system toxicity, and cytotoxicity. A growing number of studies indicate that oxidative stress played critical roles in the various toxicities associated with PER. To date, almost no review has addressed the toxicity of PER correlated with oxidative stress. The focus of this article is primarily to summarise advances in the research associated with oxidative stress as a potential mechanism for PER-induced toxicity as well as its metabolism. This review summarises the research conducted over the past decade into the reactive oxygen species (ROS) generation and oxidative stress as a consequence of PER treatments, and ultimately their correlation with the toxicity and the metabolism of PER. The metabolism of PER involves various CYP450 enzymes, alcohol or aldehyde dehydrogenases for oxidation and the carboxylesterases for hydrolysis, through which oxidative stress might occur, and such metabolic factors are also reviewed. The protection of a variety of antioxidants against PER-induced toxicity is also discussed, in order to further understand the role of oxidative stress in PER-induced toxicity. This review will throw new light on the critical roles of oxidative stress in PER-induced toxicity, as well as on the blind spots that still exist in the understanding of PER metabolism, the cellular effects in terms of apoptosis and cell signaling pathways, and finally strategies to help to protect against its oxidative

  16. 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

    Science.gov (United States)

    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 ...

  17. Kalpaamruthaa ameliorates mitochondrial and metabolic alterations in diabetes mellitus induced cardiovascular damage.

    Science.gov (United States)

    Latha, Raja; Shanthi, Palanivelu; Sachdanandam, Panchanadham

    2014-12-01

    Efficacy of Kalpaamruthaa on the activities of lipid and carbohydrate metabolic enzymes, electron transport chain complexes and mitochondrial ATPases were studied in heart and liver of experimental rats. Cardiovascular damage (CVD) was developed in 8 weeks after type 2 diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 × 35 mg/kg b.w. i.p. in 24 hr interval). In CVD-induced rats, the activities of total lipase, cholesterol ester hydrolase and cholesterol ester synthetase were increased, while lipoprotein lipase and lecithin-cholesterol acyltransferase activities were decreased. The activities of lipid-metabolizing enzymes were altered by Kalpaamruthaa in CVD-induced rats towards normal. Kalpaamruthaa modulated the activities of glycolytic enzymes (hexokinase, phosphogluco-isomerase, aldolase and glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1, 6-bisphosphatase) and glycogenolytic enzyme (glycogen phosphorylase) along with increased glycogen content in the liver of CVD-induced rats. The activities of isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, Complexes and ATPases (Na(+)/K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) were decreased in CVD-induced rats, which were ameliorated by the treatment with Kalpaamruthaa. This study ascertained the efficacy of Kalpaamruthaa for the treatment of CVD in diabetes through the modulation of metabolizing enzymes and mitochondrial dysfunction.

  18. Radiation-induced vasculopathy implicated by depressed blood flow and metabolism in a pineal glioma

    Energy Technology Data Exchange (ETDEWEB)

    Mineura, K.; Sasajima, T.; Kowada, M. (Akita University Hospital (Japan). Neurosurgical Service); Saitoh, H. (Oodate Municipal Hospital (Japan). Dept. of Neurosurgery); Shishido, F. (Research Inst. of Brain and Blood Vessels, Akita (Japan))

    1993-08-01

    A case of radiation-induced vasculopathy of a pineal glioma was presented with haemodynamic and metabolic changes before and after radiotherapy. After radiation of 60 Gy with conventional fractionation (1.8-2.0 Gy daily, 5 days per week), regional blood flow, oxygen extraction fraction, metabolic rate of oxygen, kinetic metabolic rate of glucose and the rate constants (K2, K3) were markedly depressed (20% or greater) compared with the pre-irradiated study. 7 months after radiotherapy, the patient developed transient episodes of both right and left upper limb convulsion, terminating in generalized convulsion. When she developed status epilepticus, computed tomography showed extensive low density areas in the territory supplied by the right middle cerebral and the right posterior cerebral arteries. (author).

  19. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets

    DEFF Research Database (Denmark)

    Nielsen, Troels Halfeld; Olsen, N.V.; Toft, P;

    2013-01-01

    variables related to energy metabolism. METHODS: Mitochondrial dysfunction was induced in piglets and evaluated by monitoring brain tissue oxygen tension (PbtO2 ) and cerebral levels of glucose, lactate, pyruvate, glutamate, and glycerol bilaterally. The biochemical variables were obtained by microdialysis...... metabolism and degradation of cellular membranes, respectively. CONCLUSION: Mitochondrial dysfunction is characterised by an increased LP ratio signifying a shift in cytoplasmatic redox state at normal or elevated PbtO2 . The condition is biochemically characterised by a marked increase in cerebral lactate...... with a normal or elevated pyruvate level. The metabolic pattern is different from cerebral ischemia, which is characterised by simultaneous decreases in intracerebral pyruvate and PbtO2 . The study supports the hypothesis that cerebral ischemia and mitochondrial dysfunction may be identified and separated...

  20. Green and Black Cardamom in a Diet-Induced Rat Model of Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    Maharshi Bhaswant

    2015-09-01

    Full Text Available Both black (B and green (G cardamom are used as flavours during food preparation. This study investigated the responses to B and G in a diet-induced rat model of human metabolic syndrome. Male Wistar rats were fed either a corn starch-rich diet (C or a high-carbohydrate, high-fat diet with increased simple sugars along with saturated and trans fats (H for 16 weeks. H rats showed signs of metabolic syndrome leading to visceral obesity with hypertension, glucose intolerance, cardiovascular remodelling and nonalcoholic fatty liver disease. Food was supplemented with 3% dried B or G for the final eight weeks only. The major volatile components were the closely related terpenes, 1,8-cineole in B and α-terpinyl acetate in G. HB (high-carbohydrate, high-fat + black cardamom rats showed marked reversal of diet-induced changes, with decreased visceral adiposity, total body fat mass, systolic blood pressure and plasma triglycerides, and structure and function of the heart and liver. In contrast, HG (high-carbohydrate, high-fat + green cardamom rats increased visceral adiposity and total body fat mass, and increased heart and liver damage, without consistent improvement in the signs of metabolic syndrome. These results suggest that black cardamom is more effective in reversing the signs of metabolic syndrome than green cardamom.

  1. Green and Black Cardamom in a Diet-Induced Rat Model of Metabolic Syndrome.

    Science.gov (United States)

    Bhaswant, Maharshi; Poudyal, Hemant; Mathai, Michael L; Ward, Leigh C; Mouatt, Peter; Brown, Lindsay

    2015-09-11

    Both black (B) and green (G) cardamom are used as flavours during food preparation. This study investigated the responses to B and G in a diet-induced rat model of human metabolic syndrome. Male Wistar rats were fed either a corn starch-rich diet (C) or a high-carbohydrate, high-fat diet with increased simple sugars along with saturated and trans fats (H) for 16 weeks. H rats showed signs of metabolic syndrome leading to visceral obesity with hypertension, glucose intolerance, cardiovascular remodelling and nonalcoholic fatty liver disease. Food was supplemented with 3% dried B or G for the final eight weeks only. The major volatile components were the closely related terpenes, 1,8-cineole in B and α-terpinyl acetate in G. HB (high-carbohydrate, high-fat + black cardamom) rats showed marked reversal of diet-induced changes, with decreased visceral adiposity, total body fat mass, systolic blood pressure and plasma triglycerides, and structure and function of the heart and liver. In contrast, HG (high-carbohydrate, high-fat + green cardamom) rats increased visceral adiposity and total body fat mass, and increased heart and liver damage, without consistent improvement in the signs of metabolic syndrome. These results suggest that black cardamom is more effective in reversing the signs of metabolic syndrome than green cardamom.

  2. Gene Transcriptional and Metabolic Profile Changes in Mimetic Aging Mice Induced by D-Galactose.

    Directory of Open Access Journals (Sweden)

    Yue-Yue Zhou

    Full Text Available D-galactose injection has been shown to induce many changes in mice that represent accelerated aging. This mouse model has been widely used for pharmacological studies of anti-aging agents. The underlying mechanism of D-galactose induced aging remains unclear, however, it appears to relate to glucose and 1ipid metabolic disorders. Currently, there has yet to be a study that focuses on investigating gene expression changes in D-galactose aging mice. In this study, integrated analysis of gas chromatography/mass spectrometry-based metabonomics and gene expression profiles was used to investigate the changes in transcriptional and metabolic profiles in mimetic aging mice injected with D-galactose. Our findings demonstrated that 48 mRNAs were differentially expressed between control and D-galactose mice, and 51 potential biomarkers were identified at the metabolic level. The effects of D-galactose on aging could be attributed to glucose and 1ipid metabolic disorders, oxidative damage, accumulation of advanced glycation end products (AGEs, reduction in abnormal substance elimination, cell apoptosis, and insulin resistance.

  3. Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose

    International Nuclear Information System (INIS)

    We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [18F]fluorodeoxyglucose (FDG) and [14C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum

  4. Hyperprolactinemia induced by hCG leads to metabolic disturbances in female mice.

    Science.gov (United States)

    Ratner, Laura D; Stevens, Guillermina; Bonaventura, Maria Marta; Lux-Lantos, Victoria A; Poutanen, Matti; Calandra, Ricardo S; Huhtaniemi, Ilpo T; Rulli, Susana B

    2016-07-01

    The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin β-subunit (hCGβ+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGβ+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGβ+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGβ+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies. PMID:27154336

  5. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats.

    Science.gov (United States)

    Miller, Desinia B; Snow, Samantha J; Schladweiler, Mette C; Richards, Judy E; Ghio, Andrew J; Ledbetter, Allen D; Kodavanti, Urmila P

    2016-04-01

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway. PMID:26732886

  6. Sex differences in diet and inhaled ozone (O3) induced metabolic impairment

    Science.gov (United States)

    APS 2015 abstract Sex differences in diet and inhaled ozone (O3) induced metabolic impairment U.P. Kodavanti1, V.L. Bass2, M.C. Schladweiler1, C.J. Gordon3, K.A. Jarema1, P. Phillips1, A.D. Ledbetter1, D.B. Miller4, S. Snow5, J.E. Richards1. 1 EPHD, NHEERL, USEPA, Research Triang...

  7. Regulation of endothelial metabolism by laminar shear stress and flow-induced transcription factor KLF2

    OpenAIRE

    Doddaballapur, Anuradha

    2016-01-01

    Flow hemodynamics regulates endothelial cell (EC) responses and laminar shear stress induces an atheroprotective and quiescent phenotype. The flow-responsive transcription factor KLF2 is a pivotal mediator of endothelial quiescence, but the precise mechanism is unclear. In this doctoral study, we assessed the hypothesis that laminar shear stress and KLF2 regulate endothelial quiescence by controlling endothelial metabolism. Laminar flow exposure and KLF2 over expression in HUVECs reduced g...

  8. Metabolic Alterations Induced by Sucrose Intake and Alzheimer’s Disease Promote Similar Brain Mitochondrial Abnormalities

    OpenAIRE

    Carvalho, Cristina; Cardoso, Susana; Correia, Sónia C; Santos, Renato X.; Santos, Maria S.; Baldeiras, Inês; oliveira, catarina r.; Moreira, Paula I.

    2012-01-01

    Evidence shows that diabetes increases the risk of developing Alzheimer’s disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-A...

  9. Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy

    OpenAIRE

    Ferraro, Elisabetta; Giammarioli, Anna Maria; Chiandotto, Sergio; Spoletini, Ilaria; Rosano, Giuseppe

    2014-01-01

    Significance: Skeletal muscle is a highly plastic tissue. Exercise evokes signaling pathways that strongly modify myofiber metabolism and physiological and contractile properties of skeletal muscle. Regular physical activity is beneficial for health and is highly recommended for the prevention of several chronic conditions. In this review, we have focused our attention on the pathways that are known to mediate physical training-induced plasticity. Recent Advances: An important role for redox ...

  10. Gender differences in ozone-induced pulmonary and metabolic health effects

    Science.gov (United States)

    SOT 2015 abstractGender differences in ozone-induced pulmonary and metabolic health effectsU.P. Kodavanti1, V.L. Bass2, M.C. Schladweiler1, C.J. Gordon3, K.A. Jarema3, P. Phillips3, A.D. Ledbetter1, D.B. Miller4, S. Snow5, J.E. Richards1. 1 EPHD, NHEERL, USEPA, Research Triangle ...

  11. Possible therapeutic effect of naftidrofuryl oxalate on brain energy metabolism after microsphere-induced cerebral embolism.

    OpenAIRE

    Miyake, K.; Tanonaka, K; Minematsu, R.; Inoue, K.; Takeo, S.

    1989-01-01

    1. The present study was designed to determine whether naftidrofuryl oxalate exerts a possible therapeutic effect on brain energy metabolism impaired by microsphere-induced cerebral embolism in vitro. 2. Injection of microspheres into the right carotid canal resulted in a decrease in tissue high-energy phosphates both in the right and left hemispheres, and an increase in tissue lactate in the right hemisphere, on the 3rd and the 5th day after the embolism. The embolism also induced a marked r...

  12. Effects of Silybum marianum Extract on High-Fat Diet Induced Metabolic Disorders in Rats

    OpenAIRE

    Sayin Fatma Kubra; Buyukbas Sadik; Basarali M. Kemal; Alp Harun; Toy Hatice; Ugurcu Veli

    2016-01-01

    Silybum marianum extract (SME) has been used for centuries as a natural remedy for diseases of liver and biliary tract. Lately, it has been promoted as a nutritional supplement for beneficial effects on some risk factors of diabetes and hyperlipidemia. In this study we aimed to determine the effects of SME on high-fat diet (HFD) induced metabolic disorders. Male Sprague Dawley rats were fed HFD for 11 weeks to induce obesity. SME was given to animals for two different durations, for 11 weeks ...

  13. Effect of MCI-186 on ischemia-induced changes in monoamine metabolism in rat brain.

    Science.gov (United States)

    Oishi, R; Itoh, Y; Nishibori, M; Watanabe, T; Nishi, H; Saeki, K

    1989-11-01

    We examined the effects of MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger and an inhibitor of ischemia-induced brain edema, on monoamine metabolism in the brains of both normal and ischemic rats. In normal rats, 3 mg/kg i.v. MCI-186, a dose that prevents ischemic brain edema, had no significant effect on brain concentrations of dopamine, norepinephrine, 5-hydroxytryptamine, or their metabolites. After the injection of 5 microliters of 3% polyvinyl acetate into the left internal carotid artery, concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid markedly increased, but that of norepinephrine decreased, in the left telencephalon of embolized rats compared with control rats injected with vehicle; the concentration of 5-hydroxyindoleacetic acid also increased slightly. These effects were maximal 2 hours after embolization. The turnover rate of dopamine between 6 and 8 hours after embolization was significantly higher but that of norepinephrine was slightly lower than that in vehicle-treated rats. When rats were treated with 3 mg/kg i.v. MCI-186 immediately after the injection of polyvinyl acetate, the embolization-induced changes in monoamine metabolism were less marked. Our results suggest that MCI-186 attenuates ischemia-induced changes in brain monoamine metabolism, probably due to its free radical scavenging action, although it has no marked effect in normal rats. PMID:2815191

  14. Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats

    Energy Technology Data Exchange (ETDEWEB)

    Bass, V. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Gordon, C.J.; Jarema, K.A.; MacPhail, R.C. [Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Cascio, W.E. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Phillips, P.M. [Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Ledbetter, A.D.; Schladweiler, M.C. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Andrews, D. [Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Miller, D. [Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC (United States); Doerfler, D.L. [Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Kodavanti, U.P., E-mail: kodavanti.urmila@epa.gov [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States)

    2013-12-15

    Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α{sub 2}-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2 > 1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation. - Highlights: • Air pollutants have been associated with increased diabetes in humans. • Acute ozone exposure produces profound metabolic alterations in rats. • Age influences metabolic risk factors in aging BN rats. • Acute metabolic effects are reversible and repeated exposure reduces these effects. • Ozone

  15. PGC-1alpha in exercise- and exercise training-induced metabolic adaptations

    DEFF Research Database (Denmark)

    Jørgensen, Stine Ringholm

    of gluconeogenesis, requires PGC-1α, while fasting-induced regulation of gluconeogenic capacity does not require PGC-1α. Study III demonstrates the time course of an exercise-induced uncoupling protein (UCP)1 mRNA response in WT mouse epididymal (eWAT) and inguinal (iWAT) white adipose tissue...... (PGC)-1α is required for exercise-, exercise training- and fasting-induced mRNA and protein responses, respectively, of metabolic, angiogenic and gluconeogenic proteins in liver and adipose tissue in mice, 3) PGC-1α is required for both exercise training and resveratrol mediated prevention of age...... in oxidative and/or angiogenic proteins in mouse liver and adipose tissue, while fasting-induced regulation of gluconeogenic capacity does not. In addition, resveratrol supplementation seems to have minor effects on the content of oxidative and angiogenic proteins in mouse skeletal muscle compared...

  16. Plasma proteome profiles associated with diet-induced metabolic syndrome and the early onset of metabolic syndrome in a pig model.

    Science.gov (United States)

    te Pas, Marinus F W; Koopmans, Sietse-Jan; Kruijt, Leo; Calus, Mario P L; Smits, Mari A

    2013-01-01

    Obesity and related diabetes are important health threatening multifactorial metabolic diseases and it has been suggested that 25% of all diabetic patients are unaware of their patho-physiological condition. Biomarkers for monitoring and control are available, but early stage predictive biomarkers enabling prevention of these diseases are still lacking. We used the pig as a model to study metabolic disease because humans and pigs share a multitude of metabolic similarities. Diabetes was chemically induced and control and diabetic pigs were either fed a high unsaturated fat (Mediterranean) diet or a high saturated fat/cholesterol/sugar (cafeteria) diet. Physiological parameters related to fat metabolism and diabetes were measured. Diabetic pigs' plasma proteome profiles differed more between the two diets than control pigs plasma proteome profiles. The expression levels of several proteins correlated well with (patho)physiological parameters related to the fat metabolism (cholesterol, VLDL, LDL, NEFA) and diabetes (Glucose) and to the diet fed to the animals. Studying only the control pigs as a model for metabolic syndrome when fed the two diets showed correlations to the same parameters but now more focused on insulin, glucose and abdominal fat depot parameters. We conclude that proteomic profiles can be used as a biomarker to identify pigs with developing metabolic syndrome (prediabetes) and diabetes when fed a cafeteria diet. It could be developed into a potential biomarkers for the early recognition of metabolic diseases.

  17. Plasma proteome profiles associated with diet-induced metabolic syndrome and the early onset of metabolic syndrome in a pig model.

    Directory of Open Access Journals (Sweden)

    Marinus F W te Pas

    Full Text Available Obesity and related diabetes are important health threatening multifactorial metabolic diseases and it has been suggested that 25% of all diabetic patients are unaware of their patho-physiological condition. Biomarkers for monitoring and control are available, but early stage predictive biomarkers enabling prevention of these diseases are still lacking. We used the pig as a model to study metabolic disease because humans and pigs share a multitude of metabolic similarities. Diabetes was chemically induced and control and diabetic pigs were either fed a high unsaturated fat (Mediterranean diet or a high saturated fat/cholesterol/sugar (cafeteria diet. Physiological parameters related to fat metabolism and diabetes were measured. Diabetic pigs' plasma proteome profiles differed more between the two diets than control pigs plasma proteome profiles. The expression levels of several proteins correlated well with (pathophysiological parameters related to the fat metabolism (cholesterol, VLDL, LDL, NEFA and diabetes (Glucose and to the diet fed to the animals. Studying only the control pigs as a model for metabolic syndrome when fed the two diets showed correlations to the same parameters but now more focused on insulin, glucose and abdominal fat depot parameters. We conclude that proteomic profiles can be used as a biomarker to identify pigs with developing metabolic syndrome (prediabetes and diabetes when fed a cafeteria diet. It could be developed into a potential biomarkers for the early recognition of metabolic diseases.

  18. Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

    Science.gov (United States)

    Sanchez-Alvarez, Rosa; Martinez-Outschoorn, Ubaldo E.; Lin, Zhao; Lamb, Rebecca; Hulit, James; Howell, Anthony; Sotgia, Federica; Rubin, Emanuel; Lisanti, Michael P.

    2013-01-01

    Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with “stemness,” more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This “two-compartment” metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert “low-risk” breast cancer patients to “high-risk” status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results

  19. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism

    Directory of Open Access Journals (Sweden)

    Minjiang Chen

    2016-01-01

    Full Text Available Objective. High glucose- (HG- induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM or control (25 mM groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism.

  20. SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes

    Directory of Open Access Journals (Sweden)

    Thais T. Zampieri

    2015-03-01

    Conclusions: Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances.

  1. Crosstalk between Two bZIP Signaling Pathways Orchestrates Salt-Induced Metabolic Reprogramming in Arabidopsis Roots

    NARCIS (Netherlands)

    Hartmann, Laura; Pedrotti, Lorenzo; Weiste, Christoph; Fekete, Agnes; Schierstaedt, Jasper; Göttler, Jasmin; Kempa, Stefan; Krischke, Markus; Dietrich, Katrin; Mueller, Martin J; Vicente-Carbajosa, Jesus; Hanson, Johannes; Dröge-Laser, Wolfgang

    2015-01-01

    Soil salinity increasingly causes crop losses worldwide. Although roots are the primary targets of salt stress, the signaling networks that facilitate metabolic reprogramming to induce stress tolerance are less understood than those in leaves. Here, a combination of transcriptomic and metabolic appr

  2. Halofuginone reduces the inflammatory responses of DSS-induced colitis through metabolic reprogramming.

    Science.gov (United States)

    Liu, Jing; Xiao, Hai-Tao; Wang, Hong-Sheng; Mu, Huai-Xue; Zhao, Ling; Du, Jun; Yang, Depo; Wang, Dongmei; Bian, Zhao-Xiang; Lin, Shu-Hai

    2016-06-21

    Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease.

  3. Detection of metabolic activation leading to drug-induced phospholipidosis in rat hepatocyte spheroids.

    Science.gov (United States)

    Takagi, Masashi; Sanoh, Seigo; Santoh, Masataka; Ejiri, Yoko; Kotake, Yaichiro; Ohta, Shigeru

    2016-02-01

    Drug-induced phospholipidosis (PLD) is one of the adverse reactions to treatment with cationic amphiphilic drugs. Recently, simple and reliable evaluation methods for PLD have been reported. However, the predictive power of these methods for in vivo PLD induction is insufficient in some cases. To accurately predict PLD, we focused on drug metabolism and used three-dimensional cultures of hepatocytes known as spheroids. Here we used the fluorescent phospholipid dye N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE) to detect PLD induction. After 48 hr exposure to 20 µM amiodarone and amitriptyline, PLD inducers, NBD-PE fluorescence in the spheroids was significantly higher than that in the control. In contrast, 1 mM acetaminophen, as a negative control, did not increase fluorescence. Furthermore, the combination of NBD-PE fluorescence and LysoTracker Red fluorescence and the accumulation of intrinsic phospholipids reflected PLD induction in spheroids. To evaluate metabolic activation, we assessed PLD induction by loratadine. NBD-PE fluorescence intensity was significantly increased by 50 µM loratadine treatment. However, the fluorescence was markedly decreased by co-treatment with 500 µM 1-aminobenzotriazole, a broad cytochrome P450 inhibitor. The formation of desloratadine, a metabolite of loratadine, was observed in spheroids after treatment with loratadine alone. These results showed that metabolic activation is the key factor in PLD induction by treatment with loratadine. We demonstrated that rat primary hepatocyte spheroid culture is a useful model for evaluating drug-induced PLD induction mediated by metabolic activation of the drug using the fluorescence probe technique. PMID:26763403

  4. Hydroxytyrosol prevents diet-induced metabolic syndrome and attenuates mitochondrial abnormalities in obese mice.

    Science.gov (United States)

    Cao, Ke; Xu, Jie; Zou, Xuan; Li, Yuan; Chen, Cong; Zheng, Adi; Li, Hao; Li, Hua; Szeto, Ignatius Man-Yau; Shi, Yujie; Long, Jiangang; Liu, Jiankang; Feng, Zhihui

    2014-02-01

    A Mediterranean diet rich in olive oil has profound influence on health outcomes including metabolic syndrome. However, the active compound and detailed mechanisms still remain unclear. Hydroxytyrosol (HT), a major polyphenolic compound in virgin olive oil, has received increased attention for its antioxidative activity and regulation of mitochondrial function. Here, we investigated whether HT is the active compound in olive oil exerting a protective effect against metabolic syndrome. In this study, we show that HT could prevent high-fat-diet (HFD)-induced obesity, hyperglycemia, hyperlipidemia, and insulin resistance in C57BL/6J mice after 17 weeks supplementation. Within liver and skeletal muscle tissues, HT could decrease HFD-induced lipid deposits through inhibition of the SREBP-1c/FAS pathway, ameliorate HFD-induced oxidative stress by enhancing antioxidant enzyme activities, normalize expression of mitochondrial complex subunits and mitochondrial fission marker Drp1, and eventually inhibit apoptosis activation. Moreover, in muscle tissue, the levels of mitochondrial carbonyl protein were decreased and mitochondrial complex activities were significantly improved by HT supplementation. In db/db mice, HT significantly decreased fasting glucose, similar to metformin. Notably, HT decreased serum lipid, at which metformin failed. Also, HT was more effective at decreasing the oxidation levels of lipids and proteins in both liver and muscle tissue. Similar to the results in the HFD model, HT decreased muscle mitochondrial carbonyl protein levels and improved mitochondrial complex activities in db/db mice. Our study links the olive oil component HT to diabetes and metabolic disease through changes that are not limited to decreases in oxidative stress, suggesting a potential pharmaceutical or clinical use of HT in metabolic syndrome treatment.

  5. Potato suberin induces differentiation and secondary metabolism in the genus Streptomyces.

    Science.gov (United States)

    Lerat, Sylvain; Forest, Martin; Lauzier, Annie; Grondin, Gilles; Lacelle, Serge; Beaulieu, Carole

    2012-01-01

    Bacteria of the genus Streptomyces are soil microorganisms with a saprophytic life cycle. Previous studies have revealed that the phytopathogenic agent S. scabiei undergoes metabolic and morphological modifications in the presence of suberin, a complex plant polymer. This paper investigates morphological changes induced by the presence of potato suberin in five species of the genus Streptomyces, with emphasis on S. scabiei. Streptomyces scabiei, S. acidiscabies, S. avermitilis, S. coelicolor and S. melanosporofaciens were grown both in the presence and absence of suberin. In all species tested, the presence of the plant polymer induced the production of aerial hyphae and enhanced resistance to mechanical lysis. The presence of suberin in liquid minimal medium also induced the synthesis of typical secondary metabolites in S. scabiei and S. acidiscabies (thaxtomin A), S. coelicolor (actinorhodin) and S. melanosporofaciens (geldanamycin). In S. scabiei, the presence of suberin modified the fatty acid composition of the bacterial membrane, which translated into higher membrane fluidity. Moreover, suberin also induced thickening of the bacterial cell wall. The present data indicate that suberin hastens cellular differentiation and triggers the onset of secondary metabolism in the genus Streptomyces. PMID:22129602

  6. Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

    Science.gov (United States)

    Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun; Gnana-Prakasam, Jaya P; Veeranan-Karmegam, Rajalakshmi; Huang, Lei; Ravishankar, Buvana; Bradley, Jillian; Kvirkvelia, Nino; McMenamin, Malgorzata; Xiao, Wei; Kleven, Daniel; Mellor, Andrew L; Madaio, Michael P; McGaha, Tracy L

    2015-06-15

    Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.

  7. Pyruvate metabolism: A therapeutic opportunity in radiation-induced skin injury

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Hyun; Kang, Jeong Wook [Department of Radiation Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Lee, Dong Won [Department of Plastic Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Oh, Sang Ho [Department of Dermatology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Lee, Yun-Sil [College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewah Womans University, Seoul 120-750 (Korea, Republic of); Lee, Eun-Jung [Department of Radiation Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of); Cho, Jaeho, E-mail: jjhmd@yuhs.ac [Department of Radiation Oncology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea, Republic of)

    2015-05-08

    Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. In this study, the effects of pyruvate, on radiation-induced skin injury were investigated, including the role of the pyruvate dehydrogenase kinase 2 (PDK2) signaling pathway. Next generation sequencing (NGS) identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of PDK2. This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a high cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness and inflammatory cytokine expression. These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation-induced skin damage. - Highlights: • The effects of radiation on skin thickness in mice. • Next generation sequencing revealed that radiation inhibited pyruvate dehydrogenase kinase 2 expression. • PDK2 inhibited irradiation-induced cytokine gene expression. • Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness.

  8. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    Science.gov (United States)

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. PMID:27284107

  9. Effects of celecoxib and ibuprofen on metabolic disorders induced by Walker-256 tumor in rats.

    Science.gov (United States)

    de Souza, Camila Oliveira; Kurauti, Mirian Ayumi; de Fatima Silva, Flaviane; de Morais, Hely; Borba-Murad, Glaucia Regina; de Andrade, Fábio Goulart; de Souza, Helenir Medri

    2015-01-01

    The contribution of anti-inflammatory property of celecoxib in the improvement of metabolic disorders in cancer is unknown. The purpose of this study was to compare the effects of celecoxib and ibuprofen, non-steroidal anti-inflammatory drugs (NSAIDs), on several metabolic changes observed in Walker-256 tumor-bearing rats. The effects of these NSAIDs on the tumor growth were also assessed. Celecoxib or ibuprofen (both at 25 mg/Kg) was administered orally for 12 days, beginning on the day the rats were inoculated with Walker-256 tumor cells. Celecoxib treatment prevented the losses in body mass and mass of retroperitoneal adipose tissue, gastrocnemius, and extensor digitorum longus muscles in tumor-bearing rats. Celecoxib also prevented the rise in blood levels of triacylglycerol, urea, and lactate, the inhibition of peripheral response to insulin and hepatic glycolysis, and tended to attenuate the decrease in the food intake, but had no effect on the reduction of glycemia induced by the tumor. In addition, celecoxib treatment increased the number of Walker-256 cells with signs of apoptosis and the tumor necrosis area and prevented the tumor growth. In contrast, ibuprofen treatment had no effect on metabolic parameters affected by the Walker-256 tumor or tumor growth. It can be concluded that celecoxib, unlike ibuprofen, ameliorated several metabolic changes in rats with Walker-256 tumor due to its anti-tumor effect and not its anti-inflammatory property.

  10. Metabolic Dysregulation Induced in Plasmodium falciparum by Dihydroartemisinin and Other Front-Line Antimalarial Drugs.

    Science.gov (United States)

    Cobbold, Simon A; Chua, Hwa H; Nijagal, Brunda; Creek, Darren J; Ralph, Stuart A; McConville, Malcolm J

    2016-01-15

    Detailed information on the mode of action of antimalarial drugs can be used to improve existing drugs, identify new drug targets, and understand the basis of drug resistance. In this study we describe the use of a time-resolved, mass spectrometry (MS)-based metabolite profiling approach to map the metabolic perturbations induced by a panel of clinical antimalarial drugs and inhibitors on Plasmodium falciparum asexual blood stages. Drug-induced changes in metabolite levels in P. falciparum-infected erythrocytes were monitored over time using gas chromatography-MS and liquid chromatography-MS and changes in specific metabolic fluxes confirmed by nonstationary [(13)C]-glucose labeling. Dihydroartemisinin (DHA) was found to disrupt hemoglobin catabolism within 1 hour of exposure, resulting in a transient decrease in hemoglobin-derived peptides. Unexpectedly, it also disrupted pyrimidine biosynthesis, resulting in increased [(13)C]-glucose flux toward malate production, potentially explaining the susceptibility of P. falciparum to DHA during early blood-stage development. Unique metabolic signatures were also found for atovaquone, chloroquine, proguanil, cycloguanil and methylene blue. We also show that this approach can be used to identify the mode of action of novel antimalarials, such as the compound Torin 2, which inhibits hemoglobin catabolism. PMID:26150544

  11. Salmonella Modulates Metabolism During Growth under Conditions that Induce Expression of Virulence Genes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young-Mo; Schmidt, Brian; Kidwai, Afshan S.; Jones, Marcus B.; Deatherage, Brooke L.; Brewer, Heather M.; Mitchell, Hugh D.; Palsson, Bernhard O.; McDermott, Jason E.; Heffron, Fred; Smith, Richard D.; Peterson, Scott N.; Ansong, Charles; Hyduke, Daniel R.; Metz, Thomas O.; Adkins, Joshua N.

    2013-04-05

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Excitingly, we observed possible sequestration of metabolites recently suggested to have immune modulating roles. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Model-guided analysis suggested that alterations in metabolism prioritized other activities necessary for pathogenesis instead, such as lipopolysaccharide biosynthesis.

  12. Irradiation induced injury reduces energy metabolism in small intestine of Tibet minipigs.

    Directory of Open Access Journals (Sweden)

    Yu-Jue Wang

    Full Text Available BACKGROUND: The radiation-induced energy metabolism dysfunction related to injury and radiation doses is largely elusive. The purpose of this study is to investigate the early response of energy metabolism in small intestinal tissue and its correlation with pathologic lesion after total body X-ray irradiation (TBI in Tibet minipigs. METHODS AND RESULTS: 30 Tibet minipigs were assigned into 6 groups including 5 experimental groups and one control group with 6 animals each group. The minipigs in these experimental groups were subjected to a TBI of 2, 5, 8, 11, and 14 Gy, respectively. Small intestine tissues were collected at 24 h following X-ray exposure and analyzed by histology and high performance liquid chromatography (HPLC. DNA contents in this tissue were also examined. Irradiation causes pathologic lesions and mitochondrial abnormalities. The Deoxyribonucleic acid (DNA content-corrected and uncorrected adenosine-triphosphate (ATP and total adenine nucleotides (TAN were significantly reduced in a dose-dependent manner by 2-8 Gy exposure, and no further reduction was observed over 8 Gy. CONCLUSION: TBI induced injury is highly dependent on the irradiation dosage in small intestine and inversely correlates with the energy metabolism, with its reduction potentially indicating the severity of injury.

  13. Psychosocial stress induces hyperphagia and exacerbates diet-induced insulin resistance and the manifestations of the Metabolic Syndrome.

    Science.gov (United States)

    Sanghez, Valentina; Razzoli, Maria; Carobbio, Stefania; Campbell, Mark; McCallum, Jacob; Cero, Cheryl; Ceresini, Graziano; Cabassi, Aderville; Govoni, Paolo; Franceschini, Paolo; de Santis, Valentina; Gurney, Allison; Ninkovic, Ivana; Parmigiani, Stefano; Palanza, Paola; Vidal-Puig, Antonio; Bartolomucci, Alessandro

    2013-12-01

    Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress-induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms.

  14. Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers

    Institute of Scientific and Technical Information of China (English)

    Quan Zhou; Tong-Wei Yao; Su Zeng

    2001-01-01

    AIM: To study the influence of inducers of drug metabolism enzyme, β-naphthoflavone (BNF) and dexamethasone (DEX), on the stereoselective metabolism of propafenone in the rat hepatic microsomes. METHODS: Phase I metabolism of propafenone was studied using the microsomes induced by BNF and DEX and the non-induced microsome was used as the control. The enzymatic kinetics parameters of propafenone enantiomers were calculated by regress analysis of Eadie-Hofstee Plots.Propafenone enantiomer concentrations were assayed by a chiral HPLC. RESULTS: The metabolite of propafenone, N-desalkylpropafenone, was found after incubstion of propafenone with the rat hepatic microsomes induced by BNF and DEX. In these two groups, the stereoselectivity favoring R ( - ) isomer was observed in metabolism st Iow substrate concentrations of racemic propafenone, but lost the stereoselectivity st high substrate concentrations.However; in control group, no stereeselectivity was observed. The enzyme kinetic parameters were: ① Km.Control group: R( - ) 83 ± 6, S( + ) 94 ± 7; BNF group: R (-)105 ± 6, S( + )128 ± 14; DEX group: R( - ) 86± 11, S( + ) 118 ± 16; ② vmax. Control group: R( - ) 0.75 ± 0.16, S( + ) 0.72±0.07; BNF group: R( - )1.04± 0.15, S( + )1.07±14; DEX group: R( - ) 0.93 ± 0.06, S( + ) 1.04 ± 0.09; (③)Clint. Control group: R( - ) 8.9± 1.1, S( + ) 7.6±0.7; BNFgroup: R( - )9.9±0.9, S( + )8.3±0.7; DEX group: R( - )10.9± 0.8, S( + ) 8.9 ± 0.9. The enantiomeric differences in Km and Clint were both significant, but not in Vmax, in BNF and DEX group. Whereas enantiomeric differences in three parameters were all insignificant in control group.Furthermore, Km and Umax were both significantly less than those in BNF or DEX group. In the rat liver microsorne induced by DEX, nimodipine (NDP) decreased the stereoselectivity in propafenone metabolism at Iow substrate concentration. The inhibition of NDP on the metabolism of propafenone was stereo.selective with R

  15. Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism.

    Science.gov (United States)

    Dheer, Rishu; Patterson, Jena; Dudash, Mark; Stachler, Elyse N; Bibby, Kyle J; Stolz, Donna B; Shiva, Sruti; Wang, Zeneng; Hazen, Stanley L; Barchowsky, Aaron; Stolz, John F

    2015-12-15

    Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes.

  16. Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia.

    Science.gov (United States)

    Jameel, Mohammad N; Wang, Xiaohong; Eijgelshoven, Marcel H J; Mansoor, Abdul; Zhang, Jianyi

    2008-06-01

    The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 microg x kg(-1) x min(-1) iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 +/- 0.14, 2.06 +/- 0.13, and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11, and 1.72 +/- 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 +/- 0.12, 0.52 +/- 0.10, and 0.37 +/- 0.08 for EPI, MID, and ENDO, respectively; P ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism. PMID:18424629

  17. Transmural Distribution of Metabolic Abnormalities and Glycolytic Activity during Dobutamine Induced Demand Ischemia

    Science.gov (United States)

    Jameel, Mohammad N; Wang, Xiaohong; Eijgelshoven, Marcel H.J.; Mansoor, Abdul; Zhang, Jianyi

    2008-01-01

    The heterogeneity across the LV wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high energy phosphate (HEP) and 2-deoxyglucose-6-phosphate (2DGP) levels and myocardial blood flow (MBF) were determined under basal conditions (B), during dobutamine infusion (DOB: 20 μg/kg/min iv.), and during coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting subendocardial to subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion RPP, ischemic zone (IZ) MBF and ENDO/EPI decreased significantly. IZ PCr/ATP decreased significantly (2.30 +/- 0.14, 2.06 +/- 0.13 and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11 and 1.72 +/- 0.12; EPI, MID and ENDO, respectively) and 2DG6P accumulated in all layers as evidenced by the 2DG6P/PCr (0.55 +/- 0.12, 0.52 +/- 0.10 and 0.37 +/- 0.08; EPI, MID and ENDO respectively; pENDO). In the IZ the wet weight/dry weight ratio was significantly increased as compared to the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; p<0.05). Thus, in stenotic perfused bed, during dobutamine induced high cardiac workstate, despite higher blood flow the subepicardial layers showed the greater metabolic changes that characterized by a shift toward higher carbohydrate metabolism suggesting a homeostatic responses to high cardiac workstate is characterized by more glucose utilization in energy metabolism. PMID:18424629

  18. Chronic Intake of Japanese Sake Mediates Radiation-Induced Metabolic Alterations in Mouse Liver.

    Directory of Open Access Journals (Sweden)

    Tetsuo Nakajima

    Full Text Available Sake is a traditional Japanese alcoholic beverage that is gaining popularity worldwide. Although sake is reported to have beneficial health effects, it is not known whether chronic sake consumption modulates health risks due to radiation exposure or other factors. Here, the effects of chronic administration of sake on radiation-induced metabolic alterations in the livers of mice were evaluated. Sake (junmai-shu was administered daily to female mice (C3H/He for one month, and the mice were exposed to fractionated doses of X-rays (0.75 Gy/day for the last four days of the sake administration period. For comparative analysis, a group of mice were administered 15% (v/v ethanol in water instead of sake. Metabolites in the liver were analyzed by capillary electrophoresis-time-of-flight mass spectrometry one day following the last exposure to radiation. The metabolite profiles of mice chronically administered sake in combination with radiation showed marked changes in purine, pyrimidine, and glutathione (GSH metabolism, which were only partially altered by radiation or sake administration alone. Notably, the changes in GSH metabolism were not observed in mice treated with radiation following chronic administration of 15% ethanol in water. Changes in several metabolites, including methionine and valine, were induced by radiation alone, but were not detected in the livers of mice who received chronic administration of sake. In addition, the chronic administration of sake increased the level of serum triglycerides, although radiation exposure suppressed this increase. Taken together, the present findings suggest that chronic sake consumption promotes GSH metabolism and anti-oxidative activities in the liver, and thereby may contribute to minimizing the adverse effects associated with radiation.

  19. Size of myocardial infarction induced by ischaemia/reperfusion is unaltered in rats with metabolic syndrome.

    Science.gov (United States)

    Thim, Troels; Bentzon, Jacob F; Kristiansen, Steen B; Simonsen, Ulf; Andersen, Heidi L; Wassermann, Karsten; Falk, Erling

    2006-06-01

    Obesity is associated with metabolic syndrome and increased incidence of and mortality from myocardial infarction. The aim of the present study was to develop an animal model with metabolic syndrome and examine how that influences size of myocardial infarcts induced by occlusion and reperfusion of the left anterior descending coronary artery. Sprague-Dawley rats (n = 105) were fed either LF (low-fat) or MHF (moderately high-fat) diets for 13 weeks before coronary occlusion for 45 min, followed by reperfusion for 60 min. Compared with LF-fed and lean MHF-fed rats, obese MHF-fed rats developed metabolic disturbances similar to those seen in the metabolic syndrome, including being overweight by 24% (compared with lean MHF-fed rats), having 74% more visceral fat (compared with LF-fed rats), 15% higher blood pressure (compared with LF-fed rats), 116% higher plasma insulin (compared with lean MHF-fed rats), 10% higher fasting plasma glucose (compared with LF-fed rats), 35% higher non-fasting plasma glucose (compared with lean MHF-fed rats), 36% higher plasma leptin (compared with lean MHF-fed rats) and a tendency to lower plasma adiponectin and higher plasma non-esterified fatty acids. Infarct size was similar in the three groups of rats (36+/-14, 42+/-18 and 41+/-14% in obese MHF-fed, lean MHF-fed and LF-fed rats respectively). In conclusion, rats fed a MHF diet developed metabolic syndrome, but this did not influence myocardial infarct size. PMID:16448385

  20. Glycyrrhizin ameliorates metabolic syndrome-induced liver damage in experimental rat model.

    Science.gov (United States)

    Sil, Rajarshi; Ray, Doel; Chakraborti, Abhay Sankar

    2015-11-01

    Glycyrrhizin, a major constituent of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate insulin resistance, hyperglycemia, dyslipidemia, and obesity in rats with metabolic syndrome. Liver dysfunction is associated with this syndrome. The objective of this study is to investigate the effect of glycyrrhizin treatment on metabolic syndrome-induced liver damage. After induction of metabolic syndrome in rats by high fructose (60%) diet for 6 weeks, the rats were treated with glycyrrhizin (50 mg/kg body weight, single intra-peritoneal injection). After 2 weeks of treatment, rats were sacrificed to collect blood samples and liver tissues. Compared to normal, elevated activities of serum alanine transaminase, alkaline phosphatase and aspartate transaminase, increased levels of liver advanced glycation end products, reactive oxygen species, lipid peroxidation, protein carbonyl, protein kinase Cα, NADPH oxidase-2, and decreased glutathione cycle components established liver damage and oxidative stress in fructose-fed rats. Activation of nuclear factor κB, mitogen-activated protein kinase pathways as well as signals from mitochondria were found to be involved in liver cell apoptosis. Increased levels of cyclooxygenase-2, tumor necrosis factor, and interleukin-12 proteins suggested hepatic inflammation. Metabolic syndrome caused hepatic DNA damage and poly-ADP ribose polymerase cleavage. Fluorescence-activated cell sorting using annexin V/propidium iodide staining confirmed the apoptotic hepatic cell death. Histology of liver tissue also supported the experimental findings. Treatment with glycyrrhizin reduced oxidative stress, hepatic inflammation, and apoptotic cell death in fructose-fed rats. The results suggest that glycyrrhizin possesses therapeutic potential against hepatocellular damage in metabolic syndrome. PMID:26400710

  1. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

    Directory of Open Access Journals (Sweden)

    Bell Jimmy D

    2009-04-01

    Full Text Available Abstract The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest

  2. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

    Science.gov (United States)

    Nunn, Alistair Vw; Bell, Jimmy D; Guy, Geoffrey W

    2009-01-01

    The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress

  3. Botanical and biological pesticides elicit a similar Induced Systemic Response in tomato (Solanum lycopersicum) secondary metabolism.

    Science.gov (United States)

    Pretali, Luca; Bernardo, Letizia; Butterfield, Timothy S; Trevisan, Marco; Lucini, Luigi

    2016-10-01

    Natural pesticides have attracted substantial interest due to the increase in organic agriculture and enhanced attention to environmental pollution. Plant Growth Promoting Bacteria (PGPB) are applied for both disease control and growth enhancement; PGPBs are known to elicit Induced Systemic Response (ISR) in plants. However, less is known about the effect of botanical pesticides, such as the azadirachtin-containing neem extracts, on plant metabolism. This study aimed to investigate the effects of foliar application of the above-mentioned natural pesticides on the metabolic profiling of tomato. Leaf application of Bacillus subtilis fostered Induced Systemic Resistance (ISR) in treated plants via the Jasmonic acid pathway, and enhanced production of secondary metabolites such as flavonoids, phytoalexins and auxins. Changes in sterols and terpenes, as well as an increase in glucosinolates were also observed. Interestingly, azadirachtin-treated tomatoes also showed an increase in ISR and our results revealed that most of the enriched metabolites are shared with a B. subtilis treatment, suggesting conserved biochemical responses. These (un)expected findings indicate that plants are not insensitive to application of natural pesticide and while Azadirachtin is applied as a direct pesticide, it also stimulates a defense response in tomatoes very similar to B. subtilis induced ISR. PMID:27251587

  4. Soybean Aphid Infestation Induces Changes in Fatty Acid Metabolism in Soybean.

    Directory of Open Access Journals (Sweden)

    Charles Kanobe

    Full Text Available The soybean aphid (Aphis glycines Matsumura is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of "metabolic hijacking" by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor.

  5. Effects of Silybum marianum Extract on High-Fat Diet Induced Metabolic Disorders in Rats

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    Sayin Fatma Kubra

    2016-03-01

    Full Text Available Silybum marianum extract (SME has been used for centuries as a natural remedy for diseases of liver and biliary tract. Lately, it has been promoted as a nutritional supplement for beneficial effects on some risk factors of diabetes and hyperlipidemia. In this study we aimed to determine the effects of SME on high-fat diet (HFD induced metabolic disorders. Male Sprague Dawley rats were fed HFD for 11 weeks to induce obesity. SME was given to animals for two different durations, for 11 weeks or for 7 weeks. The results showed significant increase in plasma transaminases, total cholesterol (TC, triglycerides (TG, low density lipoprotein cholesterol (LDL-C, leptin, high sensitive C-reactive protein (hsCRP, glucose and insulin along with significant increase in body mass index (BMI and liver weights in rats fed the HFD diet compared to rats fed with standard rat diet. SME supplementation for different durations raised improvement in the HFD-induced metabolic disorders such as insulin resistance, hyperlipidemia and hepatopathy at different degrees. Our study concludes that SME can be well considered as an effective supplement to improve insulin and leptin sensitivity and hyperlipidemia and to suppress body weight gain.

  6. ROS-mediated glucose metabolic reprogram induces insulin resistance in type 2 diabetes.

    Science.gov (United States)

    Dong, Kelei; Ni, Hua; Wu, Meiling; Tang, Ziqing; Halim, Michael; Shi, Dongyun

    2016-08-01

    Oxidative stress is known to contribute to insulin resistance in diabetes, however the mechanism is not clear. Here we show that reactive oxygen species (ROS) could reprogram the glucose metabolism through upregulating the pentose pathway so as to induce insulin resistance in type 2 diabetes (T2DM). By using streptozotocin-high fat diet (STZ-HFD) induced T2DM in rats, we show that diabetic rats exhibited high level of oxidative stress accompanied with insulin resistance. Hypoxia inducible factor (HIF-1α) protein expression as well as its downstream target glucokinase (GK), were upregulated; The glycogen synthesis increased accordingly; However the glycolysis was inhibited as indicated by decreased phosphofructokinase-1 (PFK-1), pyruvate kinase (PK), phospho-PFK-2/PFK-2 (p-PFK-2/PFK-2) ratio, lactate dehydrogenase (LDH) and pyruvate dehydrogenase kinase (PDK); Pyruvate dehydrogenase (PDH) which promotes pyruvate to generate acetyl-CoA declined as well. While phospho-acetyl-CoA carboxylase/acetyl-CoA carboxylase (p-ACC/ACC) ratio increased, meaning that lipid beta-oxidation increased. The pentose pathway was activated as indicated by increased G6PD activity and NADPH level. Our results suggest that diabetic rats countervail ROS stress through increasing pentose pathway, and reprogram the energy metabolic pathway from glycolysis into lipid oxidation in order to compensate the ATP requirement of the body, which causes insulin resistance. PMID:27207834

  7. Targeting the metabolic pathway of human colon cancer overcomes resistance to TRAIL-induced apoptosis.

    Science.gov (United States)

    Carr, Ryan M; Qiao, Guilin; Qin, Jianzhong; Jayaraman, Sundararajan; Prabhakar, Bellur S; Maker, Ajay V

    2016-01-01

    Colon cancer is a leading cause of cancer-related mortality for which targeted therapy is needed; however, trials using apoptosis-inducing ligand monotherapy to overcome resistance to apoptosis have not shown clinical responses. Since colon cancer cells selectively uptake and rapidly metabolize glucose, a property utilized for clinical staging, we investigated mechanisms to alter glucose metabolism in order to selectively target the cancer cells and to overcome evasion of apoptosis. We demonstrate TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance in the majority of human colon cancers tested and utilize the glucose analog 2-deoxy-d-glucose to sensitize TRAIL-resistant gastrointestinal adenocarcinoma cells, and not normal gastrointestinal epithelial cells, to TRAIL-induced apoptosis through enhanced death receptor 5 expression, downstream modulation of MAPK signaling and subsequent miRNA expression modulation by increasing the expression of miR-494 via MEK activation. Further, established human colon cancer xenografts treated with this strategy experience anti-tumor responses. These findings in colon adenocarcinoma support further investigation of manipulation of cellular energetics to selectively overcome resistance to apoptosis and to impart tumor regressions in established colon cancer tumors. PMID:27648301

  8. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    International Nuclear Information System (INIS)

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal

  9. Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases

    Science.gov (United States)

    Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S.; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. PMID:25698759

  10. Cerebral blood flow and metabolism during isoflurane-induced hypotension in patients subjected to surgery for cerebral aneurysms

    DEFF Research Database (Denmark)

    Madsen, J B; Cold, G E; Hansen, E S;

    1987-01-01

    Cerebral blood flow and cerebral metabolic rate for oxygen were measured during isoflurane-induced hypotension in 10 patients subjected to craniotomy for clipping of a cerebral aneurysm. Flow and metabolism were measured 5-13 days after the subarachnoid haemorrhage by a modification of the classi......Cerebral blood flow and cerebral metabolic rate for oxygen were measured during isoflurane-induced hypotension in 10 patients subjected to craniotomy for clipping of a cerebral aneurysm. Flow and metabolism were measured 5-13 days after the subarachnoid haemorrhage by a modification......). Controlled hypotension to an average MAP of 50-55 mm Hg was induced by increasing the dose of isoflurane, and maintained at an inspired concentration of 2.2 +/- 0.2%. This resulted in a significant decrease in CMRO2 (to 1.73 +/- 0.16 ml/100 g min-1), while CBF was unchanged. After the clipping...

  11. Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Dawei W. Dong

    2015-12-01

    Full Text Available Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO, leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca2+ sensitive Calcineurin (Ppp3ca and the expression of PI3-kinase (Pik3r4 and Pik3cb increased by two folds. This Ca2+/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01 between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10−5. Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.

  12. Plasma proteome profiles predict diet-induced metabolic syndrome and the early onset of metabolic syndrome in a pig model

    NARCIS (Netherlands)

    Pas, te M.F.W.; Koopmans, S.J.; Kruijt, L.; Smits, M.A.

    2013-01-01

    Obesity and related diabetes are important health threatening multifactorial metabolic diseases and it has been suggested that 25 % of all diabetic patients are unaware of their patho-physiological condition. Feeding behavior is often associated with the onset of the metabolic syndrome. We have deve

  13. New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism.

    Science.gov (United States)

    Teo, Adrian Kee Keong; Wagers, Amy J; Kulkarni, Rohit N

    2013-12-01

    The landmark discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has transformed regenerative biology. Previously, insights into the pathogenesis of chronic human diseases have been hindered by the inaccessibility of patient samples. However, scientists are now able to convert patient fibroblasts into iPSCs and differentiate them into disease-relevant cell types. This ability opens new avenues for investigating disease pathogenesis and designing novel treatments. In this review, we highlight the uses of human iPSCs to uncover the underlying causes and pathological consequences of diabetes and metabolic syndromes, multifactorial diseases whose etiologies have been difficult to unravel using traditional methodologies.

  14. DISTINCT TRANSCRIPTIONAL REGULATION OF LONG-CHAIN ACYL-COA SYNTHETASE ISOFORMS AND CYTOSOLIC THIOESTERASE 1 IN THE RODENT HEART BY FATTY ACIDS AND INSULIN

    Science.gov (United States)

    The molecular mechanism(s) responsible for channeling long-chain fatty acids (LCFAs) into oxidative versus nonoxidative pathways is (are) poorly understood in the heart. Intracellular LCFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoAs) by a family of long-chain acyl-CoA synthetases (ACSLs)...

  15. Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles.

    Directory of Open Access Journals (Sweden)

    Jules A Nchoutmboube

    Full Text Available All positive strand (+RNA viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3 as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+RNA viruses as well.

  16. Determination of hydrophobic coenzyme a esters and other lipids using a biosensor comprising a modified coenzyme a- and acyl-coa binding protein (acbp)

    DEFF Research Database (Denmark)

    2002-01-01

    , food and feed preparations, tissue extracts, acyl-CoA synthetase reaction media and various laboratory conditions using a modified Coenzyme A- and acyl-CoA binding protein (ACBP) is provided. Furthermore the invention relates to a construct comprising a peptide and a signal moiety for performing...

  17. Pyruvate metabolism: A therapeutic opportunity in radiation-induced skin injury.

    Science.gov (United States)

    Yoo, Hyun; Kang, Jeong Wook; Lee, Dong Won; Oh, Sang Ho; Lee, Yun-Sil; Lee, Eun-Jung; Cho, Jaeho

    2015-05-01

    Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. In this study, the effects of pyruvate, on radiation-induced skin injury were investigated, including the role of the pyruvate dehydrogenase kinase 2 (PDK2) signaling pathway. Next generation sequencing (NGS) identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of PDK2. This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a high cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness and inflammatory cytokine expression. These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation-induced skin damage. PMID:25797627

  18. Rescue of Fructose-Induced Metabolic Syndrome by Antibiotics or Faecal Transplantation in a Rat Model of Obesity.

    Directory of Open Access Journals (Sweden)

    Blanda Di Luccia

    Full Text Available A fructose-rich diet can induce metabolic syndrome, a combination of health disorders that increases the risk of diabetes and cardiovascular diseases. Diet is also known to alter the microbial composition of the gut, although it is not clear whether such alteration contributes to the development of metabolic syndrome. The aim of this work was to assess the possible link between the gut microbiota and the development of diet-induced metabolic syndrome in a rat model of obesity. Rats were fed either a standard or high-fructose diet. Groups of fructose-fed rats were treated with either antibiotics or faecal samples from control rats by oral gavage. Body composition, plasma metabolic parameters and markers of tissue oxidative stress were measured in all groups. A 16S DNA-sequencing approach was used to evaluate the bacterial composition of the gut of animals under different diets. The fructose-rich diet induced markers of metabolic syndrome, inflammation and oxidative stress, that were all significantly reduced when the animals were treated with antibiotic or faecal samples. The number of members of two bacterial genera, Coprococcus and Ruminococcus, was increased by the fructose-rich diet and reduced by both antibiotic and faecal treatments, pointing to a correlation between their abundance and the development of the metabolic syndrome. Our data indicate that in rats fed a fructose-rich diet the development of metabolic syndrome is directly correlated with variations of the gut content of specific bacterial taxa.

  19. Gastrodia elata Ameliorates High-Fructose Diet-Induced Lipid Metabolism and Endothelial Dysfunction

    Directory of Open Access Journals (Sweden)

    Min Chul Kho

    2014-01-01

    Full Text Available Overconsumption of fructose results in dyslipidemia, hypertension, and impaired glucose tolerance, which have documented correlation with metabolic syndrome. Gastrodia elata, a widely used traditional herbal medicine, was reported with anti-inflammatory and antidiabetes activities. Thus, this study examined whether ethanol extract of Gastrodia elata Blume (EGB attenuate lipid metabolism and endothelial dysfunction in a high-fructose (HF diet animal model. Rats were fed the 65% HF diet with/without EGB 100 mg/kg/day for 8 weeks. Treatment with EGB significantly suppressed the increments of epididymal fat weight, blood pressure, plasma triglyceride, total cholesterol levels, and oral glucose tolerance, respectively. In addition, EGB markedly prevented increase of adipocyte size and hepatic accumulation of triglycerides. EGB ameliorated endothelial dysfunction by downregulation of endothelin-1 (ET-1 and adhesion molecules in the aorta. Moreover, EGB significantly recovered the impairment of vasorelaxation to acetylcholine and levels of endothelial nitric oxide synthase (eNOS expression and induced markedly upregulation of phosphorylation AMP-activated protein kinase (AMPKα in the liver, muscle, and fat. These results indicate that EGB ameliorates dyslipidemia, hypertension, and insulin resistance as well as impaired vascular endothelial function in HF diet rats. Taken together, EGB may be a beneficial therapeutic approach for metabolic syndrome.

  20. Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.

    Directory of Open Access Journals (Sweden)

    Shian-Huey Chiang

    Full Text Available Nicotinamide adenine dinucleotide (NAD+ is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.

  1. Attenuation of Some Metabolic Deteriorations Induced by Diabetes Mellitus Using Carnosine

    Science.gov (United States)

    Soliman, K. M.; Mohamed, A. M.; Metwally, N. S.

    The protective ability of carnosine against some metabolic disorders and oxidative stress in Strepotzotocin (STZ) diabetic-induced model was studied. Diabetic rats showed significant increase in serum glucose and cortisol levels indicating disturbance of carbohydrate metabolism, increased triglycerides, total cholesterol, LDL-cholesterol as well as iron level indicating abnormal lipid metabolism and iron overload. Marked increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SD) were also demonstrated implying impairment of liver function. Concomitantly, the results revealed an impairment of antioxidant status of diabetic animals as evidenced by significant decrease in vitamin E and HDL-C levels. Administration of either two doses of carnosine (10 mg/100 g b.w. or 20 mg/100 g b.w.) two weeks before and after diabetic induction, was effective in ameliorating serum glucose level of diabetic animals and improving the deterioration in the studied parameters. The best results were obtained with the higher dose. No significant changes were noted in serum bilirubin level among the different studied groups. These data suggest that carnosine is a potential multi-protective agent for diabetic complications prevention or therapy.

  2. Metabolic Context of the Competence-Induced Checkpoint for Cell Replication in Streptococcus suis.

    Directory of Open Access Journals (Sweden)

    Edoardo Zaccaria

    Full Text Available Natural genetic transformation is a transient, rapidly progressing energy-consuming process characterized by expression of the transformasome and competence-associated regulatory genes. This transient state is tightly controlled to avoid potentially adverse effects of genetic recombination on genome integrity during cell division. We investigated the global response of Streptococcus suis to exposure to the SigX competence-inducing peptide (XIP, and thus to the activation of the competence machinery, using time series analysis together with PCA analysis, gene clustering followed by heatmap visualisation, and GO enrichment analysis. We explored the possible regulatory link between metabolism and competence, and predicted the physiological adaptation of S. suis during competence induction, progression and exit using transcriptome analysis. We showed that competence development is associated with a suppression of basal metabolism, which may have consequences for the microbe's resilience to fluctuations in the environment, as competence is costly in terms of use of energy and protein translation. Furthermore our data suggest that several basal metabolic pathways are incompatible with activation of competence in S. suis. This study also showed that targeting specific pathways during the development of competence, might render S. suis more vulnerable toward novel antibiotic therapies.

  3. Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility.

    Science.gov (United States)

    Chiang, Shian-Huey; Harrington, W Wallace; Luo, Guizhen; Milliken, Naphtali O; Ulrich, John C; Chen, Jing; Rajpal, Deepak K; Qian, Ying; Carpenter, Tiffany; Murray, Rusty; Geske, Robert S; Stimpson, Stephen A; Kramer, Henning F; Haffner, Curt D; Becherer, J David; Preugschat, Frank; Billin, Andrew N

    2015-01-01

    Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet. PMID:26287487

  4. Icariin Is A PPARα Activator Inducing Lipid Metabolic Gene Expression in Mice

    Directory of Open Access Journals (Sweden)

    Yuan-Fu Lu

    2014-11-01

    Full Text Available Icariin is effective in the treatment of hyperlipidemia. To understand the effect of icariin on lipid metabolism, effects of icariin on PPARα and its target genes were investigated. Mice were treated orally with icariin at doses of 0, 100, 200, and 400 mg/kg, or clofibrate (500 mg/kg for five days. Liver total RNA was isolated and the expressions of PPARα and lipid metabolism genes were examined. PPARα and its marker genes Cyp4a10 and Cyp4a14 were induced 2-4 fold by icariin, and 4-8 fold by clofibrate. The fatty acid (FA binding and co-activator proteins Fabp1, Fabp4 and Acsl1 were increased 2-fold. The mRNAs of mitochondrial FA β-oxidation enzymes (Cpt1a, Acat1, Acad1 and Hmgcs2 were increased 2-3 fold. The mRNAs of proximal β-oxidation enzymes (Acox1, Ech1, and Ehhadh were also increased by icariin and clofibrate. The expression of mRNAs for sterol regulatory element-binding factor-1 (Srebf1 and FA synthetase (Fasn were unaltered by icariin. The lipid lysis genes Lipe and Pnpla2 were increased by icariin and clofibrate. These results indicate that icariin is a novel PPARα agonist, activates lipid metabolism gene expressions in liver, which could be a basis for its lipid-lowering effects and its beneficial effects against diabetes.

  5. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption

    Science.gov (United States)

    Xie, Guoxiang; Zhong, Wei; Li, Houkai; Li, Qiong; Qiu, Yunping; Zheng, Xiaojiao; Chen, Huiyuan; Zhao, Xueqing; Zhang, Shucha; Zhou, Zhanxiang; Zeisel, Steven H.; Jia, Wei

    2013-01-01

    Our understanding of the bile acid metabolism is limited by the fact that previous analyses have primarily focused on a selected few circulating bile acids; the bile acid profiles of the liver and gastrointestinal tract pools are rarely investigated. Here, we determined how chronic ethanol consumption altered the bile acids in multiple body compartments (liver, gastrointestinal tract, and serum) of rats. Rats were fed a modified Lieber-DeCarli liquid diet with 38% of calories as ethanol (the amount equivalent of 4–5 drinks in humans). While conjugated bile acids predominated in the liver (98.3%), duodenum (97.8%), and ileum (89.7%), unconjugated bile acids comprised the largest proportion of measured bile acids in serum (81.2%), the cecum (97.7%), and the rectum (97.5%). In particular, taurine-conjugated bile acids were significantly decreased in the liver and gastrointestinal tract of ethanol-treated rats, while unconjugated and glycine-conjugated species increased. Ethanol consumption caused increased expression of genes involved in bile acid biosynthesis, efflux transport, and reduced expression of genes regulating bile acid influx transport in the liver. These results provide an improved understanding of the systemic modulations of bile acid metabolism in mammals through the gut-liver axis.—Xie, G., Zhong, W., Li, H., Li, Q., Qiu, Y., Zheng, X., Chen, H., Zhao, X., Zhang, S., Zhou, Z., Zeisel, S. H., Jia, W. Alteration of bile acid metabolism in the rat induced by chronic ethanol consumption. PMID:23709616

  6. NRF2 Orchestrates the Metabolic Shift during Induced Pluripotent Stem Cell Reprogramming

    Directory of Open Access Journals (Sweden)

    Kate E. Hawkins

    2016-03-01

    Full Text Available The potential of induced pluripotent stem cells (iPSCs in disease modeling and regenerative medicine is vast, but current methodologies remain inefficient. Understanding the cellular mechanisms underlying iPSC reprogramming, such as the metabolic shift from oxidative to glycolytic energy production, is key to improving its efficiency. We have developed a lentiviral reporter system to assay longitudinal changes in cell signaling and transcription factor activity in living cells throughout iPSC reprogramming of human dermal fibroblasts. We reveal early NF-κB, AP-1, and NRF2 transcription factor activation prior to a temporal peak in hypoxia inducible factor α (HIFα activity. Mechanistically, we show that an early burst in oxidative phosphorylation and elevated reactive oxygen species generation mediates increased NRF2 activity, which in turn initiates the HIFα-mediated glycolytic shift and may modulate glucose redistribution to the pentose phosphate pathway. Critically, inhibition of NRF2 by KEAP1 overexpression compromises metabolic reprogramming and results in reduced efficiency of iPSC colony formation.

  7. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming

    Institute of Scientific and Technical Information of China (English)

    Athanasia D Panopoulos; Margaret Lutz; W Travis Berggren; Kun Zhang; Ronald M Evans; Gary Siuzdak; Juan Carlos Izpisua Belmonte; Oscar Yanes; SergioRuiz; Yasuyuki S Kida; Dinh Diep; Ralf Tautenhahn; Aida Herrerias; Erika M Batchelder; Nongluk Plongthongkum

    2012-01-01

    Metabolism is vital to every aspect of cell function,yet the metabolome of induced pluripotent stem cells (iPSCs)remains largely unexplored.Here we report,using an untargeted metabolomics approach,that human iPSCs share a pluripotent metabolomic signature with embryonic stem cells (ESCs) that is distinct from their parental cells,and that is characterized by changes in metabolites involved in cellular respiration.Examination of cellular bioenergetics corroborated with our metabolomic analysis,and demonstrated that somatic cells convert from an oxidative state to a glycolytic state in pluripotency.Interestingly,the bioenergetics of various somatic cells correlated with their reprogramming efficiencies.We further identified metabolites that differ between iPSCs and ESCs,which revealed novel metabolic pathways that play a critical role in regulating somatic cell reprogramming.Our findings are the first to globally analyze the metabolome of iPSCs,and provide mechanistic insight into a new layer of regulation involved in inducing pluripotency,and in evaluating iPSC and ESC equivalence.

  8. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast.

    Science.gov (United States)

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida; Sanvito, Rossella; Magni, Fulvio; Coccetti, Paola; Rocchetti, Marcella; Nielsen, Jens; Alberghina, Lilia; Vanoni, Marco

    2016-06-16

    Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage.

  9. Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Sundaram, Ramalingam; Shanthi, Palanivelu; Sachdanandam, Panchanatham

    2014-05-15

    The present study was designed to evaluate the antihyperglycemic potential of tangeretin on the activities of key enzymes of carbohydrate and glycogen metabolism in control and streptozotocin induced diabetic rats. The daily oral administration of tangeretin (100mg/kg body weight) to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and increase in the levels of insulin and hemoglobin. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver of diabetic rats were significantly reverted to near normal levels by the administration of tangeretin. Further, tangeretin administration to diabetic rats improved hepatic glycogen content suggesting the antihyperglycemic potential of tangeretin in diabetic rats. The effect produced by tangeretin on various parameters was comparable to that of glibenclamide - a standard oral hypoglycemic drug. Thus, these results show that tangeretin modulates the activities of hepatic enzymes via enhanced secretion of insulin and decreases the blood glucose in streptozotocin induced diabetic rats by its antioxidant potential. PMID:24629597

  10. Fenugreek with reduced bitterness prevents diet-induced metabolic disorders in rats

    Directory of Open Access Journals (Sweden)

    Muraki Etsuko

    2012-05-01

    Full Text Available Abstract Background Various therapeutic effects of fenugreek (Trigonella foenum-graecum L. on metabolic disorders have been reported. However, the bitterness of fenugreek makes it hard for humans to eat sufficient doses of it for achieving therapeutic effects. Fenugreek contains bitter saponins such as protodioscin. Fenugreek with reduced bitterness (FRB is prepared by treating fenugreek with beta-glucosidase. This study has been undertaken to evaluate the effects of FRB on metabolic disorders in rats. Methods Forty Sprague–Dawley rats were fed with high-fat high-sucrose (HFS diet for 12 week to induce mild glucose and lipid disorders. Afterwards, the rats were divided into 5 groups. In the experiment 1, each group (n = 8 was fed with HFS, or HFS containing 2.4% fenugreek, or HFS containing 1.2%, 2.4% and 4.8% FRB, respectively, for 12 week. In the experiment 2, we examined the effects of lower doses of FRB (0.12%, 0.24% and 1.2% under the same protocol (n = 7 in each groups. Results In the experiment 1, FRB dose-dependently reduced food intake, body weight gain, epididymal white adipose tissue (EWAT and soleus muscle weight. FRB also lowered plasma and hepatic lipid levels and increased fecal lipid levels, both dose-dependently. The Plasma total cholesterol levels (mmol/L in the three FRB and Ctrl groups were 1.58 ± 0.09, 1.45 ± 0.05*, 1.29 ± 0.07* and 2.00 ± 0.18, respectively (*; P P P  Conclusions Thus we have demonstrated that FRB (1.2 ~ 4.8% prevents diet-induced metabolic disorders such as insulin resistance, dyslipidemia and fatty liver.

  11. 2-deoxy-D-glucose-induced metabolic stress enhances resistance to Listeria monocytogenes infection in mice

    Science.gov (United States)

    Miller, E. S.; Bates, R. A.; Koebel, D. A.; Fuchs, B. B.; Sonnenfeld, G.

    1998-01-01

    Exposure to different forms of psychological and physiological stress can elicit a host stress response, which alters normal parameters of neuroendocrine homeostasis. The present study evaluated the influence of the metabolic stressor 2-deoxy-D-glucose (2-DG; a glucose analog, which when administered to rodents, induces acute periods of metabolic stress) on the capacity of mice to resist infection with the facultative intracellular bacterial pathogen Listeria monocytogenes. Female BDF1 mice were injected with 2-DG (500 mg/kg b. wt.) once every 48 h prior to, concurrent with, or after the onset of a sublethal dose of virulent L. monocytogenes. Kinetics of bacterial growth in mice were not altered if 2-DG was applied concurrently or after the start of the infection. In contrast, mice exposed to 2-DG prior to infection demonstrated an enhanced resistance to the listeria challenge. The enhanced bacterial clearance in vivo could not be explained by 2-DG exerting a toxic effect on the listeria, based on the results of two experiments. First, 2-DG did not inhibit listeria replication in trypticase soy broth. Second, replication of L. monocytogenes was not inhibited in bone marrow-derived macrophage cultures exposed to 2-DG. Production of neopterin and lysozyme, indicators of macrophage activation, were enhanced following exposure to 2-DG, which correlated with the increased resistance to L. monocytogenes. These results support the contention that the host response to 2-DG-induced metabolic stress can influence the capacity of the immune system to resist infection by certain classes of microbial pathogens.

  12. Interplay between mitogen-activated protein kinase and nitric oxide in brassinosteroid-induced pesticide metabolism in Solanum lycopersicum.

    Science.gov (United States)

    Yin, Yan-Ling; Zhou, Yue; Zhou, Yan-Hong; Shi, Kai; Zhou, Jie; Yu, Yunlong; Yu, Jing-Quan; Xia, Xiao-Jian

    2016-10-01

    Nitric oxide (NO) and mitogen-activated protein kinase (MPK) play important roles in brassinosteroid (BR)-induced stress tolerance, however, their functions in BR-induced pesticides metabolism remain unclear. Here, we showed that MPK activity and transcripts of SlMPK1 and SlMPK2 were induced by chlorothalonil (CHT), a widely used fungicide, in tomato leaves. However, cosilencing of SlMPK1/2 compromised the 24-epibrassinolide (EBR)-induced upregulation of detoxification genes and CHT metabolism in tomato leaves. In addition, cosilencing of SlMPK1/2 inhibited the accumulation of S-nitrosothiol (SNO), the reservoir of nitric oxide (NO) in plants, whereas tungstate, the inhibitor of nitrate reductase (NR), blocked EBR-induced SNO accumulation and MPK activity. Inhibiting the accumulation of NO by cPTIO, the specific scavenger and tungstate abolished the EBR-induced upregulation of detoxification genes, glutathione accumulation and CHT metabolism. The results showed that MPK and NR-dependent NO were involved in BR-induced CHT metabolism. Notably, there was a positive crosstalk between the MPK and NO production. PMID:27236431

  13. Intrinsic vs. extrinsic influences on life history expression: metabolism and parentally induced temperature influences on embryo development rate

    Science.gov (United States)

    Martin, Thomas E.; Ton, Riccardo; Nikilson, Alina

    2013-01-01

    Intrinsic processes are assumed to underlie life history expression and trade-offs, but extrinsic inputs are theorised to shift trait expression and mask trade-offs within species. Here, we explore application of this theory across species. We do this based on parentally induced embryo temperature as an extrinsic input, and mass-specific embryo metabolism as an intrinsic process, underlying embryonic development rate. We found that embryonic metabolism followed intrinsic allometry rules among 49 songbird species from temperate and tropical sites. Extrinsic inputs via parentally induced temperatures explained the majority of variation in development rates and masked a relationship with metabolism; metabolism explained a minor proportion of the variation in development rates among species, and only after accounting for temperature effects. We discuss evidence that temperature further obscures the expected interspecific trade-off between development rate and offspring quality. These results demonstrate the importance of considering extrinsic inputs to trait expression and trade-offs across species.

  14. Roles of Sphingolipid Metabolism in Pancreatic β Cell Dysfunction Induced by Lipotoxicity

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    Julien Véret

    2014-06-01

    Full Text Available Pancreatic β cells secrete insulin in order to maintain glucose homeostasis. However, various environmental stresses such as obesity have been shown to induce loss of secretory responsiveness in pancreatic β cells and pancreatic β cell apoptosis which can favor the development of type 2 diabetes (T2D. Indeed, elevated levels of free fatty acids (FFAs have been shown to induce β cell apoptosis. Importantly, the chronic adverse effects of FFAs on β cell function and viability are potentiated in the presence of hyperglycaemia, a phenomenon that has been termed gluco-lipotoxicity. The molecular mechanisms underlying the pathogenesis of gluco-lipotoxicity in pancreatic β cells are not completely understood. Recent studies have shown that sphingolipid metabolism plays a key role in gluco-lipotoxicity induced apoptosis and loss of function of pancreatic β cells. The present review focuses on how the two main sphingolipid mediators, ceramides and sphingoid base-1-phosphates, regulate the deleterious effects of gluco-lipotoxicity on pancreatic β cells. The review highlights the role of a sphingolipid biostat on the dysregulation of β cell fate and function induced by gluco-lipotoxicity, offering the possibility of new therapeutic targets to prevent the onset of T2D.

  15. Glucocorticoid activity and metabolism with NaCl-induced low-grade metabolic acidosis and oral alkalization: results of two randomized controlled trials.

    Science.gov (United States)

    Buehlmeier, Judith; Remer, Thomas; Frings-Meuthen, Petra; Maser-Gluth, Christiane; Heer, Martina

    2016-04-01

    Low-grade metabolic acidosis (LGMA), as induced by high dietary acid load or sodium chloride (NaCl) intake, has been shown to increase bone and protein catabolism. Underlying mechanisms are not fully understood, but from clinical metabolic acidosis interactions of acid-base balance with glucocorticoid (GC) metabolism are known. We aimed to investigate GC activity/metabolism under alkaline supplementation and NaCl-induced LGMA. Eight young, healthy, normal-weight men participated in two crossover designed interventional studies. In Study A, two 10-day high NaCl diet (32 g/d) periods were conducted, one supplemented with 90 mmol KHCO3/day. In Study B, participants received a high and a low NaCl diet (31 vs. 3 g/day), each for 14 days. During low NaCl, the diet was moderately acidified by replacement of a bicarbonate-rich mineral water (consumed during high NaCl) with a non-alkalizing drinking water. In repeatedly collected 24-h urine samples, potentially bioactive-free GCs (urinary-free cortisol + free cortisone) were analyzed, as well as tetrahydrocortisol (THF), 5α-THF, and tetrahydrocortisone (THE). With supplementation of 90 mmol KHCO3, the marker of total adrenal GC secretion (THF + 5α-THF + THE) dropped (p = 0.047) and potentially bioactive-free GCs were reduced (p = 0.003). In Study B, however, GC secretion and potentially bioactive-free GCs did not exhibit the expected fall with NaCl-reduction as net acid excretion was raised by 30 mEq/d. Diet-induced acidification/alkalization affects GC activity and metabolism, which in case of long-term ingestion of habitually acidifying western diets may constitute an independent risk factor for bone degradation and cardiometabolic diseases. PMID:26349936

  16. Prenatal Hyperandrogenization Induces Metabolic and Endocrine Alterations Which Depend on the Levels of Testosterone Exposure

    Science.gov (United States)

    Amalfi, Sabrina; Velez, Leandro Martín; Heber, María Florencia; Vighi, Susana; Ferreira, Silvana Rocío; Orozco, Adriana Vega; Pignataro, Omar; Motta, Alicia Beatriz

    2012-01-01

    Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS

  17. Pseudomonas fluorescens induces strain-dependent and strain-independent host plant responses in defense networks, primary metabolism and photosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Pelletier, Dale A [ORNL; Morrell-Falvey, Jennifer L [ORNL; Karve, Abhijit A [ORNL; Lu, Tse-Yuan S [ORNL; Tschaplinski, Timothy J [ORNL; Tuskan, Gerald A [ORNL; Chen, Jay [ORNL; Martin, Madhavi Z [ORNL; Jawdy, Sara [ORNL; Weston, David [ORNL; Doktycz, Mitchel John [ORNL; Schadt, Christopher Warren [ORNL

    2012-01-01

    Colonization of plants by nonpathogenic Pseudomonas fluorescens strains can confer enhanced defense capacity against a broad spectrum of pathogens. Few studies, however, have linked defense pathway regulation to primary metabolism and physiology. In this study, physiological data, metabolites, and transcript profiles are integrated to elucidate how molecular networks initiated at the root-microbe interface influence shoot metabolism and whole-plant performance. Experiments with Arabidopsis thaliana were performed using the newly identified P. fluorescens GM30 or P. fluorescens Pf-5 strains. Co-expression networks indicated that Pf-5 and GM30 induced a subnetwork specific to roots enriched for genes participating in RNA regulation, protein degradation, and hormonal metabolism. In contrast, only GM30 induced a subnetwork enriched for calcium signaling, sugar and nutrient signaling, and auxin metabolism, suggesting strain dependence in network architecture. In addition, one subnetwork present in shoots was enriched for genes in secondary metabolism, photosynthetic light reactions, and hormone metabolism. Metabolite analysis indicated that this network initiated changes in carbohydrate and amino acid metabolism. Consistent with this, we observed strain-specific responses in tryptophan and phenylalanine abundance. Both strains reduced host plant carbon gain and fitness, yet provided a clear fitness benefit when plants were challenged with the pathogen P. syringae DC3000.

  18. Interleukin-17A Differentially Induces Inflammatory and Metabolic Gene Expression in the Adipose Tissues of Lean and Obese Mice.

    Science.gov (United States)

    Qu, Yine; Zhang, Qiuyang; Ma, Siqi; Liu, Sen; Chen, Zhiquan; Mo, Zhongfu; You, Zongbing

    2016-04-07

    The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) for 30 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were analyzed for IL-17A levels. SAT and VAT were treated with IL-17A and analyzed for inflammatory and metabolic gene expression. Mouse 3T3-L1 pre-adipocytes were differentiated into adipocytes, followed with IL-17A treatment and analysis for inflammatory and metabolic gene expression. We found that IL-17A levels were higher in obese SAT than lean SAT; the basal expression of inflammatory and metabolic genes was different between SAT and VAT and between lean and obese adipose tissues. IL-17A differentially induced expression of inflammatory and metabolic genes, such as tumor necrosis factor α, Il-6, Il-1β, leptin, and glucose transporter 4, in adipose tissues of lean and obese mice. IL-17A also differentially induced expression of inflammatory and metabolic genes in pre-adipocytes and adipocytes, and IL-17A selectively activated signaling pathways in adipose tissues and adipocytes. These findings suggest that IL-17A differentially induces inflammatory and metabolic gene expression in the adipose tissues of lean and obese mice.

  19. Interleukin-17A Differentially Induces Inflammatory and Metabolic Gene Expression in the Adipose Tissues of Lean and Obese Mice

    Directory of Open Access Journals (Sweden)

    Yine Qu

    2016-04-01

    Full Text Available The functions of interleukin-17A (IL-17A in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice or a high-fat diet (n = 6, obese mice for 30 weeks. Subcutaneous adipose tissue (SAT and visceral adipose tissue (VAT were analyzed for IL-17A levels. SAT and VAT were treated with IL-17A and analyzed for inflammatory and metabolic gene expression. Mouse 3T3-L1 pre-adipocytes were differentiated into adipocytes, followed with IL-17A treatment and analysis for inflammatory and metabolic gene expression. We found that IL-17A levels were higher in obese SAT than lean SAT; the basal expression of inflammatory and metabolic genes was different between SAT and VAT and between lean and obese adipose tissues. IL-17A differentially induced expression of inflammatory and metabolic genes, such as tumor necrosis factor α, Il-6, Il-1β, leptin, and glucose transporter 4, in adipose tissues of lean and obese mice. IL-17A also differentially induced expression of inflammatory and metabolic genes in pre-adipocytes and adipocytes, and IL-17A selectively activated signaling pathways in adipose tissues and adipocytes. These findings suggest that IL-17A differentially induces inflammatory and metabolic gene expression in the adipose tissues of lean and obese mice.

  20. Interleukin-17A Differentially Induces Inflammatory and Metabolic Gene Expression in the Adipose Tissues of Lean and Obese Mice.

    Science.gov (United States)

    Qu, Yine; Zhang, Qiuyang; Ma, Siqi; Liu, Sen; Chen, Zhiquan; Mo, Zhongfu; You, Zongbing

    2016-01-01

    The functions of interleukin-17A (IL-17A) in adipose tissues and adipocytes have not been well understood. In the present study, male mice were fed with a regular diet (n = 6, lean mice) or a high-fat diet (n = 6, obese mice) for 30 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were analyzed for IL-17A levels. SAT and VAT were treated with IL-17A and analyzed for inflammatory and metabolic gene expression. Mouse 3T3-L1 pre-adipocytes were differentiated into adipocytes, followed with IL-17A treatment and analysis for inflammatory and metabolic gene expression. We found that IL-17A levels were higher in obese SAT than lean SAT; the basal expression of inflammatory and metabolic genes was different between SAT and VAT and between lean and obese adipose tissues. IL-17A differentially induced expression of inflammatory and metabolic genes, such as tumor necrosis factor α, Il-6, Il-1β, leptin, and glucose transporter 4, in adipose tissues of lean and obese mice. IL-17A also differentially induced expression of inflammatory and metabolic genes in pre-adipocytes and adipocytes, and IL-17A selectively activated signaling pathways in adipose tissues and adipocytes. These findings suggest that IL-17A differentially induces inflammatory and metabolic gene expression in the adipose tissues of lean and obese mice. PMID:27070576

  1. Asiatic Acid Alleviates Hemodynamic and Metabolic Alterations via Restoring eNOS/iNOS Expression, Oxidative Stress, and Inflammation in Diet-Induced Metabolic Syndrome Rats

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    Poungrat Pakdeechote

    2014-01-01

    Full Text Available Asiatic acid is a triterpenoid isolated from Centella asiatica. The present study aimed to investigate whether asiatic acid could lessen the metabolic, cardiovascular complications in rats with metabolic syndrome (MS induced by a high-carbohydrate, high-fat (HCHF diet. Male Sprague-Dawley rats were fed with HCHF diet with 15% fructose in drinking water for 12 weeks to induce MS. MS rats were treated with asiatic acid (10 or 20 mg/kg/day or vehicle for a further three weeks. MS rats had an impairment of oral glucose tolerance, increases in fasting blood glucose, serum insulin, total cholesterol, triglycerides, mean arterial blood pressure, heart rate, and hindlimb vascular resistance; these were related to the augmentation of vascular superoxide anion production, plasma malondialdehyde and tumor necrosis factor-alpha (TNF-α levels (p < 0.05. Plasma nitrate and nitrite (NOx were markedly high with upregulation of inducible nitric oxide synthase (iNOS expression, but dowregulation of endothelial nitric oxide synthase (eNOS expression (p < 0.05. Asiatic acid significantly improved insulin sensitivity, lipid profiles, hemodynamic parameters, oxidative stress markers, plasma TNF-α, NOx, and recovered abnormality of eNOS/iNOS expressions in MS rats (p < 0.05. In conclusion, asiatic acid improved metabolic, hemodynamic abnormalities in MS rats that could be associated with its antioxidant, anti-inflammatory effects and recovering regulation of eNOS/iNOS expression.

  2. Oxidative stress disturbs energy metabolism of mitochondria in ethanol-induced gastric mucosa injury

    Institute of Scientific and Technical Information of China (English)

    Jin-Shui Pan; Shao-Zhen He; Hong-Zhi Xu; Xiao-Juan Zhan; Xiao-Ning Yang; Hong-Min Xiao; Hua-Xiu Shi; Jian-Lin Ren

    2008-01-01

    AIM: To study the role of mitochondrial energy disorder in the pathogenesis of ethanol-induced gastric mucosa injury.METHODS: Wistar rats were used in this study. A gastric mucosal injury model was established by giving the rats alcohol. Gross and microscopic appearance of gastric mucosa and ultrastructure of mitochondria were evaluated. Malondiadehyde (MDA) in gastric mucosa was measured with thiobarbituric acid. Expression of ATP synthase (ATPase) subunits 6 and 8 in mitochondrial DNA (mtDNA) was determined by reverse transcription polymerase chain reaction (RT-PCR).RESULTS: The gastric mucosal lesion index was correlated with the MDA content in gastric mucosa. As the concentration of ethanol was elevated and the exposure time to ethanol was extended, the content of MDA in gastric mucosa increased and the extent of damage aggravated. The ultrastructure of mitochondria was positively related to the ethanol concentration and exposure time. The expression of mtDNA ATPase subunits 6 and 8 mRNA declined with the increasing MDA content in gastric mucosa after gavage with ethanol.CONCLUSION: Ethanol-induced gastric mucosa injury is related to oxidative stress, which disturbs energy metabolism of mitochondria and plays a critical role in the pathogenesis of ethanol-induced gastric mucosa injury.

  3. pH gradients induced by urea metabolism in 'artificial mouth' microcosm plaques.

    Science.gov (United States)

    Sissons, C H; Wong, L; Hancock, E M; Cutress, T W

    1994-06-01

    Evidence was sought for urea-induced pH gradients in dental plaque microcosm biofilms cultured from the mixed salivary bacteria in a multi plaque 'artificial mouth'. Application of 500 mmol/l urea for short periods (6 min) to 5-8 mm maximum-thickness plaques induced intraplaque pH gradients of up to 0.7 pH units with the surface alkaline relative to the inner plaque. These pH gradients persisted for more than 5 h in the absence of a flow of fluid. With 30-min urea applications and a flow of a basal medium containing mucin (BMM, pH 7.0), the pH of the inner (deeper) plaque regions also increased. Although the pH gradient initially formed was alkaline at the plaque surface, the BMM flow lowered the surface pH to neutrality whilst the inner layers were still alkaline, thereby reversing the pH gradient. In thick microcosm dental plaques, urea-induced pH gradients can therefore form and last many hours. They probably result from the significant time taken for urea to penetrate to the inner layers of plaque, its rapid metabolism by the outer plaque layers, and a rate-limiting clearance of ammonia. Even a slow BMM flow over the plaque greatly increased the rate of return to the resting pH, causing the gradients to change polarity.

  4. Oxidative stress disturbs energy metabolism of mitochondria in ethanol-induced gastric mucosa injury

    Science.gov (United States)

    Pan, Jin-Shui; He, Shao-Zhen; Xu, Hong-Zhi; Zhan, Xiao-Juan; Yang, Xiao-Ning; Xiao, Hong-Min; Shi, Hua-Xiu; Ren, Jian-Lin

    2008-01-01

    AIM: To study the role of mitochondrial energy disorder in the pathogenesis of ethanol-induced gastric mucosa injury. METHODS: Wistar rats were used in this study. A gastric mucosal injury model was established by giving the rats alcohol. Gross and microscopic appearance of gastric mucosa and ultrastructure of mitochondria were evaluated. Malondiadehyde (MDA) in gastric mucosa was measured with thiobarbituric acid. Expression of ATP synthase (ATPase) subunits 6 and 8 in mitochondrial DNA (mtDNA) was determined by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The gastric mucosal lesion index was correlated with the MDA content in gastric mucosa. As the concentration of ethanol was elevated and the exposure time to ethanol was extended, the content of MDA in gastric mucosa increased and the extent of damage aggravated. The ultrastructure of mitochondria was positively related to the ethanol concentration and exposure time. The expression of mtDNA ATPase subunits 6 and 8 mRNA declined with the increasing MDA content in gastric mucosa after gavage with ethanol. CONCLUSION: Ethanol-induced gastric mucosa injury is related to oxidative stress, which disturbs energy metabolism of mitochondria and plays a critical role in the pathogenesis of ethanol-induced gastric mucosa injury. PMID:18855985

  5. Chronic liquid nutrition intake induces obesity and considerable but reversible metabolic alterations in Wistar rats.

    Science.gov (United States)

    Mikuska, Livia; Vrabcova, Michaela; Tillinger, Andrej; Balaz, Miroslav; Ukropec, Jozef; Mravec, Boris

    2016-06-01

    We have previously described the development of substantial, but reversible obesity in Wistar rats fed with palatable liquid nutrition (Fresubin). In this study, we investigated changes in serum hormone levels, glycemia, fat mass, adipocyte size, and gene expression of adipokines and inflammatory markers in adipose tissue of Wistar rats fed by Fresubin (i) for 5 months, (ii) up to 90 days of age, or (iii) after 90 days of age to characterize metabolic alterations and their reversibility in rats fed with Fresubin. An intra-peritoneal glucose tolerance test was also performed to determine levels of serum leptin, adiponectin, insulin, and C-peptide in 2- and 4-month-old animals. In addition, mesenteric and epididymal adipose tissue weight, adipocyte diameter, and gene expression of pro- and anti-inflammatory adipokines and other markers were determined at the end of the study. Chronic Fresubin intake significantly increased adipocyte diameter, reduced glucose tolerance, and increased serum leptin, adiponectin, insulin, and C-peptide levels. Moreover, gene expression of leptin, adiponectin, CD68, and nuclear factor kappa B was significantly increased in mesenteric adipose tissue of Fresubin fed rats. Monocyte chemotactic protein 1 messenger RNA (mRNA) levels increased in mesenteric adipose tissue only in the group fed Fresubin during the entire experiment. In epididymal adipose tissue, fatty acid binding protein 4 mRNA levels were significantly increased in rats fed by Fresubin during adulthood. In conclusion, chronic Fresubin intake induced complex metabolic alterations in Wistar rats characteristic of metabolic syndrome. However, transition of rats from Fresubin to standard diet reversed these alterations. PMID:26939586

  6. Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline.

    Science.gov (United States)

    González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L; Monleón, Santiago; Vinader-Caerols, Concepción; Parra, Andrés

    2008-05-01

    The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline. PMID:18313125

  7. Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism

    Directory of Open Access Journals (Sweden)

    Dun-Xian Tan

    2015-10-01

    Full Text Available Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin’s synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress.

  8. Similar degrees of obesity induced by diet or aging cause strikingly different immunologic and metabolic outcomes.

    Science.gov (United States)

    Krishna, Kanthi B; Stefanovic-Racic, Maja; Dedousis, Nikolaos; Sipula, Ian; O'Doherty, Robert M

    2016-03-01

    In obesity, adipose tissue (AT) and liver are infiltrated with Th-1 polarized immune cells, which are proposed to play an important role in the pathogenesis of the metabolic abnormalities of obesity. Aging is also associated with increased adiposity, but the effects of this increase on inflammation and associated metabolic dysfunction are poorly understood. To address this issue, we assessed insulin resistance (IR) andATand liver immunophenotype in aged, lean (AL) and aged, obese (AO) mice, all of whom were maintained on a standard chow diet (11% fat diet) throughout their lives. For comparison, these variables were also assessed in young, lean (YL) and young diet-induced obese mice (41% fat diet,YO). Despite similar body weight and fat accumulation,YOmice were substantially moreIRand had greater liver steatosis compared toAOmice.YOalso had elevated infiltration of macrophages/dendritic cells inATand liver, but these increases were absent inAO Furthermore, liver immune cells ofYOwere more Th-1 polarized thenAO Notably, aging was associated with accumulation of T cells, but this occurred independent of obesity. Together, the data suggest that reduced inflammation inAOunderlies the improved insulin sensitivity and lowered steatosis compared toYO.

  9. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Pacana, Tommy; Cazanave, Sophie; Verdianelli, Aurora; Patel, Vaishali; Min, Hae-Ki; Mirshahi, Faridoddin; Quinlivan, Eoin; Sanyal, Arun J

    2015-01-01

    Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, pmethionine ratio (pmethionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.

  10. Adiponectin induces A20 expression in adipose tissue to confer metabolic benefit.

    Science.gov (United States)

    Hand, Laura E; Usan, Paola; Cooper, Garth J S; Xu, Lance Y; Ammori, Basil; Cunningham, Peter S; Aghamohammadzadeh, Reza; Soran, Handrean; Greenstein, Adam; Loudon, Andrew S I; Bechtold, David A; Ray, David W

    2015-01-01

    Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. We detail that mice lacking Reverbα exhibit enhanced fat storage without the predicted increased WAT inflammation or loss of insulin sensitivity. In contrast to most animal models of obesity and obese human patients, Reverbα(-/-) mice exhibit elevated serum adiponectin levels and increased adiponectin secretion from WAT explants in vitro, highlighting a potential anti-inflammatory role of this adipokine in hypertrophic WAT. Indeed, adiponectin was found to suppress primary macrophage responses to lipopolysaccharide and proinflammatory fatty acids, and this suppression depended on glycogen synthase kinase 3β activation and induction of A20. Attenuated inflammatory responses in Reverbα(-/-) WAT depots were associated with tonic elevation of A20 protein and ex vivo shown to depend on A20. We also demonstrate that adipose A20 expression in obese human subjects exhibits a negative correlation with measures of insulin sensitivity. Furthermore, bariatric surgery-induced weight loss was accompanied by enhanced WAT A20 expression, which is positively correlated with increased serum adiponectin and improved metabolic and inflammatory markers, including C-reactive protein. The findings identify A20 as a mediator of adiponectin anti-inflammatory action in WAT and a potential target for mitigating obesity-related pathology. PMID:25190567

  11. IKK NBD peptide inhibits LPS induced pulmonary inflammation and alters sphingolipid metabolism in a murine model.

    Science.gov (United States)

    von Bismarck, Philipp; Winoto-Morbach, Supandi; Herzberg, Mona; Uhlig, Ulrike; Schütze, Stefan; Lucius, Ralph; Krause, Martin F

    2012-06-01

    Airway epithelial NF-κB is a key regulator of host defence in bacterial infections and has recently evolved as a target for therapeutical approaches. Evidence is accumulating that ceramide, generated by acid sphingomyelinase (aSMase), and sphingosine-1-phosphate (S1-P) are important mediators in host defence as well as in pathologic processes of acute lung injury. Little is known about the regulatory mechanisms of pulmonary sphingolipid metabolism in bacterial infections of the lung. The objective of this study was to evaluate the influence of NF-κB on sphingolipid metabolism in Pseudomonas aeruginosa LPS-induced pulmonary inflammation. In a murine acute lung injury model with intranasal Pseudomonas aeruginosa LPS we investigated TNF-α, KC (murine IL-8), IL-6, MCP-1 and neutrophilic infiltration next to aSMase activity and ceramide and S1-P lung tissue concentrations. Airway epithelial NF-κB was inhibited by topically applied IKK NBD, a cell penetrating NEMO binding peptide. This treatment resulted in significantly reduced inflammation and suppression of aSMase activity along with decreased ceramide and S1-P tissue concentrations down to levels observed in healthy animals. In conclusion our results confirm that changes in sphingolipid metabolim due to Pseudomonas aeruginosa LPS inhalation are regulated by NF-κB translocation. This confirms the critical role of airway epithelial NF-κB pathway for the inflammatory response to bacterial pathogens and underlines the impact of sphingolipids in inflammatory host defence mechanisms. PMID:22469869

  12. Molecular mechanism of hepatitis C virus-induced glucose metabolic disorders

    Directory of Open Access Journals (Sweden)

    Ikuo eShoji

    2012-01-01

    Full Text Available Hepatitis C virus (HCV infection causes not only intrahepatic diseases but also extrahepatic manifestations, including metabolic disorders. Chronic HCV infection is often associated with type 2 diabetes. However, the precise mechanism underlying this association is still unclear. Glucose is transported into hepatocytes via glucose transporter 2 (GLUT2. Hepatocytes play a crucial role in maintaining plasma glucose homeostasis via the gluconeogenic and glycolytic pathways. We have been investigating the molecular mechanism of HCV-related type 2 diabetes using HCV RNA replicon cells and HCV J6/JFH1 system. We found that HCV replication down-regulates cell surface expression of GLUT2 at the transcriptional level. We also found that HCV infection promotes hepatic gluconeogenesis in HCV J6/JFH1-infected Huh-7.5 cells. HCV infection transcriptionally up-regulated the genes for PEPCK and G6Pase, the rate-limiting enzymes for hepatic gluconeogenesis. Gene expression of PEPCK and G6Pase was regulated by the transcription factor forkhead box O1 (FoxO1 in HCV-infected cells. Phosphorylation of FoxO1 at Ser319 was markedly diminished in HCV-infected cells, resulting in increased nuclear accumulation of FoxO1. HCV NS5A protein was directly linked with the FoxO1-dependent increased gluconeogenesis. This paper will discuss the current model of HCV-induced glucose metabolic disorders.

  13. Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer.

    Science.gov (United States)

    Pal, Krishnendu; Cao, Ying; Gaisina, Irina N; Bhattacharya, Santanu; Dutta, Shamit K; Wang, Enfeng; Gunosewoyo, Hendra; Kozikowski, Alan P; Billadeau, Daniel D; Mukhopadhyay, Debabrata

    2014-02-01

    Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell-cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases, including type II diabetes, Alzheimer disease, bipolar disorder, inflammation, and cancer. Consequently, it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacologic and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent antiproliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The antiproliferative activity is most likely caused by G(0)-G(1) and G(2)-M phase arrest as evident from cell-cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. In addition, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft renal cell carcinoma tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. PMID:24327518

  14. High levels of glucose induce "metabolic memory" in cardiomyocyte via epigenetic histone H3 lysine 9 methylation.

    Science.gov (United States)

    Yu, Xi-Yong; Geng, Yong-Jian; Liang, Jia-Liang; Zhang, Saidan; Lei, He-Ping; Zhong, Shi-Long; Lin, Qiu-Xiong; Shan, Zhi-Xin; Lin, Shu-Guang; Li, Yangxin

    2012-09-01

    Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients. PMID:22707199

  15. Salinity induced metabolic changes in rice (oryza sativa l.) seeds during germination

    International Nuclear Information System (INIS)

    Six inbred lines of rice exhibiting differential tolerance to salinity were exposed to 0, 50, 75, 100 and 200 mM NaCl for 24, 48, 72 and 96 h. The salinity induced metabolic changes (solute leakage, K efflux and a-amylase activity) were studied during germination. Germination of rice seeds was not affected by NaCl concentration less than 100 mM. At higher salinity levels (100 and 200 mM NaCl), a delay of 3-6 days in germination was observed. In the present study, comparatively higher values of solute leakage were observed in those lines in which germination was comparatively affected more adversely (sensitive). Sodium chloride reduced alpha-amylase activity in germinating rice seeds to varying degree even at low NaCl concentrations (50 and 75 mM), where germination was not affected greatly. The tolerant lines exhibited higher enzymatic activity than the sensitive ones. (author)

  16. Melatonin May Curtail the Metabolic Syndrome: Studies on Initial and Fully Established Fructose-Induced Metabolic Syndrome in Rats

    Directory of Open Access Journals (Sweden)

    Pablo Scacchi

    2013-01-01

    Full Text Available To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases.

  17. INITIAL METABOLIC STATE AND EXERCISE-INDUCED ENDOTOXAEMIA ARE UNRELATED TO GASTROINTESTINAL SYMPTOMS DURING EXERCISE

    Directory of Open Access Journals (Sweden)

    José Moncada-Jiménez

    2009-06-01

    Full Text Available The aim of the study was to investigate the association between the initial metabolic state and exercise-induced endotoxaemia on the appearance of gastrointestinal symptoms (GIS during exercise. Eleven males (36.6 ± 4.9 yrs, 1.7 ± 0.1 m, 74.5 ± 7.7 kg, DEXA body fat % 17.2 ± 6.6, VO2max 57.4 ± 7.4 ml·kg-1·min-1 underwent two isoenergetic diets designed to change their initial metabolic status by either depleting or maintaining their hepatic and muscular glycogen content. These diets and accompanying exercise sessions were performed by each participant in the days before completing a laboratory-based duathlon (5-km run, 30-km cycling, 10-km run. Blood samples were obtained before, immediately and 1- and 2-h following the duathlon for determination of insulin (IN, glucagon (GL, endotoxin, aspartic aminotransferase (AST, and alanine aminotransferase (ALT markers. GIS were assessed by survey before and after exercise. Diet content produced a different energy status as determined by macronutrient content and the IN/GL ratio (p < 0.05, and mild exercise-induced endotoxaemia was observed in both experimental duathlons. Regardless of the diet, the AST/ALT ratio following exercise and in the recovery phase indicated hepatocyte and liver parenchyma structural damage. In spite of GIS, no significant correlations between endotoxin levels and GIS were found. In conclusion, increased markers of endotoxaemia observed with the high-intensity exercise were unrelated to hepatic function and/or GIS before and after exercise

  18. Increases in myocardial workload induced by rapid atrial pacing trigger alterations in global metabolism.

    Directory of Open Access Journals (Sweden)

    Aslan T Turer

    Full Text Available To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs.There is growing evidence that the heart influences systemic metabolism through endocrine effects and affecting pathways involved in energy homeostasis.Nineteen patients referred for cardiac catheterization were enrolled. Peripheral and selective coronary sinus (CS blood sampling was performed at serial timepoints following the initiation of pacing, and metabolite profiling was performed by liquid chromatography-mass spectrometry (LC-MS.Pacing-stress resulted in a 225% increase in the median rate·pressure product from baseline. Increased myocardial work induced significant changes in the peripheral concentration of 43 of 125 metabolites assayed, including large changes in purine [adenosine (+99%, p = 0.006, ADP (+42%, p = 0.01, AMP (+79%, p = 0.004, GDP (+69%, p = 0.003, GMP (+58%, p = 0.01, IMP (+50%, p = 0.03, xanthine (+61%, p = 0.0006], and several bile acid metabolites. The CS changes in metabolites qualitatively mirrored those in the peripheral blood in both timing and magnitude, suggesting the heart was not the major source of the metabolite release.Isolated increases in myocardial work can induce changes in the plasma metabolome, but these changes do not appear to be directly cardiac in origin. A number of these dynamic metabolites have known signaling functions. Our study provides additional evidence to a growing body of literature on metabolic 'cross-talk' between the heart and other organs.

  19. Oncogene activation induces metabolic transformation resulting in insulin-independence in human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Aliccia Bollig-Fischer

    Full Text Available Normal breast epithelial cells require insulin and EGF for growth in serum-free media. We previously demonstrated that over expression of breast cancer oncogenes transforms MCF10A cells to an insulin-independent phenotype. Additionally, most breast cancer cell lines are insulin-independent for growth. In this study, we investigated the mechanism by which oncogene over expression transforms MCF10A cells to an insulin-independent phenotype. Analysis of the effects of various concentrations of insulin and/or IGF-I on proliferation of MCF10A cells demonstrated that some of the effects of insulin were independent from those of IGF-I, suggesting that oncogene over expression drives a true insulin-independent proliferative phenotype. To test this hypothesis, we examined metabolic functions of insulin signaling in insulin-dependent and insulin-independent cells. HER2 over expression in MCF10A cells resulted in glucose uptake in the absence of insulin at a rate equal to insulin-induced glucose uptake in non-transduced cells. We found that a diverse set of oncogenes induced the same result. To gain insight into how HER2 oncogene signaling affected increased insulin-independent glucose uptake we compared HER2-regulated gene expression signatures in MCF10A and HER2 over expressing MCF10A cells by differential analysis of time series gene expression data from cells treated with a HER2 inhibitor. This analysis identified genes specifically regulated by the HER2 oncogene, including VAMP8 and PHGDH, which have known functions in glucose uptake and processing of glycolytic intermediates, respectively. Moreover, these genes specifically implicated in HER2 oncogene-driven transformation are commonly altered in human breast cancer cells. These results highlight the diversity of oncogene effects on cell regulatory pathways and the importance of oncogene-driven metabolic transformation in breast cancer.

  20. Rhinacanthus nasutus leaf improves metabolic abnormalities in high-fat diet-induced obese mice

    Institute of Scientific and Technical Information of China (English)

    Supaporn Wannasiri; Pritsana Piyabhan; Jarinyaporn Naowaboot

    2016-01-01

    Objective: To investigate the effect of Rhinacanthus nasutus (R. nasutus) leaf extract on impaired glucose and lipid metabolism in obese ICR mice. Methods: Obesity was induced in the male ICR mice by feeding them a high-fat diet (60 kcal% fat) for 12 weeks. After the first six weeks of the diet, the obese mice were administered with the water extract of R. nasutus leaves at 250 and 500 mg/kg per day for the next six weeks. Subsequently, the blood glucose, lipid profiles, insulin, leptin, and adiponectin levels were measured. The liver and adipose tissues were excised for his-topathological examination and protein expression study. Results: After six weeks of the treatment, R. nasutus extract (at 250 and 500 mg/kg per day) was found to reduce the elevated blood glucose level, improve the insulin sensitivity, decrease the serum leptin, and increase the serum adiponectin levels. The obese mice treated with R. nasutus were found to have a reduction in the increased lipid concen-trations in their serum and liver tissues. Moreover, treatment with R. nasutus reduced the fat accumulation in the liver and the large adipocyte size in the fat tissues. Interestingly, the administration with R. nasutus extract was marked by an increase in the hepatic peroxisome proliferators-activated receptor alpha, fat cell adiponectin, and glucose transporter 4 proteins. Conclusions: To the best of our knowledge, the present study is the first report on the impact of R. nasutus extract in improving the impaired glucose and lipid metabolism in high-fat diet-induced obesity in mice via stimulating the insulin sensitivity in the liver and adipose tissues.

  1. The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism.

    Directory of Open Access Journals (Sweden)

    David Vaughan

    Full Text Available A silencer region (I-allele within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE, is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle.Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER, serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS, were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc.Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09. The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively. Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon.The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in

  2. Metformin-induced metabolic reprogramming of chemoresistant ALDHbright breast cancer cells

    OpenAIRE

    Cioce, Mario; Valerio, MariaCristina; Casadei, Luca; Pulito, Claudio; Sacconi, Andrea; Mori, Federica; Biagioni, Francesca; Manetti, Cesare; Muti, Paola; Strano, Sabrina; Blandino, Giovanni

    2014-01-01

    Metabolic remodeling is a hallmark of cancer progression and may affect tumor chemoresistance. Here we investigated by 1H-NMR/PCA analysis the metabolic profile of chemoresistant breast cancer cell subpopulations (ALDHbright cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDHbright cells exhibited a different metabolic profile as compared to their chemosensitive ALDHlow counterparts. Metformin treatment strongly affected the metabolism of the ...

  3. Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice.

    Science.gov (United States)

    Pierre, Joseph F; Martinez, Kristina B; Ye, Honggang; Nadimpalli, Anuradha; Morton, Timothy C; Yang, Jinghui; Wang, Qiang; Patno, Noelle; Chang, Eugene B; Yin, Deng Ping

    2016-08-01

    The metabolic benefits induced by gastric bypass, currently the most effective treatment for morbid obesity, are associated with bile acid (BA) delivery to the distal intestine. However, mechanistic insights into BA signaling in the mediation of metabolic benefits remain an area of study. The bile diversion () mouse model, in which the gallbladder is anastomosed to the distal jejunum, was used to test the specific role of BA in the regulation of glucose and lipid homeostasis. Metabolic phenotype, including body weight and composition, glucose tolerance, energy expenditure, thermogenesis genes, total BA and BA composition in the circulation and portal vein, and gut microbiota were examined. BD improves the metabolic phenotype, which is in accord with increased circulating primary BAs and regulation of enterohormones. BD-induced hypertrophy of the proximal intestine in the absence of BA was reversed by BA oral gavage, but without influencing BD metabolic benefits. BD-enhanced energy expenditure was associated with elevated TGR5, D2, and thermogenic genes, including UCP1, PRDM16, PGC-1α, PGC-1β, and PDGFRα in epididymal white adipose tissue (WAT) and inguinal WAT, but not in brown adipose tissue. BD resulted in an altered gut microbiota profile (i.e., Firmicutes bacteria were decreased, Bacteroidetes were increased, and Akkermansia was positively correlated with higher levels of circulating primary BAs). Our study demonstrates that enhancement of BA signaling regulates glucose and lipid homeostasis, promotes thermogenesis, and modulates the gut microbiota, which collectively resulted in an improved metabolic phenotype. PMID:27340128

  4. Oxidative Inactivation of Liver Mitochondria in High Fructose Diet-Induced Metabolic Syndrome in Rats: Effect of Glycyrrhizin Treatment.

    Science.gov (United States)

    Sil, Rajarshi; Chakraborti, Abhay Sankar

    2016-09-01

    Metabolic syndrome is a serious health problem in the present world. Glycyrrhizin, a triterpenoid saponin of licorice (Glycyrrhiza glabra) root, has been reported to ameliorate the primary complications and hepatocellular damage in rats with the syndrome. In this study, we have explored metabolic syndrome-induced changes in liver mitochondrial function and effect of glycyrrhizin against the changes. Metabolic syndrome was induced in rats by high fructose (60%) diet for 6 weeks. The rats were then treated with glycyrrhizin (50 mg/kg body weight) by single intra-peritoneal injection. After 2 weeks of the treatment, the rats were sacrificed to collect liver tissue. Elevated mitochondrial ROS, lipid peroxidation and protein carbonyl, and decreased reduced glutathione content indicated oxidative stress in metabolic syndrome. Loss of mitochondrial inner membrane cardiolipin was observed. Mitochondrial complex I activity did not change but complex IV activity decreased significantly. Mitochondrial MTT reduction ability, membrane potential, phosphate utilisation and oxygen consumption decreased in metabolic syndrome. Reduced mitochondrial aconitase activity and increased aconitase carbonyl content suggested oxidative damage of the enzyme. Elevated Fe(2+) ion level in mitochondria might be associated with increased ROS generation in metabolic syndrome. Glycyrrhizin effectively attenuated mitochondrial oxidative stress and aconitase degradation, and improved electron transport chain activity. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Modulation of tissue fatty acids by L-carnitine attenuates metabolic syndrome in diet-induced obese rats.

    Science.gov (United States)

    Panchal, Sunil K; Poudyal, Hemant; Ward, Leigh C; Waanders, Jennifer; Brown, Lindsay

    2015-08-01

    Obesity and dyslipidaemia are metabolic defects resulting from impaired lipid metabolism. These impairments are associated with the development of cardiovascular disease and non-alcoholic fatty liver disease. Correcting the defects in lipid metabolism may attenuate obesity and dyslipidaemia, and reduce cardiovascular risk and liver damage. L-Carnitine supplementation was used in this study to enhance fatty acid oxidation so as to ameliorate diet-induced disturbances in lipid metabolism. Male Wistar rats (8-9 weeks old) were fed with either corn starch or high-carbohydrate, high-fat diets for 16 weeks. Separate groups were supplemented with L-carnitine (1.2% in food) on either diet for the last 8 weeks of the protocol. High-carbohydrate, high-fat diet-fed rats showed central obesity, dyslipidaemia, hypertension, impaired glucose tolerance, hyperinsulinaemia, cardiovascular remodelling and non-alcoholic fatty liver disease. L-Carnitine supplementation attenuated these high-carbohydrate, high-fat diet-induced changes, together with modifications in lipid metabolism including the inhibition of stearoyl-CoA desaturase-1 activity, reduced storage of short-chain monounsaturated fatty acids in the tissues with decreased linoleic acid content and trans fatty acids stored in retroperitoneal fat. Thus, L-carnitine supplementation attenuated the signs of metabolic syndrome through inhibition of stearoyl-CoA desaturase-1 activity, preferential β-oxidation of some fatty acids and increased storage of saturated fatty acids and relatively inert oleic acid in the tissues.

  6. Effects of proportions of dietary macronutrients on glucocorticoid metabolism in diet-induced obesity in rats.

    Directory of Open Access Journals (Sweden)

    Roland H Stimson

    Full Text Available Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1 and inactivation by 5alpha- and 5beta-reductases. A low carbohydrate diet increases hepatic 11beta-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum 'Western' diet (37% fat, n = 36 for 22 weeks, then randomised to continue this diet (n = 12 or to switch to either a low carbohydrate (n = 12 or a moderate carbohydrate (n = 12 diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12 throughout. The low and moderate carbohydrate diets decreased hepatic 11beta-HSD1 mRNA compared with the Western diet (both 0.7+/-0.0 vs 0.9+/-0.1 AU; p<0.01, but did not alter 11beta-HSD1 in adipose tissue. 5Alpha-reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11beta-HSD1 activity (1.6+/-0.1 vs 2.8+/-0.1 nmol/mcg protein/hr; p<0.001 and increased 5alpha-reductase and 5beta-reductase mRNAs (1.9+/-0.3 vs 1.0+/-0.2 and 1.6+/-0.1 vs 1.0+/-0.1 AU respectively; p<0.01 in the liver, and reduced 11beta-HSD1 mRNA and activity (both p<0.01 in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue, a low carbohydrate diet does not increase hepatic 11beta-HSD1 in obese rats as occurs in humans.

  7. Effect of mangiferin isolated from Salacia chinensis regulates the kidney carbohydrate metabolism in streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Periyar Selvam Sellamuthu; Palanisamy Arulselvan; Balu Periamallipatti Muniappan; Murugesan Kandasamy

    2012-01-01

    Objective: The present investigation was to evaluate the possible anti-diabetic effect of mangiferin from Salacia chinensis (S. chinensis) on the activities of kidney carbohydrate metabolic enzymes in chemically induced diabetic rats. Methods: Diabetes was induced by streptozotocin (STZ) in adult male rats, as a single intraperitoneal injection at a dose of 55 mg/kg body weight. The STZ-induced diabetic rats were treated by mangiferin and glibenclamide (positive control drug) for 30 days. At the end of the experiment, the rats were sacrificed and carbohydrate metabolic enzyme activities were analyzed in the kidney. Results: Diabetic control rats showed a significant increase in the level of fasting blood glucose and also increase the activities of carbohydrate metabolic enzymes in kidney on successive days of the experiment as compared with their basal values. Daily oral administration of mangiferin showed a significant decrease in the blood glucose when compared to diabetic control. The anti-hyperglycemic effect was obtained with the dose of 40 mg/kg b.wt. In addition, treatment of mangiferin shows alteration in kidney carbohydrate metabolic enzymes including gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-disphosphatase. These results were comparable with positive control drug, glibenclamide. Conclusions: The results obtained in this study provide evidence of the anti-diabetic potential of mangiferin, mediated through the regulation of carbohydrate key metabolic enzyme activities.

  8. Investigation of metabolic changes in STZ-induced diabetic rats with hyperpolarized [1-13C]acetate

    DEFF Research Database (Denmark)

    Koellisch, Ulrich; Laustsen, Christoffer; Nørlinger, Thomas S;

    2015-01-01

    In the metabolism of acetate several enzymes are involved, which play an important role in free fatty acid oxidation. Fatty acid metabolism is altered in diabetes patients and therefore acetate might serve as a marker for pathological changes in the fuel selection of cells, as these changes occur...... in diabetes patients. Acetylcarnitine is a metabolic product of acetate, which enables its transport into the mitochondria for energy production. This study investigates whether the ratio of acetylcarnitine to acetate, measured by noninvasive hyperpolarized [1-(13)C]acetate magnetic resonance spectroscopy......, could serve as a marker for myocardial, hepatic, and renal metabolic changes in rats with Streptozotocin (STZ)-induced diabetes in vivo. We demonstrate that the conversion of acetate to acetylcarnitine could be detected and quantified in all three organs of interest. More interestingly, we found...

  9. Vitamin C improves basal metabolic rate and lipid profile in alloxan-induced diabetes mellitus in rats

    Indian Academy of Sciences (India)

    D U Owu; A B Antai; K H Udofia; A O Obembe; K O Obasi; M U Eteng

    2006-12-01

    Diabetes mellitus (DM) is a multi-factorial disease which is characterized by hyperglycaemia, lipoprotein abnormalities and oxidative stress. This study evaluated effect of oral vitamin C administration on basal metabolic rate and lipid profile of alloxan-induced diabetic rats. Vitamin C was administered at 200 mg/kg body wt. by gavage for four weeks to diabetic rats after which the resting metabolic rate and plasma lipid profile was determined. The results showed that vitamin C administration significantly ( < 0.01) reduced the resting metabolic rate in diabetic rats; and also lowered plasma triglyceride, total cholesterol and low-density lipoprotein cholesterol. These results suggest that the administration of vitamin C in this model of established diabetes mellitus might be beneficial for the restoration of basal metabolic rate and improvement of lipid profile. This may at least in part reduce the risk of cardiovascular events seen in diabetes mellitus.

  10. Noninvasive Monitoring of Training Induced Muscle Adaptation with -MRS: Fibre Type Shifts Correlate with Metabolic Changes

    Directory of Open Access Journals (Sweden)

    Eike Hoff

    2013-01-01

    Full Text Available Purpose. To evaluate training induced metabolic changes noninvasively with magnetic resonance spectroscopy (-MRS for measuring muscle fibre type adaptation. Methods. Eleven volunteers underwent a 24-week training, consisting of speed-strength, endurance, and detraining (each 8 weeks. Prior to and following each training period, needle biopsies and -MRS of the resting gastrocnemius muscle were performed. Fibre type distribution was analyzed histologically and tested for correlation with the ratios of high energy phosphates ([PCr]/[], [PCr]/[βATP] and [PCr + ]/[βATP]. The correlation between the changes of the -MRS parameters during training and the resulting changes in fibre composition were also analysed. Results. We observed an increased type-II-fibre proportion after speed-strength and detraining. After endurance training the percentage of fast-twitch fibres was reduced. The progression of the [PCr]/[]-ratio was similar to that of the fast-twitch fibres during the training. We found a correlation between the type-II-fibre proportion and [PCr]/[] (, or [PCr]/[βATP] (, ; the correlations between its changes (delta and the fibre-shift were significant as well (delta[PCr]/[] , delta[PCr]/[βATP] , . Conclusion. Shifts in fibre type composition and high energy phosphate metabolite content covary in human gastrocnemius muscle. Therefore -MRS might be a feasible method for noninvasive monitoring of exercise-induced fibre type transformation.

  11. A rosiglitazone-induced increase in adiponectin does not improve glucose metabolism in HIV-infected patients with overt lipoatrophy

    NARCIS (Netherlands)

    R.M.E. Blümer; M. van der Valk; M. Ackermans; E. Endert; M.J. Serlie; P. Reiss; H.P. Sauerwein

    2009-01-01

    Blumer RM, van der Valk M, Ackermans M, Endert E, Serlie MJ, Reiss P, Sauerwein HP. A rosiglitazone-induced increase in adiponectin does not improve glucose metabolism in HIV-infected patients with overt lipoatrophy. Am J Physiol Endocrinol Metab 297: E1097-E1104, 2009. First published August 18, 20

  12. Monocrotophos induces the expression and activity of xenobiotic metabolizing enzymes in pre-sensitized cultured human brain cells.

    Directory of Open Access Journals (Sweden)

    Vinay K Tripathi

    Full Text Available The expression and metabolic profile of cytochrome P450s (CYPs is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y and glial (U373-MG cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC, cyclophosphamide (CPA, ethanol and known neurotoxicant- monocrotophos (MCP, a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against

  13. Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.

    Science.gov (United States)

    Melland-Smith, Megan; Ermini, Leonardo; Chauvin, Sarah; Craig-Barnes, Hayley; Tagliaferro, Andrea; Todros, Tullia; Post, Martin; Caniggia, Isabella

    2015-04-01

    Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stress-induced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

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

    Science.gov (United States)

    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.

  15. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity

    Science.gov (United States)

    Mueller, Karsten; Möller, Harald E.; Horstmann, Annette; Busse, Franziska; Lepsien, Jöran; Blüher, Matthias; Stumvoll, Michael; Villringer, Arno; Pleger, Burkhard

    2015-01-01

    Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM) and white matter (WM) that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging (MRI) together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training twice a week over a period of 3 months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI), reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C), and alterations of serum brain-derived neurotrophic factor (BDNF) concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing. PMID:26190989

  16. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity

    Directory of Open Access Journals (Sweden)

    Karsten eMueller

    2015-07-01

    Full Text Available Previous cross-sectional studies on body-weight-related alterations in brain structure revealed profound changes in the gray matter (GM and white matter (WM that resemble findings obtained from individuals with advancing age. This suggests that obesity may lead to structural brain changes that are comparable with brain aging. Here, we asked whether weight-loss-dependent improved metabolic and neurotrophic functioning parallels the reversal of obesity-related alterations in brain structure. To this end we applied magnetic resonance imaging together with voxel-based morphometry and diffusion-tensor imaging in overweight to obese individuals who participated in a fitness course with intensive physical training three days per week over a period of three months. After the fitness course, participants presented, with inter-individual heterogeneity, a reduced body mass index (BMI, reduced serum leptin concentrations, elevated high-density lipoprotein-cholesterol (HDL-C, and alterations of serum brain-derived neurotrophic factor (BDNF concentrations suggesting changes of metabolic and neurotrophic function. Exercise-dependent changes in BMI and serum concentration of BDNF, leptin, and HDL-C were related to an increase in GM density in the left hippocampus, the insular cortex, and the left cerebellar lobule. We also observed exercise-dependent changes of diffusivity parameters in surrounding WM structures as well as in the corpus callosum. These findings suggest that weight-loss due to physical exercise in overweight to obese participants induces profound structural brain plasticity, not primarily of sensorimotor brain regions involved in physical exercise, but of regions previously reported to be structurally affected by an increased body weight and functionally implemented in gustation and cognitive processing.

  17. Generation of rat-induced pluripotent stem cells from a new model of metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Nana Takenaka-Ninagawa

    Full Text Available We recently characterized DahlS.Z-Leprfa/Leprfa (DS/obese rats, derived from a cross between Dahl salt-sensitive rats and Zucker rats, as a new animal model of metabolic syndrome (MetS. Although the phenotype of DS/obese rats is similar to that of humans with MetS, the pathophysiological and metabolic characteristics in each cell type remain to be clarified. Hence, the establishment of induced pluripotent stem cells (iPSCs derived from MetS rats is essential for investigations of MetS in vitro. Reports of rat iPSCs (riPSCs, however, are few because of the difficulty of comparing to other rodents such as mouse. Recently, the advantage of using mesenchymal stromal cells (MSCs as a cell source for generating iPSCs was described. We aimed to establish riPSCs from MSCs in adipose tissues of both DS/obese rats and their lean littermates, DahlS.Z-Lepr+/Lepr+ (DS/lean rats using lentivirus vectors with only three factors Oct4, Klf4, and Sox2 without c-Myc. The morphology, gene expression profiles, and protein expression of established colonies showed embryonic stem cell (ESCs-like properties, and the differentiation potential into cells from all three germ layers both in vitro and in vivo (teratomas. Both riPSCs became adipocytes after induction of adipogenesis by insulin, T3, and dexamethasone. Real-time PCR analysis also revealed that both riPSCs and the adipose tissue from DS/obese and DS/lean rats possess similar expression patterns of adipocyte differentiation-related genes. We succeeded in generating riPSCs effectively from MSCs of both DS/obese and DS/lean rats. These riPSCs may well serve as highly effective tools for the investigation of MetS pathophysiology in vitro.

  18. SIRT3 participates in glucose metabolism interruption and apoptosis induced by BH3 mimetic S1 in ovarian cancer cells.

    Science.gov (United States)

    Xiang, Xi-Yan; Kang, Jin-Song; Yang, Xiao-Chun; Su, Jing; Wu, Yao; Yan, Xiao-Yu; Xue, Ya-Nan; Xu, Ye; Liu, Yu-He; Yu, Chun-Yan; Zhang, Zhi-Chao; Sun, Lian-Kun

    2016-08-01

    The Bcl-2 antiapoptotic proteins are important cancer therapy targets; however, their role in cancer cell metabolism remains unclear. We found that the BH3-only protein mimetic S1, a novel pan Bcl-2 inhibitor, simultaneously interrupted glucose metabolism and induced apoptosis in human SKOV3 ovarian cancer cells, which was related to the activation of SIRT3, a stress-responsive deacetylase. S1 interrupted the cellular glucose metabolism mainly through causing damage to mitochondrial respiration and inhibiting glycolysis. Moreover, S1 upregulated the gene and protein expression of SIRT3, and induced the translocation of SIRT3 from the nucleus to mitochondria. SIRT3 silencing reversed the effects of S1 on glucose metabolism and apoptosis through increasing the level of HK-II localized to the mitochondria, while a combination of the glycolysis inhibitor 2-DG and S1 intensified the cytotoxicity through further upregulation of SIRT3 expression. This study underscores an essential role of SIRT3 in the antitumor effect of Bcl-2 inhibitors in human ovarian cancer through regulating both metabolism and apoptosis. The manipulation of Bcl-2 inhibitors combined with the use of classic glycolysis inhibitors may be rational strategies to improve ovarian cancer therapy. PMID:27277143

  19. Metabolic and immune impairments induced by the endocrine disruptors benzo[a]pyrene and triclosan in Xenopus tropicalis.

    Science.gov (United States)

    Regnault, Christophe; Willison, John; Veyrenc, Sylvie; Airieau, Antinéa; Méresse, Patrick; Fortier, Marlène; Fournier, Michel; Brousseau, Pauline; Raveton, Muriel; Reynaud, Stéphane

    2016-07-01

    Despite numerous studies suggesting that amphibians are highly sensitive to cumulative anthropogenic stresses, the role played by endocrine disruptors (EDs) in the decline of amphibian populations remains unclear. EDs have been extensively studied in adult amphibians for their capacity to disturb reproduction by interfering with the sexual hormone axis. Here, we studied the in vivo responses of Xenopus tropicalis males exposed to environmentally relevant concentrations of each ED, benzo[a]pyrene (BaP) and triclosan (TCS) alone (10 μg L(-1)) or a mixture of the two (10 μg L(-1) each) over a 24 h exposure period by following the modulation of the transcription of key genes involved in metabolic, sexual and immunity processes and the cellular changes in liver, spleen and testis. BaP, TCS and the mixture of the two all induced a marked metabolic disorder in the liver highlighted by insulin resistance-like and non-alcoholic fatty liver disease (NAFLD)-like phenotypes together with hepatotoxicity due to the impairment of lipid metabolism. For TCS and the mixture, these metabolic disorders were concomitant with modulation of innate immunity. These results confirmed that in addition to the reproductive effects induced by EDs in amphibians, metabolic disorders and immune system disruption should also be considered. PMID:27153234

  20. Extreme hypoxic conditions induce selective molecular responses and metabolic reset in detached apple fruit

    Directory of Open Access Journals (Sweden)

    Dubravka eCukrov

    2016-02-01

    Full Text Available The ripening physiology of detached fruit is altered by low oxygen conditions with profound effects on quality parameters. To study hypoxia-related processes and regulatory mechanisms, apple (Malus domestica, cv Granny Smith fruit, harvested at commercial ripening, were kept at 1°C under normoxic (control and hypoxic (0.4 and 0.8 kPa oxygen conditions for up to 60 days. NMR analyses of cortex tissue identified eight metabolites showing significantly different accumulations between samples, with ethanol and alanine displaying the most pronounced difference between hypoxic and normoxic treatments A rapid up-regulation of alcohol dehydrogenase and pyruvate-related metabolism (lactate dehydrogenase, pyruvate decarboxylase, alanine aminotransferase gene expression was detected under both hypoxic conditions with a more pronounced effect induced by the lowest (0.4 kPa oxygen concentration. Both hypoxic conditions negatively affected ACC synthase and ACC oxidase transcript accumulation. Analysis of RNA-seq data of samples collected after 24 days of hypoxic treatment identified more than 1,000 genes differentially expressed when comparing 0.4 vs 0.8 kPa oxygen concentration samples. Genes involved in cell-wall, minor and major CHO, amino acid and secondary metabolisms, fermentation and glycolysis as well as genes involved in transport, defense responses and oxidation-reduction appeared to be selectively affected by treatments. The lowest oxygen concentration induced a higher expression of transcription factors belonging to AUX/IAA, WRKY, HB, Zinc-finger families, while MADS box family genes were more expressed when apples were kept under 0.8 kPa oxygen. Out of the eight group VII ERF members present in apple genome, two genes showed a rapid up-regulation under hypoxia, and western blot analysis showed that apple MdRAP2.12 proteins were differentially accumulated in normoxic and hypoxic samples, with the highest level reached under 0.4 kPa oxygen. These

  1. Therapeutic Roles of Heme Oxygenase-1 in Metabolic Diseases: Curcumin and Resveratrol Analogues as Possible Inducers of Heme Oxygenase-1

    Directory of Open Access Journals (Sweden)

    Yong Son

    2013-01-01

    Full Text Available Metabolic diseases, such as insulin resistance, type II diabetes, and obesity, are associated with a low-grade chronic inflammation (inflammatory stress, oxidative stress, and endoplasmic reticulum (ER stress. Because the integration of these stresses is critical to the pathogenesis of metabolic diseases, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of metabolic diseases. It has been recognized that heme oxygenase-1 (HO-1 plays an important role in cellular protection. Because HO-1 can reduce inflammatory stress, oxidative stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of metabolic diseases. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in metabolic diseases and present some emerging therapeutic options for HO-1 expression in treating metabolic diseases, together with the therapeutic potential of curcumin and resveratrol analogues that have their ability to induce HO-1 expression.

  2. High-fat diets exaggerate endocrine and metabolic phenotypes in a rat model of DHEA-induced PCOS.

    Science.gov (United States)

    Zhang, Haolin; Yi, Ming; Zhang, Yan; Jin, Hongyan; Zhang, Wenxin; Yang, Jingjing; Yan, Liying; Li, Rong; Zhao, Yue; Qiao, Jie

    2016-04-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder with unclear etiology and unsatisfactory management. Effects of diets on the phenotype of PCOS were not fully understood. In the present study, we applied 45 and 60% high-fat diets (HFDs) on a rat model of PCOS induced by postnatal DHEA injection. We found that both DHEA and DHEA+HFDs rats exhibited reproductive abnormalities, including hyperandrogenism, irregular cycles and polycystic ovaries. The addition of HFDs, especially 60% HFDs, exaggerated morphological changes of ovaries and a number of metabolic changes, including increased body weight and body fat content, impaired glucose tolerance and increased serum insulin levels. Results from qPCR showed that DHEA-induced increased expression of hypothalamic androgen receptor and LH receptor were reversed by the addition of 60% HFDs. In contrast, the ovarian expression of LH receptor and insulin receptor mRNA was upregulated only with the addition of 60% HFDs. These findings indicated that DHEA and DHEA+HFDs might influence PCOS phenotypes through distinct mechanisms: DHEA affects the normal function of hypothalamus-pituitary-ovarian axis through LH, whereas the addition of HFDs exaggerated endocrine and metabolic dysfunction through ovarian responses to insulin-related mechanisms. We concluded that the addition of HFDs yielded distinct phenotypes of DHEA-induced PCOS and could be used for studies on both reproductive and metabolic features of the syndrome. PMID:26814210

  3. Metabolomic analysis reveals metabolic disturbances in the prefrontal cortex of the lipopolysaccharide-induced mouse model of depression.

    Science.gov (United States)

    Wu, Yu; Fu, Yuying; Rao, Chenglong; Li, Wenwen; Liang, Zihong; Zhou, Chanjuan; Shen, Peng; Cheng, Pengfei; Zeng, Li; Zhu, Dan; Zhao, Libo; Xie, Peng

    2016-07-15

    Major depressive disorder (MDD) is a debilitating illness. However, the underlying molecular mechanisms of depression remain largely unknown. Increasing evidence supports that inflammatory cytokine disturbances may be associated with the pathophysiology of depression in humans. Systemic administration of lipopolysaccharide (LPS) has been used to study inflammation-associated neurobehavioral changes in rodents, but no metabonomic study has been conducted to assess differential metabolites in the prefrontal cortex (PFC) of a LPS-induced mouse model of depression. Here, we employed a gas chromatography-mass spectrometry-based metabonomic approach in the LPS-induced mouse model of depression to investigate any significant metabolic changes in the PFC. Multivariate statistical analysis, including principal component analysis (PCA), partial least squares-discriminate analysis (PLS-DA), and pair-wise orthogonal projections to latent structures discriminant analysis (OPLS-DA), was implemented to identify differential PFC metabolites between LPS-induced depressed mice and healthy controls. A total of 20 differential metabolites were identified. Compared with control mice, LPS-treated mice were characterized by six lower level metabolites and 14 higher level metabolites. These molecular changes were closely related to perturbations in neurotransmitter metabolism, energy metabolism, oxidative stress, and lipid metabolism, which might be evolved in the pathogenesis of MDD. These findings provide insight into the pathophysiological mechanisms underlying MDD and could be of valuable assistance in the clinical diagnosis of MDD. PMID:27102340

  4. New Nordic Diet induced weight loss is accompanied by changes in metabolism and AMPK signalling in adipose tissue

    DEFF Research Database (Denmark)

    Fritzen, Andreas Mæchel; Lundsgaard, Anne-Marie; Jordy, Andreas Børsting;

    2015-01-01

    CONTEXT: The molecular mechanisms behind diet-induced metabolic improvements remain to be studied. The Objective was to investigate whether expression of proteins in skeletal muscle or adipose tissue could explain improvements in glucose and lipid homeostasis after weight loss. DESIGN: Volunteers...... adipose tissue (SCAT) were obtained at week 0 and 26. OUTCOME: Gene and protein expressions were analysed by real time PCR and western blotting. RESULTS: Improved HOMA-IR index and lowered plasma triacylglycerol concentration after NND coincided with molecular adaptations in SCAT, but not in skeletal...... regulation of key glucose and lipid handling proteins suggests an improved metabolic capacity in adipose tissue after weight loss....

  5. Testicular Metabolic Reprogramming in Neonatal Streptozotocin-Induced Type 2 Diabetic Rats Impairs Glycolytic Flux and Promotes Glycogen Synthesis

    OpenAIRE

    Rato, L; M. G. Alves; T. R. Dias; J. E. Cavaco; Oliveira, Pedro F.

    2015-01-01

    Defects in testicular metabolism are directly implicated with male infertility, but most of the mechanisms associated with type 2 diabetes- (T2DM) induced male infertility remain unknown. We aimed to evaluate the effects of T2DM on testicular glucose metabolism by using a neonatal-streptozotocin- (n-STZ) T2DM animal model. Plasma and testicular hormonal levels were evaluated using specific kits. mRNA and protein expression levels were assessed by real-time PCR and Western Blot, respectively. ...

  6. 2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria.

    Science.gov (United States)

    Amaral, Alexandre Umpierrez; Cecatto, Cristiane; Castilho, Roger Frigério; Wajner, Moacir

    2016-04-01

    Accumulation of 2-methylcitric acid (2MCA) is observed in methylmalonic and propionic acidemias, which are clinically characterized by severe neurological symptoms. The exact pathogenetic mechanisms of brain abnormalities in these diseases are poorly established and very little has been reported on the role of 2MCA. In the present work we found that 2MCA markedly inhibited ADP-stimulated and uncoupled respiration in mitochondria supported by glutamate, with a less significant inhibition in pyruvate plus malate respiring mitochondria. However, no alterations occurred when α-ketoglutarate or succinate was used as respiratory substrates, suggesting a defect on glutamate oxidative metabolism. It was also observed that 2MCA decreased ATP formation in glutamate plus malate or pyruvate plus malate-supported mitochondria. Furthermore, 2MCA inhibited glutamate dehydrogenase activity at concentrations as low as 0.5 mM. Kinetic studies revealed that this inhibitory effect was competitive in relation to glutamate. In contrast, assays of osmotic swelling in non-respiring mitochondria suggested that 2MCA did not significantly impair mitochondrial glutamate transport. Finally, 2MCA provoked a significant decrease in mitochondrial membrane potential and induced swelling in Ca(2+)-loaded mitochondria supported by different substrates. These effects were totally prevented by cyclosporine A plus ADP or ruthenium red, indicating induction of mitochondrial permeability transition. Taken together, our data strongly indicate that 2MCA behaves as a potent inhibitor of glutamate oxidation by inhibiting glutamate dehydrogenase activity and as a permeability transition inducer, disturbing mitochondrial energy homeostasis. We presume that 2MCA-induced mitochondrial deleterious effects may contribute to the pathogenesis of brain damage in patients affected by methylmalonic and propionic acidemias. We propose that brain glutamate oxidation is disturbed by 2-methylcitric acid (2MCA), which

  7. Neurochemistry of Pressure-Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System.

    Science.gov (United States)

    Rostain, Jean-Claude; Lavoute, Cécile

    2016-01-01

    Gases that are not metabolized by the organism are thus chemically inactive under normal conditions. Such gases include the "noble gases" of the Periodic Table as well as hydrogen and nitrogen. At increasing pressure, nitrogen induces narcosis at 4 absolute atmospheres (ATAs) and more in humans and at 11 ATA and more in rats. Electrophysiological and neuropharmacological studies suggest that the striatum is a target of nitrogen narcosis. Glutamate and dopamine release from the striatum in rats are decreased by exposure to nitrogen at a pressure of 31 ATA (75% of the anesthetic threshold). Striatal dopamine levels decrease during exposure to compressed argon, an inert gas more narcotic than nitrogen, or to nitrous oxide, an anesthetic gas. Inversely, striatal dopamine levels increase during exposure to compressed helium, an inert gas with a very low narcotic potency. Exposure to nitrogen at high pressure does not change N-methyl-d-aspartate (NMDA) glutamate receptor activities in Substantia Nigra compacta and striatum but enhances gama amino butyric acidA (GABAA) receptor activities in Substantia Nigra compacta. The decrease in striatal dopamine levels in response to hyperbaric nitrogen exposure is suppressed by recurrent exposure to nitrogen narcosis, and dopamine levels increase after four or five exposures. This change, the lack of improvement of motor disturbances, the desensitization of GABAA receptors on dopamine cells during recurrent exposures and the long-lasting decrease of glutamate coupled with the higher sensitivity of NMDA receptors, suggest a nitrogen toxicity induced by repetitive exposures to narcosis. These differential changes in different neurotransmitter receptors would support the binding protein theory. © 2016 American Physiological Society. Compr Physiol 6:1579-1590, 2016. PMID:27347903

  8. Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

    International Nuclear Information System (INIS)

    Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXRβ activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element. - Highlights: → Arsenic causes cardiovascular and cerebrovascular diseases through atherosclerosis. → Arsenic may promote atherosclerosis with transient increase in HSP 70 and hs

  9. PEG-induced osmotic stress in Mentha x piperita L.: Structural features and metabolic responses.

    Science.gov (United States)

    Búfalo, Jennifer; Rodrigues, Tatiane Maria; de Almeida, Luiz Fernando Rolim; Tozin, Luiz Ricardo Dos Santos; Marques, Marcia Ortiz Mayo; Boaro, Carmen Silvia Fernandes

    2016-08-01

    The present study investigated whether osmotic stress induced by the exposure of peppermint (Mentha x piperita L.) to moderate and severe stress for short periods of time changes the plant's physiological parameters, leaf anatomy and ultrastructure and essential oil. Plants were exposed to two levels of polyethyleneglycol (50 g L(-1) and 100 g L(-1) of PEG) in a hydroponic experiment. The plants exposed to 50 g L(-1) maintained metabolic functions similar to those of the control group (0 g L(-1)) without changes in gas exchange or structural characteristics. The increase in antioxidant enzyme activity reduced the presence of free radicals and protected membranes, including chloroplasts and mitochondria. In contrast, the osmotic stress caused by 100 g L(-1) of PEG inhibited leaf gas exchange, reduced the essential oil content and changed the oil composition, including a decrease in menthone and an increase in menthofuran. These plants also showed an increase in peroxidase activity, but this increase was not sufficient to decrease the lipid peroxidation level responsible for damaging the membranes of organelles. Morphological changes were correlated with the evaluated physiological features: plants exposed to 100 g L(-1) of PEG showed areas with collapsed cells, increases in mesophyll thickness and the area of the intercellular space, cuticle shrinkage, morphological changes in plastids, and lysis of mitochondria. In summary, our results revealed that PEG-induced osmotic stress in M. x piperita depends on the intensity level of the osmotic stress applied; severe osmotic stress changed the structural characteristics, caused damage at the cellular level, and reduced the essential oil content and quality.

  10. PEG-induced osmotic stress in Mentha x piperita L.: Structural features and metabolic responses.

    Science.gov (United States)

    Búfalo, Jennifer; Rodrigues, Tatiane Maria; de Almeida, Luiz Fernando Rolim; Tozin, Luiz Ricardo Dos Santos; Marques, Marcia Ortiz Mayo; Boaro, Carmen Silvia Fernandes

    2016-08-01

    The present study investigated whether osmotic stress induced by the exposure of peppermint (Mentha x piperita L.) to moderate and severe stress for short periods of time changes the plant's physiological parameters, leaf anatomy and ultrastructure and essential oil. Plants were exposed to two levels of polyethyleneglycol (50 g L(-1) and 100 g L(-1) of PEG) in a hydroponic experiment. The plants exposed to 50 g L(-1) maintained metabolic functions similar to those of the control group (0 g L(-1)) without changes in gas exchange or structural characteristics. The increase in antioxidant enzyme activity reduced the presence of free radicals and protected membranes, including chloroplasts and mitochondria. In contrast, the osmotic stress caused by 100 g L(-1) of PEG inhibited leaf gas exchange, reduced the essential oil content and changed the oil composition, including a decrease in menthone and an increase in menthofuran. These plants also showed an increase in peroxidase activity, but this increase was not sufficient to decrease the lipid peroxidation level responsible for damaging the membranes of organelles. Morphological changes were correlated with the evaluated physiological features: plants exposed to 100 g L(-1) of PEG showed areas with collapsed cells, increases in mesophyll thickness and the area of the intercellular space, cuticle shrinkage, morphological changes in plastids, and lysis of mitochondria. In summary, our results revealed that PEG-induced osmotic stress in M. x piperita depends on the intensity level of the osmotic stress applied; severe osmotic stress changed the structural characteristics, caused damage at the cellular level, and reduced the essential oil content and quality. PMID:27107175

  11. Ablation of succinate production from glucose metabolism in the procyclic trypanosomes induces metabolic switches to the glycerol 3-phosphate/dihydroxyacetone phosphate shuttle and to proline metabolism.

    Science.gov (United States)

    Ebikeme, Charles; Hubert, Jane; Biran, Marc; Gouspillou, Gilles; Morand, Pauline; Plazolles, Nicolas; Guegan, Fabien; Diolez, Philippe; Franconi, Jean-Michel; Portais, Jean-Charles; Bringaud, Frédéric

    2010-10-15

    Trypanosoma brucei is a parasitic protist that undergoes a complex life cycle during transmission from its mammalian host (bloodstream forms) to the midgut of its insect vector (procyclic form). In both parasitic forms, most glycolytic steps take place within specialized peroxisomes, called glycosomes. Here, we studied metabolic adaptations in procyclic trypanosome mutants affected in their maintenance of the glycosomal redox balance. T. brucei can theoretically use three strategies to maintain the glycosomal NAD(+)/NADH balance as follows: (i) the glycosomal succinic fermentation branch; (ii) the glycerol 3-phosphate (Gly-3-P)/dihydroxyacetone phosphate (DHAP) shuttle that transfers reducing equivalents to the mitochondrion; and (iii) the glycosomal glycerol production pathway. We showed a hierarchy in the use of these glycosomal NADH-consuming pathways by determining metabolic perturbations and adaptations in single and double mutant cell lines using a combination of NMR, ion chromatography-MS/MS, and HPLC approaches. Although functional, the Gly-3-P/DHAP shuttle is primarily used when the preferred succinate fermentation pathway is abolished in the Δpepck knock-out mutant cell line. In the absence of these two pathways (Δpepck/(RNAi)FAD-GPDH.i mutant), glycerol production is used but with a 16-fold reduced glycolytic flux. In addition, the Δpepck mutant cell line shows a 3.3-fold reduced glycolytic flux compensated by an increase of proline metabolism. The inability of the Δpepck mutant to maintain a high glycolytic flux demonstrates that the Gly-3-P/DHAP shuttle is not adapted to the procyclic trypanosome context. In contrast, this shuttle was shown earlier to be the only way used by the bloodstream forms of T. brucei to sustain their high glycolytic flux.

  12. Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.

    Science.gov (United States)

    Dando, I; Donadelli, M; Costanzo, C; Dalla Pozza, E; D'Alessandro, A; Zolla, L; Palmieri, M

    2013-06-13

    The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear. We used cannabinoids specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake. Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.

  13. Small for Gestational Age and Magnesium: Intrauterine magnesium deficiency may induce metabolic syndrome in later life

    Directory of Open Access Journals (Sweden)

    Junji Takaya

    2015-12-01

    Full Text Available Magnesium deficiency during pregnancy as a result of insufficient or low intake of magnesium is common in developing and developed countries. Previous reports have shown that intracellular magnesium of cord blood platelets is lower among small for gestational age (SGA groups than that of appropriate for gestational age (AGA groups, suggesting that intrauterine magnesium deficiency may result in SGA. Additionally, the risk of adult-onset diseases such as insulin resistance syndrome is greater among children whose mothers were malnourished during pregnancy, and who consequently had a low birth weight. In a number of animal models, poor nutrition during pregnancy leads to offspring that exhibit pathophysiological changes similar to human diseases. The offspring of pregnant rats fed a magensium restricted diet have developed hypermethylation in the hepatic 11β-hydroxysteroid dehydrogenase-2 promoter. These findings indicate that maternal magnesium deficiencies during pregnancy influence regulation of non-imprinted genes by altering the epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. Magnesium deficiency during pregnancy may be responsible for not only maternal and fetal nutritional problems, but also lifelong consequences that affect the offspring throughout their life. Epidemiological, clinical, and basic research on the effects of magnesium deficiency now indicates underlying mechanisms, especially epigenetic processes.

  14. Effects of telmisartan and pioglitazone on high fructose induced metabolic syndrome in rats.

    Science.gov (United States)

    Shahataa, Mary Girgis; Mostafa-Hedeab, Gomaa; Ali, Esam Fouaad; Mahdi, Emad Ahmed; Mahmoud, Fatma Abd Elhaleem

    2016-08-01

    Metabolic syndrome (MS) is a cluster of hypertension, insulin resistance, dyslipidaemia, and hyperuricemia. This study was designed to assess the effect of telmisartan and pioglitazone on high fructose induced MS. Thirty-five male albino rats were classified into 5 groups: A, normal diet; B, high-fructose diet (HFD) subdivided into B1 (HFD only), B2 (telmisartan, 5 mg/kg), B3 (pioglitazone, 10 mg/kg), and B4 (telmisartan + pioglitazone). Administration of the drugs was started after the rats had been on HFD for 4 weeks and continued for 4 weeks. Body mass (BM), blood pressure (BP), uric acid (UA), total cholesterol, triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), blood urea nitrogen (BUN), creatinine, and nitric oxide (NO) were measured and the levels of fasting glucose and fasting insulin were estimated. Compared with group B1, telmisartan treatment significantly decreased BP, BM, serum glucose, insulin, UA, urea, cholesterol, TGA, and LDL and significantly increased HDL, whereas pioglitazone treatment significantly decreased BP, serum glucose, insulin, UA, urea, creatinine, cholesterol, TGA, and LDL and significantly increased HDL. Co-administration of pioglitazone + telmisartan significantly decreased insulin, urea, and creatinine compared with telmisartan alone. Combined telmisartan + pioglitazone allowed better control of BP, hyperglycaemia, insulin resistance, and the amelioration of BM increase that may be associated with pioglitazone treatment. PMID:27245695

  15. A virus-induced gene silencing approach to understanding alkaloid metabolism in Catharanthus roseus

    Science.gov (United States)

    Liscombe, David K.; O’Connor, Sarah E.

    2011-01-01

    The anticancer agents vinblastine and vincristine are bisindole alkaloids derived from coupling vindoline and catharanthine, monoterpenoid indole alkaloids produced exclusively by Madagascar periwinkle (Catharanthus roseus) plants. Industrial production of vinblastine and vincristine currently relies on isolation from C. roseus leaves, a process that affords these compounds in 0.0003–0.01% yields. Metabolic engineering efforts to improve alkaloid content or provide alternative sources of the bisindole alkaloids ultimately rely on the isolation and characterization of the genes involved. Several vindoline biosynthetic genes have been isolated, and the cellular and subcellular organization of the corresponding enzymes has been well studied. However, due to the leaf-specific localization of vindoline biosynthesis, and the lack of production of this precursor in cell suspension and hairy root cultures of C. roseus, further elucidation of this pathway demands the development of reverse genetics approaches to assay gene function in planta. The bipartite pTRV vector system is a Tobacco Rattle Virus-based virus-induced gene silencing (VIGS) platform that has provided efficient and effective means to assay gene function in diverse plant systems. We have developed a VIGS method to investigate gene function in C. roseus plants using the pTRV vector system. The utility of this approach in understanding gene function in C. roseus leaves is demonstrated by silencing known vindoline biosynthetic genes previously characterized in vitro. PMID:21802100

  16. 3'-Azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta

    International Nuclear Information System (INIS)

    The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is the drug of choice for preventing maternal-fetal HIV transmission during pregnancy. Our aim was to assess the cytotoxic effects of AZT on human placenta in vitro. The mechanisms of AZT-induced effects were investigated using JEG-3 choriocarcinoma cells and primary explant cultures from term and first-trimester human placentas. Cytotoxicity measures included trypan blue exclusion, MTT, and reactive oxygen species (ROS) assays. Apoptosis was measured with an antibody specific to cleaved caspase-3 and by rescue of cells by the general caspase inhibitor Boc-D-FMK. The effect of AZT on the activities of glutathione-S-transferase, β-glucuronidase, UDP-glucuronosyl transferase, cytochrome P450 (CYP) 1A, and CYP reductase (CYPR) in the placenta was assessed using biochemical assays and immunoblotting. AZT increased ROS levels, decreased cellular proliferation rates, was toxic to mitochondria, and initiated cell death by a caspase-dependent mechanism in the human placenta in vitro. In the absence of serum, the effects of AZT were amplified in all the models used. AZT also increased the amounts of activity of GST, β-glucuronidase, and CYP1A, whereas UGT and CYPR were decreased. We conclude that AZT causes apoptosis in the placenta and alters metabolizing enzymes in human placental cells. These findings have implications for the safe administration of AZT in pregnancy with respect to the maintenance of integrity of the maternal-fetal barrier

  17. Orphan Nuclear Receptor ERRα Controls Macrophage Metabolic Signaling and A20 Expression to Negatively Regulate TLR-Induced Inflammation.

    Science.gov (United States)

    Yuk, Jae-Min; Kim, Tae Sung; Kim, Soo Yeon; Lee, Hye-Mi; Han, Jeongsu; Dufour, Catherine Rosa; Kim, Jin Kyung; Jin, Hyo Sun; Yang, Chul-Su; Park, Ki-Sun; Lee, Chul-Ho; Kim, Jin-Man; Kweon, Gi Ryang; Choi, Hueng-Sik; Vanacker, Jean-Marc; Moore, David D; Giguère, Vincent; Jo, Eun-Kyeong

    2015-07-21

    The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming.

  18. Sublethal Concentrations of Antibiotics Cause Shift to Anaerobic Metabolism in Listeria monocytogenes and Induce Phenotypes Linked to Antibiotic Tolerance

    DEFF Research Database (Denmark)

    Knudsen, Gitte Maegaard; Fromberg, Arvid; Ng, Yin;

    2016-01-01

    antibiotic concentrations would affect the bacterial physiology and induce antibiotic tolerance. Transcriptomic analyses demonstrated that each of the four antibiotics tested caused an antibiotic-specific gene expression pattern related to mode-of-action of the particular antibiotic. All four antibiotics...... caused the same changes in expression of several metabolic genes indicating a shift from aerobic to anaerobic metabolism and higher ethanol production. A mutant in the bifunctional acetaldehyde-CoA/alcohol dehydrogenase encoded by Imo1634 did not have altered antibiotic tolerance. However, a mutant...... in Imo1179 (eutE) encoding an aldehyde oxidoreductase where rerouting caused increased ethanol production was tolerant to three of four antibiotics tested. This shift in metabolism could be a survival strategy in response to antibiotics to avoid generation of ROS production from respiration by oxidation...

  19. Testosterone deficiency induced by progressive stages of diabetes mellitus impairs glucose metabolism and favors glycogenesis in mature rat Sertoli cells.

    Science.gov (United States)

    Rato, Luís; Alves, Marco G; Duarte, Ana I; Santos, Maria S; Moreira, Paula I; Cavaco, José E; Oliveira, Pedro F

    2015-09-01

    The incidence of type 2 diabetes mellitus and its prodromal stage, pre-diabetes, is rapidly increasing among young men, leading to disturbances in testosterone synthesis. However, the impact of testosterone deficiency induced by these progressive stages of diabetes on the metabolic behavior of Sertoli cells remains unknown. We evaluated the effects of testosterone deficiency associated with pre-diabetes and type 2 diabetes on Sertoli cells metabolism, by measuring (1) the expression and/or activities of glycolysis and glycogen metabolism-related proteins and (2) the metabolite secretion/consumption in Sertoli cells obtained from rat models of different development stages of the disease, to unveil the mechanisms by which testosterone deregulation may affect spermatogenesis. Glucose and pyruvate uptake were decreased in cells exposed to the testosterone concentration found in pre-diabetic rats (600nM), whereas the decreased testosterone concentrations found in type 2 diabetic rats (7nM) reversed this profile. Lactate production was not altered, although the expression and/or activity of lactate dehydrogenase and monocarboxylate transporter 4 were affected by progressive testosterone-deficiency. Sertoli cells exposed to type 2 diabetic conditions exhibited intracellular glycogen accumulation. These results illustrate that gradually reduced levels of testosterone, induced by progressive stages of diabetes mellitus, favor a metabolic reprogramming toward glycogen synthesis. Our data highlights a pivotal role for testosterone in the regulation of spermatogenesis metabolic support by Sertoli cells, particularly in individuals suffering from metabolic diseases. Such alterations may be in the basis of male subfertility/infertility associated with the progression of diabetes mellitus. PMID:26148570

  20. Effects of olive oil and its minor phenolic constituents on obesity-induced cardiac metabolic changes

    Directory of Open Access Journals (Sweden)

    Rocha Katiucha KHR

    2010-10-01

    Full Text Available Abstract Background Olive oil and its minor constituents have been recommended as important dietary therapeutic interventions in preventive medicine. However, a question remains to be addressed: what are the effects of olive oil and its phenolic compounds on obesity-induced cardiac metabolic changes? Methods Male Wistar rats were divided into two groups (n = 24/group: (C receiving standard-chow; (Ob receiving hypercaloric-chow. After 21 days C and Ob groups were divided into four subgroups (n = 6/group:(C standard-chow and saline; (C-Olivestandard-chow and olive-oil (3.0 g/kg.day; (C-Oleuropeinstandard-chow and oleuropein (0.023 mg/kg/day; (C-Cafeic standard-chow and cafeic-acid (2.66 mg/kg/day; (Obreceiving hypercaloric-chow and saline;(Ob-Olive hypercaloric-chow and olive-oil;(Ob-Oleuropein hypercaloric-chow and oleuropein;(Ob-Cafeic hypercaloric-chow and cafeic-acid. Treatments were given twice a week during 21 days. Results After 42 days, obesity was evidenced in Ob rats from enhanced body-weight, surface-area, and body-mass-index. Energy-expenditure, oxygen consumption(VO2 and fat-oxidation were lower in Ob-group than in C. Despite no morphometric changes, Ob-Olive, Ob-Oleuropein and Ob-Cafeic groups had higher VO2, fat-oxidation, myocardial beta-hydroxyacyl coenzyme-A dehydrogenase and lower respiratory-quotient than Ob. Citrate-synthase was highest in Ob-Olive group. Myocardial lipid-hydroperoxide(LH and antioxidant enzymes were unaffected by olive-oil and its compounds in obesity condition, whereas LH was lower and total-antioxidant-substances were higher in C-Olive and C-Oleuropein than in C. Conclusions The present study demonstrated for the first time that olive-oil, oleuropein and cafeic-acid enhanced fat-oxidation and optimized cardiac energy metabolism in obesity conditions. Olive oil and its phenolic compounds improved myocardial oxidative stress in standard-fed conditions.

  1. Exercise training reverses impaired skeletal muscle metabolism induced by artificial selection for low aerobic capacity

    OpenAIRE

    Lessard, Sarah J.; Rivas, Donato A.; Stephenson, Erin J.; Yaspelkis, Ben B.; Koch, Lauren G.; Britton, Steven L.; Hawley, John A.

    2010-01-01

    We have used a novel model of genetically imparted endurance exercise capacity and metabolic health to study the genetic and environmental contributions to skeletal muscle glucose and lipid metabolism. We hypothesized that metabolic abnormalities associated with low intrinsic running capacity would be ameliorated by exercise training. Selective breeding for 22 generations resulted in rat models with a fivefold difference in intrinsic aerobic capacity. Low (LCR)- and high (HCR)-capacity runner...

  2. Serum proteomic analysis of diet-induced steatohepatitis and metabolic syndrome in the Ossabaw miniature swine

    OpenAIRE

    Bell, Lauren N.; Lee, Lydia; Saxena, Romil; Bemis, Kerry G.; Wang, Mu; Theodorakis, Janice L.; Vuppalanchi, Raj; ALLOOSH, MOUHAMAD; Sturek, Michael; Chalasani, Naga

    2010-01-01

    We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet (n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steato...

  3. Molecular mechanisms governing contraction-induced metabolic responses and skeletal muscle reprogramming

    OpenAIRE

    Glund, Stephan

    2007-01-01

    Physical exercise enhances skeletal muscle responsiveness to insulin and regulates metabolism by an insulin-independent mechanism. Elucidation of contraction-mediated molecular mechanisms is imperative for a better understanding of skeletal muscle metabolism and function, and may lead to the identification or validation of possible drug targets for the prevention or treatment of metabolic disorders. This thesis focuses on the role of AMPK and Interleukin (IL)-6 in skeletal m...

  4. Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Ketmanee Senaphan

    2015-08-01

    Full Text Available Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high-carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05. Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF-induced MS may be realized through suppression of oxidative stress by down-regulation of p47phox, increased nitric oxide (NO bioavailability with up-regulation of endothelial nitric oxide synthase (eNOS and suppression of tumor necrosis factor-α (TNF-α. Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms.

  5. [Relationships of glucose transporter 4 with cognitive changes induced by high fat diet and glucose metabolism in hippocampus].

    Science.gov (United States)

    Zhang, Yun-Li; Wang, Lin

    2016-06-25

    The hippocampus not only plays a role in appetite and energy balance, but also is particularly important in learning and memory. Figuring out the relationships of hippocampal glucose transporter 4 (GLUT4) with hippocampal glucose metabolism and hippocampus-dependent cognitive function is very important to clearly understand the pathophysiological basis of nutritional obesity and diabetes-related diseases, and treat obesity and cognitive dysfunction. Therefore, this study reviewed recent researches conducted on hippocampal GLUT4, hippocampal glucose metabolism, and hippocampus-dependent cognitive function. In this review, we mainly discussed: (1) The structure of GLUT4 and the distribution and function of GLUT4 in the hippocampus; (2) The translocation of GLUT4 in the hippocampus; (3) The relationships of the PI3K-Akt-GLUT4 signaling pathway with the high fat diet-induced changes of cognitive function and the glucose metabolism in the hippocampus; (4) The associations of the PI3K-Akt-GLUT4 signaling pathway with the diabetes-related cognitive dysfunction in the hippocampus; (5) The potential mechanisms of cognitive dysfunction induced by glucose metabolic disorder. PMID:27350206

  6. Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet.

    Science.gov (United States)

    Senaphan, Ketmanee; Kukongviriyapan, Upa; Sangartit, Weerapon; Pakdeechote, Poungrat; Pannangpetch, Patchareewan; Prachaney, Parichat; Greenwald, Stephen E; Kukongviriyapan, Veerapol

    2015-08-04

    Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA) is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high-carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS) in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF) diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg) was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05). Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF-induced MS may be realized through suppression of oxidative stress by down-regulation of p47phox, increased nitric oxide (NO) bioavailability with up-regulation of endothelial nitric oxide synthase (eNOS) and suppression of tumor necrosis factor-α (TNF-α). Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms.

  7. β3-Adrenoceptor Mediates Metabolic Protein Remodeling in a Rabbit Model of Tachypacing-Induced Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Yixi Liu

    2013-12-01

    Full Text Available Background: The beta 3-adrenoceptor (β3-AR is closely associated with energy metabolism. This study aimed to explore the role of β3-AR in energy remodeling in a rabbit model of pacing-induced atrial fibrillation (AF. Methods: Rabbits with a sham-operation or pacing-induced AF were used for this study, and the latter group was further divided into three subgroups: 1 the pacing group, 2 the β3-AR agonist (BRL37344-treated group, and 3 the β3-AR antagonist (SR59230A-treated group. Atrial electrogram morphology and surface ECG were used to monitor the induction of AF and atrial effective refractory period (AERP. RT-PCR and western blot (WB were used to show alterations in β3-AR and metabolic-related protein. Results: RT-PCR and WB results showed that β3-AR was significantly upregulated in the pacing group, and that it corresponded with high AF inducibility and significantly decreased AERP200 and ATP production in this group. Inhibition of β3-AR decreased the AF induction rate, reversed AERP200 reduction, and restored ATP levels in the AF rabbits. Further activation of β3-AR using agonist BRL37344 exacerbated AF-induced metabolic disruption. Periodic acid Schiff (PAS and Oil Red O staining showed β3-AR-dependent glycogen and lipid droplet accumulation in cardiac myocytes with AF. Glucose transporter-4 (GLUT-4 and CD36, key transporters of glucose and fatty acids, were downregulated in the pacing group. Expression of carnitine-palmitoyltransferase I (CPT-1, a key regulator in fatty acid metabolism, was also significantly downregulated in the pacing group. Reduced glucose transportation and fatty acid oxidation could be restored by inhibition of β3-AR. Furthermore, key regulators of metabolism, peroxisome proliferator-activated receptor-α (PPARα and PPAR co-activator (PGC-1α can be regulated by pharmacological intervention of the β3-AR. Conclusions: β3-AR is involved in metabolic protein remodeling in AF. PPARα/PGC-1α signaling pathway

  8. MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer

    Science.gov (United States)

    Chaika, Nina V.; Gebregiworgis, Teklab; Lewallen, Michelle E.; Purohit, Vinee; Radhakrishnan, Prakash; Liu, Xiang; Zhang, Bo; Mehla, Kamiya; Brown, Roger B.; Caffrey, Thomas; Yu, Fang; Johnson, Keith R.; Powers, Robert; Hollingsworth, Michael A.; Singh, Pankaj K.

    2012-01-01

    Aberrant glucose metabolism is one of the hallmarks of cancer that facilitates cancer cell survival and proliferation. Here, we demonstrate that MUC1, a large, type I transmembrane protein that is overexpressed in several carcinomas including pancreatic adenocarcinoma, modulates cancer cell metabolism to facilitate growth properties of cancer cells. MUC1 occupies the promoter elements of multiple genes directly involved in glucose metabolism and regulates their expression. Furthermore, MUC1 expression enhances glycolytic activity in pancreatic cancer cells. We also demonstrate that MUC1 expression enhances in vivo glucose uptake and expression of genes involved in glucose uptake and metabolism in orthotopic implantation models of pancreatic cancer. The MUC1 cytoplasmic tail is known to activate multiple signaling pathways through its interactions with several transcription factors/coregulators at the promoter elements of various genes. Our results indicate that MUC1 acts as a modulator of the hypoxic response in pancreatic cancer cells by regulating the expression/stability and activity of hypoxia-inducible factor-1α (HIF-1α). MUC1 physically interacts with HIF-1α and p300 and stabilizes the former at the protein level. By using a ChIP assay, we demonstrate that MUC1 facilitates recruitment of HIF-1α and p300 on glycolytic gene promoters in a hypoxia-dependent manner. Also, by metabolomic studies, we demonstrate that MUC1 regulates multiple metabolite intermediates in the glucose and amino acid metabolic pathways. Thus, our studies indicate that MUC1 acts as a master regulator of the metabolic program and facilitates metabolic alterations in the hypoxic environments that help tumor cells survive and proliferate under such conditions. PMID:22869720

  9. Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron -Astrocyte Metabolic Coupling in Long Term Memory.

    Directory of Open Access Journals (Sweden)

    Monika Tadi

    Full Text Available We examined the expression of genes related to brain energy metabolism and particularly those encoding glia (astrocyte-specific functions in the dorsal hippocampus subsequent to learning. Context-dependent avoidance behavior was tested in mice using the step-through Inhibitory Avoidance (IA paradigm. Animals were sacrificed 3, 9, 24, or 72 hours after training or 3 hours after retention testing. The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner. Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4, alpha2 subunit of the Na/K-ATPase and glucose transporter type 1. To assess the functional role for one of these genes in learning, we studied MCT1 deficient mice and found that they exhibit impaired memory in the inhibitory avoidance task. Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

  10. Testicular Metabolic Reprogramming in Neonatal Streptozotocin-Induced Type 2 Diabetic Rats Impairs Glycolytic Flux and Promotes Glycogen Synthesis.

    Science.gov (United States)

    Rato, L; Alves, M G; Dias, T R; Cavaco, J E; Oliveira, Pedro F

    2015-01-01

    Defects in testicular metabolism are directly implicated with male infertility, but most of the mechanisms associated with type 2 diabetes- (T2DM) induced male infertility remain unknown. We aimed to evaluate the effects of T2DM on testicular glucose metabolism by using a neonatal-streptozotocin- (n-STZ) T2DM animal model. Plasma and testicular hormonal levels were evaluated using specific kits. mRNA and protein expression levels were assessed by real-time PCR and Western Blot, respectively. Testicular metabolic profile was assessed by (1)H-NMR spectroscopy. T2DM rats showed increased glycemic levels, impaired glucose tolerance and hyperinsulinemia. Both testicular and serum testosterone levels were decreased, whereas those of 17β-estradiol were not altered. Testicular glycolytic flux was not favored in testicles of T2DM rats, since, despite the increased expression of both glucose transporters 1 and 3 and the enzyme phosphofructokinase 1, lactate dehydrogenase activity was severely decreased contributing to lower testicular lactate content. However, T2DM enhanced testicular glycogen accumulation, by modulating the availability of the precursors for its synthesis. T2DM also affected the reproductive sperm parameters. Taken together these results indicate that T2DM is able to reprogram testicular metabolism by enhancing alternative metabolic pathways, particularly glycogen synthesis, and such alterations are associated with impaired sperm parameters. PMID:26064993

  11. Testicular Metabolic Reprogramming in Neonatal Streptozotocin-Induced Type 2 Diabetic Rats Impairs Glycolytic Flux and Promotes Glycogen Synthesis

    Directory of Open Access Journals (Sweden)

    L. Rato

    2015-01-01

    Full Text Available Defects in testicular metabolism are directly implicated with male infertility, but most of the mechanisms associated with type 2 diabetes- (T2DM induced male infertility remain unknown. We aimed to evaluate the effects of T2DM on testicular glucose metabolism by using a neonatal-streptozotocin- (n-STZ T2DM animal model. Plasma and testicular hormonal levels were evaluated using specific kits. mRNA and protein expression levels were assessed by real-time PCR and Western Blot, respectively. Testicular metabolic profile was assessed by 1H-NMR spectroscopy. T2DM rats showed increased glycemic levels, impaired glucose tolerance and hyperinsulinemia. Both testicular and serum testosterone levels were decreased, whereas those of 17β-estradiol were not altered. Testicular glycolytic flux was not favored in testicles of T2DM rats, since, despite the increased expression of both glucose transporters 1 and 3 and the enzyme phosphofructokinase 1, lactate dehydrogenase activity was severely decreased contributing to lower testicular lactate content. However, T2DM enhanced testicular glycogen accumulation, by modulating the availability of the precursors for its synthesis. T2DM also affected the reproductive sperm parameters. Taken together these results indicate that T2DM is able to reprogram testicular metabolism by enhancing alternative metabolic pathways, particularly glycogen synthesis, and such alterations are associated with impaired sperm parameters.

  12. Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron -Astrocyte Metabolic Coupling in Long Term Memory

    KAUST Repository

    Tadi, Monika

    2015-10-29

    We examined the expression of genes related to brain energy metabolism and particularly those encoding glia (astrocyte)-specific functions in the dorsal hippocampus subsequent to learning. Context-dependent avoidance behavior was tested in mice using the step-through Inhibitory Avoidance (IA) paradigm. Animals were sacrificed 3, 9, 24, or 72 hours after training or 3 hours after retention testing. The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner. Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K-ATPase and glucose transporter type 1. To assess the functional role for one of these genes in learning, we studied MCT1 deficient mice and found that they exhibit impaired memory in the inhibitory avoidance task. Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

  13. The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling.

    Science.gov (United States)

    Pérez-Schindler, Joaquín; Summermatter, Serge; Santos, Gesa; Zorzato, Francesco; Handschin, Christoph

    2013-12-10

    Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.

  14. Small for Gestational Age and Magnesium in Cord Blood Platelets: Intrauterine Magnesium Deficiency May Induce Metabolic Syndrome in Later Life

    Directory of Open Access Journals (Sweden)

    Junji Takaya

    2011-01-01

    Full Text Available Magnesium deficiency in pregnancy frequently occurs because of inadequate or low intake of magnesium. Magnesium deficiency during pregnancy can induce not only maternal and fetal nutritional problems, but also consequences that might last in offspring throughout life. Many epidemiological studies have disclosed that small for gestational age (SGA is associated with an increased risk of insulin resistance in adult life. We reported that intracellular magnesium of cord blood platelets is lower in SGA groups than that in appropriate for gestational age groups, suggesting that intrauterine magnesium deficiency may result in SGA. Taken together, intrauterine magnesium deficiency in the fetus may lead to or at least program insulin resistance after birth. In this review, we propose that intrauterine magnesium deficiency may induce metabolic syndrome in later life. We discuss the potential contribution of aberrant magnesium regulation to SGA and to the pathogenesis of metabolic syndrome.

  15. Water deprivation induces appetite and alters metabolic strategy in Notomys alexis: unique mechanisms for water production in the desert

    OpenAIRE

    Takei, Yoshio; Bartolo, Ray C.; Fujihara, Hiroaki; Ueta, Yoichi; Donald, John A

    2012-01-01

    Like many desert animals, the spinifex hopping mouse, Notomys alexis, can maintain water balance without drinking water. The role of the kidney in producing a small volume of highly concentrated urine has been well-documented, but little is known about the physiological mechanisms underpinning the metabolic production of water to offset obligatory water loss. In Notomys, we found that water deprivation (WD) induced a sustained high food intake that exceeded the pre-deprivation level, which wa...

  16. Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats

    OpenAIRE

    Awwad, Hibah O.; Gonzalez, Larry P.; Tompkins, Paul; Lerner, Megan; Brackett, Daniel J.; Awasthi, Vibhudutta; Standifer, Kelly M.

    2015-01-01

    Physiological alterations, anxiety, and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI), and are common symptoms in service personnel exposed to blasts. Since 2006, 25,000–30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to ...

  17. Subcutaneous adipose tissue transplantation in diet-induced obese mice attenuates metabolic dysregulation while removal exacerbates it

    OpenAIRE

    Foster, Michelle T.; Softic, Samir; Caldwell, Jody; Kohli, Rohit; deKloet, Annette D; Seeley, Randy J.

    2013-01-01

    Adipose tissue distribution is an important determinant of obesity-related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance, and type-2-diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet-induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the...

  18. Alcoholic Stem Extract of Coscinium fenestratum Regulates Carbohydrate Metabolism and Improves Antioxidant Status in Streptozotocin–Nicotinamide Induced Diabetic Rats

    OpenAIRE

    Punitha, I. R.; Rajendran, K.; Arun Shirwaikar; Annie Shirwaikar

    2005-01-01

    Alcoholic extract of the stems of Coscinium fenestratum, a medicinal plant indigenous to India and Sri Lanka used in ayurveda and siddha medicine for treating diabetes, was studied for its carbohydrate metabolism effect and antioxidant status in streptozotocin–nicotinamide induced type 2 diabetic rats. Oral administration of C. fenestratum stem extract in graded doses caused a significant increase in enzymatic antioxidants such as catalase, superoxide dismutase, glutathione synthetase, pero...

  19. Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4

    Directory of Open Access Journals (Sweden)

    Sarah L. Ullevig

    2014-01-01

    Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

  20. Metabolic Profiling-based Data-mining for an Effective Chemical Combination to Induce Apoptosis of Cancer Cells

    OpenAIRE

    Motofumi Kumazoe; Yoshinori Fujimura; Shiori Hidaka; Yoonhee Kim; Kanako Murayama; Mika Takai; Yuhui Huang; Shuya Yamashita; Motoki Murata; Daisuke Miura; Hiroyuki Wariishi; Mari Maeda-Yamamoto; Hirofumi Tachibana

    2015-01-01

    Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE; however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid ...

  1. Avocado Oil Supplementation Modifies Cardiovascular Risk Profile Markers in a Rat Model of Sucrose-Induced Metabolic Changes

    OpenAIRE

    Octavio Carvajal-Zarrabal; Cirilo Nolasco-Hipolito; M. Guadalupe Aguilar-Uscanga; Guadalupe Melo-Santiesteban; Patricia M. Hayward-Jones; Barradas-Dermitz, Dulce M.

    2014-01-01

    The purpose of this study was to evaluate the effects of avocado oil administration on biochemical markers of cardiovascular risk profile in rats with metabolic changes induced by sucrose ingestion. Twenty-five rats were divided into five groups: a control group (CG; basic diet), a sick group (MC; basic diet plus 30% sucrose solution), and three other groups (MCao, MCac, and MCas; basic diet plus 30% sucrose solution plus olive oil and avocado oil extracted by centrifugation or using solvent,...

  2. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit.

    OpenAIRE

    Vignozzi L; Filippi S; Comeglio P; Cellai I; Sarchielli E; Morelli A; Rastrelli G; Maneschi E; Galli A; Vannelli GB; Saad F; Mannucci E; Adorini L; Maggi M.

    2014-01-01

    A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at valuating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T...

  3. Implications of Altered Glutathione Metabolism in Aspirin-Induced Oxidative Stress and Mitochondrial Dysfunction in HepG2 Cells

    OpenAIRE

    Raza, Haider; John, Annie

    2012-01-01

    We have previously reported that acetylsalicylic acid (aspirin, ASA) induces cell cycle arrest, oxidative stress and mitochondrial dysfunction in HepG2 cells. In the present study, we have further elucidated that altered glutathione (GSH)-redox metabolism in HepG2 cells play a critical role in ASA-induced cytotoxicity. Using selected doses and time point for ASA toxicity, we have demonstrated that when GSH synthesis is inhibited in HepG2 cells by buthionine sulfoximine (BSO), prior to ASA tre...

  4. Effects of olive leave extract on metabolic disorders and oxidative stress induced by 2.45 GHz WIFI signals.

    Science.gov (United States)

    Salah, Myriam Ben; Abdelmelek, Hafedh; Abderraba, Manef

    2013-11-01

    We investigated the effect of olive leaves extract administration on glucose metabolism and oxidative response in liver and kidneys of rats exposed to radio frequency (RF). The exposure of rats to RF (2.45 GHz, 1h/day during 21 consecutive days) induced a diabetes-like status. Moreover, RF decreased the activities of glutathione peroxidase (GPx, -33.33% and -49.40%) catalase (CAT, -43.39% and -39.62%) and the superoxide dismutase (SOD, -59.29% and -68.53%) and groups thiol amount (-62.68% and -34.85%), respectively in liver and kidneys. Indeed, exposure to RF increased the malondialdehyde (MDA, 29.69% and 51.35%) concentration respectively in liver and kidneys. Olive leaves extract administration (100 mg/kg, ip) in RF-exposed rats prevented glucose metabolism disruption and restored the activities of GPx, CAT and SOD and thiol group amount in liver and kidneys. Moreover, olive leave extract administration was able to bring down the elevated levels of MDA in liver but not in kidneys. Our investigations suggested that RF exposure induced a diabetes-like status through alteration of oxidative response. Olive leaves extract was able to correct glucose metabolism disorder by minimizing oxidative stress induced by RF in rat tissues. PMID:23994945

  5. Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome.

    Science.gov (United States)

    Roopchand, Diana E; Carmody, Rachel N; Kuhn, Peter; Moskal, Kristin; Rojas-Silva, Patricio; Turnbaugh, Peter J; Raskin, Ilya

    2015-08-01

    Dietary polyphenols protect against metabolic syndrome, despite limited absorption and digestion, raising questions about their mechanism of action. We hypothesized that one mechanism may involve the gut microbiota. To test this hypothesis, C57BL/6J mice were fed a high-fat diet (HFD) containing 1% Concord grape polyphenols (GP). Relative to vehicle controls, GP attenuated several effects of HFD feeding, including weight gain, adiposity, serum inflammatory markers (tumor necrosis factor [TNF]α, interleukin [IL]-6, and lipopolysaccharide), and glucose intolerance. GP lowered intestinal expression of inflammatory markers (TNFα, IL-6, inducible nitric oxide synthase) and a gene for glucose absorption (Glut2). GP increased intestinal expression of genes involved in barrier function (occludin) and limiting triglyceride storage (fasting-induced adipocyte factor). GP also increased intestinal gene expression of proglucagon, a precursor of proteins that promote insulin production and gut barrier integrity. 16S rRNA gene sequencing and quantitative PCR of cecal and fecal samples demonstrated that GP dramatically increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes, consistent with prior reports that similar changes in microbial community structure can protect from diet-induced obesity and metabolic disease. These data suggest that GP act in the intestine to modify gut microbial community structure, resulting in lower intestinal and systemic inflammation and improved metabolic outcomes. The gut microbiota may thus provide the missing link in the mechanism of action of poorly absorbed dietary polyphenols. PMID:25845659

  6. Metformin-induced metabolic reprogramming of chemoresistant ALDHbright breast cancer cells.

    Science.gov (United States)

    Cioce, Mario; Valerio, MariaCristina; Casadei, Luca; Pulito, Claudio; Sacconi, Andrea; Mori, Federica; Biagioni, Francesca; Manetti, Cesare; Muti, Paola; Strano, Sabrina; Blandino, Giovanni

    2014-06-30

    Metabolic remodeling is a hallmark of cancer progression and may affect tumor chemoresistance. Here we investigated by 1H-NMR/PCA analysis the metabolic profile of chemoresistant breast cancer cell subpopulations (ALDHbright cells) and their response to metformin, a promising anticancer metabolic modulator. The purified ALDHbright cells exhibited a different metabolic profile as compared to their chemosensitive ALDHlow counterparts. Metformin treatment strongly affected the metabolism of the ALDHbright cells thereby affecting, among the others, the glutathione metabolism, whose upregulation is a feature of progenitor-like, chemoresistant cell subpopulations. Globally, metformin treatment reduced the differences between ALDHbright and ALDHlow cells, making the former more similar to the latter. Metformin broadly modulated microRNAs in the ALDHbright cells, with a large fraction of them predicted to target the same metabolic pathways experimentally identified by 1H-NMR. Additionally, metformin modulated the levels of c-MYC and IRS-2, and this correlated with changes of the microRNA-33a levels. In summary, we observed, both by 1H-NMR and microRNA expression studies, that metformin treatment reduced the differences between the chemoresistant ALDHbright cells and the chemosensitive ALDHlow cells. This works adds on the potential therapeutic relevance of metformin and shows the potential for metabolic reprogramming to modulate cancer chemoresistance. PMID:24980829

  7. Thyroid Hormone Receptor beta Mediates Acute Illness-Induced Alterations in Central Thyroid Hormone Metabolism

    NARCIS (Netherlands)

    A. Boelen; J. Kwakkel; O. Chassande; E. Fliers

    2009-01-01

    Acute illness in mice profoundly affects thyroid hormone metabolism in the hypothalamus and pituitary gland. It remains unknown whether the thyroid hormone receptor (TR)-beta is involved in these changes. In the present study, we investigated central thyroid hormone metabolism during lipopolysacchar

  8. Aflatoxin B1 metabolism by 3-methylcholanthrene-induced hamster hepatic cytochrome P-450s.

    Science.gov (United States)

    Lai, T S; Chiang, J Y

    1990-01-01

    We have studied the activation of aflatoxin B1 by hamster liver microsomes and purified hamster cytochrome P-450 isozymes using a umu mutagen test. The hamster liver microsomes or S-9 fractions were much more active than rat liver microsomes or S-9 fractions in the activation of umu gene expression by aflatoxin B1 metabolites. 3-Methyl-cholanthrene treatment increased aflatoxin B1 activation by hamster liver microsomes. Two major 3-methylcholanthrene-inducible cytochrome P-450 isozymes, P-450 MC1 (IIA) and P-450 MC4 (IA2), were purified from 3-methylcholanthrene-treated hamster liver microsomes, and the metabolism of aflatoxin B1 by these two cytochromes was studied. In the reconstituted enzyme system, both P-450 MC1 and P-450 MC4 were highly active in the activation of aflatoxin B1, and antibodies against these P-450s specifically inhibited these activities. Antibody against P-450 MC1 inhibited the activation of aflatoxin B1 by 20% in the presence of 3-methyl-cholanthrene-treated hamster liver microsomes. In contrast, antibody against P-450 MC4 stimulated the activity by 175%. These results indicated that hamster P-450 MC1 might convert aflatoxin B1 to more toxic metabolite(s), whereas P-450 MC4 might convert aflatoxin B1 to less toxic metabolite(s), than aflatoxin B1 in liver microsomes. The metabolite(s) produced by both hamster cytochrome P-450 MC1 and MC4 were genotoxic in the umu mutagen test. PMID:2126562

  9. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.

    Directory of Open Access Journals (Sweden)

    Manoj K Bhasin

    Full Text Available The relaxation response (RR is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS as top upregulated critical molecules (focus hubs and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress.

  10. Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Vethakanraj, Helen Shiphrah; Babu, Thabraz Ahmed; Sudarsanan, Ganesh Babu; Duraisamy, Prabhu Kumar; Ashok Kumar, Sekar, E-mail: sekarashok@gmail.com

    2015-08-28

    The sphingolipid ceramide is a pro apoptotic molecule of ceramide metabolic pathway and is hydrolyzed to proliferative metabolite, sphingosine 1 phosphate by the action of acid ceramidase. Being upregulated in the tumors of breast, acid ceramidase acts as a potential target for breast cancer therapy. We aimed at targeting this enzyme with a small molecule acid ceramidase inhibitor, Ceranib 2 in human breast cancer cell lines MCF 7 and MDA MB 231. Ceranib 2 effectively inhibited the growth of both the cell lines in dose and time dependant manner. Morphological apoptotic hallmarks such as chromatin condensation, fragmented chromatin were observed in AO/EtBr staining. Moreover, ladder pattern of fragmented DNA observed in DNA gel electrophoresis proved the apoptotic activity of Ceranib 2 in breast cancer cell lines. The apoptotic events were associated with significant increase in the expression of pro-apoptotic genes (Bad, Bax and Bid) and down regulation of anti-apoptotic gene (Bcl 2). Interestingly, increase in sub G1 population of cell cycle phase analysis and elevated Annexin V positive cells after Ceranib 2 treatment substantiated its apoptotic activity in MCF 7 and MDA MB 231 cell lines. Thus, we report Ceranib 2 as a potent therapeutic agent against both ER{sup +} and ER{sup −} breast cancer cell lines. - Highlights: • Acid Ceramidase inhibitor, Ceranib 2 induced apoptosis in Breast cancer cell lines (MCF 7 and MDA MB 231 cell lines). • Apoptosis is mediated by DNA fragmentation and cell cycle arrest. • Ceranib 2 upregulated the expression of pro-apoptotic genes and down regulated anti-apoptotic gene expression. • More potent compared to the standard drug Tamoxifen.

  11. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.

    Science.gov (United States)

    Bhasin, Manoj K; Dusek, Jeffery A; Chang, Bei-Hung; Joseph, Marie G; Denninger, John W; Fricchione, Gregory L; Benson, Herbert; Libermann, Towia A

    2013-01-01

    The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress. PMID:23650531

  12. Metformin and Resveratrol Inhibited High Glucose-Induced Metabolic Memory of Endothelial Senescence through SIRT1/p300/p53/p21 Pathway

    OpenAIRE

    Erli Zhang; Qianyun Guo; Haiyang Gao; Ruixia Xu; Siyong Teng; Yongjian Wu

    2015-01-01

    Endothelial senescence plays crucial roles in diabetic vascular complication. Recent evidence indicated that transient hyperglycaemia could potentiate persistent diabetic vascular complications, a phenomenon known as "metabolic memory." Although SIRT1 has been demonstrated to mediate high glucose-induced endothelial senescence, whether and how "metabolic memory" would affect endothelial senescence through SIRT1 signaling remains largely unknown. In this study, we investigated the involvement ...

  13. Short-chain fructo-oligosaccharides modulate intestinal microbiota and metabolic parameters of humanized gnotobiotic diet induced obesity mice.

    Directory of Open Access Journals (Sweden)

    Frederique Respondek

    Full Text Available Prebiotic fibres like short-chain fructo-oligosaccharides (scFOS are known to selectively modulate the composition of the intestinal microbiota and especially to stimulate Bifidobacteria. In parallel, the involvement of intestinal microbiota in host metabolic regulation has been recently highlighted. The objective of the study was to evaluate the effect of scFOS on the composition of the faecal microbiota and on metabolic parameters in an animal model of diet-induced obesity harbouring a human-type microbiota. Forty eight axenic C57BL/6J mice were inoculated with a sample of faecal human microbiota and randomly assigned to one of 3 diets for 7 weeks: a control diet, a high fat diet (HF, 60% of energy derived from fat or an isocaloric HF diet containing 10% of scFOS (HF-scFOS. Mice fed with the two HF gained at least 21% more weight than mice from the control group. Addition of scFOS partially abolished the deposition of fat mass but significantly increased the weight of the caecum. The analysis of the taxonomic composition of the faecal microbiota by FISH technique revealed that the addition of scFOS induced a significant increase of faecal Bifidobacteria and the Clostridium coccoides group whereas it decreased the Clostridium leptum group. In addition to modifying the composition of the faecal microbiota, scFOS most prominently affected the faecal metabolome (e.g. bile acids derivatives, hydroxyl monoenoic fatty acids as well as urine, plasma hydrophilic and plasma lipid metabolomes. The increase in C. coccoides and the decrease in C. leptum, were highly correlated to these metabolic changes, including insulinaemia, as well as to the weight of the caecum (empty and full but not the increase in Bifidobacteria. In conclusion scFOS induce profound metabolic changes by modulating the composition and the activity of the intestinal microbiota, that may partly explain their effect on the reduction of insulinaemia.

  14. Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection.

    Directory of Open Access Journals (Sweden)

    Tracie Delgado

    Full Text Available Like cancer cells, virally infected cells have dramatically altered metabolic requirements. We analyzed global metabolic changes induced by latent infection with an oncogenic virus, Kaposi's Sarcoma-associated herpesvirus (KSHV. KSHV is the etiologic agent of Kaposi's Sarcoma (KS, the most common tumor of AIDS patients. Approximately one-third of the nearly 200 measured metabolites were altered following latent infection of endothelial cells by KSHV, including many metabolites of anabolic pathways common to most cancer cells. KSHV induced pathways that are commonly altered in cancer cells including glycolysis, the pentose phosphate pathway, amino acid production and fatty acid synthesis. Interestingly, over half of the detectable long chain fatty acids detected in our screen were significantly increased by latent KSHV infection. KSHV infection leads to the elevation of metabolites involved in the synthesis of fatty acids, not degradation from phospholipids, and leads to increased lipid droplet organelle formation in the infected cells. Fatty acid synthesis is required for the survival of latently infected endothelial cells, as inhibition of key enzymes in this pathway led to apoptosis of infected cells. Addition of palmitic acid to latently infected cells treated with a fatty acid synthesis inhibitor protected the cells from death indicating that the products of this pathway are essential. Our metabolomic analysis of KSHV-infected cells provides insight as to how oncogenic viruses can induce metabolic alterations common to cancer cells. Furthermore, this analysis raises the possibility that metabolic pathways may provide novel therapeutic targets for the inhibition of latent KSHV infection and ultimately KS tumors.

  15. Hydrogen peroxide functions as a secondary messenger for brassinosteroids-induced CO2 assimilation and carbohydrate metabolism in Cucumis sativus

    Institute of Scientific and Technical Information of China (English)

    Yu-ping JIANG; Fei CHENG; Yan-hong ZHOU; Xiao-jian XIA; Wei-hua MAO; Kai SHI; Zhi-xiang CHEN; Jing-quan YU

    2012-01-01

    Brassinosteroids (BRs) are potent regulators of photosynthesis and crop yield in agricultural crops;however,the mechanism by which BRs increase photosynthesis is not fully understood.Here,we show that foliar application of 24-epibrassinolide (EBR) resulted in increases in CO2 assimilation,hydrogen peroxide (H2O2) accumulation,and leaf area in cucumber.H2O2 treatment induced increases in CO2 assimilation whilst inhibition of the H2O2 accumulation by its generation inhibitor or scavenger completely abolished EBR-induced CO2 assimilation.Increases of light harvesting due to larger leaf areas in EBR- and H2O2-treated plants were accompanied by increases in the photochemical efficiency of photosystem Ⅱ (ΦPSⅡ) and photochemical quenching coefficient (qp).EBR and H2O2 both activated carboxylation efficiency of ribulose-1,5-bisphosphate oxygenase/carboxylase (Rubisco) from analysis of CO2 response curve and in vitro measurement of Rubisco activities.Moreover,EBR and H2O2 increased contents of total soluble sugar,sucrose,hexose,and starch,followed by enhanced activities of sugar metabolism such as sucrose phosphate synthase,sucrose synthase,and invertase.Interestingly,expression of transcripts of enzymes involved in starch and sugar utilization were inhibited by EBR and H2O2.However,the effects of EBR on carbohydrate metabolisms were reversed by the H2O2 generation inhibitor diphenyleneodonium (DPI) or scavenger dimethylthiourea (DMTU) pretreatment.All of these results indicate that H2O2 functions as a secondary messenger for EBR-induced CO2 assimilation and carbohydrate metabolism in cucumber plants.Our study confirms that H2O2 mediates the regulation of photosynthesis by BRs and suggests that EBR and H2O2 regulate Calvin cycle and sugar metabolism via redox signaling and thus increase the photosynthetic potential and yield of crops.

  16. The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome

    OpenAIRE

    Steiner, Michel A.; Sciarretta, Carla; Pasquali, Anne; Jenck, Francois

    2013-01-01

    The orexin system regulates feeding, nutrient metabolism and energy homeostasis. Acute pharmacological blockade of orexin receptor 1 (OXR-1) in rodents induces satiety and reduces normal and palatable food intake. Genetic OXR-1 deletion in mice improves hyperglycemia under high-fat (HF) diet conditions. Here we investigated the effects of chronic treatment with the novel selective OXR-1 antagonist ACT-335827 in a rat model of diet-induced obesity (DIO) associated with metabolic syndrome (MetS...

  17. PHO13 deletion-induced transcriptional activation prevents sedoheptulose accumulation during xylose metabolism in engineered Saccharomyces cerevisiae.

    Science.gov (United States)

    Xu, Haiqing; Kim, Sooah; Sorek, Hagit; Lee, Youngsuk; Jeong, Deokyeol; Kim, Jungyeon; Oh, Eun Joong; Yun, Eun Ju; Wemmer, David E; Kim, Kyoung Heon; Kim, Soo Rin; Jin, Yong-Su

    2016-03-01

    The deletion of PHO13 (pho13Δ) in Saccharomyces cerevisiae, encoding a phosphatase enzyme of unknown specificity, results in the transcriptional activation of genes related to the pentose phosphate pathway (PPP) such as TAL1 encoding transaldolase. It has been also reported that the pho13Δ mutant of S. cerevisiae expressing a heterologous xylose pathway can metabolize xylose efficiently compared to its parental strain. However, the interaction between the pho13Δ-induced transcriptional changes and the phenotypes of xylose fermentation was not understood. Thus we investigated the global metabolic changes in response to pho13Δ when cells were exponentially growing on xylose. Among the 134 intracellular metabolites that we identified, the 98% reduction of sedoheptulose was found to be the most significant change in the pho13Δ mutant as compared to its parental strain. Because sedoheptulose-7-phosphate (S7P), a substrate of transaldolase, reduced significantly in the pho13Δ mutant as well, we hypothesized that limited transaldolase activity in the parental strain might cause dephosphorylation of S7P, leading to carbon loss and inefficient xylose metabolism. Mutants overexpressing TAL1 at different degrees were constructed, and their TAL1 expression levels and xylose consumption rates were positively correlated. Moreover, as TAL1 expression levels increased, intracellular sedoheptulose concentration dropped significantly. Therefore, we concluded that TAL1 upregulation, preventing the accumulation of sedoheptulose, is the most critical mechanism for the improved xylose metabolism by the pho13Δ mutant of engineered S. cerevisiae.

  18. Continuous administration of polyphenols from aqueous rooibos (Aspalathus linearis) extract ameliorates dietary-induced metabolic disturbances in hyperlipidemic mice.

    Science.gov (United States)

    Beltrán-Debón, R; Rull, A; Rodríguez-Sanabria, F; Iswaldi, I; Herranz-López, M; Aragonès, G; Camps, J; Alonso-Villaverde, C; Menéndez, J A; Micol, V; Segura-Carretero, A; Joven, J

    2011-03-15

    The incidence of obesity and related metabolic diseases is increasing globally. Current medical treatments often fail to halt the progress of such disturbances, and plant-derived polyphenols are increasingly being investigated as a possible way to provide safe and effective complementary therapy. Rooibos (Aspalathus linearis) is a rich source of polyphenols without caloric and/or stimulant components. We have tentatively characterized 25 phenolic compounds in rooibos extract and studied the effects of continuous aqueous rooibos extract consumption in mice. The effects of this extract, which contained 25% w/w of total polyphenol content, were negligible in animals with no metabolic disturbance but were significant in hyperlipemic mice, especially in those in which energy intake was increased via a Western-type diet that increased the risk of developing metabolic complications. In these mice, we found hypolipemiant activity when given rooibos extract, with significant reductions in serum cholesterol, triglyceride and free fatty acid concentrations. Additionally, we found changes in adipocyte size and number as well as complete prevention of dietary-induced hepatic steatosis. These effects were not related to changes in insulin resistance. Among other possible mechanisms, we present data indicating that the activation of AMP-activated protein kinase (AMPK) and the resulting regulation of cellular energy homeostasis may play a significant role in these effects of rooibos extract. Our findings suggest that adding polyphenols to the daily diet is likely to help in the overall management of metabolic diseases. PMID:21211952

  19. Characterization of oncogene-induced metabolic alterations in hepatic cells by using ultrahigh performance liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Tang, Zhi; Cao, Tingting; Lin, Shuhai; Fu, Li; Li, Shangfu; Guan, Xin-Yuan; Cai, Zongwei

    2016-05-15

    Elucidation of altered metabolic pathways by using metabolomics may open new avenues for basic research on disease mechanisms and facilitate the development of novel therapeutic strategies. Here, we report the development of ultrahigh performance liquid chromatography-tandem mass spectrometry-based metabolomics platform with capability of measuring both cationic and anionic intermediates in cellular metabolism. The platform was established based on the hydrophobic ion-pairing interaction chromatography coupled with tandem mass spectrometry in multiple reaction monitoring (MRM) mode. The MRM transitions were created and optimized via energy-resolved collision-induced dissociation experiments, serving as an essential reference point for the quantification and identification. For chromatographic separation, application of hydrophobic ion-pairing interaction led to dramatic enhancement on retention of water-soluble metabolites and provision of good peak shapes. Two volatile ion-pairing reagents, namely heptafluorobutyric acid and tributylamine, were used with dedicated C18 columns as complementary separation systems coupled with the MRM analysis, allowing measurement of the metabolites of interest at nanomolar levels. The developed platform was successfully applied to investigate the altered metabolism in hepatic cells with over-expression of an oncogene, thus can provide important information on the rewired metabolism. PMID:26992502

  20. Control of Nutrient Stress-Induced Metabolic Reprogramming by PKCζ in Tumorigenesis

    Science.gov (United States)

    Ma, Li; Tao, Yongzhen; Duran, Angeles; Llado, Victoria; Galvez, Anita; Barger, Jennifer F.; Castilla, Elias A.; Chen, Jing; Yajima, Tomoko; Porollo, Aleksey; Medvedovic, Mario; Brill, Laurence M.; Plas, David R.; Riedl, Stefan J.; Leitges, Michael; Diaz-Meco, Maria T.; Richardson, Adam D.; Moscat, Jorge

    2013-01-01

    SUMMARY Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer. PMID:23374352

  1. Gastrodia elata Ameliorates High-Fructose Diet-Induced Lipid Metabolism and Endothelial Dysfunction

    OpenAIRE

    Min Chul Kho; Yun Jung Lee; Jeong Dan Cha; Kyung Min Choi; Dae Gill Kang; Ho Sub Lee

    2014-01-01

    Overconsumption of fructose results in dyslipidemia, hypertension, and impaired glucose tolerance, which have documented correlation with metabolic syndrome. Gastrodia elata, a widely used traditional herbal medicine, was reported with anti-inflammatory and antidiabetes activities. Thus, this study examined whether ethanol extract of Gastrodia elata Blume (EGB) attenuate lipid metabolism and endothelial dysfunction in a high-fructose (HF) diet animal model. Rats were fed the 65% HF diet with/...

  2. Fenugreek with reduced bitterness prevents diet-induced metabolic disorders in rats

    OpenAIRE

    村木, 悦子; 千葉, 大成; Taketani, Keiko; Hoshino, Shohei; Tsuge, Nobuaki; 角田, 伸代; 加園, 恵三

    2012-01-01

    Background: Various therapeutic effects of fenugreek (Trigonella foenum-graecum L.) on metabolic disorders have been reported. However, the bitterness of fenugreek makes it hard for humans to eat sufficient doses of it for achieving therapeutic effects. Fenugreek contains bitter saponins such as protodioscin. Fenugreek with reduced bitterness (FRB) is prepared by treating fenugreek with beta-glucosidase. This study has been undertaken to evaluate the effects of FRB on metabolic disorders in r...

  3. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

    OpenAIRE

    Catoire, Milène; Alex, Sheril; Paraskevopulos, Nicolas; Mattijssen, Frits; Evers-van Gogh, Inkie; Schaart, Gert; Jeppesen, Jacob; Kneppers, Anita; Mensink, Marco; Voshol, Peter J.; Olivecrona, Gunilla; Tan, Nguan Soon; Hesselink, Matthijs K. C.; Berbée, Jimmy F.; Rensen, Patrick C N

    2014-01-01

    Physical exercise causes profound changes in energy metabolism in humans. In this study we show that resting skeletal muscle has a crucial role in the metabolic response to acute exercise. During endurance exercise, selective induction of the protein angiopoietin-like 4 (ANGPTL4) in nonexercising muscle reduces local fatty acid uptake, presumably to prevent fat overload, while directing fatty acids to the active skeletal muscle as fuel. Our data thus suggest that nonexercising muscle has a ke...

  4. Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells.

    Science.gov (United States)

    Li, Baomin; Iglesias-Pedraz, Juan Manuel; Chen, Leng-Ying; Yin, Fei; Cadenas, Enrique; Reddy, Sita; Comai, Lucio

    2014-04-01

    The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress.

  5. Ameliorating effect of eugenol on hyperglycemia by attenuating the key enzymes of glucose metabolism in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Srinivasan, Subramani; Sathish, Gajendren; Jayanthi, Mahadevan; Muthukumaran, Jayachandran; Muruganathan, Udaiyar; Ramachandran, Vinayagam

    2014-01-01

    Epidemiological studies have demonstrated that diabetes mellitus is a serious health burden for both governments and healthcare providers. This study was hypothesized to evaluate the antihyperglycemic potential of eugenol by determine the activities of key enzymes of glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced into male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg body weight (b.w.)). Eugenol was administered to diabetic rats intragastrically at 2.5, 5, and 10 mg/kg b.w. for 30 days. The dose 10 mg/kg b.w. significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and liver marker enzymes (AST, ALT, and ALP), creatine kinase and blood urea nitrogen in serum and blood of diabetic rats were significantly reverted to near normal levels by the administration of eugenol. Further, eugenol administration to diabetic rats improved body weight and hepatic glycogen content demonstrated the antihyperglycemic potential of eugenol in diabetic rats. The present findings suggest that eugenol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes, and it is sensible to broaden the scale of use of eugenol in a trial to alleviate the adverse effects of diabetes.

  6. Peripheral nerve metabolism and zinc levels in streptozotocin induced diabetic rats. Effect of diets high in fish and corn oil

    Energy Technology Data Exchange (ETDEWEB)

    Burke, J.P.; Fenton, M.R. (Pennsylvania College of Podiatric Medicine, Philadelphia (United States))

    1991-03-15

    This study was designed to assess the effects of diets high in fish and corn oil on peripheral nerve metabolism in streptozotocin (STZ) induced diabetic rats. A type I diabetic state was induced in female Sprague-Dawley rats by injection of STZ. Animals were divided into three dietary groups; normal rat chow, high corn oil diet and high fish oil diet. After 4 weeks animals were analyzed for nerve conduction velocity, bled and then sacrificed. Sciatic nerves were removed, processed and several biochemical parameters determined. Plasma zinc levels were elevated in the STZ normal chow group compared to non-diabetic controls. Both corn oil and fish oil diets tended to eliminate the rise in plasma zinc. Differences in subcellular distribution of zinc in sciatic nerves were also observed. Normal chow STZ animals displayed a 20% decrease in nerve conduction velocity compared to control. Dietary supplementation with either fish or corn oil seemed to ameliorate these effects. Biochemical analysis of Na{sup +}-K{sup +}-ATPase and protein kinase C revealed a decrease in activity in normal chow animals compared to control groups. Again, dietary intervention with either fish or corn oil seemed to return these activities back to normal. The results suggest a link between zinc metabolism and peripheral nerve metabolism which can be modified by dietary intervention.

  7. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    Science.gov (United States)

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  8. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    Directory of Open Access Journals (Sweden)

    Yi-Chieh Li

    Full Text Available Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  9. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    Science.gov (United States)

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome. PMID:24816278

  10. Subcutaneous Adipose Tissue Transplantation in Diet-Induced Obese Mice Attenuates Metabolic Dysregulation While Removal Exacerbates It.

    Science.gov (United States)

    Foster, M T; Softic, S; Caldwell, J; Kohli, R; de Kloet, A D; Seeley, R J

    2013-08-01

    Adipose tissue distribution is an important determinant of obesity-related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance and type-2-diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet-induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the liver via the portal vein. This metabolic pathology is not exclusively due to increases in visceral adipose tissue mass but also driven by intrinsic characteristics of this particular depot. In Experiment 1, high fat diet (HFD)-induced obese control (abdominal incision, but no fat manipulation) or autologous (excision and subsequent relocation of adipose tissue) subcutaneous tissue transplantation to the visceral cavity. In Experiment 2 mice received control surgery, subcutaneous fat removal or hetero-transplantation (tissue from obese donor) to the visceral cavity. Body composition analysis and glucose tolerance tests were performed 4 weeks post-surgery. Adipose mass and portal adipokines, cytokines, lipids and insulin were measured from samples collected at 5 weeks post-surgery. Auto- and hetero- transplantation in obese mice improved glucose tolerance, decreased systemic insulin concentration and reduced portal lipids and hepatic triglycerides compared with HFD controls. Hetero-transplantation of subcutaneous adipose tissue to the visceral cavity in obese mice restored hepatic insulin sensitivity and reduced insulin and leptin concentrations to chow control levels. Fat removal, however, as an independent procedure exacerbated obesity-induced increases in leptin and insulin concentrations. Overall subcutaneous adipose tissue protects against aspects of metabolic dysregulation in obese mice. Transplantation-induced improvements do not occur via enhanced storage of lipid in

  11. Silencing an N-acyltransferase-like involved in lignin biosynthesis in Nicotiana attenuata dramatically alters herbivory-induced phenolamide metabolism.

    Directory of Open Access Journals (Sweden)

    Emmanuel Gaquerel

    Full Text Available In a transcriptomic screen of Manduca sexta-induced N-acyltransferases in leaves of Nicotiana attenuata, we identified an N-acyltransferase gene sharing a high similarity with the tobacco lignin-biosynthetic hydroxycinnamoyl-CoA:shikimate/quinate hydroxycinnamoyl transferase (HCT gene whose expression is controlled by MYB8, a transcription factor that regulates the production of phenylpropanoid polyamine conjugates (phenolamides, PAs. To evaluate the involvement of this HCT-like gene in lignin production as well as the resulting crosstalk with PA metabolism during insect herbivory, we transiently silenced (by VIGs the expression of this gene and performed non-targeted (UHPLC-ESI/TOF-MS metabolomics analyses. In agreement with a conserved function of N. attenuata HCT-like in lignin biogenesis, HCT-silenced plants developed weak, soft stems with greatly reduced lignin contents. Metabolic profiling demonstrated large shifts (up to 12% deregulation in total extracted ions in insect-attacked leaves due to a large diversion of activated coumaric acid units into the production of developmentally and herbivory-induced coumaroyl-containing PAs (N',N''-dicoumaroylspermidine, N',N''-coumaroylputrescine, etc and to minor increases in the most abundant free phenolics (chlorogenic and cryptochlorogenic acids, all without altering the production of well characterized herbivory-responsive caffeoyl- and feruloyl-based putrescine and spermidine PAs. These data are consistent with a strong metabolic tension, exacerbated during herbivory, over the allocation of coumaroyl-CoA units among lignin and unusual coumaroyl-containing PAs, and rule out a role for HCT-LIKE in tuning the herbivory-induced accumulation of other PAs. Additionally, these results are consistent with a role for lignification as an induced anti-herbivore defense.

  12. Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1 beta-induced chronic inflammation

    NARCIS (Netherlands)

    Liang, Wen; Lindeman, Jan H.; Menke, Aswin L.; Koonen, Debby P.; Morrison, Martine; Havekes, Louis M.; van den Hoek, Anita M.; Kleemann, Robert

    2014-01-01

    The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1 beta

  13. Metabolic costs of force generation for constant-frequency and catchlike-inducing electrical stimulation in human tibialis anterior muscle

    DEFF Research Database (Denmark)

    Ratkevicius, Aivaras; Quistorff, Bjørn

    2002-01-01

    at 37.5 ms. One train was delivered to the peroneal nerve every 2.5 s for 36 times under ischemic conditions. Anaerobic adenosine triphosphate (ATP) turnover was determined using 31-phosphorus magnetic resonance spectroscopy (P-MRS) of the human tibialis anterior muscle. Compared with constant....../minus 1.0 micromol ATP/kg wet weight/Ncenter dots, respectively, P = 0.601). This suggests that the positive effects of catchlike-inducing stimulation on force maintenance are mediated by potentiated Ca(2+) release from the sarcoplasmic reticulum rather than by lower metabolic costs of muscle force......-frequency trains, catchlike-inducing trains produced a faster force generation and were more effective in maintaining the force--time integral as well as peak force. However, ATP costs of force generation were similar for the catchlike-inducing and constant-frequency stimulation (6.7 plus/minus 1.1 and 6.6 plus...

  14. Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy

    DEFF Research Database (Denmark)

    Strøm, Claes C; Aplin, Mark; Ploug, Thorkil;

    2005-01-01

    by quantitative PCR. The exercise program resulted in cardiac hypertrophy without impaired cardiac function. Principal component analysis identified an exercise-induced change in gene expression that was distinct from the program observed in maladaptive hypertrophy. Statistical analysis identified 267 upregulated...... genes and 62 downregulated genes in response to exercise. Expression changes in genes encoding extracellular matrix proteins, cytoskeletal elements, signalling factors and ribosomal proteins mimicked changes previously described in maladaptive hypertrophy. Our most striking observation...... was that expression changes of genes involved in beta-oxidation of fatty acids and glucose metabolism differentiate adaptive from maladaptive hypertrophy. Direct comparison to maladaptive hypertrophy was enabled by quantitative PCR of key metabolic enzymes including uncoupling protein 2 (UCP2) and fatty acid...

  15. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat.

    Directory of Open Access Journals (Sweden)

    Marie S A Palmnäs

    Full Text Available Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat or high fat (HF, 60% kcal fat and further into ad libitum water control (W or low-dose aspartame (A, 5-7 mg/kg/d in drinking water treatments for 8 week (n = 10-12 animals/treatment. Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (P<0.05. Within HF, aspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation.

  16. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat.

    Science.gov (United States)

    Palmnäs, Marie S A; Cowan, Theresa E; Bomhof, Marc R; Su, Juliet; Reimer, Raylene A; Vogel, Hans J; Hittel, Dustin S; Shearer, Jane

    2014-01-01

    Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat) or high fat (HF, 60% kcal fat) and further into ad libitum water control (W) or low-dose aspartame (A, 5-7 mg/kg/d in drinking water) treatments for 8 week (n = 10-12 animals/treatment). Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (Paspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation.

  17. Characterization of rational biomarkers accompanying fever in yeast-induced pyrexia rats using urine metabolic footprint analysis.

    Science.gov (United States)

    Guo, Mingxing; Gu, Hao; Song, Yuelin; Peng, Long; Liu, Haiyu; Zhang, Li; Lin, Zhaozhou; Wang, Yun; Gao, Xiaoyan; Qiao, Yanjiang

    2014-07-01

    Fever is a prominent feature of diseases and is an ongoing process that is always accompanied by metabolic changes in the body system. Despite the success of temperature regulation theory, the underlying biological process remains unclear. To truly understand the nature of the febrile response, it is crucial to confirm the biomarkers during the entire biological process. In the current study, a 73-h metabolic footprint analysis of the urine from yeast-induced pyrexia rats was performed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Potential biomarkers were selected using orthogonal partial least squares-discriminate analysis (OPLS-DA), the rational biomarkers were verified by Pearson correlation analysis, and the predictive power was evaluated using receiver operator characteristic (ROC) curves. A metabolic network constructed using traditional Chinese medicine (TCM) grammar systems was used to validate the rationality of the verified biomarkers. Finally, five biomarkers, including indoleacrylic acid, 3-methyluridine, tryptophan, nicotinuric acid and PI (37:3), were confirmed as rational biomarkers because their correlation coefficients were all greater than 0.87 and because all of the correlation coefficients between any pair of these biomarkers were higher than 0.75. The areas under the ROC curves were all greater than 0.84, and their combined predictive power was considered reliable because the greatest area under the ROC curve was 0.968. A metabolic network also demonstrated the rationality of these five biomarkers. Therefore, these five metabolites can be adopted as rational biomarkers to reflect the process of the febrile response in inflammation-induced pyrexia. PMID:24631712

  18. Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

    International Nuclear Information System (INIS)

    Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards

  19. Musa Paradisiaca flower extract improves carbohydrate metabolism in hepatic tissues of streptozotocin-induced experimental diabetes in rats

    Institute of Scientific and Technical Information of China (English)

    Shanmuga Sundaram.C; Subramanian.S

    2012-01-01

    Objective: Musa Paradisiaca, commonly known as plantains have been traditionally used for various medicinal purposes. In the absence of an ideal drug to alleviate the primary and secondary complications of diabetes mellitus, search for novel drugs without side effects, preferably from plant origin continues. Recently, we have reported the presence of biologically active phytochemicals as well as the hypoglycemic activity of Musa paradisiaca tepals extract in STZ induced experimental diabetes in rats. The present study was aimed to evaluate the role of tepals, an integrated part of Musa paradisiaca flowers on carbohydrate metabolism in hepatic tissues of experimental diabetic rats. Methods: Streptozotocin-induced diabetic rats were treated with ethanolic extract of tepals at a concentration of 200mg/kg body weight/day for 30 days. The levels of fasting blood glucose, plasma insulin and glycosylated hemoglobin were estimated. The activities of key enzymes in carbohydrate metabolism such as glucokinase, pyruvate kinase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in hepatic tissues were assayed. The levels of glycogen in hepatic tissues were also estimated. Results: Oral administration ofMusa paradisiaca tepals extract significantly improved the altered levels of blood glucose, plasma insulin, glycosylated hemoglobin and modulated the activities of carbohydrate metabolizing enzymes. The glycogen content in hepatic tissues was significantly increased in diabetic rats treated with tepals extract. Conclusions: The results of the present study clearly indicate that the tepals extract plays pivotal role to maintain normoglycemia in diabetes by modulating the activities of carbohydrate metabolic enzymes.

  20. CB1 receptor blockade counters age-induced insulin resistance and metabolic dysfunction.

    Science.gov (United States)

    Lipina, Christopher; Vaanholt, Lobke M; Davidova, Anastasija; Mitchell, Sharon E; Storey-Gordon, Emma; Hambly, Catherine; Irving, Andrew J; Speakman, John R; Hundal, Harinder S

    2016-04-01

    The endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant-mediated insulin sensitization in aged adipose tissue coincided with amelioration of low-grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging-related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging. PMID:26757949

  1. Oral Gingival Cell Cigarette Smoke Exposure Induces Muscle Cell Metabolic Disruption

    Directory of Open Access Journals (Sweden)

    Andrea C. Baeder

    2016-01-01

    Full Text Available Cigarette smoke exposure compromises health through damaging multiple physiological systems, including disrupting metabolic function. The purpose of this study was to determine the role of oral gingiva in mediating the deleterious metabolic effects of cigarette smoke exposure on skeletal muscle metabolic function. Using an in vitro conditioned medium cell model, skeletal muscle cells were incubated with medium from gingival cells treated with normal medium or medium containing suspended cigarette smoke extract (CSE. Following incubation of muscle cells with gingival cell conditioned medium, muscle cell mitochondrial respiration and insulin signaling and action were determined as an indication of overall muscle metabolic health. Skeletal muscle cells incubated with conditioned medium of CSE-treated gingival cells had a profound reduction in mitochondrial respiration and respiratory control. Furthermore, skeletal muscle cells had a greatly reduced response in insulin-stimulated Akt phosphorylation and glycogen synthesis. Altogether, these results provide a novel perspective on the mechanism whereby cigarette smoke affects systemic metabolic function. In conclusion, we found that oral gingival cells treated with CSE create an altered milieu that is sufficient to both disrupted skeletal muscle cell mitochondrial function and insulin sensitivity.

  2. Yuanhuapine-induced intestinal and hepatotoxicity were correlated with disturbance of amino acids, lipids, carbohydrate metabolism and gut microflora function: A rat urine metabonomic study.

    Science.gov (United States)

    Chen, Yanyan; Duan, Jin-Ao; Guo, Jianming; Shang, Erxin; Tang, Yuping; Qian, Yefei; Tao, Weiwei; Liu, Pei

    2016-07-15

    This research was designed to study metabonomic characteristics of the toxicity induced by yuanhuapine, a major bioactive diterpenoid in a well-known traditional Chinese medicine-Genkwa Flos. General observation, blood biochemistry and histopathological examination were used to reflect yuanhuapine-induced toxicity. Urine samples from rats in control and yuanhuapine treated rats were analyzed by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Pattern recognition methods including principal components analysis (PCA), partial least-squared discriminant analysis (PLS-DA), orthogonal partial least-squared discriminant analysis (OPLS-DA) and computational system analysis were integrated to obtain comprehensive metabonomic profiling and pathways of the biological data sets. The results suggested that yuanhuapine could induce intestinal and liver damage. And 14 endogenous metabolites as biomarkers related to the amino acids metabolism, lipids metabolism, carbohydrate metabolism and gut microflora were significantly changed in the urine of yuanhuapine treated rats, which were firstly constructed the metabolomic feature profiling and metabolite interaction network of yuanhuapine-induced injury using pattern recognition methods and Ingenuity Pathway Analysis (IPA) approach. The present study showed that yuanhuapine-induced intestinal and hepatic toxicity were correlated with disturbance of amino acids metabolism, lipids metabolism, carbohydrate metabolism and gut microflora. PMID:26341729

  3. White spot syndrome virus induces metabolic changes resembling the warburg effect in shrimp hemocytes in the early stage of infection.

    Science.gov (United States)

    Chen, I-Tung; Aoki, Takashi; Huang, Yun-Tzu; Hirono, Ikuo; Chen, Tsan-Chi; Huang, Jiun-Yan; Chang, Geen-Dong; Lo, Chu-Fang; Wang, Han-Ching

    2011-12-01

    The Warburg effect is an abnormal glycolysis response that is associated with cancer cells. Here we present evidence that metabolic changes resembling the Warburg effect are induced by a nonmammalian virus. When shrimp were infected with white spot syndrome virus (WSSV), changes were induced in several metabolic pathways related to the mitochondria. At the viral genome replication stage (12 h postinfection [hpi]), glucose consumption and plasma lactate concentration were both increased in WSSV-infected shrimp, and the key enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PDH), showed increased activity. We also found that at 12 hpi there was no alteration in the ADP/ATP ratio and that oxidative stress was lower than that in uninfected controls. All of these results are characteristic of the Warburg effect as it is present in mammals. There was also a significant decrease in triglyceride concentration starting at 12 hpi. At the late stage of the infection cycle (24 hpi), hemocytes of WSSV-infected shrimp showed several changes associated with cell death. These included the induction of mitochondrial membrane permeabilization (MMP), increased oxidative stress, decreased glucose consumption, and disrupted energy production. A previous study showed that WSSV infection led to upregulation of the voltage-dependent anion channel (VDAC), which is known to be involved in both the Warburg effect and MMP. Here we show that double-stranded RNA (dsRNA) silencing of the VDAC reduces WSSV-induced mortality and virion copy number. For these results, we hypothesize a model depicting the metabolic changes in host cells at the early and late stages of WSSV infection.

  4. Genetically Engineered Escherichia coli Nissle 1917 Synbiotics Reduce Metabolic Effects Induced by Chronic Consumption of Dietary Fructose

    Science.gov (United States)

    Somabhai, Chaudhari Archana; Raghuvanshi, Ruma; Nareshkumar, G.

    2016-01-01

    Aims To assess protective efficacy of genetically modified Escherichia coli Nissle 1917 (EcN) on metabolic effects induced by chronic consumption of dietary fructose. Materials and Methods EcN was genetically modified with fructose dehydrogenase (fdh) gene for conversion of fructose to 5-keto-D-fructose and mannitol-2-dehydrogenase (mtlK) gene for conversion to mannitol, a prebiotic. Charles foster rats weighing 150–200 g were fed with 20% fructose in drinking water for two months. Probiotic treatment of EcN (pqq), EcN (pqq-glf-mtlK), EcN (pqq-fdh) was given once per week 109 cells for two months. Furthermore, blood and liver parameters for oxidative stress, dyslipidemia and hyperglycemia were estimated. Fecal samples were collected to determine the production of short chain fatty acids and pyrroloquinoline quinone (PQQ) production. Results EcN (pqq-glf-mtlK), EcN (pqq-fdh) transformants were confirmed by restriction digestion and functionality was checked by PQQ estimation and HPLC analysis. There was significant increase in body weight, serum glucose, liver injury markers, lipid profile in serum and liver, and decrease in antioxidant enzyme activity in high-fructose-fed rats. However the rats treated with EcN (pqq-glf-mtlK) and EcN (pqq-fdh) showed significant reduction in lipid peroxidation along with increase in serum and hepatic antioxidant enzyme activities. Restoration of liver injury marker enzymes was also seen. Increase in short chain fatty acids (SCFA) demonstrated the prebiotic effects of mannitol and gluconic acid. Conclusions Our study demonstrated the effectiveness of probiotic EcN producing PQQ and fructose metabolizing enzymes against the fructose induced hepatic steatosis suggesting that its potential for use in treating fructose induced metabolic syndrome. PMID:27760187

  5. Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.

    Science.gov (United States)

    Murase, Takatoshi; Misawa, Koichi; Haramizu, Satoshi; Minegishi, Yoshihiko; Hase, Tadashi

    2010-08-01

    AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver. PMID:20501876

  6. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.

    Science.gov (United States)

    Xu, Dan; Zhang, Benjian; Liang, Gai; Ping, Jie; Kou, Hao; Li, Xiaojun; Xiong, Jie; Hu, Dongcai; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in

  7. Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Manuela Sailer

    Full Text Available In humans, plasma amino acid concentrations of branched-chain amino acids (BCAA and aromatic amino acids (AAA increase in states of obesity, insulin resistance and diabetes. We here assessed whether these putative biomarkers can also be identified in two different obesity and diabetic mouse models. C57BL/6 mice with diet-induced obesity (DIO mimic the metabolic impairments of obesity in humans characterized by hyperglycemia, hyperinsulinemia and hepatic triglyceride accumulation. Mice treated with streptozotocin (STZ to induce insulin deficiency were used as a type 1 diabetes model. Plasma amino acid profiling of two high fat (HF feeding trials revealed that citrulline and ornithine concentrations are elevated in obese mice, while systemic arginine bioavailability (ratio of plasma arginine to ornithine + citrulline is reduced. In skeletal muscle, HF feeding induced a reduction of arginine levels while citrulline levels were elevated. However, arginine or citrulline remained unchanged in their key metabolic organs, intestine and kidney. Moreover, the intestinal conversion of labeled arginine to ornithine and citrulline in vitro remained unaffected by HF feeding excluding the intestine as prime site of these alterations. In liver, citrulline is mainly derived from ornithine in the urea cycle and DIO mice displayed reduced hepatic ornithine levels. Since both amino acids share an antiport mechanism for mitochondrial import and export, elevated plasma citrulline may indicate impaired hepatic amino acid handling in DIO mice. In the insulin deficient mice, plasma citrulline and ornithine levels also increased and additionally these animals displayed elevated BCAA and AAA levels like insulin resistant and diabetic patients. Therefore, type 1 diabetic mice but not DIO mice show the "diabetic fingerprint" of plasma amino acid changes observed in humans. Additionally, citrulline may serve as an early indicator of the obesity-dependent metabolic

  8. Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism.

    Science.gov (United States)

    Duivenvoorde, Loes P M; van Schothorst, Evert M; Derous, Davina; van der Stelt, Inge; Masania, Jinit; Rabbani, Naila; Thornalley, Paul J; Keijer, Jaap

    2015-06-01

    Challenge tests stress homeostasis and may reveal deviations in health that remain masked under unchallenged conditions. Ideally, challenge tests are non-invasive and applicable in an early phase of an animal experiment. Oxygen restriction (OxR; based on ambient, mild normobaric hypoxia) is a non-invasive challenge test that measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome. To test whether OxR can be used to reveal early diet-induced health effects, we exposed mice to a low-fat (LF) or high-fat (HF) diet for only 5 days. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and epididymal white adipose tissue (eWAT) and serum markers for e.g. protein glycation and oxidation. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR; however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. Cumulatively, OxR is a promising new method to test food products on potential beneficial effects for human health. PMID:24974902

  9. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.

    Directory of Open Access Journals (Sweden)

    Dan Xu

    Full Text Available Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR and cholesterol side-chain cleavage enzyme (P450scc, as well as the level of fetal adrenal endogenous corticosterone (CORT, were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2. Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR, and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be

  10. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit.

    Science.gov (United States)

    Vignozzi, Linda; Filippi, Sandra; Comeglio, Paolo; Cellai, Ilaria; Sarchielli, Erica; Morelli, Annamaria; Rastrelli, Giulia; Maneschi, Elena; Galli, Andrea; Vannelli, Gabriella Barbara; Saad, Farid; Mannucci, Edoardo; Adorini, Luciano; Maggi, Mario

    2014-03-25

    A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS-associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction. We used a non-genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFα mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFα), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFα expression and Ach response was confirmed. Accordingly, circulating levels of TNFα were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFα liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFα with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS-induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFα, as indicated by treatments reducing liver and circulating TNFα levels (T or OCA), or neutralizing TNFα action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits. PMID:24486698

  11. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity.

    Directory of Open Access Journals (Sweden)

    Paola Gauffin Cano

    Full Text Available BACKGROUND: Associations have been made between obesity and reduced intestinal numbers of members of the phylum Bacteroidetes, but there is no direct evidence of the role these bacteria play in obesity. Herein, the effects of Bacteroides uniformis CECT 7771 on obesity-related metabolic and immune alterations have been evaluated. METHODS AND FINDINGS: Adult (6-8 week male wild-type C57BL-6 mice were fed a standard diet or a high-fat-diet HFD to induce obesity, supplemented or not with B. uniformis CECT 7771 for seven weeks. Animal weight was monitored and histologic, biochemical, immunocompetent cell functions, and features of the faecal microbiota were analysed after intervention. The oral administration of B. uniformis CECT 7771 reduced body weight gain, liver steatosis and liver cholesterol and triglyceride concentrations and increased small adipocyte numbers in HFD-fed mice. The strain also reduced serum cholesterol, triglyceride, glucose, insulin and leptin levels, and improved oral tolerance to glucose in HFD fed mice. The bacterial strain also reduced dietary fat absorption, as indicated by the reduced number of fat micelles detected in enterocytes. Moreover, B. uniformis CECT 7771 improved immune defence mechanisms, impaired in obesity. HFD-induced obesity led to a decrease in TNF-α production by peritoneal macrophages stimulated with LPS, conversely, the administration of B. uniformis CECT 7771 increased TNF-α production and phagocytosis. Administering this strain also increased TNF-α production by dendritic cells (DCs in response to LPS stimulation, which was significantly reduced by HFD. B. uniformis CECT 7771 also restored the capacity of DCs to induce a T-cell proliferation response, which was impaired in obese mice. HFD induced marked changes in gut microbiota composition, which were partially restored by the intervention. CONCLUSIONS: Altogether, the findings indicate that administration of B. uniformis CECT 7771 ameliorates HFD-induced

  12. Analysis of hormone-induced changes of phosphoinositide metabolism in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Wallace, M.A.; Fain, J.N.

    1985-01-01

    The relationship between hormone-stimulated phosphoinositide turnover and Ca/sup 2 +/ flux can be investigated using radiolabelled hepatocytes and the subcellular fractions derived from them or from whole liver. Comparison of the results obtained using intact cells to those from subcellular fractions should ultimately lead to a reconstruction of the transmembrane signaling events through which hormone such as vasopressin, angiotensin, and catecholamines acutely activate liver glycogenolysis. The paper reviews hormone-stimulated phosphoinositide metabolism in intact hepatocytes as well as hepatic enzymes involved in phosphoinositide metabolism. Also discussed is the current status of studies on hormone action in broken cell preparations in liver.

  13. Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome

    DEFF Research Database (Denmark)

    Shoaie, Saeed; Ghaffari, Pouyan; Kovatcheva-Datchary, Petia;

    2015-01-01

    of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal......The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet...

  14. Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction

    OpenAIRE

    Cameron, Kerry M; Miwa, Satomi; Walker, Cornelia; von Zglinicki, Thomas

    2012-01-01

    Background Chronic dietary restriction (DR) has been shown to have beneficial effects on glucose homeostasis and insulin sensitivity. These factors show rapid and robust improvements when rodents were crossed over from an ad libitum (AL) diet to DR in mid life. We aimed to determine whether the beneficial effects induced by short-term exposure to DR can be retained as a ‘metabolic memory’ when AL feeding is resumed (AL-DR-AL) and vice versa: whether the effects of long-term DR can be reversed...

  15. Dose-dependent effects, safety and tolerability of fenugreek in diet-induced metabolic disorders in rats

    OpenAIRE

    Muraki Etsuko; Hayashi Yukie; Chiba Hiroshige; Tsunoda Nobuyo; Kasono Keizo

    2011-01-01

    Abstract Background We previously reported that fenugreek (Trigonella foenum-graecum L.) improved diet-induced metabolic disorders in rats. The purpose of the present study was to examine the dose-dependent effects, safety and tolerability of fenugreek. Methods The diets used in this study were the high-fat high-sucrose diet (HFS; lard 50%kcal, sucrose 25%kcal) as a control (Ctrl group) or the HFS containing 0.25% (VL group), 1.25% (L group), 2.50% (M group), 5.00% (H group) or 12.30% (VH gro...

  16. Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

    OpenAIRE

    Adebiyi, Oluwafeyisetan O.; Olubunmi A. Adebiyi; Owira, Peter M. O.

    2015-01-01

    Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) an...

  17. L-CARNITINE-INDUCED MODULATION OF PLASMA FATTY ACIDS METABOLISM IN HYPERLIPIDEMIC RABBITS

    Directory of Open Access Journals (Sweden)

    Frank Hernández Rosales PhD

    2006-02-01

    mejoramiento del metabolismo de las lipoproteínas. ABSTRACTThe present study was designed to examine whether the hipocholesterolemic effect of L-carnitine supplementation is related with lipoprotein fatty acid metabolism. Fatty acid compositional and cholesterol content changes were measured in lipoproteins of six different groups of rabbits. Group 1, rabbits fed a standard diet; group 2, rabbits fed standard diet plus L-carnitine 80 mg/kg bw; group 3, rabbits fed a 0.5 % cholesterol diet; group 4, rabbits fed a 0.5 % cholesterol diet plus L-carnitine 80 mg/kg b.w. These four groups were fed their diets during 126 days. Group 5 and 6 were fed the same diet as group 4 in a previous period of 126 days, and after this time, group 5 was fed the same diet as group 1, and group 6 fed the same diet as group 2, during a second period of 65 days.However, the progression of hypercholesterolemia was reduced 50 % by L-carnitine administration in those animals fed cholesterol diet. Fatty acid compositional changes in lipoprotein-cholesteryl esters were found in all groups of animals supplemented with L-carnitine. During the standard-fed period the saturated and unsaturated fatty acid ratio was increased in VLDL and HDL particles whereas was decreased in LDL. In the hyperlipidemia progression period the saturated to unsaturated fatty acid ratio in HDL fraction was slightly enhanced and in the VLDL+LDL modified particle was diminished. In the hyperlipidemia regression period, plasma cholesterol level was additionally reduced in a 33 % in the group 6; and the saturated to unsaturated fatty ratio had the same behaviour from that observed in the progression period for HDL and VLDL+LDL particles. A remarkable reduction (75% of aorta atherosclerotic plaques in the group 6 was found. From these results we concluded that L-carnitine, in this experimental model, induces an improved lipoprotein metabolism.

  18. Dietary Fiber-Induced Improvement in Glucose Metabolism Is Associated with Increased Abundance of Prevotella

    DEFF Research Database (Denmark)

    Kovatcheva-Datchary, Petia; Nilsson, Anne; Akrami, Rozita;

    2015-01-01

    The gut microbiota plays an important role in human health by interacting with host diet, but there is substantial inter-individual variation in the response to diet. Here we compared the gut microbiota composition of healthy subjects who exhibited improved glucose metabolism following 3-day cons...

  19. Separation Anxiety: Detachment from the Extracellular Matrix Induces Metabolic Changes that Can Stimulate Tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Magdalena A. Cichon; Derek C. Radisky

    2010-01-01

    @@ One of the earliest stages of tumor progression involves the ability of cells to survive and proliferate when not attached to the extracellular matrix (ECM). New research using a physiologically relevant breast cancer model reveals how separation from the ECM stimulates metabolic changes characteristic of developing tumors.

  20. Coconut, Fish, and Olive Oil-Rich Diets Modify Ozone-Induced Metabolic Effects

    Science.gov (United States)

    Pulmonary health effects of ozone (O3) exposure are well known; however, the cardiovascular and metabolic consequences are still under investigation. Fish oil (FO) and olive oil (OO) dietary supplementation have several cardioprotective benefits, but it is not established if thes...

  1. Metabolic disruptions induced by reduced ambulatory activity in free-living humans

    DEFF Research Database (Denmark)

    Thyfault, John P; Krogh-Madsen, Rikke

    2011-01-01

    Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool t...

  2. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia

    NARCIS (Netherlands)

    den Hoed, M. A. H.; Lopez-Lopez, E.; te Winkel, M. L.; Tissing, W.; de Rooij, J. D. E.; Gutierrez-Camino, A.; Garcia-Orad, A.; den Boer, E.; Pieters, R.; Pluijm, S. M. F.; de Jonge, R.; van den Heuvel-Eibrink, M. M.

    2015-01-01

    Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treat

  3. Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

    NARCIS (Netherlands)

    Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

    2015-01-01

    In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreci

  4. Exercise- and Hypoxia-Induced Anaerobic Metabolism and Recovery: A Student Laboratory Exercise Using Teleost Fish

    Science.gov (United States)

    Rees, B. B.; Boily, P.; Williamson, L. A. C.

    2009-01-01

    Anaerobic metabolism is recruited in vertebrates under conditions of intense exercise or lowered environmental oxygen availability (hypoxia), typically resulting in the accumulation of lactate in blood and tissues. Lactate will be cleared over time after the reoxygenation of tissues, eventually returning to control levels. Here, we present a…

  5. Illness-induced changes in thyroid hormone metabolism: focus on the tissue level

    NARCIS (Netherlands)

    J. Kwakkel; E. Fliers; A. Boelen

    2011-01-01

    During illness changes in thyroid hormone metabolism occur, collectively known as the non-thyroidal illness syndrome (NTIS). NTIS is characterised by low serum thyroid hormone levels without the expected rise in serum thyroid-stimulating hormone, indicating a major change in thyroid hormone feedback

  6. Nitrogen deficiency in barley (Hordeum vulgare) seedlings induces molecular and metabolic adjustments that trigger aphid resistance.

    Science.gov (United States)

    Comadira, Gloria; Rasool, Brwa; Karpinska, Barbara; Morris, Jenny; Verrall, Susan R; Hedley, Peter E; Foyer, Christine H; Hancock, Robert D

    2015-06-01

    Agricultural nitrous oxide (N2O) pollution resulting from the use of synthetic fertilizers represents a significant contribution to anthropogenic greenhouse gas emissions, providing a rationale for reduced use of nitrogen (N) fertilizers. Nitrogen limitation results in extensive systems rebalancing that remodels metabolism and defence processes. To analyse the regulation underpinning these responses, barley (Horedeum vulgare) seedlings were grown for 7 d under N-deficient conditions until net photosynthesis was 50% lower than in N-replete controls. Although shoot growth was decreased there was no evidence for the induction of oxidative stress despite lower total concentrations of N-containing antioxidants. Nitrogen-deficient barley leaves were rich in amino acids, sugars and tricarboxylic acid cycle intermediates. In contrast to N-replete leaves one-day-old nymphs of the green peach aphid (Myzus persicae) failed to reach adulthood when transferred to N-deficient barley leaves. Transcripts encoding cell, sugar and nutrient signalling, protein degradation and secondary metabolism were over-represented in N-deficient leaves while those associated with hormone metabolism were similar under both nutrient regimes with the exception of mRNAs encoding proteins involved in auxin metabolism and responses. Significant similarities were observed between the N-limited barley leaf transcriptome and that of aphid-infested Arabidopsis leaves. These findings not only highlight significant similarities between biotic and abiotic stress signalling cascades but also identify potential targets for increasing aphid resistance with implications for the development of sustainable agriculture.

  7. Nitrogen deficiency in barley (Hordeum vulgare) seedlings induces molecular and metabolic adjustments that trigger aphid resistance.

    Science.gov (United States)

    Comadira, Gloria; Rasool, Brwa; Karpinska, Barbara; Morris, Jenny; Verrall, Susan R; Hedley, Peter E; Foyer, Christine H; Hancock, Robert D

    2015-06-01

    Agricultural nitrous oxide (N2O) pollution resulting from the use of synthetic fertilizers represents a significant contribution to anthropogenic greenhouse gas emissions, providing a rationale for reduced use of nitrogen (N) fertilizers. Nitrogen limitation results in extensive systems rebalancing that remodels metabolism and defence processes. To analyse the regulation underpinning these responses, barley (Horedeum vulgare) seedlings were grown for 7 d under N-deficient conditions until net photosynthesis was 50% lower than in N-replete controls. Although shoot growth was decreased there was no evidence for the induction of oxidative stress despite lower total concentrations of N-containing antioxidants. Nitrogen-deficient barley leaves were rich in amino acids, sugars and tricarboxylic acid cycle intermediates. In contrast to N-replete leaves one-day-old nymphs of the green peach aphid (Myzus persicae) failed to reach adulthood when transferred to N-deficient barley leaves. Transcripts encoding cell, sugar and nutrient signalling, protein degradation and secondary metabolism were over-represented in N-deficient leaves while those associated with hormone metabolism were similar under both nutrient regimes with the exception of mRNAs encoding proteins involved in auxin metabolism and responses. Significant similarities were observed between the N-limited barley leaf transcriptome and that of aphid-infested Arabidopsis leaves. These findings not only highlight significant similarities between biotic and abiotic stress signalling cascades but also identify potential targets for increasing aphid resistance with implications for the development of sustainable agriculture. PMID:26038307

  8. Genetic polymorphism of metabolic enzymes modifies the risk of chronic solvent-induced encephalopathy

    NARCIS (Netherlands)

    S. Kezic; F. Calkoen; M.A.M. Wenker; J.J.L. Jacobs; M.M. Verberk

    2006-01-01

    In the present study, we investigate whether genetic polymorphism in enzymes involved in the metabolism of organic solvents influences susceptibility to chronic solvent encephalopathy (CSE), which is one of the major effects of long-term exposure to organic solvents. Polymorphisms in the genes encod

  9. Cyanidin 3-glucoside improves diet-induced metabolic syndrome in rats.

    Science.gov (United States)

    Bhaswant, Maharshi; Fanning, Kent; Netzel, Michael; Mathai, Michael L; Panchal, Sunil K; Brown, Lindsay

    2015-12-01

    Increased consumption of dark-coloured fruits and vegetables may mitigate metabolic syndrome. This study has determined the changes in metabolic parameters, and in cardiovascular and liver structure and function, following chronic administration of either cyanidin 3-glucoside (CG) or Queen Garnet plum juice (QG) containing cyanidin glycosides to rats fed either a corn starch (C) or a high-carbohydrate, high-fat (H) diet. Eight to nine-week-old male Wistar rats were randomly divided into six groups for 16-week feeding with C, C with CG or QG, H or H with CG or QG. C or H were supplemented with CG or QG at a dose of ∼ 8 mg/kg/day cyanidin glycosides from week 8 to 16. H rats developed signs of metabolic syndrome including visceral adiposity, impaired glucose tolerance, hypertension, cardiovascular remodelling, increased collagen deposition in left ventricle, non-alcoholic fatty liver disease, increased plasma liver enzymes and increased inflammatory cell infiltration in the heart and liver. Both CG and QG reversed these cardiovascular, liver and metabolic signs. However, no intact anthocyanins or common methylated/conjugated metabolites could be detected in the plasma samples and plasma hippuric acid concentrations were unchanged. Our results suggest CG is the most likely mediator of the responses to QG but that further investigation of the pharmacokinetics of oral CG in rats is required.

  10. Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

    Science.gov (United States)

    Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-08-01

    Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns.

  11. Decolorization of acid and basic dyes: understanding the metabolic degradation and cell-induced adsorption/precipitation by Escherichia coli.

    Science.gov (United States)

    Cerboneschi, Matteo; Corsi, Massimo; Bianchini, Roberto; Bonanni, Marco; Tegli, Stefania

    2015-10-01

    Escherichia coli strain DH5α was successfully employed in the decolorization of commercial anthraquinone and azo dyes, belonging to the general classes of acid or basic dyes. The bacteria showed an aptitude to survive at different pH values on any dye solution tested, and a rapid decolorization was obtained under aerobic conditions for the whole collection of dyes. A deep investigation about the mode of action of E. coli was carried out to demonstrate that dye decolorization mainly occurred via three different pathways, specifically bacterial induced precipitation, cell wall adsorption, and metabolism, whose weight was correlated with the chemical nature of the dye. In the case of basic azo dyes, an unexpected fast decolorization was observed after just 2-h postinoculation under aerobic conditions, suggesting that metabolism was the main mechanism involved in basic azo dye degradation, as unequivocally demonstrated by mass spectrometric analysis. The reductive cleavage of the azo group by E. coli on basic azo dyes was also further demonstrated by the inhibition of decolorization occurring when glucose was added to the dye solution. Moreover, no residual toxicity was found in the E. coli-treated basic azo dye solutions by performing Daphnia magna acute toxicity assays. The results of the present study demonstrated that E. coli can be simply exploited for its natural metabolic pathways, without applying any recombinant technology. The high versatility and adaptability of this bacterium could encourage its involvement in industrial bioremediation of textile and leather dyeing wastewaters.

  12. Fructose-induced aberration of metabolism in familial gout identified by sup 31 P magnetic resonance spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Seegmiller, J.E. (John Radcliffe Hospital, Oxford (England) Univ. of California, San Diego (United States)); Dixon, R.M.; Kemp, G.J.; Rajagopalan, B.; Radda, G.K. (John Radcliffe Hospital, Oxford (England)); Angus, P.W. (John Radcliffe Hospital, Oxford (England) Austin Hospital, Heidelburg, Victoria (Australia)); McAlindon, T.E.; Dieppe, P. (Univ. of Bristol (England))

    1990-11-01

    The hyperuricemia responsible for the development of gouty arthritis results from a wide range of environmental factors and underlying genetically determined aberrations of metabolism. {sup 31}P magnetic resonance spectroscopy studies of children with hereditary fructose intolerance revealed a readily detectable rise in phosphomonoesters with a marked fall in inorganic phosphate in their liver in vivo and a rise in serum urate in response to very low doses of oral fructose. Parents and some family members heterozygous for this enzyme deficiency showed a similar pattern when given a substantially larger dose of fructose. Three of the nine heterozygotes thus identified also had clinical gout, suggesting the possibility of this defect being a fairly common cause of gout. In the present study this same noninvasive technology was used to identify the same spectral pattern in 2 of the 11 families studied with hereditary gout. In one family, the index patient's three brothers and his mother all showed the fructose-induced abnormality of metabolism, in agreement with the maternal inheritance of metabolism, in agreement with the maternal inheritance of the gout in this family group. The test dose of fructose used produced a significantly larger increment in the concentration of serum urate in the patients showing the changes in {sup 31}P magnetic resonance spectra than in the other patients with familial gout or in nonaffected members, thus suggesting a simpler method for initial screening for the defect.

  13. Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders.

    Science.gov (United States)

    Ferrell, Jessica M; Boehme, Shannon; Li, Feng; Chiang, John Y L

    2016-07-01

    Cholesterol 7α-hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. In addition to absorption and digestion of nutrients, bile acids play a critical role in the regulation of lipid, glucose, and energy homeostasis. We have backcrossed Cyp7a1(-/-) mice in a mixed B6/129Sv genetic background to C57BL/6J mice to generate Cyp7a1(-/-) mice in a near-pure C57BL/6J background. These mice survive well and have normal growth and a bile acid pool size ∼60% of WT mice. The expression of the genes in the alternative bile acid synthesis pathway are upregulated, resulting in a more hydrophilic bile acid composition with reduced cholic acid (CA). Surprisingly, Cyp7a1(-/-) mice have improved glucose sensitivity with reduced liver triglycerides and fecal bile acid excretion, but increased fecal fatty acid excretion and respiratory exchange ratio (RER) when fed a high-fat/high-cholesterol diet. Supplementing chow and Western diets with CA restored bile acid composition, reversed the glucose tolerant phenotype, and reduced the RER. Our current study points to a critical role of bile acid composition, rather than bile acid pool size, in regulation of glucose, lipid, and energy metabolism to improve glucose and insulin tolerance, maintain metabolic homeostasis, and prevent high-fat diet-induced metabolic disorders. PMID:27146480

  14. Plant biostimulants: physiological responses induced by protein hydrolyzed-based products and humic substances in plant metabolism

    Directory of Open Access Journals (Sweden)

    Serenella Nardi

    2016-02-01

    Full Text Available ABSTRACT In recent years, the use of biostimulants in sustainable agriculture has been growing. Biostimulants can be obtained from different organic materials and include humic substances (HS, complex organic materials, beneficial chemical elements, peptides and amino acids, inorganic salts, seaweed extracts, chitin and chitosan derivatives, antitranspirants, amino acids and other N-containing substances. The application of biostimulants to plants leads to higher content of nutrients in their tissue and positive metabolic changes. For these reasons, the development of new biostimulants has become a focus of scientific interest. Among their different functions, biostimulants influence plant growth and nitrogen metabolism, especially because of their content in hormones and other signalling molecules. A significant increase in root hair length and density is often observed in plants treated with biostimulants, suggesting that these substances induce a “nutrient acquisition response” that favors nutrient uptake in plants via an increase in the absorptive surface area. Furthermore, biostimulants positively influence the activity and gene expression of enzymes functioning in the primary and secondary plant metabolism. This article reviews the current literature on two main classes of biostimulants: humic substances and protein-based biostimulants. The characteristic of these biostimulants and their effects on plants are thoroughly described.

  15. Metabolic changes at the early stage of sepsis induced by cecal ligation and puncture in rats and the interventional effects of Huang-Lian-Jie-Du-Tang.

    Science.gov (United States)

    Wei, Yufen; Gao, Na; Zhang, Zhongxiao; Zu, Xianpeng; Hu, Zhenlin; Zhang, Weidong; Yin, Jun; Liu, Xinru

    2016-07-15

    Sepsis is a disease with high mortality that requires rapid diagnosis and treatment. This study used a metabolomic approach to profile the metabolic changes at the early stage of sepsis induced by cecal ligation and puncture (CLP) in rats and investigated the interventional effects of Huang-Lian-Jie-Du-Tang (HLJDT). Male SD rats were intragastrically administered 270mg/kg HLJDT 2h prior to CLP, serum extracts were profiled by liquid chromatography/quadrupole time-of-flight mass spectrometer (LC-Q-TOF-MS) and multivariate analytical (MVA) methods were employed to evaluate the metabolic changes of extracts. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that septic rats undergo significant metabolic changes 2h after CLP, and HLJDT administration could reverse the metabolic changes induced by CLP. Sixteen biomarkers involved in amino acid metabolism, unsaturated fatty acid metabolism, purine metabolism, and lipid metabolism were identified after Orthogonal Partial Least-Squares Analysis (OPLS). Among the 16 metabolites, 10 were regulated by HLJDT. This study established the foundation for further research of the early diagnosis biomarkers and therapeutic evaluation biomarkers discovery of sepsis. PMID:26365787

  16. Ginseng Extracts Restore High-Glucose Induced Vascular Dysfunctions by Altering Triglyceride Metabolism and Downregulation of Atherosclerosis-Related Genes

    Directory of Open Access Journals (Sweden)

    Gabriel Hoi-huen Chan

    2013-01-01

    Full Text Available The king of herbs, Panax ginseng, has been used widely as a therapeutic agent vis-à-vis its active pharmacological and physiological effects. Based on Chinese pharmacopeia Ben Cao Gang Mu and various pieces of literature, Panax ginseng was believed to exert active vascular protective effects through its antiobesity and anti-inflammation properties. We investigated the vascular protective effects of ginseng by administrating ginseng extracts to rats after the induction of diabetes. We found that Panax ginseng can restore diabetes-induced impaired vasorelaxation and can reduce serum triglyceride but not cholesterol level in the diabetic rats. The ginseng extracts also suppressed the expression of atherosclerosis-related genes and altered the expression of lipid-related genes. The results provide evidence that Panax ginseng improves vascular dysfunction induced by diabetes and the protective effects may possibly be due to the downregulation of atherosclerosis-related genes and altered lipid metabolism, which help to restore normal endothelium functions.

  17. Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism.

    Directory of Open Access Journals (Sweden)

    Deborah Lai

    Full Text Available Papillomavirus E2 proteins are predominantly retained in the nuclei of infected cells, but oncogenic (high-risk HPV-18 and 16 E2 can shuttle between the host nucleus and cytoplasm. We show here that cytoplasmic HPV-18 E2 localizes to mitochondrial membranes, and independent mass spectrometry analyses of the E2 interactome revealed association to the inner mitochondrial membrane including components of the respiratory chain. Mitochondrial E2 association modifies the cristae morphology when analyzed by electron microscopy and increases production of mitochondrial ROS. This ROS release does not induce apoptosis, but instead correlates with stabilization of HIF-1α and increased glycolysis. These mitochondrial functions are not shared by the non-oncogenic (low-risk HPV-6 E2 protein, suggesting that modification of cellular metabolism by high-risk HPV E2 proteins could play a role in carcinogenesis by inducing the Warburg effect.

  18. Organic extracts of coke oven emissions can induce genetic damage in metabolically competent HepG2 cells.

    Science.gov (United States)

    Xin, Lili; Wang, Jianshu; Guo, Sifan; Wu, Yanhu; Li, Xiaohai; Deng, Huaxin; Kuang, Dan; Xiao, Wei; Wu, Tangchun; Guo, Huan

    2014-05-01

    Coke oven emissions (COEs) containing various carcinogenic polycyclic aromatic hydrocarbons (PAHs) represent the coal-burning pollution in the air. Organic pollutants in the aerosol and particulate matter of COEs were collected from the bottom, side, and top of a coke oven. The Comet assay and cytokinesis-block micronucleus cytome assay were conducted to analyze the genetic damage of extractable organic matter (EOM) of COEs on HepG2 cells. All the three EOMs could induce significant dose-dependent increases in Olive tail moment, tail DNA, and tail length, micronuclei, nucleoplasmic bridges, and nuclear buds frequencies, which were mostly positively correlated with the total PAHs concentration in each EOM. In conclusion, EOMs of COEs in the three typical working places of coke oven can induce DNA strand breaks and genomic instability in the metabolically competent HepG2 cells. The PAHs in EOMs may be important causative agents for the genotoxic effects of COEs. PMID:24709322

  19. Oral salmon calcitonin enhances insulin action and glucose metabolism in diet-induced obese streptozotocin-diabetic rats

    DEFF Research Database (Denmark)

    Feigh, Michael; Hjuler, Sara T; Andreassen, Kim V;

    2014-01-01

    We previously reported that oral delivery of salmon calcitonin (sCT) improved energy and glucose homeostasis and attenuated diabetic progression in animal models of diet-induced obesity (DIO) and type 2 diabetes, although the glucoregulatory mode of action was not fully elucidated. In the present...... study we hypothesized that oral sCT as pharmacological intervention 1) exerted anti-hyperglycemic efficacy, and 2) enhanced insulin action in DIO-streptozotocin (DIO-STZ) diabetic rats. Diabetic hyperglycemia was induced in male selectively bred DIO rats by a single low dose (30mg/kg) injection of STZ...... was enhanced in conjunction with protection of pancreatic insulin content. The results of the present study indicate that oral sCT exerts a novel insulin-sensitizing effect to improve glucose metabolism in obesity and type 2 diabetes....

  20. Anticonvulsant effect of time-restricted feeding in a pilocarpine-induced seizure model: Metabolic and epigenetic implications.

    Directory of Open Access Journals (Sweden)

    Jorge eLandgrave-Gómez

    2016-01-01

    Full Text Available A new generation of antiepileptic drugs has emerged; however, one-third of epilepsy patients do not properly respond to pharmacological treatments. The purpose of the present study was to investigate whether time-restricted feeding has an anticonvulsant effect and whether this restrictive diet promotes changes in energy metabolism and epigenetic modifications in a pilocarpine-induced seizure model. To resolve our hypothesis, one group of rats had free access to food and water ad libitum (AL and a second group underwent a time-restricted feeding (TRF schedule. We used the lithium-pilocarpine model to induce status epilepticus (SE, and behavioral seizure monitoring was analyzed. Additionally, an electroencephalography (EEG recording was performed to verify the effect of TRF on cortical electrical activity after a pilocarpine injection. For biochemical analysis, animals were sacrificed 24 hours after SE and hippocampal homogenates were used to evaluate the proteins related to metabolism and chromatin structure. Our results showed that TRF had an anticonvulsant effect as measured by the prolonged latency of forelimb clonus seizure, a decrease in the seizure severity score and fewer animals reaching SE. Additionally, the power of the late phase EEG recordings in the AL group was significantly higher than the TRF group. Moreover, we found that TRF is capable of inducing alterations in signaling pathways that regulate energy metabolism, including an increase in the phosphorylation of AMP dependent kinase (AMPK and a decrease in the phosphorylation of Akt kinase. Furthermore, we found that TRF was able to significantly increase the beta hydroxybutyrate (β-HB concentration, an endogenous inhibitor of histone deacetylases (HDACs. Finally, we found a significant decrease in HDAC activity as well as an increase in acetylation on histone 3 (H3 in hippocampal homogenates from the TRF group. These findings suggest that alterations in energy metabolism and the

  1. Anticonvulsant Effect of Time-Restricted Feeding in a Pilocarpine-Induced Seizure Model: Metabolic and Epigenetic Implications.

    Science.gov (United States)

    Landgrave-Gómez, Jorge; Mercado-Gómez, Octavio Fabián; Vázquez-García, Mario; Rodríguez-Molina, Víctor; Córdova-Dávalos, Laura; Arriaga-Ávila, Virginia; Miranda-Martínez, Alfredo; Guevara-Guzmán, Rosalinda

    2016-01-01

    A new generation of antiepileptic drugs has emerged; however, one-third of epilepsy patients do not properly respond to pharmacological treatments. The purpose of the present study was to investigate whether time-restricted feeding (TRF) has an anticonvulsant effect and whether this restrictive diet promotes changes in energy metabolism and epigenetic modifications in a pilocarpine-induced seizure model. To resolve our hypothesis, one group of rats had free access to food and water ad libitum (AL) and a second group underwent a TRF schedule. We used the lithium-pilocarpine model to induce status epilepticus (SE), and behavioral seizure monitoring was analyzed. Additionally, an electroencephalography (EEG) recording was performed to verify the effect of TRF on cortical electrical activity after a pilocarpine injection. For biochemical analysis, animals were sacrificed 24 h after SE and hippocampal homogenates were used to evaluate the proteins related to metabolism and chromatin structure. Our results showed that TRF had an anticonvulsant effect as measured by the prolonged latency of forelimb clonus seizure, a decrease in the seizure severity score and fewer animals reaching SE. Additionally, the power of the late phase EEG recordings in the AL group was significantly higher than the TRF group. Moreover, we found that TRF is capable of inducing alterations in signaling pathways that regulate energy metabolism, including an increase in the phosphorylation of AMP dependent kinase (AMPK) and a decrease in the phosphorylation of Akt kinase. Furthermore, we found that TRF was able to significantly increase the beta hydroxybutyrate (β-HB) concentration, an endogenous inhibitor of histone deacetylases (HDACs). Finally, we found a significant decrease in HDAC activity as well as an increase in acetylation on histone 3 (H3) in hippocampal homogenates from the TRF group. These findings suggest that alterations in energy metabolism and the increase in β-HB mediated by TRF

  2. Protein kinase A induces UCP1 expression in specific adipose depots to increase energy expenditure and improve metabolic health.

    Science.gov (United States)

    Dickson, Lorna M; Gandhi, Shriya; Layden, Brian T; Cohen, Ronald N; Wicksteed, Barton

    2016-07-01

    Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial function. PKA transduces the cAMP signal downstream of G protein-coupled receptors, which are being explored for therapeutic manipulation to reduce obesity and improve metabolic health. This study aimed to determine the overall physiological consequences of PKA activation in adipose tissue. Mice expressing an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose tissue (WAT) depots and brown adipose tissue (BAT) compared with controls. Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26 wk of age were protected from diet-induced weight gain. Metabolic health was improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell function. Adipose tissue health was improved, with smaller adipocyte size and reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that Adipoq-caPKA mice were shown to have increased energy expenditure, but no difference to littermate controls in physical activity or food consumption. Immunoblotting of adipose tissue showed increased expression of uncoupling protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no induction in the visceral depots. Feeding a HFD increased PKA activity in epididymal WAT of wild-type mice compared with chow, but did not change PKA activity in subcutaneous WAT or BAT. This was associated with changes in PKA regulatory subunit expression. This study shows that adipose tissue PKA activity is sufficient to increase energy expenditure and indicates that PKA is a beneficial target in metabolic health. PMID:27097660

  3. Navigating natural variation in herbivory-induced secondary metabolism in coyote tobacco populations using MS/MS structural analysis.

    Science.gov (United States)

    Li, Dapeng; Baldwin, Ian T; Gaquerel, Emmanuel

    2015-07-28

    Natural variation can be extremely useful in unraveling the determinants of phenotypic trait evolution but has rarely been analyzed with unbiased metabolic profiling to understand how its effects are organized at the level of biochemical pathways. Native populations of Nicotiana attenuata, a wild tobacco species, have been shown to be highly genetically diverse for traits important for their interactions with insects. To resolve the chemodiversity existing in these populations, we developed a metabolomics and computational pipeline to annotate leaf metabolic responses to Manduca sexta herbivory. We selected seeds from 43 accessions of different populations from the southwestern United States--including the well-characterized Utah 30th generation inbred accession--and grew 183 plants in the glasshouse for standardized herbivory elicitation. Metabolic profiles were generated from elicited leaves of each plant using a high-throughput ultra HPLC (UHPLC)-quadrupole TOFMS (qTOFMS) method, processed to systematically infer covariation patterns among biochemically related metabolites, as well as unknown ones, and finally assembled to map natural variation. Navigating this map revealed metabolic branch-specific variations that surprisingly only partly overlapped with jasmonate accumulation polymorphisms and deviated from canonical jasmonate signaling. Fragmentation analysis via indiscriminant tandem mass spectrometry (idMS/MS) was conducted with 10 accessions that spanned a large proportion of the variance found in the complete accession dataset, and compound spectra were computationally assembled into spectral similarity networks. The biological information captured by this networking approach facilitates the mining of the mass spectral data of unknowns with high natural variation, as demonstrated by the annotation of a strongly herbivory-inducible phenolic derivative, and can guide pathway analysis. PMID:26170304

  4. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.

    Science.gov (United States)

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-11-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  5. Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

    Directory of Open Access Journals (Sweden)

    Oluwafeyisetan O. Adebiyi

    2015-12-01

    Full Text Available Nucleoside Reverse Transcriptase Inhibitors (NRTIs have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7 were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT (groups I, II III, 50 mg/kg stavudine (d4T (groups IV, V, VI and 3 mL/kg of distilled water (group VII. Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy.

  6. Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α*

    Science.gov (United States)

    Zhao, Wei; Chang, Cunjie; Cui, Yangyan; Zhao, Xiaozhi; Yang, Jun; Shen, Lan; Zhou, Ji; Hou, Zhibo; Zhang, Zhen; Ye, Changxiao; Hasenmayer, Donald; Perkins, Robert; Huang, Xiaojing; Yao, Xin; Yu, Like; Huang, Ruimin; Zhang, Dianzheng; Guo, Hongqian; Yan, Jun

    2014-01-01

    Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as “Warburg effect,” to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy. PMID:24584933

  7. Virus-induced gene silencing of pea CHLI and CHLD affects tetrapyrrole biosynthesis, chloroplast development and the primary metabolic network.

    Science.gov (United States)

    Luo, Tao; Luo, Sha; Araújo, Wagner L; Schlicke, Hagen; Rothbart, Maxi; Yu, Jing; Fan, Tingting; Fernie, Alisdair R; Grimm, Bernhard; Luo, Meizhong

    2013-04-01

    The first committed and highly regulated step of chlorophyll biosynthesis is the insertion of Mg(2+) into protoporphyrin IX, which is catalyzed by Mg chelatase that consists of CHLH, CHLD and CHLI subunits. In this study, CHLI and CHLD genes were suppressed by virus-induced gene silencing (VIGS-CHLI and VIGS-CHLD) in pea (Pisum sativum), respectively. VIGS-CHLI and VIGS-CHLD plants both showed yellow leaf phenotypes with the reduced Mg chelatase activity and the inactivated synthesis of 5-aminolevulinic acid. The lower chlorophyll accumulation correlated with undeveloped thylakoid membranes, altered chloroplast nucleoid structure, malformed antenna complexes and compromised photosynthesis capacity in the yellow leaf tissues of the VIGS-CHLI and VIGS-CHLD plants. Non-enzymatic antioxidant contents and the activities of antioxidant enzymes were altered in response to enhanced accumulation of reactive oxygen species (ROS) in the chlorophyll deficient leaves of VIGS-CHLI and VIGS-CHLD plants. Furthermore, the results of metabolite profiling indicate a tight correlation between primary metabolic pathways and Mg chelatase activity. We also found that CHLD induces a feedback-regulated change of the transcription of photosynthesis-associated nuclear genes. CHLD and CHLI silencing resulted in a rapid reduction of photosynthetic proteins. Taken together, Mg chelatase is not only a key regulator of tetrapyrrole biosynthesis but its activity also correlates with ROS homeostasis, primary interorganellar metabolism and retrograde signaling in plant cells. PMID:23416492

  8. Endotoxin-induced basal respiration alterations of renal HK-2 cells: A sign of pathologic metabolism down-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Quoilin, C., E-mail: cquoilin@ulg.ac.be [Laboratory of Biomedical Spectroscopy, Department of Physics, University of Liege, 4000 Liege (Belgium); Mouithys-Mickalad, A. [Center of Oxygen Research and Development, Department of Chemistry, University of Liege, 4000 Liege (Belgium); Duranteau, J. [Department of Anaesthesia and Surgical ICU, CHU Bicetre, University Paris XI Sud, 94275 Le Kremlin Bicetre (France); Gallez, B. [Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Universite catholique de Louvain, 1200 Brussels (Belgium); Hoebeke, M. [Laboratory of Biomedical Spectroscopy, Department of Physics, University of Liege, 4000 Liege (Belgium)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer A HK-2 cells model of inflammation-induced acute kidney injury. Black-Right-Pointing-Pointer Two oximetry methods: high resolution respirometry and ESR spectroscopy. Black-Right-Pointing-Pointer Oxygen consumption rates of renal cells decrease when treated with LPS. Black-Right-Pointing-Pointer Cells do not recover normal respiration when the LPS treatment is removed. Black-Right-Pointing-Pointer This basal respiration alteration is a sign of pathologic metabolism down-regulation. -- Abstract: To study the mechanism of oxygen regulation in inflammation-induced acute kidney injury, we investigate the effects of a bacterial endotoxin (lipopolysaccharide, LPS) on the basal respiration of proximal tubular epithelial cells (HK-2) both by high-resolution respirometry and electron spin resonance spectroscopy. These two complementary methods have shown that HK-2 cells exhibit a decreased oxygen consumption rate when treated with LPS. Surprisingly, this cellular respiration alteration persists even after the stress factor was removed. We suggested that this irreversible decrease in renal oxygen consumption after LPS challenge is related to a pathologic metabolic down-regulation such as a lack of oxygen utilization by cells.

  9. Endotoxin-induced basal respiration alterations of renal HK-2 cells: A sign of pathologic metabolism down-regulation

    International Nuclear Information System (INIS)

    Highlights: ► A HK-2 cells model of inflammation-induced acute kidney injury. ► Two oximetry methods: high resolution respirometry and ESR spectroscopy. ► Oxygen consumption rates of renal cells decrease when treated with LPS. ► Cells do not recover normal respiration when the LPS treatment is removed. ► This basal respiration alteration is a sign of pathologic metabolism down-regulation. -- Abstract: To study the mechanism of oxygen regulation in inflammation-induced acute kidney injury, we investigate the effects of a bacterial endotoxin (lipopolysaccharide, LPS) on the basal respiration of proximal tubular epithelial cells (HK-2) both by high-resolution respirometry and electron spin resonance spectroscopy. These two complementary methods have shown that HK-2 cells exhibit a decreased oxygen consumption rate when treated with LPS. Surprisingly, this cellular respiration alteration persists even after the stress factor was removed. We suggested that this irreversible decrease in renal oxygen consumption after LPS challenge is related to a pathologic metabolic down-regulation such as a lack of oxygen utilization by cells.

  10. Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications.

    Science.gov (United States)

    Adebiyi, Oluwafeyisetan O; Adebiyi, Olubunmi A; Owira, Peter M O

    2015-12-01

    Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin's effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy. PMID:26690471

  11. Modulators of hepatic lipoprotein metabolism identified in a search for small-molecule inducers of tribbles pseudokinase 1 expression.

    Directory of Open Access Journals (Sweden)

    Marek M Nagiec

    Full Text Available Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1 to the risk of coronary artery disease (CAD. Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging.

  12. SU-E-J-122: Detecting Treatment-Induced Metabolic Abnormalities in Craniopharyngioma Patients Undergoing Surgery and Proton Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hua, C; Shulkin, B; Li, Y; LI, X; Merchant, T [St. Jude Children' s Research Hospital, Memphis, TN (United States); Indelicato, D [University of Florida Proton Therapy Institute, Jacksonville, FL (United States); Boop, F [Semmes-Murphey Neurologic and Spine Institute, Memphis, TN (United States)

    2014-06-01

    Purpose: To identify treatment-induced defects in the brain of children with craniopharyngioma receiving surgery and proton therapy using fluorodeoxyglucose positron emission tomography (FDG PET). Methods: Forty seven patients were enrolled on a clinical trial for craniopharyngioma with serial imaging and functional evaluations. Proton therapy was delivered using the double-scattered beams with a prescribed dose of 54 Cobalt Gray Equivalent. FDG tracer uptake in each of 63 anatomical regions was computed after warping PET images to a 3D reference template in Talairach coordinates. Regional uptake was deemed significantly low or high if exceeding two standard deviations of normal population from the mean. For establishing the normal ranges, 132 children aged 1–20 years with noncentral nervous system related diseases and normal-appearing cerebral PET scans were analyzed. Age- and gender-dependent regional uptake models were developed by linear regression and confidence intervals were calculated. Results: Most common PET abnormality before proton therapy was significantly low uptake in the frontal lobe, the occipital lobe (particularly in cuneus), the medial and ventral temporal lobe, cingulate gyrus, caudate nuclei, and thalamus. They were related to injury from surgical corridors, tumor mass effect, insertion of a ventricular catheter, and the placement of an Ommaya reservoir. Surprisingly a significantly high uptake was observed in temporal gyri and the parietal lobe. In 13 patients who already completed 18-month PET scans, metabolic abnormalities improved in 11 patients from baseline. One patient had persistent abnormalities. Only one revealed new uptake abnormalities in thalamus, brainstem, cerebellum, and insula. Conclusion: Postoperative FDG PET of craniopharyngioma patients revealed metabolic abnormalities in specific regions of the brain. Proton therapy did not appear to exacerbate these surgery- and tumor-induced defects. In patients with persistent and

  13. Short-term captivity influences maximal cold-induced metabolic rates and their repeatability in summer-acclimatized American goldfinches Spinus tristis

    Directory of Open Access Journals (Sweden)

    David L. SWANSON, Marisa O. KING

    2013-08-01

    Full Text Available Studies of metabolic variation in birds have involved both wild and captive individuals, but few studies have investigated whether captivity directly influences metabolic rates, despite such variation potentially confounding conclusions regarding how metabolic rates respond to the conditions under study. In addition, whether short-term captivity influences metabolic rate repeatability in birds is currently uninvestigated. In this study, we measured Msum (maximal cold-induced metabolic rates in summer acclimatized American goldfinches Spinus tristis directly after capture from wild populations, after approximately 2 weeks of indoor captivity (Captive 1, and again after an additional 1–2 weeks of captivity (Captive 2. Msum increased significantly (16.9% following the initial captive period, but remained stable thereafter. Body mass (Mb also increased significantly (9.2% during the initial captive period but remained stable thereafter, suggesting that muscle growth and/or remodeling of body composition produced the observed metabolic variation. Mb and Msum were not significantly repeatable between wild and Captive 1 birds, but were significantly repeatable between Captive 1 and Captive 2 groups. These data suggest that caution must be exercised when extrapolating metabolic rates from short-term captive to wild populations. In addition, Msum was a repeatable trait for birds under conditions where mean metabolic rates remained stable, but Msum repeatability disappeared during acclimation to conditions promoting phenotypically flexible metabolic responses. This suggests that the capacity for phenotypic flexibility varies among individuals, and such variation could have fitness consequences [Current Zoology 59 (4: 439–448, 2013].

  14. L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Madsen, Andreas Nygaard; Smajilovic, Sanela;

    2012-01-01

    L: -Arginine (L: -Arg) is a conditionally essential amino acid and a natural constituent of dietary proteins. Studies in obese rats and type 2 diabetic humans have indicated that dietary supplementation with L: -Arg can diminish gain in white adipose tissue (WAT) and improve insulin sensitivity...... on locomotor activity, substrate metabolism or expression of uncoupling proteins (UCP1 and UCP2) in adipose tissues was displayed. In conclusion, dietary L: -Arg supplementation substantially affects an array of metabolic-associated parameters including a reduction in WAT, hyperphagia, improved insulin...... groups. Glucose homeostasis experiments revealed a major effect of L: -Arg supplementation on glucose tolerance and insulin sensitivity, interestingly, independent of a parallel regulation in whole-body adiposity. Increased L: -Arg ingestion also raised energy expenditure; however, no concurrent effect...

  15. Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.

    Science.gov (United States)

    Yuan, Yuan; Zheng, Jiyue; Wang, Meiyu; Li, Yuan; Ruan, Jianqing; Zhang, Hongjian

    2016-07-20

    Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human. PMID:27362917

  16. Killed but Metabolically Active Bacillus anthracis Vaccines Induce Broad and Protective Immunity against Anthrax▿

    OpenAIRE

    Skoble, Justin; Beaber, John W.; Gao, Yi; Lovchik, Julie A.; Sower, Laurie E.; Liu, Weiqun; Luckett, William; Johnny W. Peterson; Calendar, Richard; Daniel A Portnoy; Lyons, C. Rick; Dubensky, Thomas W

    2009-01-01

    Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which ...

  17. Adiponectin Induces A20 Expression in Adipose Tissue To Confer Metabolic Benefit

    OpenAIRE

    Hand LE, Usan P, Cooper GJS, Xu LY, Ammori B, Cunningham PS, Aghamohammadzadeh R, Soran H, Greenstein A, Loudon ASI, Bechtold DA, Ray DW

    2014-01-01

    Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. We detail that mice lacking Reverbα exhibit enhanced fat storage without the predicted increased WAT inflammation or loss of insulin sensitivity. In contrast to most animal models of obesity and obese human patients, Reverbα−/− mice exhibit elevated serum adiponectin levels and increased adiponectin secretion from WAT explants in vitro, highlighting ...

  18. Rat lung fibroblast collagen metabolism in bleomycin-induced pulmonary fibrosis.

    OpenAIRE

    Phan, S. H.; Varani, J.; Smith, D.

    1985-01-01

    Endotracheal bleomycin administration in rats and other animal species causes rapid development of pulmonary fibrosis, characterized by increased lung collagen synthesis and deposition. To clarify the mechanism, lung fibroblasts from bleomycin-treated rats (BRF) were isolated and maintained in tissue culture. They were then compared with those from normal untreated control animals, with respect to several key parameters of collagen metabolism. BRF synthesized collagen at a rate 35-82% above n...

  19. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

    OpenAIRE

    Prakash, Satya

    2011-01-01

    Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, un...

  20. Metabolic and transcriptomic responses of weaned pigs induced by different dietary amylose and amylopectin ratio.

    Directory of Open Access Journals (Sweden)

    He Jun

    Full Text Available Starch is one of the major dietary energy sources for mammals. However, the nutritional value of starch largely depends on its amylose and amylopectin ratio. In this study, the overall metabolic and transcriptomic responses of weaned pigs fed with different dietary starches were assessed. Sixteen weaned pigs were randomly allotted to two experimental diets containing either of pure cassava starch (CS or maize starch (MS as the sole energy source (the amylose-amylopectin ratio were 0.25 and 0.43, respectively. Results indicated that the body weight gain was not affected by different dietary starches. However, a moderate fatty liver was observed in CS-fed group. Long-term ingestion of CS not only increased the total liver fat content, but significantly elevated the liver triglyceride and cholesterol content (P<0.05. In addition, the serum insulin and cholesterol concentrations were both elevated in CS-fed group (P<0.05. Microarray analysis led to the identification of 648 genes differentially expressed in liver (P<0.05, and a lot of them were involved in lipid and carbohydrate metabolism. Additionally, pathway analysis indicated that both the insulin and PPAR signaling pathways were acutely affected by dietary amylose-amylopectin ratio. Long-term ingestion of CS activated the transcription of lipogenic genes such as hmgr and fasn, but decreased the expression of lipolytic genes such as aox1, ppara and fbp. The microarray results correlated well with the measurements of several key enzymes involved in hepatic lipid metabolism. Our results suggested that both the metabolic and transcriptomic responses of weaned pigs were tightly regulated by dietary starch composition, and a high amylose ratio starch (i.e MS may be more healthful for mammals as the long-term energy source by down-regulation of hepatic lipogenesis and steroidogenesis.

  1. A virus-induced gene silencing approach to understanding alkaloid metabolism in Catharanthus roseus

    OpenAIRE

    Liscombe, David K.; O’Connor, Sarah E.

    2011-01-01

    The anticancer agents vinblastine and vincristine are bisindole alkaloids derived from coupling vindoline and catharanthine, monoterpenoid indole alkaloids produced exclusively by Madagascar periwinkle (Catharanthus roseus) plants. Industrial production of vinblastine and vincristine currently relies on isolation from C. roseus leaves, a process that affords these compounds in 0.0003–0.01% yields. Metabolic engineering efforts to improve alkaloid content or provide alternative sources of the ...

  2. Genetic Ablation of CD38 Protects against Western Diet-Induced Exercise Intolerance and Metabolic Inflexibility

    OpenAIRE

    Shian-Huey Chiang; W. Wallace Harrington; Guizhen Luo; Naphtali O. Milliken; John C Ulrich; Jing Chen; Rajpal, Deepak K.; Ying Qian; Tiffany Carpenter; Rusty Murray; Robert S Geske; Stimpson, Stephen A.; Kramer, Henning F.; Curt D Haffner; J David Becherer

    2015-01-01

    Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of...

  3. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

    OpenAIRE

    Bell Jimmy D; Nunn Alistair VW; Guy Geoffrey W

    2009-01-01

    Abstract The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membran...

  4. Waterlogging-induced changes in fermentative metabolism in roots and nodules of soybean genotypes

    Directory of Open Access Journals (Sweden)

    Junior Borella

    2014-12-01

    Full Text Available Waterlogging blocks the oxygen supply to the root system which inhibits respiration, and greatly reduces the energy status of cells that affect important metabolic processes. This study evaluated fermentative metabolism and carbohydrate contents in the root system of two soybean (Glycine max L. Merril genotypes under hypoxic and post-hypoxic conditions. Nodulated plants (genotypes Fundacep 53 RR and BRS Macota were grown in vermiculite and transferred to a hydroponic system at the reproductive stage. The root system was submitted to hypoxia by flowing N2 (nitrogen gas in a solution for 24 and 72 h. For recovery, plants returned to normoxia condition by transfer to vermiculite for 24 and 72 h. Fermentative enzyme activity, levels of anaerobic metabolites and carbohydrate content were all quantified in roots and nodules. The activity of alcohol dehydrogenase, pyruvate decarboxylase and lactate dehydrogenase enzymes, as well as the content of ethanol and lactate, increased with hypoxia in roots and nodules, and subsequently returned to pre-hypoxic levels in the recovery phase in both genotypes. Pyruvate content increased in nodules and decreased in roots. Sugar and sucrose levels increased in roots and decreased in nodules under hypoxia in both genotypes. Fundacep RR 53 was more responsive to the metabolic effects caused by hypoxia and post-hypoxia than BRS Macota, and it is likely that these characteristics contribute positively to improving adaptation to oxygen deficiency.

  5. New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism

    Science.gov (United States)

    Currently available inducibleCre/loxPsystems, despite their considerable utility in gene manipulation, have pitfalls in certain scenarios, such as unsatisfactory recombination rates and deleterious effects on physiology and behavior. To overcome these limitations, we designed a new, inducible gene-t...

  6. Peroxisome proliferator-activated receptor alpha (PPARalpha) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

    DEFF Research Database (Denmark)

    Frigerio, F; Brun, T; Bartley, C;

    2009-01-01

    and investigated key metabolic pathways and genes responsible for metabolism-secretion coupling during a culture period of 3 days in the presence of 0.4 mmol/l oleate. RESULTS: In INS-1E cells, the secretory dysfunction primarily induced by oleate was aggravated by silencing of PPARalpha. Conversely, PPARalpha...... enzyme pyruvate carboxylase. PPARalpha overproduction increased both beta-oxidation and fatty acid storage in the form of neutral triacylglycerol, revealing overall induction of lipid metabolism. These observations were substantiated by expression levels of associated genes. CONCLUSIONS....../INTERPRETATION: PPARalpha protected INS-1E beta cells from oleate-induced dysfunction, promoting both preservation of glucose metabolic pathways and fatty acid turnover....

  7. Oximetry: a new non-invasive method to detect metabolic effects induced by a local application of mechanical vibration

    Science.gov (United States)

    Felici, A.; Trombetta, C.; Abundo, P.; Foti, C.; Rosato, N.

    2012-10-01

    Mechanical vibrations application is increasingly common in clinical practice due to the effectiveness induced by these stimuli on the human body. Local vibration (LV) application allows to apply and act only where needed, focusing the treatment on the selected body segment. An experimental device for LV application was used to generate the vibrations. The aim of this study was to detect and analyze the metabolic effects induced by LV on the brachial bicep muscle by means of an oximeter. This device monitors tissue and muscle oxygenation using NIRS (Near Infrared Spectroscopy) and is able to determine the concentration of haemoglobin and oxygen saturation in the tissue. In a preliminary stage we also investigated the effects induced by LV application, by measuring blood pressure, heart rate, oxygen saturation and temperature. These data confirmed that the effects induced by LV application are actually localized. The results of the measurements obtained using the oximeter during the vibration application, have shown a variation of the concentrations. In particular an increase of oxygenate haemoglobin was shown, probably caused by an increased muscle activity and/or a rise in local temperature detected during the application.

  8. Targeted metabolomic study indicating glycyrrhizin’s protection against acetaminophen-induced liver damage through reversing fatty acid metabolism.

    Science.gov (United States)

    Yu, Jian; Jiang, Yang-Shen; Jiang, Yuan; Peng, Yan-Fang; Sun, Zhuang; Dai, Xiao-Nan; Cao, Qiu-Ting; Sun, Ying-Ming; Han, Jing-Chun; Gao, Ya-Jie

    2014-06-01

    The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin-treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism.

  9. Oximetry: a new non-invasive method to detect metabolic effects induced by a local application of mechanical vibration

    International Nuclear Information System (INIS)

    Mechanical vibrations application is increasingly common in clinical practice due to the effectiveness induced by these stimuli on the human body. Local vibration (LV) application allows to apply and act only where needed, focusing the treatment on the selected body segment. An experimental device for LV application was used to generate the vibrations. The aim of this study was to detect and analyze the metabolic effects induced by LV on the brachial bicep muscle by means of an oximeter. This device monitors tissue and muscle oxygenation using NIRS (Near Infrared Spectroscopy) and is able to determine the concentration of haemoglobin and oxygen saturation in the tissue. In a preliminary stage we also investigated the effects induced by LV application, by measuring blood pressure, heart rate, oxygen saturation and temperature. These data confirmed that the effects induced by LV application are actually localized. The results of the measurements obtained using the oximeter during the vibration application, have shown a variation of the concentrations. In particular an increase of oxygenate haemoglobin was shown, probably caused by an increased muscle activity and/or a rise in local temperature detected during the application.

  10. Beneficial effects of flaxseed oil and fish oil diet are through modulation of different hepatic genes involved in lipid metabolism in streptozotocin–nicotinamide induced diabetic rats

    OpenAIRE

    Devarshi, Prasad P.; Jangale, Nivedita M.; Ghule, Arvindkumar E.; Bodhankar, Subhash L.; Harsulkar, Abhay M.

    2012-01-01

    Dietary omega-3 fatty acids have been demonstrated to have positive physiological effects on lipid metabolism, cardiovascular system and insulin resistance. Type-2 diabetes (T2DM) is known for perturbations in fatty acid metabolism leading to dyslipidemia. Our objective was to investigate beneficial effects of dietary flaxseed oil and fish oil in streptozotocin–nicotinamide induced diabetic rats. Thirty-six adult, male, Wistar rats were divided into six groups: three diabetic and three non-di...

  11. Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain*

    Science.gov (United States)

    Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G.; Dagda, Marisela; Dagda, Raul; Moaddel, Ruin; Balbo, Silvia; Sanghvi, Mitesh; Chen, Yukun; Hogue, Ryan J.; Bergeson, Susan E.; Henderson, George I.; Kruman, Inna I.

    2012-01-01

    The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr+/− mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain. PMID:23118224

  12. Metabolic encephalopathies.

    Science.gov (United States)

    Angel, Michael J; Young, G Bryan

    2011-11-01

    Kinnier Wilson coined the term metabolic encephalopathy to describe a clinical state of global cerebral dysfunction induced by systemic stress that can vary in clinical presentation from mild executive dysfunction to deep coma with decerebrate posturing; the causes are numerous. Some mechanisms by which cerebral dysfunction occurs in metabolic encephalopathies include focal or global cerebral edema, alterations in transmitter function, the accumulation of uncleared toxic metabolites, postcapillary venule vasogenic edema, and energy failure. This article focuses on common causes of metabolic encephalopathy, and reviews common causes, clinical presentations and, where relevant, management.

  13. High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity.

    Science.gov (United States)

    Denou, Emmanuel; Marcinko, Katarina; Surette, Michael G; Steinberg, Gregory R; Schertzer, Jonathan D

    2016-06-01

    Diet and exercise underpin the risk of obesity-related metabolic disease. Diet alters the gut microbiota, which contributes to aspects of metabolic disease during obesity. Repeated exercise provides metabolic benefits during obesity. We assessed whether exercise could oppose changes in the taxonomic and predicted metagenomic characteristics of the gut microbiota during diet-induced obesity. We hypothesized that high-intensity interval training (HIIT) would counteract high-fat diet (HFD)-induced changes in the microbiota without altering obesity in mice. Compared with chow-fed mice, an obesity-causing HFD decreased the Bacteroidetes-to-Firmicutes ratio and decreased the genetic capacity in the fecal microbiota for metabolic pathways such as the tricarboxylic acid (TCA) cycle. After HFD-induced obesity was established, a subset of mice were HIIT for 6 wk, which increased host aerobic capacity but did not alter body or adipose tissue mass. The effects of exercise training on the microbiota were gut segment dependent and more extensive in the distal gut. HIIT increased the alpha diversity and Bacteroidetes/Firmicutes ratio of the distal gut and fecal microbiota during diet-induced obesity. Exercise training increased the predicted genetic capacity related to the TCA cycle among other aspects of metabolism. Strikingly, the same microbial metabolism indexes that were increased by exercise were all decreased in HFD-fed vs. chow diet-fed mice. Therefore, exercise training directly opposed some of the obesity-related changes in gut microbiota, including lower metagenomic indexes of metabolism. Some host and microbial pathways appeared similarly affected by exercise. These exercise- and diet-induced microbiota interactions can be captured in feces.

  14. Alcoholic leaf extract of Plectranthus amboinicus regulates carbohydrate metabolism in alloxan-induced diabetic rats

    OpenAIRE

    Koti, B. C.; Aparna Gore; Thippeswamy, A.H.M.; A. H. M. Viswanatha Swamy; Rucha Kulkarni

    2011-01-01

    Objective: The present investigation was undertaken to explore the possible mechanisms of Plectranthus amboinicus leaf extract in alloxan-induced diabetic rats. Materials and Methods: Control and alloxan-induced diabetic albino rats received different treatments; orally control (vehicle), 200 mg/kg and 400 mg/kg of ethanol extract of Plectranthus amboinicus (PAEE) and 600 μg/kg of glibenclamide (standard) for 15 days. At the end of the experiment, the animals were sacrificed and enzyme ac...

  15. Increased excitability and metabolism in pilocarpine induced epileptic rats: effect of Bacopa monnieri.

    Science.gov (United States)

    Mathew, Jobin; Paul, Jes; Nandhu, M S; Paulose, C S

    2010-09-01

    We have evaluated the acetylcholine esterase and malate dehydrogenase activity in the muscle, epinephrine, norepinephrine, insulin and T3 content in the serum of epileptic rats. Acetylcholine esterase and malate dehydrogenase activity increased in the muscle and decreased in the heart of the epileptic rats compared to control. Insulin and T3 content were increased significantly in the serum of the epileptic rats. Our results suggest that repetitive seizures resulted in increased metabolism and excitability in epileptic rats. Bacopa monnieri and Bacoside-A treatment prevents the occurrence of seizures there by reducing the impairment on peripheral nervous system.

  16. The model of rat lipid metabolism disorder induced by chronic stress accompanying high-fat-diet

    OpenAIRE

    Shaodong Chen; Jing Li; Haihong Zhou; Manting Lin; Yihua Liu

    2011-01-01

    Abstract Objective To develop an animal model of Lipid Metabolism Disorder, which conforms to human clinical characteristic. Methods: There were 24 male Wistar rats that were randomly divided into 3 groups with 8 rats in each. They were group A (normal diet), group B (high-fat-diet), group C (chronic stress+ high-fat-diet). Group A was fed with normal diet, while group B and C were fed with high-fat-diet, going on for 55 days. From the 35th day, group B and C received one time of daily chroni...

  17. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue

    OpenAIRE

    Yin, Jun; Gao, Zhanguo; He, Qing; Zhou, Dequan; Guo, ZengKui; Ye, Jianping

    2008-01-01

    Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipocytes. We determined the dynamic relationship of ATH and adiposity in ob/ob mice. The interstitial oxygen pressure (Po2) was monitored in the epididymal fat pads for ATH. During weight gain from 39.5 to 55.5 g, Po2 declined from 34.8 to 20.1 mmHg, which are 40–60% lower than those in the lean mice. ...

  18. Mechanisms of Indomethacin-Induced Alterations in the Choline Phospholipid Metabolism of Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Kristine Glunde

    2006-09-01

    Full Text Available Human mammary epithelial cells (HMECs exhibit an increase in phosphocholine (PC and total cholinecontaining compounds, as well as a switch from high glycerophosphocholine (GPC/low PC to low GPC/high PC, with progression to malignant phenotype. The treatment of human breast cancer cells with a nonsteroidal anti-inflammatory agent, indomethacin, reverted the high PC/low GPC pattern to a low PC/high GPC pattern indicative of a less malignant phenotype, supported by decreased invasion. Here, we have characterized mechanisms underlying indomethacininduced alterations in choline membrane metabolism in malignant breast cancer cells and nonmalignant HMECs labeled with [1,2-13C]choline using 1H and 13C magnetic resonance spectroscopy. Microarray gene expression analysis was performed to understand the molecular mechanisms underlying these changes. In breast cancer cells, indomethacin treatment activated phospholipases that, combined with an increased choline phospholipid biosynthesis, led to increased GPC and decreased PC levels. However, in nonmalignant HMECs, activation of the anabolic pathway alone was detected following indomethacin treatment. Following indomethacin treatment in breast cancer cells, several candidate genes, such as interleukin 8, NGFB, CSF2, RHOB, EDN1, and JUNB, were differentially expressed, which may have contributed to changes in choline metabolism through secondary effects or signaling cascades leading to changes in enzyme activity.

  19. Metabolic Effects of CX3CR1 Deficiency in Diet-Induced Obese Mice.

    Directory of Open Access Journals (Sweden)

    Rachana Shah

    Full Text Available The fractalkine (CX3CL1-CX3CR1 chemokine system is associated with obesity-related inflammation and type 2 diabetes, but data on effects of Cx3cr1 deficiency on metabolic pathways is contradictory. We examined male C57BL/6 Cx3cr1-/- mice on chow and high-fat diet to determine the metabolic effects of Cx3cr1 deficiency. We found no difference in body weight and fat content or feeding and energy expenditure between Cx3cr1-/- and WT mice. Cx3cr1-/- mice had reduced glucose intolerance assessed by intraperitoneal glucose tolerance tests at chow and high-fat fed states, though there was no difference in glucose-stimulated insulin values. Cx3cr1-/- mice also had improved insulin sensitivity at hyperinsulinemic-euglycemic clamp, with higher glucose infusion rate, rate of disposal, and hepatic glucose production suppression compared to WT mice. Enhanced insulin signaling in response to acute intravenous insulin injection was demonstrated in Cx3cr1-/- by increased liver protein levels of phosphorylated AKT and GSK3β proteins. There were no differences in adipose tissue macrophage populations, circulating inflammatory monocytes, adipokines, lipids, or inflammatory markers. In conclusion, we demonstrate a moderate and reproducible protective effect of Cx3cr1 deficiency on glucose intolerance and insulin resistance.

  20. Fumonisin B₁ (FB₁) Induces Lamellar Separation and Alters Sphingolipid Metabolism of In Vitro Cultured Hoof Explants.

    Science.gov (United States)

    Reisinger, Nicole; Dohnal, Ilse; Nagl, Veronika; Schaumberger, Simone; Schatzmayr, Gerd; Mayer, Elisabeth

    2016-03-24

    One of the most important hoof diseases is laminitis. Yet, the pathology of laminitis is not fully understood. Different bacterial toxins, e.g. endotoxins or exotoxins, seem to play an important role. Additionally, ingestion of mycotoxins, toxic secondary metabolites of fungi, might contribute to the onset of laminitis. In this respect, fumonsins are of special interest since horses are regarded as species most susceptible to this group of mycotoxins. The aim of our study was to investigate the influence of fumonisin B₁ (FB₁) on primary isolated epidermal and dermal hoof cells, as well as on the lamellar tissue integrity and sphingolipid metabolism of hoof explants in vitro. There was no effect of FB₁ at any concentration on dermal or epidermal cells. However, FB₁ significantly reduced the separation force of explants after 24 h of incubation. The Sa/So ratio was significantly increased in supernatants of explants incubated with FB₁ (2.5-10 µg/mL) after 24 h. Observed effects on Sa/So ratio were linked to significantly increased sphinganine concentrations. Our study showed that FB₁ impairs the sphingolipid metabolism of explants and reduces lamellar integrity at non-cytotoxic concentrations. FB₁ might, therefore, affect hoof health. Further in vitro and in vivo studies are necessary to elucidate the effects of FB₁ on the equine hoof in more detail.

  1. Fumonisin B₁ (FB₁) Induces Lamellar Separation and Alters Sphingolipid Metabolism of In Vitro Cultured Hoof Explants.

    Science.gov (United States)

    Reisinger, Nicole; Dohnal, Ilse; Nagl, Veronika; Schaumberger, Simone; Schatzmayr, Gerd; Mayer, Elisabeth

    2016-04-01

    One of the most important hoof diseases is laminitis. Yet, the pathology of laminitis is not fully understood. Different bacterial toxins, e.g. endotoxins or exotoxins, seem to play an important role. Additionally, ingestion of mycotoxins, toxic secondary metabolites of fungi, might contribute to the onset of laminitis. In this respect, fumonsins are of special interest since horses are regarded as species most susceptible to this group of mycotoxins. The aim of our study was to investigate the influence of fumonisin B₁ (FB₁) on primary isolated epidermal and dermal hoof cells, as well as on the lamellar tissue integrity and sphingolipid metabolism of hoof explants in vitro. There was no effect of FB₁ at any concentration on dermal or epidermal cells. However, FB₁ significantly reduced the separation force of explants after 24 h of incubation. The Sa/So ratio was significantly increased in supernatants of explants incubated with FB₁ (2.5-10 µg/mL) after 24 h. Observed effects on Sa/So ratio were linked to significantly increased sphinganine concentrations. Our study showed that FB₁ impairs the sphingolipid metabolism of explants and reduces lamellar integrity at non-cytotoxic concentrations. FB₁ might, therefore, affect hoof health. Further in vitro and in vivo studies are necessary to elucidate the effects of FB₁ on the equine hoof in more detail. PMID:27023602

  2. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.

    Science.gov (United States)

    Zheng, P; Zeng, B; Zhou, C; Liu, M; Fang, Z; Xu, X; Zeng, L; Chen, J; Fan, S; Du, X; Zhang, X; Yang, D; Yang, Y; Meng, H; Li, W; Melgiri, N D; Licinio, J; Wei, H; Xie, P

    2016-06-01

    Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metabolism. PMID:27067014

  3. Olanzapine-induced cerebral metabolic changes related to symptom improvement in schizophrenia.

    Science.gov (United States)

    Molina, Vicente; Gispert, Juan D; Reig, Santiago; Pascau, Javier; Martínez, Raúl; Sanz, Javier; Palomo, Tomás; Desco, Manuel

    2005-01-01

    The pattern of brain metabolic changes produced by olanzapine has yet to be described, despite the theoretical and clinical interest of this new antipsychotic. We studied a group of 17 schizophrenic patients who underwent two fluoro-deoxyglucose-positron emission tomography (FDG-PET) studies under two different conditions: a baseline scan during treatment with either conventional antipsychotics (n=15) or risperidone (n=2) and a second scan performed 17-24 weeks after switching to olanzapine. PET scans were obtained while performing a standard cognitive paradigm (Continuous Performance Test) and analysed by means of Statistical Parametric Mapping. No significant metabolic changes were found in the comparison between pre- and post-olanzapine conditions. A brain map of the statistical power of our design showed that changes up to 3% in the frontal and up to 8% in the occipital region were not likely to exist (1-beta=0.8). The degree of improvement in positive symptoms was related to the amount of activity decrease in the right orbital region and to the amount of activity increase in the primary visual area. Improvement in negative symptoms was associated with an activity increase in the dorsal prefrontal cortex, and a higher baseline activity in both temporal poles. These correlation patterns suggest that the functional mechanism of action of olanzapine may share traits from both typical and atypical neuroleptics.

  4. UV-B stress induced metabolic rearrangements explored with comparative proteomics in three Anabaena species.

    Science.gov (United States)

    Shrivastava, Alok Kumar; Chatterjee, Antra; Yadav, Shivam; Singh, Prashant Kumar; Singh, Shilpi; Rai, L C

    2015-09-01

    Comparative proteomics together with physiological variables revealed different responses among three species of diazotrophic cyanobacterium Anabaena exposed to UV-B stress at the same time points. Perceptible decline in PSII activity, ATP pool, nitrogenase activity and respiration rate was observed for all the three species; this being maximum in Anabaena doliolum, followed by Anabaena sp. PCC 7120 and minimum in Anabaena L31. Statistical analysis of the protein abundance divided majority of them as early accumulated in A. L31, late accumulated in A. sp. PCC 7120 and downregulated in A. doliolum. Tolerance of A. L31 may be ascribed to post-translational modification reflected through the highest number of protein isoforms in its proteome followed by A. PCC 7120 and A. doliolum. Furthermore, increase in abundance of cyanophycinase, glutamine synthetase and succinate semialdehyde dehydrogenase in A. L31 suggests operation of an alternate pathway for assimilation of nitrogen and carbon under UV-B stress. An early accumulation of four proteins viz., glutamate ammonia ligase (Alr2328), transketolase (Alr3344), inorganic pyrophosphatase (All3570), and trigger protein (Alr3681) involved respectively in amino acid metabolism, energy metabolism, biosynthesis of cofactor and trigger protein and chaperone like activity across three species, suggests them to be marker of UV-B stress in Anabaena spp. This article is part of a Special Issue entitled: Proteomics in India.

  5. Associations between endotoxin-induced metabolic changes and temperament in Brahman bulls.

    Science.gov (United States)

    Burdick Sanchez, N C; Carroll, J A; Randel, R D; Vann, R C; Welsh, T H

    2014-02-01

    The influence of temperament on the alteration of metabolic parameters in response to a lipopolysaccharide(LPS) challenge was investigated. Brahman bulls were selected based on temperament score. Bulls (10 months; 211±5kg BW; n = 6, 8 and 7 for Calm, Intermediate and Temperamental groups, respectively) were fitted with indwelling jugular catheters to evaluate peripheral blood concentrations of glucose, blood urea nitrogen (BUN),non-esterified fatty acids (NEFA), insulin, epinephrine and cortisol before and after LPS administration (0.5 μg/kg BW LPS). Feed intake was also recorded. Intermediate bulls consumed more feed than the Temperamental bulls during the challenge (p = 0.046). Pre-LPS glucose (p = 0.401) and BUN (p = 0.222) did not differ among the temperament groups. However, pre-LPS insulin (p = 0.023) was lower, whereas pre-LPS NEFA (p Brahman bulls following a provocative endotoxin challenge.Specifically, Temperamental bulls may preferentially utilize an alternate energy source (i.e. NEFA) to a greater degree than do bulls of Calm and Intermediate temperaments. The use of circulating NEFA from lipolysis may reduce the negative metabolic consequences of an immune response by allowing for a prompt answer to increasing energy demands required during immunological challenge, compared with the time required for glycogenolysis and gluconeogenesis. PMID:25225707

  6. Impact of adrenaline and metabolic stress on exercise-induced intracellular signaling and PGC-1α mRNA response in human skeletal muscle

    DEFF Research Database (Denmark)

    Brandt, Nina; Gunnarsson, Thomas Gunnar Petursson; Hostrup, Morten;

    2016-01-01

    This study tested the hypothesis that elevated plasma adrenaline or metabolic stress enhances exercise-induced PGC-1α mRNA and intracellular signaling in human muscle. Trained (VO2-max: 53.8 ± 1.8 mL min(-1) kg(-1)) male subjects completed four different exercise protocols (work load of the legs...... exercise than at rest in all protocols, and higher (P adrenaline nor muscle metabolic stress determines the magnitude of PGC-1α mRNA response in human muscle. Furthermore, higher exercise-induced changes in AMPK, p38, and CREB...

  7. Blast overpressure waves induce transient anxiety and regional changes in cerebral glucose metabolism and delayed hyperarousal in rats

    Directory of Open Access Journals (Sweden)

    Hibah Omar Awwad

    2015-06-01

    Full Text Available Physiological alterations, anxiety and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI and are common symptoms in service personnel exposed to blasts. Since 2006, 25-30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to the head in the absence of thoracic contributions from the periphery were examined following a single blast wave directed to the head of male Sprague-Dawley rats protected by a lead shield over the torso. An 80 psi head blast produced cognitive deficits that were detected in working memory. Blast TBI rats displayed increased anxiety as determined by elevated plus maze at day 9 post-blast compared to sham rats; blast TBI rats spent significantly more time than the sham controls in the closed arms (p<0.05; n=8-11. Interestingly, anxiety symptoms were absent at days 22 and 48 post-blast. Instead, blast TBI rats displayed hyperactivity and increased rearing behavior at day 48 post-blast compared to sham rats. Blast TBI rats also exhibited suppressed acoustic startle responses, but similar pre-pulse inhibition at day 15 post-blast compared to sham rats. Acute physiological alterations in cerebral glucose metabolism were determined by positron emission tomography 1 and 9 days post-blast using F-18-fluorodeoxyglucose. Global glucose uptake in blast TBI rat brains increased at day 1 post-blast (p<0.05; n=4-6 and returned to sham levels by day 9. Our results indicate a transient increase in cerebral metabolism following a blast injury. Markers for reactive astrogliosis and neuronal damage were noted by immunoblotting motor cortex tissue from day 10 post-blast in blast TBI rats compared to sham controls (p<0.05; n=5-6.

  8. Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice.

    Science.gov (United States)

    Roat, Regan; Rao, Vandana; Doliba, Nicolai M; Matschinsky, Franz M; Tobias, John W; Garcia, Eden; Ahima, Rexford S; Imai, Yumi

    2014-01-01

    The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet. PMID:24505268

  9. Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice.

    Directory of Open Access Journals (Sweden)

    Regan Roat

    Full Text Available The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF, the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP. To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1 and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.

  10. Effects of exercise training on myocardial fatty acid metabolism in rats with depressed cardiac function induced by transient ischemia

    International Nuclear Information System (INIS)

    The effects of exercise training on metabolic and functional recovery after myocardial transient ischemia were investigated in a rat model. Male Wistar Kyoto rats were subjected either to a 30-min left coronary artery occlusion followed by reperfusion or to a sham operation. At 4 weeks after operation, the rats were randomly assigned either to sedentary conditions or to exercise training for 6 weeks. In the ischemic rats, pinhole SPECT (single photon emission computed tomography) imaging with thallium-201 (201Tl) and 123I-(ρ-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) showed a reduction of both myocardial perfusion and fatty acid metabolism in the risk zone of the left ventricle (LV). The LV was dilated and the ejection fraction was decreased after ischemic injury. The severity score showed a significant decrease on both 201Tl and BMIPP (201Tl, from 19.9±2.7 to 17.0±2.2, p<0.05; BMIPP, from 21.5±2.4 to 18.6±1.9, p<0.05) after exercise training in the ischemic trained rats, but did not change significantly in their sedentary counterparts. Plasma levels of free fatty acids normalized in the ischemic trained rats, but elevated in the ischemic sedentary rats (0.53±0.05 vs 0.73±0.06 mmol/L, p<0.05). Furthermore, the trained rats had a significant increase in LV stroke volume (0.25±0.02 vs 0.21±0.01 ml/beat, p<0.05) and adaptive cardiac hypertrophy. These findings demonstrate that adaptive improvements in myocardial perfusion, fatty-acid metabolism and LV function were induced by exercise training after transient ischemia. (author)

  11. Avocado Oil Supplementation Modifies Cardiovascular Risk Profile Markers in a Rat Model of Sucrose-Induced Metabolic Changes

    Directory of Open Access Journals (Sweden)

    Octavio Carvajal-Zarrabal

    2014-01-01

    Full Text Available The purpose of this study was to evaluate the effects of avocado oil administration on biochemical markers of cardiovascular risk profile in rats with metabolic changes induced by sucrose ingestion. Twenty-five rats were divided into five groups: a control group (CG; basic diet, a sick group (MC; basic diet plus 30% sucrose solution, and three other groups (MCao, MCac, and MCas; basic diet plus 30% sucrose solution plus olive oil and avocado oil extracted by centrifugation or using solvent, resp.. Glucose, total cholesterol, triglycerides, phospholipids, low- and high-density lipoproteins (LDL, HDL, very low-density lipoprotein (VLDL, lactic dehydrogenase, creatine kinase, and high sensitivity C-reactive protein concentration were analyzed. Avocado oil reduces TG, VLDL, and LDL levels, in the LDL case significantly so, without affecting HDL levels. An effect was exhibited by avocado oil similar to olive oil, with no significant difference between avocado oil extracted either by centrifugation or solvent in myocardial injury biochemical indicators. Avocado oil decreased hs-CRP levels, indicating that inflammatory processes were partially reversed. These findings suggested that avocado oil supplementation has a positive health outcome because it reduces inflammatory events and produces positive changes in the biochemical indicators studied, related to the development of metabolic syndrome.

  12. Avocado oil supplementation modifies cardiovascular risk profile markers in a rat model of sucrose-induced metabolic changes.

    Science.gov (United States)

    Carvajal-Zarrabal, Octavio; Nolasco-Hipolito, Cirilo; Aguilar-Uscanga, M Guadalupe; Melo-Santiesteban, Guadalupe; Hayward-Jones, Patricia M; Barradas-Dermitz, Dulce M

    2014-01-01

    The purpose of this study was to evaluate the effects of avocado oil administration on biochemical markers of cardiovascular risk profile in rats with metabolic changes induced by sucrose ingestion. Twenty-five rats were divided into five groups: a control group (CG; basic diet), a sick group (MC; basic diet plus 30% sucrose solution), and three other groups (MCao, MCac, and MCas; basic diet plus 30% sucrose solution plus olive oil and avocado oil extracted by centrifugation or using solvent, resp.). Glucose, total cholesterol, triglycerides, phospholipids, low- and high-density lipoproteins (LDL, HDL), very low-density lipoprotein (VLDL), lactic dehydrogenase, creatine kinase, and high sensitivity C-reactive protein concentration were analyzed. Avocado oil reduces TG, VLDL, and LDL levels, in the LDL case significantly so, without affecting HDL levels. An effect was exhibited by avocado oil similar to olive oil, with no significant difference between avocado oil extracted either by centrifugation or solvent in myocardial injury biochemical indicators. Avocado oil decreased hs-CRP levels, indicating that inflammatory processes were partially reversed. These findings suggested that avocado oil supplementation has a positive health outcome because it reduces inflammatory events and produces positive changes in the biochemical indicators studied, related to the development of metabolic syndrome.

  13. Anti-Diabetic Activity and Metabolic Changes Induced by Andrographis paniculata Plant Extract in Obese Diabetic Rats.

    Science.gov (United States)

    Akhtar, Muhammad Tayyab; Bin Mohd Sarib, Mohamad Syakir; Ismail, Intan Safinar; Abas, Faridah; Ismail, Amin; Lajis, Nordin Hj; Shaari, Khozirah

    2016-01-01

    Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM). Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM). Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy in combination with multivariate data analyses was used to evaluate the A. paniculata and metformin induced metabolic effects on the obese and obese-diabetic (obdb) rat models. Compared to the normal rats, high levels of creatinine, lactate, and allantoin were found in the urine of obese rats, whereas, obese-diabetic rats were marked by high glucose, choline and taurine levels, and low lactate, formate, creatinine, citrate, 2-oxoglutarate, succinate, dimethylamine, acetoacetate, acetate, allantoin and hippurate levels. Treatment of A. paniculata leaf water extract was found to be quite effective in restoring the disturbed metabolic profile of obdb rats back towards normal conditions. Thisstudy shows the anti-diabetic potential of A. paniculata plant extract and strengthens the idea of using this plant against the diabetes. Further classical genetic methods and state of the art molecular techniques could provide insights into the molecular mechanisms involved in the pathogenesis of diabetes mellitus and anti-diabetic effects of A. paniculata water extract. PMID:27517894

  14. Changes in metabolic proteins in ex vivo rat retina during glutamate-induced neural progenitor cell induction.

    Science.gov (United States)

    Tokuda, Kazuhiro; Kuramitsu, Yasuhiro; Baron, Byron; Kitagawa, Takao; Tokuda, Nobuko; Kobayashi, Masaaki; Kimura, Kazuhiro; Sonoda, Koh-Hei; Nakamura, Kazuyuki

    2016-08-01

    Understanding how energy metabolism and related proteins influence neural progenitor cells in adult tissues is critical for developing new strategies in clinical tissue regeneration therapy. We have recently reported that a subtoxic concentration of glutamate-induced neural progenitor cells in the mature ex vivo rat retina. We herein explore changes in the metabolic pathways during the process. We firstly observed an increase in lactate and lactate dehydrogenase concentration in the glutamate-treated retina. We then investigated the levels of glycolytic enzymes and confirmed significant upregulation of pyruvate kinase M type (PKM), especially PKM2, enolase, phosphoglycerate mutase 1 (PGAM1), and inosine-5'-monophosphate dehydrogenase (IMPDH1) in the glutamate-treated retina compared to the untreated retina. An analysis of the subcellular localization of PKM2 revealed nuclear translocation in the treated retina, which has been reported to regulate cell cycle proliferation and glycolytic enzymes. Our findings indicate that the mature rat retina undergoes an increase in aerobic glycolysis. PKM2, both in the cytoplasm and in the nucleus, may thus play an important role during neural progenitor cell induction, as it does in other proliferating cells. PMID:27421851

  15. Mitochondrial physiology and gene expression analyses reveal metabolic and translational dysregulation in oocyte-induced somatic nuclear reprogramming.

    Directory of Open Access Journals (Sweden)

    Telma C Esteves

    Full Text Available While reprogramming a foreign nucleus after somatic cell nuclear transfer (SCNT, the enucleated oocyte (ooplasm must signal that biomass and cellular requirements changed compared to the nucleus donor cell. Using cells expressing nuclear-encoded but mitochondria-targeted EGFP, a strategy was developed to directly distinguish maternal and embryonic products, testing ooplasm demands on transcriptional and post-transcriptional activity during reprogramming. Specifically, we compared transcript and protein levels for EGFP and other products in pre-implantation SCNT embryos, side-by-side to fertilized controls (embryos produced from the same oocyte pool, by intracytoplasmic injection of sperm containing the EGFP transgene. We observed that while EGFP transcript abundance is not different, protein levels are significantly lower in SCNT compared to fertilized blastocysts. This was not observed for Gapdh and Actb, whose protein reflected mRNA. This transcript-protein relationship indicates that the somatic nucleus can keep up with ooplasm transcript demands, whilst transcription and translation mismatch occurs after SCNT for certain mRNAs. We further detected metabolic disturbances after SCNT, suggesting a place among forces regulating post-transcriptional changes during reprogramming. Our observations ascribe oocyte-induced reprogramming with previously unsuspected regulatory dimensions, in that presence of functional proteins may no longer be inferred from mRNA, but rather depend on post-transcriptional regulation possibly modulated through metabolism.

  16. Anti-Diabetic Activity and Metabolic Changes Induced by Andrographis paniculata Plant Extract in Obese Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Muhammad Tayyab Akhtar

    2016-08-01

    Full Text Available Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM. Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM. Proton Nuclear Magnetic Resonance (1H-NMR spectroscopy in combination with multivariate data analyses was used to evaluate the A. paniculata and metformin induced metabolic effects on the obese and obese–diabetic (obdb rat models. Compared to the normal rats, high levels of creatinine, lactate, and allantoin were found in the urine of obese rats, whereas, obese-diabetic rats were marked by high glucose, choline and taurine levels, and low lactate, formate, creatinine, citrate, 2-oxoglutarate, succinate, dimethylamine, acetoacetate, acetate, allantoin and hippurate levels. Treatment of A. paniculata leaf water extract was found to be quite effective in restoring the disturbed metabolic profile of obdb rats back towards normal conditions. Thisstudy shows the anti-diabetic potential of A. paniculata plant extract and strengthens the idea of using this plant against the diabetes. Further classical genetic methods and state of the art molecular techniques could provide insights into the molecular mechanisms involved in the pathogenesis of diabetes mellitus and anti-diabetic effects of A. paniculata water extract.

  17. The programming effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in adult mice.

    Science.gov (United States)

    Zheng, Jia; Xiao, Xinhua; Zhang, Qian; Yu, Miao; Xu, Jianping; Qi, Cuijuan; Wang, Tong

    2016-04-01

    Substantial evidence indicated that catch-up growth could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes mellitus in adulthood. However, investigations into the "programming" effects of catch-up growth on gut microbiota in the offspring are limited. C57/BL6 mice were fed on either low protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the offspring were randomly weaned to either NC or high fat (HF) diet until 32 weeks of age, generating four experimental groups: NC-NC, NC-HF, LP-NC, and LP-HF. Metabolic parameters and gut microbiota were examined in the offspring. It showed that the NC-HF and LP-HF offspring displayed higher body weight (P percentage was negatively associated with blood glucose concentrations of intraperitoneal glucose tolerance test (r = -0.886, P = 0.019). In conclusion, catch-up growth predisposes the offspring to gut microbiota perturbation, obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia. Our study is novel in showing the "programming" effects of nutrition-induced catch-up growth on gut microbiota and metabolic diseases in later life. PMID:26749443

  18. Attenuation of Helicteres isora L. bark extracts on streptozotocin-induced alterations in glycogen and carbohydrate metabolism in albino rats.

    Science.gov (United States)

    Kumar, G; Sharmila Banu, G; Murugesan, A G

    2009-11-01

    The present study was undertaken to assess the effect of Helicteres isora L. on four important enzymes of carbohydrate metabolism (glucokinase [GK], hexokinase [HK] phosphofructokinase [PFK] and fructose-1, 6-bisphosphatase [FBP]) along with glycogen content of insulin-dependent (skeletal muscle and liver) and insulin-independent tissues (kidneys and brain) in streptozotocin (STZ; 60 mg/kg)-induced model of diabetes for 30 days. Administration of bark extracts (100, 200 mg/kg) for 30 days led to decrease in plasma glucose levels by approximately 9.60% and 22.04% and 19.18% and 33.93% on 15th and 30th day, respectively, of the experiment. Liver and two-kidney weight expressed as percentage of body weight significantly increased in diabetics (P bark extract of H. isora partially corrected this alteration. The efficacy of the bark extract was comparable with Tolbutamide, a well-known hypoglycemic drug.

  19. Effect of high-intensity training on exercise-induced gene expression specific to ion homeostasis and metabolism

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai; Bangsbo, Jens; Pilegaard, Henriette

    2003-01-01

    Changes in gene expression during recovery from high-intensity, intermittent, one-legged exercise were studied before and after 5.5 wk of training. Genes related to metabolism, as well as Na+, K+, and pH homeostasis, were selected for analyses. After the same work was performed before and after the...... training period, several muscle biopsies were obtained from vastus lateralis muscle. In the untrained state, the Na+-K+-ATPase alpha1-subunit mRNA level was approximately threefold higher (P < 0.01) at 0, 1, and 3 h after exercise, relative to the preexercise resting level. After 3-5 h of recovery in the...... resting mRNA levels were observed as a result of training. In conclusion, cellular adaptations to high-intensity exercise training may, in part, be induced by transcriptional regulation. After training, the transcriptional response to an exercise bout at a given workload is diminished....

  20. Alcoholic Stem Extract of Coscinium fenestratum Regulates Carbohydrate Metabolism and Improves Antioxidant Status in Streptozotocin–Nicotinamide Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    I. R. Punitha

    2005-01-01

    Full Text Available Alcoholic extract of the stems of Coscinium fenestratum, a medicinal plant indigenous to India and Sri Lanka used in ayurveda and siddha medicine for treating diabetes, was studied for its carbohydrate metabolism effect and antioxidant status in streptozotocin–nicotinamide induced type 2 diabetic rats. Oral administration of C. fenestratum stem extract in graded doses caused a significant increase in enzymatic antioxidants such as catalase, superoxide dismutase, glutathione synthetase, peroxidase, and glutathione peroxidase and in the nonenzymatic antioxidants ascorbic acid, ceruloplasmin and tocopherol. Effects of alcoholic extract on glycolytic enzymes such as glucose-6-phosphate dehydrogenase, lactate dehydrogenase and hexokinase showed a significant increase in their levels, whereas a significant decrease was observed in the levels of gluconeogenic enzyme, glucose-6-phosphatase and alanine aminotransferase in treated diabetic rats. Serum creatinine and urea levels also declined significantly. This investigation demonstrates significant antidiabetic activity of C. fenestratum.

  1. Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Keller, Charlotte; Steensberg, Adam;

    2002-01-01

    to lower muscle glycogen content in one leg and then, the following day, completed 2.5 h low intensity two-legged cycling exercise. Nuclei and mRNA were isolated from biopsies obtained from the vastus lateralis muscle of the control and reduced glycogen (pre-exercise glycogen = 609 +/- 47 and 337 +/- 33...... in response to exercise, raising the possibility that signalling mechanisms sensitive to glycogen content and/or FFA availability may be linked to the transcriptional control of exercise-responsive genes.......Transcription of metabolic genes is transiently induced during recovery from exercise in skeletal muscle of humans. To determine whether pre-exercise muscle glycogen content influences the magnitude and/or duration of this adaptive response, six male subjects performed one-legged cycling exercise...

  2. Dietary Njavara rice bran oil reduces experimentally induced hypercholesterolaemia by regulating genes involved in lipid metabolism.

    Science.gov (United States)

    Chithra, Pushpan K; Sindhu, G; Shalini, V; Parvathy, Rathnam; Jayalekshmy, Ananthasankaran; Helen, Antony

    2015-04-28

    The present study was carried out to evaluate the anti-atherogenic effect of Njavara rice bran oil (NjRBO) on atherosclerosis by modulating enzymes and genes involved in lipid metabolism in rats fed a high-cholesterol diet (HCD). Adult male rats (Sprague-Dawley strain, weighing 100-120 g) were divided into three groups of nine animals each. Group I served as the control, group II were fed a HCD and group III were fed a HCD and NjRBO (100 mg/kg body weight). The study duration was 60 d. Serum and tissue lipid profile, atherogenic index, enzymes of lipid metabolism, plasma C-reactive protein levels, serum paraoxonase and arylesterase activities, thiobarbituric acid-reactive substances, gene and protein expression of paraoxonase 1 (PON1), PPARα, ATP-binding cassette transporter A1 (ABCA1), apoB and apoA1 in the liver were quantified. Total cholesterol, TAG, phospholipid, NEFA, LDL-cholesterol concentrations in the serum and liver, lipogenic enzyme activities, hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and atherogenic index were significantly increased in HCD-fed rats, but they decreased after treatment with NjRBO. HDL-cholesterol level and lecithin cholesterol acyl transferase activity were increased in the NjRBO-treated group, but decreased in the HCD-fed group. The expression levels of ABCA1, apoA1, PON1 and PPARα were found to be significantly increased in NjRBO-treated group compared with the HCD-fed group; however, the expression level of apoB was found to be higher in HCD-fed group and lower in the NjRBO-treated group. These data suggest that NjRBO possesses an anti-atherogenic property by modulating lipid metabolism and up-regulating genes involved in reverse cholesterol transport and antioxidative defence mechanism through the induction of the gene expression PON1. PMID:25823019

  3. Ca2+-induced changes in energy metabolism and viability of melanoma cells

    OpenAIRE

    Glass-Marmor, L; Penso, J; Beitner, R

    1999-01-01

    Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca2+), induced by Ca2+-ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca2+-ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and...

  4. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders

    OpenAIRE

    Valérie Grandjean; Sandra Fourré; Diana Andrea Fernandes De Abreu; Marie-Alix Derieppe; Jean-Jacques Remy; Minoo Rassoulzadegan

    2015-01-01

    The paternal heredity of obesity and diabetes induced by a high-fat and/or high-sugar diet (Western-like diet) has been demonstrated through epidemiological analysis of human cohorts and experimental analysis, but the nature of the hereditary vector inducing this newly acquired phenotype is not yet well defined. Here, we show that microinjection of either testis or sperm RNA of male mice fed a Western-like diet into naive one-cell embryos leads to the establishment of the Western-like diet-in...

  5. Three-dimensional imaging of the metabolic state of c-MYC-induced mammary tumor with the cryo-imager

    Science.gov (United States)

    Zhang, Zhihong; Liu, Qian; Luo, Qingming; Zhang, Min Z.; Blessington, Dana M.; Zhou, Lanlan; Chodosh, Lewis A.; Zheng, Gang; Chance, Britton

    2003-07-01

    This study imaged the metabolic state of a growing tumor and the relationship between energy metabolism and the ability of glucose uptake in whole tumor tissue with cryo-imaging at 77° K. A MTB/TOM mouse model, bearing c-MYC-induced mammary tumor, was very rapidly freeze-trapped 2 hrs post Pyro-2DG injection. The fluorescence signals of oxidized flavoprotein (Fp), reduced pyridine nucleotide (PN), pyro-2DG, and the reflection signal of deoxy-hemoglobin were imaged every 100 μm from the top surface to the bottom of the tumor sequentially, 9 sections in total. Each of the four signals was constructed into 3D images with Amira software. Both Fp and PN signals could be detected in the growing tumor regions, and a higher reduction state where was shown in the ratio images. The necrotic tumor regions displayed a very strong Fp signal and weak PN signal. In the bloody extravasation regions, Fp and PN signals were observably diminished. Therefore, the regions of high growth and necrosis in the tumor could be determined according to the Fp and PN signals. The content of deoxy-hemoglobin (Hb) in the tumor was positively correlated with the reduced PN signal. Pyro-2DG signal was only evident in the growing condition region in the tumor. Normalized 3D cross-correlation showed that Pyro-2DG signal was similar to the redox ratio. The results indicated that glucose uptake in the tumor was consistent with the redox state of the tumor. And both Pyro-2DG and mitochondrial NADH fluorescence showed bimodal histograms suggesting that the two population of c-MYC induced mammary tumor, one of which could be controlled by c-MYC transgene.

  6. Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway.

    Science.gov (United States)

    Li, Jinmei; Ding, Lili; Song, Baoliang; Xiao, Xu; Qi, Meng; Yang, Qiaoling; Yang, Qiming; Tang, Xiaowen; Wang, Zhengtao; Yang, Li

    2016-01-01

    Currently, obesity has become a worldwide epidemic associated with Type 2 diabetes, dyslipidemia, cardiovascular disease and chronic metabolic diseases. Emodin is one of the active anthraquinone derivatives from Rheum palmatum and some other Chinese herbs with anti-inflammatory, anticancer and hepatoprotective properties. In the present study, we investigated the anti-obesity effects of emodin in obese mice and explore its potential pharmacological mechanisms. Male C57BL/6 mice were fed with high-fat diet for 12 weeks to induce obesity. Then the obese mice were divided into four groups randomly, HFD or emodin (40mg/kg/day and 80mg/kg/day) or lovastatin (30mg/kg/ day) for another 6 weeks. Body weight and food intake were recorded every week. At the end of the treatment, the fasting blood glucose, glucose and insulin tolerance test, serum and hepatic lipid levels were assayed. The gene expressions of liver and adipose tissues were analyzed with a quantitative PCR assay. Here, we found that emodin inhibited sterol regulatory element-binding proteins (SREBPs) transactivity in huh7 cell line. Furthermore, emodin (80mg/kg/day) treatment blocked body weight gain, decreased blood lipids, hepatic cholesterol and triglyceride content, ameliorated insulin sensitivity, and reduced the size of white and brown adipocytes. Consistently, SREBP-1 and SREBP-2 mRNA levels were significantly reduced in the liver and adipose tissue after emodin treatment. These data demonstrated that emodin could improve high-fat diet-induced obesity and associated metabolic disturbances. The underlying mechanism is probably associated with regulating SREBP pathway. PMID:26626587

  7. Improved Mitochondrial and Methylglyoxal-Related Metabolisms Support Hyperproliferation Induced by 50 Hz Magnetic Field in Neuroblastoma Cells.

    Science.gov (United States)

    Falone, Stefano; Santini, Silvano; di Loreto, Silvia; Cordone, Valeria; Grannonico, Marta; Cesare, Patrizia; Cacchio, Marisa; Amicarelli, Fernanda

    2016-09-01

    Extremely low frequency magnetic fields (ELF-MF) are common environmental agents that are suspected to promote later stages of tumorigenesis, especially in brain-derived malignancies. Even though ELF magnetic fields have been previously linked to increased proliferation in neuroblastoma cells, no previous work has studied whether ELF-MF exposure may change key biomolecular features, such as anti-glycative defence and energy re-programming, both of which are currently considered as crucial factors involved in the phenotype and progression of many malignancies. Our study investigated whether the hyperproliferation that is induced in SH-SY5Y human neuroblastoma cells by a 50 Hz, 1 mT ELF magnetic field is supported by an improved defense towards methylglyoxal (MG), which is an endogenous cancer-static and glycating α-oxoaldehyde, and by rewiring of energy metabolism. Our findings show that not only the ELF magnetic field interfered with the biology of neuron-derived malignant cells, by de-differentiating further the cellular phenotype and by increasing the proliferative activity, but also triggered cytoprotective mechanisms through the enhancement of the defense against MG, along with a more efficient management of metabolic energy, presumably to support the rapid cell outgrowth. Intriguingly, we also revealed that the MF-induced bioeffects took place after an initial imbalance of the cellular homeostasis, which most likely created a transient unstable milieu. The biochemical pathways and molecular targets revealed in this research could be exploited for future approaches aimed at limiting or suppressing the deleterious effects of ELF magnetic fields. J. Cell. Physiol. 231: 2014-2025, 2016. © 2016 Wiley Periodicals, Inc. PMID:26757151

  8. Ocean warming alters cellular metabolism and induces mortality in fish early life stages: A proteomic approach.

    Science.gov (United States)

    Madeira, D; Araújo, J E; Vitorino, R; Capelo, J L; Vinagre, C; Diniz, M S

    2016-07-01

    Climate change has pervasive effects on marine ecosystems, altering biodiversity patterns, abundance and distribution of species, biological interactions, phenology, and organisms' physiology, performance and fitness. Fish early life stages have narrow thermal windows and are thus more vulnerable to further changes in water temperature. The aim of this study was to address the sensitivity and underlying molecular changes of larvae of a key fisheries species, the sea bream Sparus aurata, towards ocean warming. Larvae were exposed to three temperatures: 18°C (control), 24°C (warm) and 30°C (heat wave) for seven days. At the end of the assay, i) survival curves were plotted for each temperature treatment and ii) entire larvae were collected for proteomic analysis via 2D gel electrophoresis, image analysis and mass spectrometry. Survival decreased with increasing temperature, with no larvae surviving at 30°C. Therefore, proteomic analysis was only carried out for 18°C and 24°C. Larvae up-regulated protein folding and degradation, cytoskeletal re-organization, transcriptional regulation and the growth hormone while mostly down-regulating cargo transporting and porphyrin metabolism upon exposure to heat stress. No changes were detected in proteins related to energetic metabolism suggesting that larval fish may not have the energetic plasticity needed to sustain cellular protection in the long-term. These results indicate that despite proteome modulation, S. aurata larvae do not seem able to fully acclimate to higher temperatures as shown by the low survival rates. Consequently, elevated temperatures seem to have bottleneck effects during fish early life stages, and future ocean warming can potentially compromise recruitment's success of key fisheries species. PMID:27062348

  9. Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Damon T. Jacobs

    2016-07-01

    Full Text Available Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139 encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease.

  10. Dysfunction of intraflagellar transport-A causes hyperphagia-induced obesity and metabolic syndrome.

    Science.gov (United States)

    Jacobs, Damon T; Silva, Luciane M; Allard, Bailey A; Schonfeld, Michael P; Chatterjee, Anindita; Talbott, George C; Beier, David R; Tran, Pamela V

    2016-07-01

    Primary cilia extend from the plasma membrane of most vertebrate cells and mediate signaling pathways. Ciliary dysfunction underlies ciliopathies, which are genetic syndromes that manifest multiple clinical features, including renal cystic disease and obesity. THM1 (also termed TTC21B or IFT139) encodes a component of the intraflagellar transport-A complex and mutations in THM1 have been identified in 5% of individuals with ciliopathies. Consistent with this, deletion of murine Thm1 during late embryonic development results in cystic kidney disease. Here, we report that deletion of murine Thm1 during adulthood results in obesity, diabetes, hypertension and fatty liver disease, with gender differences in susceptibility to weight gain and metabolic dysfunction. Pair-feeding of Thm1 conditional knock-out mice relative to control littermates prevented the obesity and related disorders, indicating that hyperphagia caused the obese phenotype. Thm1 ablation resulted in increased localization of adenylyl cyclase III in primary cilia that were shortened, with bulbous distal tips on neurons of the hypothalamic arcuate nucleus, an integrative center for signals that regulate feeding and activity. In pre-obese Thm1 conditional knock-out mice, expression of anorexogenic pro-opiomelanocortin (Pomc) was decreased by 50% in the arcuate nucleus, which likely caused the hyperphagia. Fasting of Thm1 conditional knock-out mice did not alter Pomc nor orexogenic agouti-related neuropeptide (Agrp) expression, suggesting impaired sensing of changes in peripheral signals. Together, these data indicate that the Thm1-mutant ciliary defect diminishes sensitivity to feeding signals, which alters appetite regulation and leads to hyperphagia, obesity and metabolic disease. PMID:27482817

  11. Pregnancy and maternal behavior induce changes in glia, glutamate and its metabolism within the cingulate cortex.

    Directory of Open Access Journals (Sweden)

    Natalina Salmaso

    Full Text Available An upregulation of the astrocytic proteins GFAP and bFGF within area 2 of the cingulate cortex (Cg2 occurs within 3 hours of parturition in rats. These changes are the result of an interaction between hormonal state and maternal experience and are associated with increased dendritic spine density in this area. Here, we examined whether this upregulation of astrocytic proteins generalized to other glial markers and, in particular those associated with glutamate metabolism. We chose glial markers commonly used to reflect different aspects of glial function: vimentin, like GFAP, is a marker of intermediate filaments; glutamine synthetase (GS, and S-100beta, are used as markers for mature astrocytes and GS has also been used as a specific marker for glutamatergic enzymatic activity. In addition, we examined levels of proteins associated with glutamine synthetase, glutamate, glutamine and two excitatory amino acid transporters found in astrocytes, glt-1 and glast. S100beta immunoreactivity did not vary with reproductive state in either Cg2 or MPOA suggesting no change in the number of mature astrocytes across these conditions. Vimentin-ir did not differ across groups in Cg2, but expression of this protein decreased from Day 1 postpartum onwards in the MPOA. By contrast, GS-ir was increased within 24 h postpartum in Cg2 but not MPOA and similarly to GFAP and bFGF this upregulation of GS resulted from an interaction between hormonal state and maternal experience. Within Cg2, upregulation of GS was not accompanied by changes in the astrocytic glutamatergic transporters, glt-1 and glast, however, an increase in both glutamate and glutamine proteins were observed within the Cg2 of postpartum animals. Together, these changes suggest postpartum upregulation of glutamatergic activity and metabolism within Cg2 that is stimulated by pregnancy hormones and maternal experience.

  12. Metabolic and transcriptomic changes induced in Arabidopsis by the rhizobacterium Pseudomonas fluorescens SS101

    NARCIS (Netherlands)

    Mortel, van de J.E.; Vos, de R.C.H.; Dekkers, E.; Pineda, A.; Guillod, L.; Bouwmeester, K.; Loon, van J.J.A.; Dicke, M.; Raaijmakers, J.M.

    2012-01-01

    Systemic resistance induced in plants by nonpathogenic rhizobacteria is typically effective against multiple pathogens. Here, we show that root-colonizing Pseudomonas fluorescens strain SS101 (Pf.SS101) enhanced resistance in Arabidopsis (Arabidopsis thaliana) against several bacterial pathogens, in

  13. Pb2+ exposure induced microsatellite instability in Pisum sativum in a locus related with glutamine metabolism.

    Science.gov (United States)

    Rodriguez, E; Azevedo, R; Moreira, H; Souto, L; Santos, Conceição

    2013-01-01

    Lead (Pb) is a toxic element, but its putative mutagenic effects in plant cells, using molecular markers, remain to unveil. To evaluate if Pb induces mutagenicity, Pisum sativum L. seedlings were exposed to Pb(2+) (up to 2000 mg L(-1)) for 28 days and the instability of microsatellites (or Simple Sequence Repeats, SSR) was analyzed in leaves and roots. The analysis of eight selected microsatellites (SSR1-SSR8) demonstrated that only at the highest dosage microsatellite instability (MSI) occurred, at a frequency of 4.2%. Changes were detected in one microsatellite (SSR6) that is inserted in the locus for glutamine synthetase. SSR6 products of roots exposed to the highest concentration of Pb were 3 bp larger than those of the control. Our data demonstrate that: (a) SSR technique is sensitive to detect Pb-induced mutagenicity in plants. MSI instability is Pb dose dependent and organ dependent (roots are more sensitive); (b) the Pb-sensitive SSR6 is inserted in the glutamine synthetase locus, with still unknown relation with functional changes of this enzyme; (c) Pb levels inducing MSI are much above the maximum admitted levels in some European Union countries for agricultural purpose waters. In conclusion, we propose here the potential use of SSR to evaluate Pb(2+)-induced mutagenicity, in combination with other genetic markers.

  14. Effect of luteolin on glycoproteins metabolism in 1, 2-dimethylhydrazine induced experimental colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Manju Vaiyapuri

    2008-12-01

    carcinogenesis. Thus, the present study indicates that luteolin has protected the cell surface and maintained the structural integrity of the cell membranes during DMH induced colon carcinogenesis. Keywords: Colon cancer, 1, 2-dimethylhydrazine, luteolin, glycoproteins Received: 23 January 2009 / Received in revised form: 17 February 2009, Accepted: 28 February 2009, Published online: 3 March 2009

  15. Dynamic metabolic profiling of urine biomarkers in rats with alcohol‑induced liver damage following treatment with Zhi‑Zi‑Da‑Huang decoction.

    Science.gov (United States)

    An, Li; Lang, Qiaoling; Shen, Wenbin; Shi, Qingshui; Feng, Fang

    2016-09-01

    Alcoholic liver disease (ALD) is a leading cause of liver‑associated morbidity and mortality. Zhi‑Zi‑Da‑Huang decoction (ZZDHD), a traditional Chinese medicine formula, has been frequently used to treat or alleviate the symptoms of the various stages of ALD. To identify metabolic changes and the ZZDHD mechanism of action on ALD, potential urine biomarkers involved in the effects of ZZDHD were identified. Additionally, dynamic metabolomic profiles were systematically analyzed using nuclear magnetic resonance (NMR) spectroscopy in conjunction with statistical analysis. Alcohol administration to experimental rats disrupted multiple metabolic pathways, including methionine, gut bacterial, energy and amino acid metabolism. However, ZZDHD relieved certain effects of alcohol on the metabolism and regulated changes in potential characteristic biomarkers, including dimethylglycine, hippurate, lactate and creatine. The present study investigated time‑dependent metabolomic changes in the development of alcohol‑induced liver injury, including the effect of ZZDHD intervention. These findings elucidated important information regarding the metabolic responses to the protective effects of ZZDHD. 1H NMR‑based metabolomics method a reliable and useful tool for determining the metabolic progression of alcohol‑induced liver injury and elucidating the underlying mechanisms of the effect of traditional Chinese medicine formulas. This study also demonstrated that NMR‑based metabolomics approach is a powerful tool for understanding the molecular basis of pathogenesis and drug intervention processes. PMID:27430289

  16. Dietary enrichment with fish oil prevents high fat-induced metabolic dysfunction in skeletal muscle in mice.

    Directory of Open Access Journals (Sweden)

    Lisa K Philp

    Full Text Available High saturated fat (HF-S diets increase intramyocellular lipid, an effect ameliorated by omega-3 fatty acids in vitro and in vivo, though little is known about sex- and muscle fiber type-specific effects. We compared effects of standard chow, HF-S, and 7.5% HF-S replaced with fish oil (HF-FO diets on the metabolic profile and lipid metabolism gene and protein content in red (soleus and white (extensor digitorum longus muscles of male and female C57BL/6 mice (n = 9-12/group. Weight gain was similar in HF-S- and HF-FO-fed groups. HF-S feeding increased mesenteric fat mass and lipid marker, Oil Red O, in red and mixed muscle; HF-FO increased interscapular brown fat mass. Compared to chow, HF-S and HF-FO increased expression of genes regulating triacylglycerol synthesis and fatty acid transport, HF-S suppressed genes and proteins regulating fatty acid oxidation, whereas HF-FO increased oxidative genes, proteins and enzymes and lipolytic gene content, whilst suppressing lipogenic genes. In comparison to HF-S, HF-FO further increased fat transporters, markers of fatty acid oxidation and mitochondrial content, and reduced lipogenic genes. No diet-by-sex interactions were observed. Neither diet influenced fiber type composition. However, some interactions between muscle type and diet were observed. HF-S induced changes in triacylglycerol synthesis and lipogenic genes in red, but not white, muscle, and mitochondrial biogenesis and oxidative genes were suppressed by HF-S and increased by HF-FO in red muscle only. In conclusion, HF-S feeding promotes lipid storage in red muscle, an effect abrogated by the fish oil, which increases mediators of lipolysis, oxidation and thermogenesis while inhibiting lipogenic genes. Greater storage and synthesis, and lower oxidative genes in red, but not white, muscle likely contribute to lipid accretion encountered in red muscle. Despite several gender-dimorphic genes, both sexes exhibited a similar HF-S-induced metabolic

  17. Dietary enrichment with fish oil prevents high fat-induced metabolic dysfunction in skeletal muscle in mice.

    Science.gov (United States)

    Philp, Lisa K; Heilbronn, Leonie K; Janovska, Alena; Wittert, Gary A

    2015-01-01

    High saturated fat (HF-S) diets increase intramyocellular lipid, an effect ameliorated by omega-3 fatty acids in vitro and in vivo, though little is known about sex- and muscle fiber type-specific effects. We compared effects of standard chow, HF-S, and 7.5% HF-S replaced with fish oil (HF-FO) diets on the metabolic profile and lipid metabolism gene and protein content in red (soleus) and white (extensor digitorum longus) muscles of male and female C57BL/6 mice (n = 9-12/group). Weight gain was similar in HF-S- and HF-FO-fed groups. HF-S feeding increased mesenteric fat mass and lipid marker, Oil Red O, in red and mixed muscle; HF-FO increased interscapular brown fat mass. Compared to chow, HF-S and HF-FO increased expression of genes regulating triacylglycerol synthesis and fatty acid transport, HF-S suppressed genes and proteins regulating fatty acid oxidation, whereas HF-FO increased oxidative genes, proteins and enzymes and lipolytic gene content, whilst suppressing lipogenic genes. In comparison to HF-S, HF-FO further increased fat transporters, markers of fatty acid oxidation and mitochondrial content, and reduced lipogenic genes. No diet-by-sex interactions were observed. Neither diet influenced fiber type composition. However, some interactions between muscle type and diet were observed. HF-S induced changes in triacylglycerol synthesis and lipogenic genes in red, but not white, muscle, and mitochondrial biogenesis and oxidative genes were suppressed by HF-S and increased by HF-FO in red muscle only. In conclusion, HF-S feeding promotes lipid storage in red muscle, an effect abrogated by the fish oil, which increases mediators of lipolysis, oxidation and thermogenesis while inhibiting lipogenic genes. Greater storage and synthesis, and lower oxidative genes in red, but not white, muscle likely contribute to lipid accretion encountered in red muscle. Despite several gender-dimorphic genes, both sexes exhibited a similar HF-S-induced metabolic and gene

  18. Generation of enterocyte-like cells from human induced pluripotent stem cells for drug absorption and metabolism studies in human small intestine.

    Science.gov (United States)

    Ozawa, Tatsuya; Takayama, Kazuo; Okamoto, Ryota; Negoro, Ryosuke; Sakurai, Fuminori; Tachibana, Masashi; Kawabata, Kenji; Mizuguchi, Hiroyuki

    2015-11-12

    Enterocytes play an important role in drug absorption and metabolism. However, a widely used enterocyte model, Caco-2 cell, has difficulty in evaluating both drug absorption and metabolism because the expression levels of some drug absorption and metabolism-related genes in these cells differ largely from those of human enterocytes. Therefore, we decided to generate the enterocyte-like cells from human induced pluripotent stem (iPS) cells (hiPS-ELCs), which are applicable to drug absorption and metabolism studies. The efficiency of enterocyte differentiation from human iPS cells was significantly improved by using EGF, SB431542, and Wnt3A, and extending the differentiation period. The gene expression levels of cytochrome P450 3A4 (CYP3A4) and peptide transporter 1 in the hiPS-ELCs were higher than those in Caco-2 cells. In addition, CYP3A4 expression in the hiPS-ELCs was induced by treatment with 1, 25-dihydroxyvitamin D3 or rifampicin, which are known to induce CYP3A4 expression, indicating that the hiPS-ELCs have CYP3A4 induction potency. Moreover, the transendothelial electrical resistance (TEER) value of the hiPS-ELC monolayer was approximately 240 Ω*cm(2), suggesting that the hiPS-ELC monolayer could form a barrier. In conclusion, we succeeded in establishing an enterocyte model from human iPS cells which have potential to be applied for drug absorption and metabolism studies.

  19. Cadmium Induces Retinoic Acid Signaling by Regulating Retinoic Acid Metabolic Gene Expression*

    OpenAIRE

    Cui, Yuxia; Freedman, Jonathan H.

    2009-01-01

    The transition metal cadmium is an environmental teratogen. In addition, cadmium and retinoic acid can act synergistically to induce forelimb malformations. The molecular mechanism underlying the teratogenicity of cadmium and the synergistic effect with retinoic acid has not been addressed. An evolutionarily conserved gene, β,β-carotene 15,15′-monooxygenase (BCMO), which is involved in retinoic acid biosynthesis, was studied in both Caenorhabditis elegans and murine Hepa 1–6 cells. In C. eleg...

  20. AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells

    OpenAIRE

    Kim, Nami; Lee, Jung Ok; Lee, Hye Jeong; Lee, Yong Woo; Kim, Hyung Ip; Kim, Su Jin; Park, Sun Hwa; Lee, Chul Su; Ryoo, Sun Woo; Hwang, Geum-Sook; Kim, Hyeon Soo

    2016-01-01

    Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phospho...

  1. Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids

    OpenAIRE

    Pujos-Guillot, Estelle; Pickering, Gisèle; Lyan, Bernard; Ducheix, Gilles; Brandolini-Bunlon, Marion; Glomot, Françoise; Dardevet, Dominique; Dubray, Claude; PAPET, Isabelle

    2011-01-01

    Sulfur amino acids are determinant for the detoxification of paracetamol (N-acetyl-p-aminophenol) through sulfate and glutathione conjugations. Long-term paracetamol treatment is common in the elderly, despite a potential cysteine/glutathione deficiency. Detoxification could occur at the expense of anti-oxidative defenses and whole body protein stores in elderly. We tested how older persons satisfy the extra demand in sulfur amino acids induced by long-term paracetamol treatment, focusing on ...

  2. Calpain-1 Mediated Disorder of Pyrophosphate Metabolism Contributes to Vascular Calcification Induced by oxLDL.

    Science.gov (United States)

    Tang, Futian; Chan, Erqing; Lu, Meili; Zhang, Xiaowen; Dai, Chunmei; Mei, Meng; Zhang, Suping; Wang, Hongxin; Song, Qing

    2015-01-01

    metabolism disorder. The results also implied that Mito-ROS might contribute to the PPi metabolism disorder through regulation of the activity and expression of ALP. PMID:26047104

  3. Elevation of IGFBP2 contributes to mycotoxin T-2-induced chondrocyte injury and metabolism.

    Science.gov (United States)

    Wang, Xiaoqing; Zhang, Yan; Chang, Yanhai; Duan, Dapeng; Sun, Zhengming; Guo, Xiong

    2016-09-01

    Kashin-Beck disease (KBD) is an endemic degenerative osteoarthropathy. The mycotoxin of T-2 toxin is extensively accepted as a major etiological contributor to KBD. However, its function and mechanism in KBD remains unclearly elucidated. Here, T-2 toxin treatment induced chondrocyte injury in a time- and dose-dependent manner by repressing cell viability and promoting cell necrosis and apoptosis. Importantly, T-2 suppressed the transcription of type II collagen and aggrecan, as well as the release of sulphated glycosaminoglycan (sGAG). Furthermore, exposure to T-2 enhanced the transcription of matrix metalloproteinases (MMPs), including MMP-1, -2, -3 and -9. In contrast to control groups, higher expression of insulin-like growth factor binding protein 2 (IGFBP2) was observed in chondrocytes from KBD patients. Interestingly, T-2 toxin caused a dramatical elevation of IGFBP2 expression in chondrocytes. Mechanism analysis corroborated that cessation of IGFBP2 expression alleviated T-2-induced damage to chondrocytes. Simultaneously, transfection with IGFBP2 siRNA also attenuated matrix synthesis and catabolism-related gene expressions of MMPs. Together, this study validated that T-2 toxin exposure might promote the progression of KBD by inducing chondrocyte injury, suppressing matrix synthesis and accelerating cellular catabolism through IGFBP2. Therefore, this research will elucidate a new insight about how T-2 toxin participate in the pathogenesis of KBD. PMID:27416762

  4. Hypoglycemic effects of Zanthoxylum alkylamides by enhancing glucose metabolism and ameliorating pancreatic dysfunction in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    You, Yuming; Ren, Ting; Zhang, Shiqi; Shirima, Gerald Gasper; Cheng, YaJiao; Liu, Xiong

    2015-09-01

    This study aimed to evaluate the hypoglycemic effect of Zanthoxylum alkylamides and explore the potential mechanism in streptozotocin (STZ)-induced diabetic rats. Diabetic rats were orally treated with 3, 6, and 9 mg per kg bw alkylamides daily for 28 days. As the alkylamide dose increased, the relative weights of the liver and kidney, fasting blood glucose, and fructosamine levels were significantly decreased. The alkylamides also significantly increased the body weight and improved the oral glucose tolerance of the rats. Likewise, the alkylamides significantly increased the levels of liver and muscle glycogen and plasma insulin. These substances further alleviated the histopathological changes in the pancreas of the diabetic rats. The beneficial effects of high-dose alkylamides showed a comparable activity to the anti-diabetic drug glibenclamide. Western blot and real-time PCR results revealed that the alkylamide treatment significantly decreased the expression levels of the key enzymes (phosphoenolpyruvate caboxykinase and glucose-6-phosphatase) involved in gluconeogenesis and increased the glycolysis enzyme (glucokinase) in the liver, and enhanced the expression levels of pancreatic duodenal homeobox-1, glucokinase, and glucose transporter 2 in the pancreas. In addition, it was also observed that the alkylamides, unlike glibenclamide, increased the transient receptor potential cation channel subfamily V member 1 and decreased cannabinoid receptor 1 expressions in the liver and pancreas. Therefore, alkylamides can prevent STZ-induced hyperglycemia by altering the expression levels of the genes related to glucose metabolism and by ameliorating pancreatic dysfunction.

  5. Effect of linseed oil and macadamia oil on metabolic changes induced by high-fat diet in mice.

    Science.gov (United States)

    Barrena, Helenton C; Schiavon, Fabiana P M; Cararra, Marcia A; Marques, Any de Castro R; Schamber, Christiano R; Curi, Rui; Bazotte, Roberto B

    2014-06-01

    The effects of linseed oil (LO) and macadamia oil (MO) on the metabolic changes induced by a high-fat diet (HFD) rich in saturated fatty acid were investigated. For the purpose of this study, the vegetable oil present in the HFD, i.e. soybean oil (SO) was replaced with LO (HFD-LO) or MO (HFD-MO). For comparative purposes, a group was included, which received a normal fat diet (NFD). Male Swiss mice (6-week old) were used. After 14 days under the dietary conditions, the mice were fasted for 18 h, and experiments were then performed. The HFD-SO, HFD-LO and HFD-MO groups showed higher glycaemia (p fat weights were higher (p < 0.05) in the HFD-SO and HFD-MO groups as compared with the NFD group. However, there was no significant difference in these parameters between the NFD and HFD-LO groups. Thus, the protective role of LO on lipid accumulation induced by an HFD rich in saturated fatty acid is potentially mediated by the high content of ɷ-3 polyunsaturated fatty acid in LO.

  6. Senescence-inducible expression of isopentenyl transferase extends leaf life, increases drought stress resistance and alters cytokinin metabolism in cassava.

    Science.gov (United States)

    Zhang, Peng; Wang, Wen-Quan; Zhang, Gen-Liang; Kaminek, Miroslav; Dobrev, Petre; Xu, Jia; Gruissem, Wilhelm

    2010-07-01

    Cassava (Manihot esculenta Crantz) sheds its leaves during growth, especially within the tropical dry season. With the production of SAG12-IPT transgenic cassava we want to test the level of leaf retention and altered cytokinin metabolism of transgenic plants via the autoregulatory senescence inhibition system. After confirmation of transgene expression by molecular analysis and phenotype examination in greenhouse plants, two transgenic plant lines, 529-28 and 529-48, were chosen for further investigation. Detached mature leaves of 529-28 plants retained high levels of chlorophyll compared with wild-type leaves after dark-induced senescence treatment. Line 529-28 showed significant drought tolerance as indicated by stay-green capacity after drought stress treatment. Field experiments proved that leaf senescence syndrome was significantly delayed in 529-28 plants in comparison with wild-type and 529-48 plants. Physiological and agronomical characterizations of these plants also revealed that the induced expression of IPT had effects on photosynthesis, sugar allocation and nitrogen partitioning. Importantly, the 529-28 plants accumulated a high level of trans-zeatin-type cytokinins particularly of corresponding storage O-glucosides to maintain cytokinin homeostasis. Our study proves the feasibility of prolonging the leaf life of woody cassava and also sheds light on the control of cytokinin homeostasis in cassava leaves.

  7. Acute Ozone (O3) Exposure Accelerates Diet-Induced Pulmonary Injury and Metabolic Alterations in a Rat Model of Type II Diabetes

    Science.gov (United States)

    Abstract for Society of Toxicology, March 22-25, 2015, San Diego, CAAcute Ozone (O3) Exposure Accelerates Diet-Induced Pulmonary Injury and Metabolic Alterations in a Rat Model of Type II DiabetesS.J. Snow1,3, D. Miller2, V. Bass2, M. Schladweiler3, A. Ledbetter3, J. Richards3, C...

  8. The Impact of Streptozotocin-induced Diabetes Mellitus on Cyclic Nucleotide Regulation of Skeletal Muscle Amino Acid Metabolism in the Rat

    OpenAIRE

    Garber, Alan J.

    1980-01-01

    The impact of diabetes on cyclic nucleotide-associated mechanisms regulating skeletal muscle protein and amino acid metabolism was assessed using epitrochlaris preparations from streptozotocin-induced diabetic rats. 1 nM epinephrine inhibited alanine and glutamine release from control preparations, but no inhibition was observed from diabetic preparations with

  9. Microscopic analysis of cell death by metabolic stress-induced autophagy in prostate cancer

    Science.gov (United States)

    Changou, Chun; Cheng, R. Holland; Bold, Richard; Kung, Hsing-Jien; Chuang, Frank Y. S.

    2013-02-01

    Autophagy is an intracellular recycling mechanism that helps cells to survive against environmental stress and nutritional starvation. We have recently shown that prostate cancers undergo metabolic stress and caspase-independent cell death following exposure to arginine deiminase (ADI, an enzyme that degrades arginine in tissue). The aims of our current investigation into the application of ADI as a novel cancer therapy are to identify the components mediating tumor cell death, and to determine the role of autophagy (stimulated by ADI and/or rapamycin) on cell death. Using advanced fluorescence microscopy techniques including 3D deconvolution and superresolution structured-illumination microscopy (SIM), we show that prostate tumor cells that are killed after exposure to ADI for extended periods, exhibit a morphology that is distinct from caspase-dependent apoptosis; and that autophagosomes forming as a result of ADI stimulation contain DAPI-stained nuclear material. Fluorescence imaging (as well as cryo-electron microscopy) show a breakdown of both the inner and outer nuclear membranes at the interface between the cell nucleus and aggregated autophagolysosomes. Finally, the addition of N-acetyl cysteine (or NAC, a scavenger for reactive oxygen species) effectively abolishes the appearance of autophagolysosomes containing nuclear material. We hope to continue this research to understand the processes that govern the survival or death of these tumor cells, in order to develop methods to improve the efficacy of cancer pharmacotherapy.

  10. Cadmium Induced Changes in Metabolic Function of Mitochondrial Isolated from Potato Tissue (Solanum tuberosum L.

    Directory of Open Access Journals (Sweden)

    Chagra Ali

    2009-01-01

    Full Text Available Problem statement: Cadmium is highly toxic at low concentrations, but the mechanism of its toxicity is still not understood particularly at the cellular and subcellular level. Approach: In this study we examined the effects of cadmium on the oxidophosphorylation properties of mitochondria isolated from potatoes. Results: Cadmium strongly disturbed the respiratory metabolism of mitochondria isolated especially in the transfer of electrons by cyanide pathway. Meanwhile, cadmium altered the composition of lipid fatty acids polar while inhibiting catalase activity, a key enzyme in the detoxification (antioxidant process. In addition, cadmium caused an increase in mitochondrial volume associated with strong inhibition of ATPase activity, which could be explained by a transport of the potassium ion stimulation at the origin of the massive influx of H+ by antiport through the K+/H+ leading to a decoupling (cut of mitochondrial oxidative phosphorylation. The swelling of mitochondria was accompanied by the rupture of the mitochondrial outer membrane and thus the release of Cytochrome C, which appears to be the initial phase of apoptosis. Conclusion: Following this study, it appeared that cadmium generates in potato the isolated mitochondria a concentration-dependent oxidative stress.

  11. Dietary fat interacts with PCBs to induce changes in lipid metabolism in LDL receptor deficient mice

    Energy Technology Data Exchange (ETDEWEB)

    Hennig, B.; Reiterer, G.; Toborek, M.; Matveev, S.V.; Daugherty, A.; Smart, E. [Univ. of Kentucky, Lexington (United States); Robertson, L.W. [Univ. of Iowa, Iowa City (United States)

    2004-09-15

    From epidemiological studies, there is substantial evidence that cardiovascular diseases are linked to environmental pollution and that exposure to polycyclic and/or polyhalogenated aromatic hydrocarbons can lead to human cardiovascular toxicity. A major route of exposure to PCBs in humans is via oral ingestion of contaminated food products. Therefore, circulating environmental contaminants derived from diets, such as PCBs, are in intimate contact with the vascular endothelium. Endothelial activation and dysfunction is an important factor in the overall regulation of vascular lesion pathology. In addition to endothelial barrier dysfunction, another functional change in atherosclerosis is the activation of the endothelium that is manifested as an increase in the expression of specific cytokines and adhesion molecules. These cytokines and adhesion molecules are proposed to mediate the inflammatory aspects of the disease by regulating the vascular entry of leukocytes. Alterations in lipid profile and lipid metabolism as a result of exposure to PCBs may be important components of endothelial cell dysfunction. Little is known about the interaction of dietary fats and PCBs in the pathology of atherosclerosis. We have reported a significant disruption in endothelial barrier function when cells were exposed to linoleic acid. In the current study we aimed to demonstrate the PCB-fatty acid interaction in vivo and hypothesized that PCB toxicity can be modulated by the type of fat consumed.

  12. Oxidative state and oxidative metabolism in the brain of rats with adjuvant-induced arthritis.

    Science.gov (United States)

    Wendt, Mariana Marques Nogueira; de Sá-Nakanishi, Anacharis Babeto; de Castro Ghizoni, Cristiane Vizioli; Bersani Amado, Ciomar Aparecida; Peralta, Rosane Marina; Bracht, Adelar; Comar, Jurandir Fernando

    2015-06-01

    The purpose of the present study was to evaluate the oxidative status of the brain of arthritic rats, based mainly on the observation that arthritis induces a pronounced oxidative stress in the liver of arthritis rats and that morphological alterations have been reported to occur in patients with rheumatoid arthritis. Rats with adjuvant-induced arthritis were used. These animals presented higher levels of reactive oxygen species (ROS) in the total brain homogenate (25% higher) and in the mitochondria (+55%) when compared to healthy rats. The nitrite plus nitrate contents, nitric oxide (NO) markers, were also increased in both mitochondria (+27%) and cytosol (+14%). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (+43%), mitochondria (+69%) and cytosol (+145%). Arthritis caused a diminution of oxygen consumption in isolated brain mitochondria only when ascorbate was the electron donor. The disease diminished the mitochondrial cytochrome c oxidase activity by 55%, but increased the transmembrane potential by 16%. The pro-oxidant enzyme xanthine oxidase was 150%, 110% and 283% higher, respectively, in the brain homogenate, mitochondria and cytosol of arthritic animals. The same occurred with the calcium-independent NO-synthase activity that was higher in the brain homogenate (90%) and cytosol (122%) of arthritic rats. The catalase activity, on the other hand, was diminished by arthritis in all cellular fractions (between 30 and 40%). It is apparent that the brain of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and a significant injury to lipids and proteins, a situation that possibly contributes to the brain symptoms of the arthritis disease.

  13. Effect of luteolin on glycoproteins metabolism in 1, 2-dimethylhydrazine induced experimental colon carcinogenesis

    OpenAIRE

    Manju Vaiyapuri; Nalini Namasivayam

    2008-01-01

    We have investigated the effect of luteolin, a flavonoid on colon cancer induced in rats by a colon specific carcinogen 1, 2 dimethylhydrazine (DMH). Rats were randomized into 5 groups of 10 animals each. Rats in group 1 received 1.0 ml of 0.5% carboxymethyl cellulose (CMC) everyday via intragastric intubation and served as the untreated control. Group 2 rats received luteolin via intragastric intubation (p.o.) at a daily dose of 0.2 mg/kg body weight. The rats in groups 3 to 5 received DM...

  14. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast

    DEFF Research Database (Denmark)

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida;

    2016-01-01

    respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections...... reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular...

  15. Short-term captivity influences maximal cold-induced metabolic rates and their repeatability in summer-acclimatized American goldfinches Spinus tristis

    Institute of Scientific and Technical Information of China (English)

    David L.SWANSON; Marisa O.KING

    2013-01-01

    Studies of metabolic variation in birds have involved both wild and captive individuals,but few studies have investigated whether captivity directly influences metabolic rates,despite such variation potentially confounding conclusions regarding how metabolic rates respond to the conditions under study.In addition,whether short-term captivity influences metabolic rate repeatability in birds is currently uninvestigated.In this study,we measured Msum (maximal cold-induced metabolic rates) in summer acclimatized American goldfinches Spinus tristis directly after capture from wild populations,after approximately 2 weeks of indoor captivity (Captive 1),and again after an additional 1-2 weeks of captivity (Captive 2).Msum increased significantly (16.9%) following the initial captive period,but remained stable thereafter.Body mass (Mb) also increased significantly (9.2%) during the initial captive period but remained stable thereafter,suggesting that muscle growth and/or remodeling of body composition produced the observed metabolic variation.Mb and Msum were not significantly repeatable between wild and Captive 1 birds,but were significantly repeatable between Captive 1 and Captive 2 groups.These data suggest that caution must be exercised when extrapolating metabolic rates from short-term captive to wild populations.In addition,Msum was a repeatable trait for birds under conditions where mean metabolic rates remained stable,but Msum repeatability disappeared during acclimation to conditions promoting phenotypically flexible metabolic responses.This suggests that the capacity for phenotypic flexibility varies among individuals,and such variation could have fitness consequences.

  16. Implications of altered glutathione metabolism in aspirin-induced oxidative stress and mitochondrial dysfunction in HepG2 cells.

    Directory of Open Access Journals (Sweden)

    Haider Raza

    Full Text Available We have previously reported that acetylsalicylic acid (aspirin, ASA induces cell cycle arrest, oxidative stress and mitochondrial dysfunction in HepG2 cells. In the present study, we have further elucidated that altered glutathione (GSH-redox metabolism in HepG2 cells play a critical role in ASA-induced cytotoxicity. Using selected doses and time point for ASA toxicity, we have demonstrated that when GSH synthesis is inhibited in HepG2 cells by buthionine sulfoximine (BSO, prior to ASA treatment, cytotoxicity of the drug is augmented. On the other hand, when GSH-depleted cells were treated with N-acetyl cysteine (NAC, cytotoxicity/apoptosis caused by ASA was attenuated with a significant recovery in oxidative stress, GSH homeostasis, DNA fragmentation and some of the mitochondrial functions. NAC treatment, however, had no significant effects on the drug-induced inhibition of mitochondrial aconitase activity and ATP synthesis in GSH-depleted cells. Our results have confirmed that aspirin increases apoptosis by increased reactive oxygen species production, loss of mitochondrial membrane potential and inhibition of mitochondrial respiratory functions. These effects were further amplified when GSH-depleted cells were treated with ASA. We have also shown that some of the effects of aspirin might be associated with reduced GSH homeostasis, as treatment of cells with NAC attenuated the effects of BSO and aspirin. Our results strongly suggest that GSH dependent redox homeostasis in HepG2 cells is critical in preserving mitochondrial functions and preventing oxidative stress associated complications caused by aspirin treatment.

  17. Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic β-cells

    Directory of Open Access Journals (Sweden)

    Muto Takashi

    2011-04-01

    Full Text Available Abstract Background Glycated albumin (GA is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic β cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA and GA was measured under three different glucose concentrations, 3 mM (G3, 7 mM (G7, and 15 mM (G15, with various stimulators. Insulin secretion was measured with antagonists of inducible nitric oxide synthetase (iNOS, and the expression of iNOS-mRNA was investigated by real-time PCR. Results Insulin secretion in the presence of HA and GA was 20.9 ± 3.9 and 21.6 ± 5.5 μU/3 islets/h for G3 (P = 0.920, and 154 ± 9.3 and 126.1 ± 7.3 μU/3 islets/h (P = 0.046, for G15, respectively. High extracellular potassium and 10 mM tolbutamide abrogated the inhibition of insulin secretion by GA. Glyceraldehyde, dihydroxyacetone, methylpyruvate, GLP-1, and forskolin, an activator of adenylate cyclase, did not abrogate the inhibition. Real-time PCR showed that GA did not induce iNOS-mRNA expression. Furthermore, an inhibitor of nitric oxide synthetase, aminoguanidine, and NG-nitro-L-arginine methyl ester did not abrogate the inhibition of insulin secretion. Conclusion GA suppresses glucose-induced insulin secretion from rat pancreatic β-cells through impairment of intracellular glucose metabolism.

  18. Cardiorenal Involvement in Metabolic Syndrome Induced by Cola Drinking in Rats: Proinflammatory Cytokines and Impaired Antioxidative Protection.

    Science.gov (United States)

    Otero-Losada, Matilde; Gómez Llambí, Hernán; Ottaviano, Graciela; Cao, Gabriel; Müller, Angélica; Azzato, Francisco; Ambrosio, Giuseppe; Milei, José

    2016-01-01

    We report experimental evidence confirming renal histopathology, proinflammatory mediators, and oxidative metabolism induced by cola drinking. Male Wistar rats drank ad libitum regular cola (C, n = 12) or tap water (W, n = 12). Measures. Body weight, nutritional data, plasma glucose, cholesterol fractions, TG, urea, creatinine, coenzyme Q10, SBP, and echocardiograms (0 mo and 6 mo). At 6 months euthanasia was performed. Kidneys were processed for histopathology and immunohistochemistry (semiquantitative). Compared with W, C rats showed (I) overweight (+8%, p < 0.05), hyperglycemia (+11%, p < 0.05), hypertriglyceridemia (2-fold, p < 0.001), higher AIP (2-fold, p < 0.01), and lower Q10 level (-55%, p < 0.05); (II) increased LV diastolic diameter (+9%, p < 0.05) and volume (systolic +24%, p < 0.05), posterior wall thinning (-8%, p < 0.05), and larger cardiac output (+24%, p < 0.05); (III) glomerulosclerosis (+21%, p < 0.05), histopathology (+13%, p < 0.05), higher tubular expression of IL-6 (7-fold, p < 0.001), and TNFα (4-fold, p < 0.001). (IV) Correlations were found for LV dimensions with IL-6 (74%, p < 0.001) and TNFα (52%, p < 0.001) and fully abolished after TG and Q10 control. Chronic cola drinking induced cardiac remodeling associated with increase in proinflammatory cytokines and renal damage. Hypertriglyceridemia and oxidative stress were key factors. Hypertriglyceridemic lipotoxicity in the context of defective antioxidant/anti-inflammatory protection due to low Q10 level might play a key role in cardiorenal disorder induced by chronic cola drinking in rats. PMID:27340342

  19. Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism

    Science.gov (United States)

    Guo, Yizhu; Wang, Xin; Zhang, Xinyan; Sun, Zheng; Chen, Xiaoxin

    2011-01-01

    Alcohol drinking is a known risk factor for oral cancer in humans. However, previous animal studies on the promoting effect of ethanol on oral carcinogenesis were inconclusive. It is necessary to develop an animal model with which the molecular mechanism of ethanol-related oral carcinogenesis may be elucidated in order to develop effective prevention strategies. In this study, mice were first treated with 4-nitroquinoline-1-oxide (4NQO, 100μg/ml in drinking water) for 8 weeks, and then given water or ethanol (8%) as the sole drink for another 16 weeks. During the experiment, 8% ethanol was well tolerated by mice. The incidence of squamous cell carcinoma (SCC) increased from 20% (8/41) to 43% (17/40; p<0.05). Expression of 5-lipoxygenase (5-Lox) and cyclooxygenase 2 (Cox-2) was increased in dysplasia and SCC of 4NQO-treated tongues, and further enhanced by ethanol. Using this mouse model, we further demonstrated that fewer cancers were induced in Alox5−/− mice, as were cell proliferation, inflammation, and angiogenesis in the tongue, as compared with Alox5+/+ mice. Interestingly, Cox-2 expression was induced by ethanol in knockout mice, while 5-Lox and leukotriene A4 hydrolase (LTA4H) expression and leukotriene B4 (LTB4) biosynthesis were dramatically reduced. Moreover, ethanol enhanced expression and nuclear localization of 5-Lox and stimulated LTB4 biosynthesis in human tongue SCC cells (SCC-15 and SCC-4) in vitro. In conclusion, this study clearly demonstrated that ethanol promoted 4NQO-induced oral carcinogenesis, at least in part, through further activation of the 5-Lox pathway of arachidonic acid metabolism. PMID:21881027

  20. Oleanolic Acid Inhibits High Salt-Induced Exaggeration of Warburg-like Metabolism in Breast Cancer Cells.

    Science.gov (United States)

    Amara, Suneetha; Zheng, Mu; Tiriveedhi, Venkataswarup

    2016-09-01

    Cancer cells have a proliferative advantage by utilizing intermediates of aerobic glycolysis (Warburg effect) for their macromolecule synthesis. Although the exact causes of this Warburg effect are unclear, high osmotic stress in solid tumor microenvironment is considered one of the important factors. Oleanolic acid (OA) is known to exert anti-inflammatory and anti-cancer effect. In our current studies, using breast cancer cell lines, we determined the protective role of OA in high salt-mediated osmotic stress-induced cancer growth. Hypertonic (0.16 M NaCl) culture conditions enhanced the cancer cell growth (26 %, p effect was associated with increased expression and activity of key rate-limiting enzymes of aerobic glycolysis, namely hexokinase, pyruvate kinase type M2, and lactate dehydrogenase A. Interestingly, this high salt-mediated enhanced expression of aerobic glycolytic enzymes was efficiently reversed by OA along with the decreased cancer cell proliferation. In cancer cells, enhanced aerobic glycolysis is associated with the decreased mitochondrial activity and mitochondrial-associated caspase activity. As expected, high salt further inhibited the mitochondrial related cytochrome oxidase and caspase-3 activity. However, OA efficiently reversed the high salt-mediated inhibition of cytochrome oxidase, caspase activity, and pro-apoptotic Bax expression, thus suggesting that OA induced mitochondrial activity and enhanced apoptosis. Taken together, our data indicate that OA efficiently reverses the enhanced Warburg-like metabolism induced by high salt-mediated osmotic stress along with potential application of OA in anti-cancer therapy. PMID:27236294

  1. Hypoxic culture conditions induce increased metabolic rate and collagen gene expression in ACL-derived cells.

    Science.gov (United States)

    Kowalski, Tomasz J; Leong, Natalie L; Dar, Ayelet; Wu, Ling; Kabir, Nima; Khan, Adam Z; Eliasberg, Claire D; Pedron, Andrew; Karayan, Ashant; Lee, Siyoung; Di Pauli von Treuheim, Theodor; Jiacheng, Jin; Wu, Ben M; Evseenko, Denis; McAllister, David R; Petrigliano, Frank A

    2016-06-01

    There has been substantial effort directed toward the application of bone marrow and adipose-derived mesenchymal stromal cells (MSCs) in the regeneration of musculoskeletal tissue. Recently, resident tissue-specific stem cells have been described in a variety of mesenchymal structures including ligament, tendon, muscle, cartilage, and bone. In the current study, we systematically characterize three novel anterior cruciate ligament (ACL)-derived cell populations with the potential for ligament regeneration: ligament-forming fibroblasts (LFF: CD146(neg) , CD34(neg) CD44(pos) , CD31(neg) , CD45(neg) ), ligament perivascular cells (LPC: CD146(pos) CD34(neg) CD44(pos) , CD31(neg) , CD45(neg) ) and ligament interstitial cells (LIC: CD34(pos) CD146(neg) , CD44(pos) , CD31(neg) , CD45(neg) )-and describe their proliferative and differentiation potential, collagen gene expression and metabolism in both normoxic and hypoxic environments, and their trophic potential in vitro. All three groups of cells (LIC, LPC, and LFF) isolated from adult human ACL exhibited progenitor cell characteristics with regard to proliferation and differentiation potential in vitro. Culture in low oxygen tension enhanced the collagen I and III gene expression in LICs (by 2.8- and 3.3-fold, respectively) and LFFs (by 3- and 3.5-fold, respectively) and increased oxygen consumption rate and extracellular acidification rate in LICs (by 4- and 3.5-fold, respectively), LFFs (by 5.5- and 3-fold, respectively), LPCs (by 10- and 4.5-fold, respectively) as compared to normal oxygen concentration. In summary, this study demonstrates for the first time the presence of three novel progenitor cell populations in the adult ACL that demonstrate robust proliferative and matrix synthetic capacity; these cells may play a role in local ligament regeneration, and consequently represent a potential cell source for ligament engineering applications. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc

  2. Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism

    Directory of Open Access Journals (Sweden)

    Jessica R. Gooding

    2015-10-01

    Full Text Available Pancreatic islet failure, involving loss of glucose-stimulated insulin secretion (GSIS from islet β cells, heralds the onset of type 2 diabetes (T2D. To search for mediators of GSIS, we performed metabolomics profiling of the insulinoma cell line 832/13 and uncovered significant glucose-induced changes in purine pathway intermediates, including a decrease in inosine monophosphate (IMP and an increase in adenylosuccinate (S-AMP, suggesting a regulatory role for the enzyme that links the two metabolites, adenylosuccinate synthase (ADSS. Inhibition of ADSS or a more proximal enzyme in the S-AMP biosynthesis pathway, adenylosuccinate lyase, lowers S-AMP levels and impairs GSIS. Addition of S-AMP to the interior of patch-clamped human β cells amplifies exocytosis, an effect dependent upon expression of sentrin/SUMO-specific protease 1 (SENP1. S-AMP also overcomes the defect in glucose-induced exocytosis in β cells from a human donor with T2D. S-AMP is, thus, an insulin secretagogue capable of reversing β cell dysfunction in T2D.

  3. Emersion induces nitrogen release and alteration of nitrogen metabolism in the intertidal genus Porphyra.

    Directory of Open Access Journals (Sweden)

    Jang K Kim

    Full Text Available We investigated emersion-induced nitrogen (N release from Porphyra umbilicalis Kütz. Thallus N concentration decreased during 4 h of emersion. Tissue N and soluble protein contents of P. umbilicalis were positively correlated and decreased during emersion. Growth of P. umbilicalis did not simply dilute the pre-emersion tissue N concentration. Rather, N was lost from tissues during emersion. We hypothesize that emersion-induced N release occurs when proteins are catabolized. While the δ(15N value of tissues exposed to emersion was higher than that of continuously submerged tissues, further discrimination of stable N isotopes did not occur during the 4 h emersion. We conclude that N release from Porphyra during emersion did not result from bacterial denitrification, but possibly as a consequence of photorespiration. The release of N by P. umbilicalis into the environment during emersion suggests a novel role of intertidal seaweeds in the global N cycle. Emersion also altered the physiological function (nitrate uptake, nitrate reductase and glutamine synthetase activity, growth rate of P. umbilicalis and the co-occurring upper intertidal species P. linearis Grev., though in a seasonally influenced manner. Individuals of the year round perennial species P. umbilicalis were more tolerant of emersion than ephemeral, cold temperate P. linearis in early winter. However, the mid-winter populations of both P. linearis and P. umbilicalis, had similar temporal physiological patterns during emersion.

  4. Kojibiose ameliorates arachidic acid-induced metabolic alterations in hyperglycaemic rats.

    Science.gov (United States)

    Moisés Laparra, José; Díez-Municio, Marina; Javier Moreno, F; Herrero, Miguel

    2015-11-14

    Herein we hypothesise the positive effects of kojibiose (KJ), a prebiotic disaccharide, selected for reducing hepatic expression of inflammatory markers in vivo that could modulate the severity of saturated arachidic acid (ARa)-induced liver dysfunction in hyperglycaemic rats. Animals were fed daily (20 d) with ARa (0·3 mg) together or not with KJ (22 mg approximately 0·5 %, w/w diet). Glucose, total TAG and cholesterol contents and the phospholipid profile were determined in serum samples. Liver sections were collected for the expression (mRNA) of enzymes and innate biomarkers, and intrahepatic macrophage and T-cell populations were analysed by flow cytometry. ARa administration increased the proportion of liver to body weight that was associated with an increased (by 11 %) intrahepatic macrophage population. These effects were ameliorated when feeding with KJ, which also normalised the plasmatic levels of TAG and N-acyl-phosphatidylethenolamine in response to tissue damage. These results indicate that daily supplementation of KJ significantly improves the severity of ARa-induced hepatic alterations. PMID:26344377

  5. Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats.

    Science.gov (United States)

    Awwad, Hibah O; Gonzalez, Larry P; Tompkins, Paul; Lerner, Megan; Brackett, Daniel J; Awasthi, Vibhudutta; Standifer, Kelly M

    2015-01-01

    Physiological alterations, anxiety, and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI), and are common symptoms in service personnel exposed to blasts. Since 2006, 25,000-30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to the head in the absence of thoracic contributions from the periphery were examined, following a single blast wave directed to the head of male Sprague-Dawley rats protected by a lead shield over the torso. An 80 psi head blast produced cognitive deficits that were detected in working memory. Blast TBI rats displayed increased anxiety as determined by elevated plus maze at day 9 post-blast compared to sham rats; blast TBI rats spent significantly more time than the sham controls in the closed arms (p blast. Instead, blast TBI rats displayed increased rearing behavior at day 48 post-blast compared to sham rats. Blast TBI rats also exhibited suppressed acoustic startle responses, but similar pre-pulse inhibition at day 15 post-blast compared to sham rats. Acute physiological alterations in cerebral glucose metabolism were determined by positron emission tomography 1 and 9 days post-blast using (18)F-fluorodeoxyglucose ((18)F-FDG). Global glucose uptake in blast TBI rat brains increased at day 1 post-blast (p blast injury. Markers for reactive astrogliosis and neuronal damage were noted by immunoblotting motor cortex tissue from day 10 post-blast in blast TBI rats compared to sham controls (p < 0.05; n = 5-6). PMID:26136722

  6. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    Science.gov (United States)

    Cai, Zhiyou; Yan, Yong; Wang, Yonglong

    2013-01-01

    Background Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions

  7. Melatonin ameliorates metabolic risk factors, modulates apoptotic proteins, and protects the rat heart against diabetes-induced apoptosis.

    Science.gov (United States)

    Amin, Ali H; El-Missiry, Mohamed A; Othman, Azza I

    2015-01-15

    The present study investigated the ability of melatonin in reducing metabolic risk factors and cardiac apoptosis induced by diabetes. Streptozotocin (60 mg/kg, i.p.) was injected into male rats, and after diabetic induction melatonin (10mg/kg i.g.) was administered orally for 21 days. Diabetic hearts showed increased number of apoptotic cells with downregulation of Bcl-2 and activation of p53 and CD95 as well as the caspases 9, 8 and 3. In addition, there was a significant decrease in insulin level, hyperglycemia, elevated HOMA-IR, glycosylated hemoglobin (HbA1c), total lipids, triglycerides, total cholesterol, low and very low-density lipoprotein and decreased high-density lipoprotein. These changes were coupled with a significant increase in the activities of creatin kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum of the diabetic rats indicating myocardium injury. Oral administration of melatonin for 3 weeks after diabetes induction ameliorated the levels of hyperglycemia, insulin, HbA1c, lipids profile and HOMA-IR. The oral melatonin treatment of diabetic rats significantly decreased the number of apoptotic cells in the heart compared to diabetic rats. It enhanced Bcl-2 expression and blocked the activation of CD95 as well as caspases 9, 8 and 3. These changes were accompanied with significant improvement of CK-MB and LDH in the serum indicating the ameliorative effect of melatonin on myocardium injury. Melatonin effectively ameliorated diabetic myocardium injury, apoptosis, reduced the metabolic risk factors and modulated important steps in both extrinsic and intrinsic pathways of apoptosis. Thus, melatonin may be a promising pharmacological agent for ameliorating potential cardiomyopathy associated with diabetes. PMID:25510232

  8. Transport and metabolism at blood-brain interfaces and in neural cells: relevance to bilirubin-induced encephalopathy

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    Silvia eGazzin

    2012-05-01

    Full Text Available Bilirubin, the end-product of heme catabolism, circulates in non pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood-brain interfaces into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, blood-brain interfaces act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of blood-brain interfaces in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood-brain and blood-CSF barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as with the potential role of transporters such as ABCC-1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed.

  9. High-fat diet combined with low-dose streptozotocin injections induces metabolic syndrome in Macaca mulatta.

    Science.gov (United States)

    Li, Linzhao; Liao, Guangneng; Yang, Guang; Lu, Yanrong; Du, Xiaojiong; Liu, Jingping; Li, Lan; Wang, Chengshi; Li, Li; Ren, Yan; Zhong, Zhihui; Cheng, Jingqiu; Chen, Younan

    2015-08-01

    Metabolic syndrome (MetS) is associated with abdominal obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus, and increases the risk of cardiovascular disease. Given the complex multifactorial pathogenesis of MetS, qualified animal models are currently seriously limited for researchers. The aim of our study was to develop a MetS model in juvenile rhesus monkeys (Macaca mulatta). Rhesus monkeys (1-year-old) fed a high-fat diet (15 % fat, 2 % cholesterol) were used as the HF group (n = 6), and those on a normal diet (5 % fat) were used as the control group (n = 4). After being fed a high-fat diet for approximately 12 months, 2 monkeys (HF + STZ group) were injected with low-dose streptozotocin (STZ, 25 mg/kg) twice, with a 7 days interval, and were then fed the same diet continuously for another 24 months. After 36 months of treatment, the high-fat diet monkeys, including the HF and HF + STZ groups, had acquired increased body weights, abnormal serum lipids, and impaired glucose tolerance compared to the control group. In addition, much more marked metabolic changes were observed in the two monkeys of the HF + STZ group, particularly in terms of high-blood glucose level and insulin resistance. Morphological observation of biopsies of liver and pancreatic tissues showed decreased islet number and mass and decreased insulin staining in the monkeys of the HF + STZ group. In addition, Oil red O staining suggested remarkable accumulation of lipid droplets in the hepatocytes. Our study suggested that a long-term high-fat diet followed with a low-dose STZ was able to induce MetS in juvenile rhesus monkeys with faster pathophysiological progress compared with high-fat diet induction alone. Our primary data showed that this method may have potentials to develop MetS animal model in non-human primates.

  10. Antidepressant-induced akathisia-related homicides associated with diminishing mutations in metabolizing genes of the CYP450 family

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    Lucire Y

    2011-08-01

    Full Text Available Yolande Lucire, Christopher CrottyEdgecliff Centre, Edgecliff, NSW, AustraliaPurpose: To examine the relation between variant alleles in 3 CYP450 genes (CYP2D6, CYP2C9 and CYP2C19, interacting drugs and akathisia in subjects referred to a forensic psychiatry practice in Sydney, Australia.Patients and methods: This paper concerns 10/129 subjects who had been referred to the first author’s practice for expert opinion or treatment. More than 120 subjects were diagnosed with akathisia/serotonin toxicity after taking psychiatric medication that had been prescribed for psychosocial distress. They were tested for variant alleles in CYP450 genes, which play a major role in Phase I metabolism of all antidepressant and many other medications. Eight had committed homicide and many more became extremely violent while on antidepressants. Ten representative case histories involving serious violence are presented in detail.Results: Variant CYP450 allele frequencies were higher in akathisia subjects compared with random primary care patients tested at the same facility. Ten subjects described in detail had variant alleles for one or more of their tested CYP450 genes. All but two were also on interacting drugs, herbals or illicit substances, impairing metabolism further. All those described were able to stop taking antidepressants and return to their previously normal personalities.Conclusion: The personal, medical, and legal problems arising from overuse of antidepressant medications and resulting toxicity raise the question: how can such toxicity events be understood and prevented? The authors suggest that the key lies in understanding the interplay between the subject’s CYP450 genotype, substrate drugs and doses, co-prescribed inhibitors and inducers and the age of the subject. The results presented here concerning a sample of persons given antidepressants for psychosocial distress demonstrate the extent to which the psychopharmacology industry has

  11. Weight Loss After Bariatric Surgery Reverses Insulin-Induced Increases in Brain Glucose Metabolism of the Morbidly Obese

    OpenAIRE

    Tuulari, Jetro J.; Henry K Karlsson; Hirvonen, Jussi; Hannukainen, Jarna C.; Bucci, Marco; Helmiö, Mika; Ovaska, Jari; Soinio, Minna; Salminen, Paulina; Savisto, Nina; Nummenmaa, Lauri; Nuutila, Pirjo

    2013-01-01

    Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not dif...

  12. Multiple univariate data analysis reveals the inulin effects on the high-fat-diet induced metabolic alterations in rat myocardium and testicles in the preobesity state.

    Science.gov (United States)

    Duan, Yixuan; An, Yanpeng; Li, Ning; Liu, Bifeng; Wang, Yulan; Tang, Huiru

    2013-07-01

    Obesity is a worldwide epidemic and a well-known risk factor for many diseases affecting billions of people's health and well-being. However, little information is available for metabolic changes associated with the effects of obesity development and interventions on cardiovascular and reproduction systems. Here, we systematically analyzed the effects of high-fat diet (HFD) and inulin intake on the metabolite compositions of myocardium and testicle using NMR spectroscopy. We developed a useful high-throughput method based on multiple univariate data analysis (MUDA) to visualize and efficiently extract information on metabolites significantly affected by an intervention. We found that HFD caused widespread metabolic changes in both rat myocardium and testicles involving fatty acid β-oxidation together with the metabolisms of choline, amino acids, purines and pyrimidines even before HFD caused significant body-weight increases. Inulin intake ameliorated some of the HFD-induced metabolic changes in both myocardium (3-HB, lactate and guanosine) and testicle tissues (3-HB, inosine and betaine). A remarkable elevation of scyllo-inositol was also observable with inulin intake in both tissues. These findings offered essential information for the inulin effects on the HFD-induced metabolic changes and demonstrated this MUDA method as a powerful alternative to traditionally used multivariate data analysis for metabonomics.

  13. Compost-induced suppression of Pythium damping-off is mediated by fatty-acid-metabolizing seed-colonizing microbial communities.

    Science.gov (United States)

    McKellar, Mary E; Nelson, Eric B

    2003-01-01

    Leaf composts were studied for their suppressive effects on Pythium ultimum sporangium germination, cottonseed colonization, and the severity of Pythium damping-off of cotton. A focus of the work was to assess the role of fatty-acid-metabolizing microbial communities in disease suppression. Suppressiveness was expressed within the first few hours of seed germination as revealed by reduced P. ultimum sporangium germination, reduced seed colonization, and reduced damping-off in transplant experiments. These reductions were not observed when cottonseeds were sown in a conducive leaf compost. Microbial consortia recovered from the surface of cottonseeds during the first few hours of germination in suppressive compost (suppressive consortia) induced significant levels of damping-off suppression, whereas no suppression was induced by microbial consortia recovered from cottonseeds germinated in conducive compost (conducive consortia). Suppressive consortia rapidly metabolized linoleic acid, whereas conducive consortia did not. Furthermore, populations of fatty-acid-metabolizing bacteria and actinobacteria were higher in suppressive consortia than in conducive consortia. Individual bacterial isolates varied in their ability to metabolize linoleic acid and protect seedlings from damping-off. Results indicate that communities of compost-inhabiting microorganisms colonizing cottonseeds within the first few hours after sowing in a Pythium-suppressive compost play a major role in the suppression of P. ultimum sporangium germination, seed colonization, and damping-off. Results further indicate that fatty acid metabolism by these seed-colonizing bacterial consortia can explain the Pythium suppression observed. PMID:12514027

  14. GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

    Science.gov (United States)

    Efanov, Alexander M.; Fang, Xiankang; Beavers, Lisa S.; Wang, Xuesong; Wang, Jingru; Gonzalez Valcarcel, Isabel C.; Ma, Tianwei

    2016-01-01

    GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes. PMID:27322810

  15. GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism.

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    Hua V Lin

    Full Text Available GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes.

  16. Metabolic effects of quail eggs in diabetes-induced rats: comparison with chicken eggs

    Science.gov (United States)

    Lontchi-Yimagou, Eric; Tanya, Agatha; Tchankou, Carine; Ngondi, Judith; Oben, Julius

    2016-01-01

    Background Quail eggs as a food item have recently been introduced into the diet of some Cameroonians. These eggs are being sold in local markets, but with many unfounded health claims. One claim is that quail eggs can reduce blood glucose levels in diabetics. It was therefore necessary to evaluate the effect of consuming quail eggs on blood glucose levels, lipid profiles, and oxidative stress parameters in diabetes-induced rats. Methods Twenty Wistar rats weighing, on average, 250 g were divided into four groups of five rats each. Group 1 consisted of rats with normal blood glucose, and the other three groups (2, 3, and 4) consisted of diabetes-induced rats achieved by intravenous injection of streptozotocin. During 16 days, rats in groups 1 and 2 received distilled water; and rats in groups 3 and 4 received quail and chicken eggs, respectively, with gastroesophageal probe at a dose of 1 mL/200 g body weight. Fasting blood glucose levels were determined in all the groups on the 1st, 7th, 14th, and 17th days after induction of diabetes. On the 17th day, the fasting rats were sacrificed, and blood and liver samples were collected for biochemical analyses. Results In 17 days, the consumption of quail and chicken eggs had no effect on blood glucose levels of diabetic rats. Total cholesterol levels were higher in groups 3 (75.59 mg/dL) and 4 (59.41 mg/dL) compared to group 2 (55.67 mg/dl), although these differences were not significant (all p>0.05). Triglyceride levels were significantly higher (pdiabetic rats at the tested dose had no effect on blood glucose level and oxidative stress parameters and may have a negative effect on lipid profile. PMID:27717410

  17. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice.

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    Yan Y Lam

    Full Text Available We investigated the relationship between gut health, visceral fat dysfunction and metabolic disorders in diet-induced obesity. C57BL/6J mice were fed control or high saturated fat diet (HFD. Circulating glucose, insulin and inflammatory markers were measured. Proximal colon barrier function was assessed by measuring transepithelial resistance and mRNA expression of tight-junction proteins. Gut microbiota profile was determined by 16S rDNA pyrosequencing. Tumor necrosis factor (TNF-α and interleukin (IL-6 mRNA levels were measured in proximal colon, adipose tissue and liver using RT-qPCR. Adipose macrophage infiltration (F4/80⁺ was assessed using immunohistochemical staining. HFD mice had a higher insulin/glucose ratio (P = 0.020 and serum levels of serum amyloid A3 (131%; P = 0.008 but reduced circulating adiponectin (64%; P = 0.011. In proximal colon of HFD mice compared to mice fed the control diet, transepithelial resistance and mRNA expression of zona occludens 1 were reduced by 38% (P<0.001 and 40% (P = 0.025 respectively and TNF-α mRNA level was 6.6-fold higher (P = 0.037. HFD reduced Lactobacillus (75%; P<0.001 but increased Oscillibacter (279%; P = 0.004 in fecal microbiota. Correlations were found between abundances of Lactobacillus (r = 0.52; P = 0.013 and Oscillibacter (r = -0.55; P = 0.007 with transepithelial resistance of the proximal colon. HFD increased macrophage infiltration (58%; P = 0.020, TNF-α (2.5-fold, P<0.001 and IL-6 mRNA levels (2.5-fold; P = 0.008 in mesenteric fat. Increased macrophage infiltration in epididymal fat was also observed with HFD feeding (71%; P = 0.006 but neither TNF-α nor IL-6 was altered. Perirenal and subcutaneous adipose tissue showed no signs of inflammation in HFD mice. The current results implicate gut dysfunction, and attendant inflammation of contiguous adipose, as salient features of the metabolic dysregulation of diet-induced obesity.

  18. Plasma Proteome Profiles Associated with Diet-Induced Metabolic Syndrome and the Early Onset of Metabolic Syndrome in a Pig Model

    NARCIS (Netherlands)

    Pas, te M.F.W.; Koopmans, S.J.; Kruijt, L.; Calus, M.P.L.; Smits, M.A.

    2013-01-01

    Obesity and related diabetes are important health threatening multifactorial metabolic diseases and it has been suggested that 25% of all diabetic patients are unaware of their patho-physiological condition. Biomarkers for monitoring and control are available, but early stage predictive biomarkers e

  19. A hypothalamic–pituitary–adrenal axis-associated neuroendocrine metabolic programmed alteration in offspring rats of IUGR induced by prenatal caffeine ingestion

    Energy Technology Data Exchange (ETDEWEB)

    Xu, D. [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Wu, Y.; Liu, F.; Liu, Y.S.; Shen, L.; Lei, Y.Y.; Liu, J. [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Ping, J. [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Qin, J. [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Zhang, C. [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Chen, L.B. [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, J. [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Wang, H., E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2012-11-01

    Caffeine is a definite factor of intrauterine growth retardation (IUGR). Previously, we have confirmed that prenatal caffeine ingestion inhibits the development of hypothalamic–pituitary–adrenal (HPA) axis, and alters the glucose and lipid metabolism in IUGR fetal rats. In this study, we aimed to verify a programmed alteration of neuroendocrine metabolism in prenatal caffeine ingested-offspring rats. The results showed that prenatal caffeine (120 mg/kg.day) ingestion caused low body weight and high IUGR rate of pups; the concentrations of blood adrenocorticotropic hormone (ACTH) and corticosterone in caffeine group were significantly increased in the early postnatal period followed by falling in late stage; the level of blood glucose was unchanged, while blood total cholesterol (TCH) and triglyceride (TG) were markedly enhanced in adult. After chronic stress, the concentrations and the gain rates of blood ACTH and corticosterone were obviously increased, meanwhile, the blood glucose increased while the TCH and TG decreased in caffeine group. Further, the hippocampal mineralocorticoid receptor (MR) expression in caffeine group was initially decreased and subsequently increased after birth. After chronic stress, the 11β-hydroxysteroid dehydrogenase-1, glucocorticoid receptor (GR), MR as well as the MR/GR ratio were all significantly decreased. These results suggested that prenatal caffeine ingestion induced the dysfunction of HPA axis and associated neuroendocrine metabolic programmed alteration in IUGR offspring rats, which might be related with the functional injury of hippocampus. These observations provide a valuable experimental basis for explaining the susceptibility of IUGR offspring to metabolic syndrome and associated diseases. -- Highlights: ► Prenatal caffeine ingestion induced HPA axis dysfunction in IUGR offspring rats. ► Caffeine induced a neuroendocrine metabolic programmed alteration in offspring rats. ► Caffeine induced a functional injury

  20. A hypothalamic–pituitary–adrenal axis-associated neuroendocrine metabolic programmed alteration in offspring rats of IUGR induced by prenatal caffeine ingestion

    International Nuclear Information System (INIS)

    Caffeine is a definite factor of intrauterine growth retardation (IUGR). Previously, we have confirmed that prenatal caffeine ingestion inhibits the development of hypothalamic–pituitary–adrenal (HPA) axis, and alters the glucose and lipid metabolism in IUGR fetal rats. In this study, we aimed to verify a programmed alteration of neuroendocrine metabolism in prenatal caffeine ingested-offspring rats. The results showed that prenatal caffeine (120 mg/kg.day) ingestion caused low body weight and high IUGR rate of pups; the concentrations of blood adrenocorticotropic hormone (ACTH) and corticosterone in caffeine group were significantly increased in the early postnatal period followed by falling in late stage; the level of blood glucose was unchanged, while blood total cholesterol (TCH) and triglyceride (TG) were markedly enhanced in adult. After chronic stress, the concentrations and the gain rates of blood ACTH and corticosterone were obviously increased, meanwhile, the blood glucose increased while the TCH and TG decreased in caffeine group. Further, the hippocampal mineralocorticoid receptor (MR) expression in caffeine group was initially decreased and subsequently increased after birth. After chronic stress, the 11β-hydroxysteroid dehydrogenase-1, glucocorticoid receptor (GR), MR as well as the MR/GR ratio were all significantly decreased. These results suggested that prenatal caffeine ingestion induced the dysfunction of HPA axis and associated neuroendocrine metabolic programmed alteration in IUGR offspring rats, which might be related with the functional injury of hippocampus. These observations provide a valuable experimental basis for explaining the susceptibility of IUGR offspring to metabolic syndrome and associated diseases. -- Highlights: ► Prenatal caffeine ingestion induced HPA axis dysfunction in IUGR offspring rats. ► Caffeine induced a neuroendocrine metabolic programmed alteration in offspring rats. ► Caffeine induced a functional injury

  1. Mitochondrial dysfunction induced by frataxin deficiency is associated with cellular senescence and abnormal calcium metabolism

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    Arantxa eBolinches-Amorós

    2014-05-01

    Full Text Available Friedreich ataxia is considered a neurodegenerative disorder involving both the peripheral and central nervous systems. Dorsal root ganglia (DRG are the major target tissue structures. This neuropathy is caused by mutations in the FXN gene that encodes frataxin. Here, we investigated the mitochondrial and cell consequences of frataxin depletion in a cellular model based on frataxin silencing in SH-SY5Y human neuroblastoma cells, a cell line that has been used widely as in vitro models for studies on neurological diseases. We showed that the reduction of frataxin induced mitochondrial dysfunction due to a bioenergetic deficit and abnormal Ca2+ homeostasis in the mitochondria that were associated with oxidative and endoplasmic reticulum stresses. The depletion of frataxin did not cause cell death but increased autophagy, which may have a cytoprotective effect against cellular insults such as oxidative stress. Frataxin silencing provoked slow cell growth associated with cellular senescence, as demonstrated by increased SA-βgal activity and cell cycle arrest at the G1 phase. We postulate that cellular senescence might be related to a hypoplastic defect in the DRG during neurodevelopment, as suggested by necropsy studies.

  2. Effects of liver damage induced by polychlorinated biphenyls (PCB) on cadmium metabolism in mice

    International Nuclear Information System (INIS)

    Polychlorinated biphenyls (PCB) were added to the diets of mice at different concentrations. Mice fed these diets were given a sc or oral doses of 109Cd. The uptake and excretion of Cd was followed by whole-body counting. The gastrointestinal absorption of Cd after an oral dose of 109Cd was less in animals fed on 66 ppm PCB diet, compared with a control group, and the body elimination of Cd was faster. In the liver, the amount of Cd was reduced by dietary PCB exposure, after both oral and sc administration of 109Cd, and the data suggest a faster transport of Cd from liver to kidneys in PCB-exposed animals than in controls. The mobilized liver Cd was not quantitatively recovered in the kidneys, thus increased urinary excretion due to PCB exposure may have taken place. Histological examination of the livers revealed a dose-dependent induction of liver changes characterized by centrilobular enlargement of liver cells and centrilobular focal necroses. In four of eight livers from animals fed 200 ppm PCB for 32 weeks there were five liver cell tumors with cytological signs of malignancy. In the control group and in groups fed lower doses of PCB (10-100 ppm) no such tumors were found among 28 animals. The results support observations made with agents inducing acute liver damage, that liver damage increases the rate of redistribution of cadmium from the liver to the kidney

  3. Modulation of (14) C-labeled glucose metabolism by zinc during aluminium induced neurodegeneration.

    Science.gov (United States)

    Singla, Neha; Dhawan, D K

    2015-09-01

    Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders.

  4. Induced mutations in tomato SlExp1 alter cell wall metabolism and delay fruit softening.

    Science.gov (United States)

    Minoia, Silvia; Boualem, Adnane; Marcel, Fabien; Troadec, Christelle; Quemener, Bernard; Cellini, Francesco; Petrozza, Angelo; Vigouroux, Jacqueline; Lahaye, Marc; Carriero, Filomena; Bendahmane, Abdelhafid

    2016-01-01

    Fruit ripening and softening are key traits for many fleshy fruit. Since cell walls play a key role in the softening process, expansins have been investigated to control fruit over ripening and deterioration. In tomato, expression of Expansin 1 gene, SlExp1, during fruit ripening was associated with fruit softening. To engineer tomato plants with long shelf life, we screened for mutant plants impaired in SlExp1 function. Characterization of two induced mutations, Slexp1-6_W211S, and Slexp1-7_Q213Stop, showed that SlExp1 loss of function leads to enhanced fruit firmness and delayed fruit ripening. Analysis of cell wall polysaccharide composition of Slexp1-7_Q213Stop mutant pointed out significant differences for uronic acid, neutral sugar and total sugar contents. Hemicelluloses chemistry analysis by endo-β-1,4-d-glucanase hydrolysis and MALDI-TOF spectrometry revealed that xyloglucan structures were affected in the fruit pericarp of Slexp1-7_Q213Stop mutant. Altogether, these results demonstrated that SlExp1 loss of function mutants yield firmer and late ripening fruits through modification of hemicellulose structure. These SlExp1 mutants represent good tools for breeding long shelf life tomato lines with contrasted fruit texture as well as for the understanding of the cell wall polysaccharide assembly dynamics in fleshy fruits.

  5. Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

    Directory of Open Access Journals (Sweden)

    Xiuwei Wang

    Full Text Available DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs. However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS, microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005, 5-formyltetrahydrofolate (5-FoTHF, P = 0.040, S-adenosylmethionine (SAM, P = 0.004 and higher concentrations of folic acid (P = 0.041, homocysteine (Hcy, P = 0.006 and S-adenosylhomocysteine (SAH, P = 0.045 compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions were selected by microarray. Two genes (Siah1b, Prkx in Wnt signal pathway demonstrated lower methylated regions (peak and higher expression in NTDs (P<0.05; P<0.05. Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs.

  6. Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism.

    Science.gov (United States)

    Wang, Xiuwei; Guan, Zhen; Chen, Yan; Dong, Yanting; Niu, Yuhu; Wang, Jianhua; Zhang, Ting; Niu, Bo

    2015-01-01

    DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs.

  7. Metabolic and electric brain patterns during pleasant and unpleasant emotions induced by music masterpieces.

    Science.gov (United States)

    Flores-Gutiérrez, Enrique O; Díaz, José-Luís; Barrios, Fernando A; Favila-Humara, Rafael; Guevara, Miguel Angel; del Río-Portilla, Yolanda; Corsi-Cabrera, María

    2007-07-01

    Brain correlates comparing pleasant and unpleasant states induced by three dissimilar masterpiece excerpts were obtained. Related emotional reactions to the music were studied using Principal Component Analysis of validated reports, fMRI, and EEG coherent activity. A piano selection by Bach and a symphonic passage from Mahler widely differing in musical features were used as pleasing pieces. A segment by Prodromidès was used as an unpleasing stimulus. Ten consecutive 30 s segments of each piece alternating with random static noise were played to 19 non-musician volunteers for a total of 30 min of auditory stimulation. Both brain approaches identified a left cortical network involved with pleasant feelings (Bach and Mahler vs. Prodromidès) including the left primary auditory area, posterior temporal, inferior parietal and prefrontal regions. While the primary auditory zone may provide an early affective quality, left cognitive areas may contribute to pleasant feelings when melodic sequences follow expected rules. In contrast, unpleasant emotions (Prodromidès vs. Bach and Mahler) involved the activation of the right frontopolar and paralimbic areas. Left activation with pleasant and right with unpleasant musical feelings is consistent with right supremacy in novel situations and left in predictable processes. When all musical excerpts were jointly compared to noise, in addition to bilateral auditory activation, the left temporal pole, inferior frontal gyrus, and frontopolar area were activated suggesting that cognitive and language processes were recruited in general responses to music. Sensory and cognitive integration seems required for musical emotion.

  8. Modulation of (14) C-labeled glucose metabolism by zinc during aluminium induced neurodegeneration.

    Science.gov (United States)

    Singla, Neha; Dhawan, D K

    2015-09-01

    Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders. PMID:25908409

  9. Molecular fingerprint of high fat diet induced urinary bladder metabolic dysfunction in a rat model.

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    Andreas Oberbach

    Full Text Available AIMS/HYPOTHESIS: Diabetic voiding dysfunction has been reported in epidemiological dimension of individuals with diabetes mellitus. Animal models might provide new insights into the molecular mechanisms of this dysfunction to facilitate early diagnosis and to identify new drug targets for therapeutic interventions. METHODS: Thirty male Sprague-Dawley rats received either chow or high-fat diet for eleven weeks. Proteomic alterations were comparatively monitored in both groups to discover a molecular fingerprinting of the urinary bladder remodelling/dysfunction. Results were validated by ELISA, Western blotting and immunohistology. RESULTS: In the proteome analysis 383 proteins were identified and canonical pathway analysis revealed a significant up-regulation of acute phase reaction, hypoxia, glycolysis, β-oxidation, and proteins related to mitochondrial dysfunction in high-fat diet rats. In contrast, calcium signalling, cytoskeletal proteins, calpain, 14-3-3η and eNOS signalling were down-regulated in this group. Interestingly, we found increased ubiquitin proteasome activity in the high-fat diet group that might explain the significant down-regulation of eNOS, 14-3-3η and calpain. CONCLUSIONS/INTERPRETATION: Thus, high-fat diet is sufficient to induce significant remodelling of the urinary bladder and alterations of the molecular fingerprint. Our findings give new insights into obesity related bladder dysfunction and identified proteins that may indicate novel pathophysiological mechanisms and therefore constitute new drug targets.

  10. Grape pomace and grape pomace extract improve insulin signaling in high-fat-fructose fed rat-induced metabolic syndrome.

    Science.gov (United States)

    Rodriguez Lanzi, Cecilia; Perdicaro, Diahann Jeanette; Antoniolli, Andrea; Fontana, Ariel Ramón; Miatello, Roberto Miguel; Bottini, Rubén; Vazquez Prieto, Marcela Alejandra

    2016-03-01

    In this study the effect of diet supplementation with grape pomace (GP) and grape pomace extract (GPE) on insulin sensitive tissues (adipose, liver and muscle) was evaluated in an experimental model of metabolic syndrome (MetS). MetS was developed by giving a high-fat-fructose (HFF) diet to Wistar rats. Six weeks of HFF diet induced weight gain, which was partially attenuated by GP (1 g per kg per day) and GPE (300 mg per kg per day) supplementation. HFF diet increased systolic blood pressure, triglycerides, insulin resistance (HOMA:IR) and inflammation (c-reactive protein (CRP)). Supplementation with GP prevented SBP, triglycerides and CRP increased and partially attenuated insulin resistance. On the other hand, GPE partially reduced SBP and triglycerides and significantly prevented insulin resistance and inflammation. Also, HFF diet induced higher triglycerides content and enhanced NADPH oxidase activity in the liver. Also, HFF diet increased the epididymal adipose tissue weight, enlarged adipocyte size, and c-jun N-terminal kinase (JNK) activation, probably contributing to a pro-inflammatory cytokine pattern (higher resistin) and lower adiponectin protein expression. These alterations may result in an impairment of insulin signaling cascade observed in adipose, liver and muscle tissue (IRS1, Akt, and extracellular signal-regulated kinases (ERK1/2)) from HFF rats. Supplementation with GP and to a greater extent GPE attenuated liver triglyceride content and adiposity and restored adipose, liver and muscle response to insulin. These findings show that supplementation with GP and GPE to a greater extent can counteract adiposity, inflammation, liver damage and impaired insulin signaling associated to MetS, supporting the utilization of winemaking residues in food industry/human health due to their high amount of bioactive compounds. PMID:26901521

  11. Clodronate liposomes improve metabolic profile and reduce visceral adipose macrophage content in diet-induced obese mice.

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    Bin Feng

    Full Text Available BACKGROUND: Obesity-related adipose inflammation has been thought to be a causal factor for the development of insulin resistance and type 2 diabetes. Infiltrated macrophages in adipose tissue of obese animals and humans are an important source for inflammatory cytokines. Clodronate liposomes can ablate macrophages by inducing apoptosis. In this study, we aim to determine whether peritoneal injection of clodronate liposomes has any beneficial effect on systemic glucose homeostasis/insulin sensitivity and whether macrophage content in visceral adipose tissue will be reduced in diet-induced obese (DIO mice. METHODOLOGY/PRINCIPAL FINDINGS: Clodronate liposomes were used to deplete macrophages in lean and DIO mice. Macrophage content in visceral adipose tissue, metabolic parameters, glucose and insulin tolerance, adipose and liver histology, adipokine and cytokine production were examined. Hyperinsulinemic-euglycemic clamp study was also performed to assess systemic insulin sensitivity. Peritoneal injection of clodronate liposomes significantly reduced blood glucose and insulin levels in DIO mice. Systemic glucose tolerance and insulin sensitivity were mildly improved in both lean and DIO mice treated with clodronate liposomes by intraperitoneal (i.p. injection. Hepatosteatosis was dramatically alleviated and suppression of hepatic glucose output was markedly increased in DIO mice treated with clodronate liposomes. Macrophage content in visceral adipose tissue of DIO mice was effectively decreased without affecting subcutaneous adipose tissue. Interestingly, levels of insulin sensitizing hormone adiponectin, including the high molecular weight form, were significantly elevated in circulation. CONCLUSIONS/SIGNIFICANCE: Intraperitoneal injection of clodronate liposomes reduces visceral adipose tissue macrophages, improves systemic glucose homeostasis and insulin sensitivity in DIO mice, which can be partially attributable to increased adiponectin

  12. 3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system.

    Science.gov (United States)

    Valenti, Daniela; Vacca, Rosa A; de Bari, Lidia

    2015-12-01

    3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 μM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate-dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment. PMID:26530987

  13. Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.

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    Thomas Galbo

    Full Text Available In type 2 Diabetes (T2D free fatty acids (FFAs in plasma are increased and hepatic insulin resistance is "selective", in the sense that the insulin-mediated decrease of glucose production is blunted while insulin's effect on stimulating lipogenesis is maintained. We investigated the molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish the physiological relevance of the in vitro findings, we also studied insulin-resistant Zucker Diabetic Fatty (ZDF rats. While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1 was inhibited in palmitate-exposed cells. Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. In contrast, similar to findings in human T2D, the ability of insulin to induce triglyceride (TG accumulation and transcription of the enzymes that catalyze de novo lipogenesis and TG assembly was unaffected. Insulin-induction of these genes could, however, be blocked by inhibition of the atypical PKCs (aPKCs. The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A was increased in the insulin-resistant cells. Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity.

  14. Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6

    International Nuclear Information System (INIS)

    Exposure of fully differentiated L6 myotubes to a crude monokine preparation from endotoxin-stimulated RAW 264.7 cells resulted in a rapid and substantial (70%) increase in fructose 2,6-bisphosphate concentration coincident with a depletion of cellular glycogen and an increased lactate production. During the time required for glycogen depletion (3 hr), stimulation of 3-O-methyl-D-glucose and 2-deoxy-D-glucose uptake was initiated and observed to reach a maximum enhancement of 200% 12-15 hr later. The monokine had no effect on the K/sub m/ value for 2-deoxy-D-glucose uptake (1.1 mM), while V/sub max/ was increased from 912 to 2400 pmol/min per mg of protein. The increase was cytochalasin B inhibitable and was dependent on protein synthesis. Photoaffinity labeling and equilibrium binding studies with [3H]cytochalasin B support the hypothesis that this increase in hexose transport was due to an increase in hexose transporters present in the plasma membrane. Purified recombinant interleukin-1α had no effect on hexose transport, whereas purified recombinant cachectin/tumor necrosis factor did stimulate hexose uptake, with half-maximal stimulation occurring at 36 nM. Although cachectin accounts for most of the biological activity associated with the crude monokine preparation, it is not the only monokine capable of inducing glucose transport in L6 cells. Specific immunoabsorption of cachectin/tumor necrosis factor from the crude monokine preparation revealed a monokine that had a similar bioactivity at extremely low concentrations on L6 cells

  15. Cardiac responses to induced lactate oxidation: NMR analysis of metabolic equilibria.

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    Lewandowski, E D; Damico, L A; White, L T; Yu, X

    1995-07-01

    The role of lactate as a source of pyruvate oxidation in supporting cardiac work, energetics, and formation of oxidative metabolites was examined in normal myocardium. 13C- and 31P-nuclear magnetic resonance (NMR) spectra were acquired from isolated rabbit hearts supplied 2.5 mM [3-13C]lactate or [3-13C]pyruvate with or without stimulation of pyruvate dehydrogenase (PDH) by dichloroacetate (DCA). Similar workloads determined by rate-pressure products were noted with pyruvate (21,700 +/- 2,400; mean +/- SE) and lactate (18,970 +/- 1,510). Oxygen consumption was similar in all four groups with means between 19.0 and 22.2 mumol.min-1.g dry weight-1 (SE = 1.6-2.0) as was the ratio of phosphocreatine to ATP with means between 1.8 and 2.1 (SE = 0.1-0.6). Intracellular pH, determined from 31P-NMR spectra, was essentially the same with pyruvate (7.06 +/- 0.02) and lactate (7.05 +/- 0.04). 13C enrichment of glutamate was higher with lactate (92%) than with pyruvate (70%). Pyruvate plus DCA induced no change in glutamate content at 9-10 mumol/g, but 13C enrichment increased to 83%, while lactate plus DCA maintained enrichment at 90%. Levels of alpha-ketoglutarate were lower with lactate (1.81 mumol/g) than with pyruvate (2.36 mumol/g). Lactate plus DCA elevated glutamate by 60% with a proportional increase in alpha-ketoglutarate. Thus the balance between glutamate and alpha-ketoglutarate was affected by substrate supply only and not by PDH activation. The results suggest that the equilibrium between alpha-ketoglutarate and glutamate is sensitive to cytosolic redox state, an important consideration for 13C-NMR analyses that rely on glutamate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7631845

  16. Separation and purification of the tonoplast ATPase and pyrophosphatase from plants with constitutive and inducible Crassulacean acid metabolism.

    Science.gov (United States)

    Bremberger, C; Haschke, H P; Lüttge, U

    1988-10-01

    Tonoplast vesicles were isolated from Kalanchoe daigremontiana Hamet et Pierrer de la Bâthie and Mesembryanthemum crystallinum L., exhibiting constitutive and inducible crassulacean acid metabolism (CAM), respectively. Membrane-bound proteins were detergent-solubilized with 2% of Triton X-100. During CAM induction in M. crystallinum, ATPase activity increases four-fold, whereas pyrophosphatase activity decreases somewhat. With all plants, ATPase and pyrophosphatase could be separated by size-exclusion chromatography (SEC, Sephacryl S 400), and the ATPase was further purified by diethylaminoethyl-ion-exchange chromatography. Sodium-dodecyl-sulfate electrophoresis of the SEC fractions from K. daigremontiana containing maximum ATPase activity separates several protein bands, indicating subunits of 72, 56, 48, 42, 28, and 16 kDa. Purified ATPase from M. crystallinum in the C3 and CAM states shows a somewhat different protein pattern. With M. crystallinum, an increase in ATP-hydrolysis and changes in the subunit composition of the native enzyme indicate that the change from the C3 to the CAM state is accompanied by de-novo synthesis and by structural changes of the tonoplast ATPase. PMID:24221927

  17. Radio-induced neuropathology: from early effects to late sequelae. Rat behavioural and metabolic studies after sublethal total body irradiation

    International Nuclear Information System (INIS)

    The radioresistance dogma of Central Nervous System (CNS) is now obsolete. Recent progress in neuroscience allow us to reconsider the radiation-induced cognitive dysfunctions observed after radiation therapy or after a nuclear accident, and to devise appropriate diagnostic and therapeutic means. We have developed a Rat model to study the effects of total body irradiation at a sublethal dose (4.5 Gy). This leads to impaired learning and memory of a task being acquired during the first month - which is prevented by administration of a radioprotector (amifostine) - while it does not appear to affect retrograde memory. Early, an apoptotic wave occurs in the sub-ventricular zone, 5 to 9 hours after exposure, while neuro-genesis is suppressed. Two days after irradiation, the metabolic study conducted by NMR HRMAS (High Resolution Magic Angle Spinning) suggests the presence of cerebral oedema and the study of brain lipids in liquid NMR confirms the membrane damages (elevated cholesterol and phospholipids). The lipid profile is then normalized while a gliosis appears. Finally, 1 month post-irradiation, the elevation of GABA, an inhibitory neurotransmitter, in 2 separate brain structures, occurs simultaneously with a taurine decrease in the hippocampus that lasts 6 months. Our integrated model allows validating bio-markers measurable in vivo NMR spectroscopy - the next experimental stage - and testing new radiation-protective agents. (author)

  18. Chlorella Protein Hydrolysate Attenuates Glucose Metabolic Disorder and Fatty Liver in High-fat Diet-induced Obese Mice.

    Science.gov (United States)

    Noguchi, Naoto; Yanagita, Teruyoshi; Rahman, Shaikh Mizanoor; Ando, Yotaro

    2016-07-01

    Chlorella (Parachlorella beijerinckii) powder is reported to show a preventive effect against metabolic syndromes such as arteriosclerosis, hyperlipidemia, and hypertension. Approximately 60% of the chlorella content is protein. In order to understand the role of chlorella protein, we prepared a chlorella protein hydrolysate (CPH) by protease treatment. Male C57BL/6 mice were divided into three groups: a normal diet group, high-fat diet (HFD) group, and high-fat diet supplemented with CPH (HFD+CPH) group. The CPH administration improved glucose intolerance, insulin sensitivity, and adipose tissue hypertrophy in the high-fat diet-fed mice. In addition, the HFD+CPH group had significantly decreased liver total cholesterol and triglyceride levels compared with those in the HFD group. Furthermore, the HFD+CPH group had a decreased level of monocyte chemotactic protein-1 (MCP-1) in serum and a lower MCP-1 mRNA expression level in adipose tissue compared with the HFD group. The present study suggests that chlorella protein hydrolysate can prevent a high-fat diet-induced glucose disorder and fatty liver by inhibiting adipocyte hypertrophy and reducing the MCP-1 protein and gene expression. PMID:27321121

  19. Arachidonic acid metabolism in TNS-induced chronic and immunologic enteritis in rats, and the effect of 5-ASA

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    F. J. Zijlstra

    1993-01-01

    Full Text Available Inflammation of the rat distal intestine was induced by intradermal sensitization and subsequent multiple intrajejunal challenge with the hapten 2,4,6-trinitrobenzenesulphonic acid (TNBS via an implanted catheter. The time course of the inflammatory reaction was followed by determination of the enteritis score and measurement of in vitro eicosanoid formation of homogenates of the gut after 0, 1, 2, 4, 7, 14 and 21 days of local daily challenge with 0.08% TNBS. There was a small initial increase of eicosanoid formation, reached at days 1 and 2, followed by a significant increase in metabolism of arachidonic acid on day 21. Although at day 1 a four-fold increase in inflammation score was reached, no further significant changes were observed during the following 3 weeks. The greatest increase in metabolite formation was observed in prostanoids TxB2, PGE2. and PGD2 and the 5-lipoxygenase product LTC4, whereas minor changes were found for LTB4 and other lipoxygenase products such as 12- and 15-HETE. The formation of these metabolites was already inhibited by low-dose 5-aminosalicylic acid (5-ASA, given orally twice daily during the 3 weeks challenge period, while the enteritis score was affected dosedependently.

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

    Science.gov (United States)

    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

    2016-02-01

    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

  1. DBiochemical effect of Ginko biloba extract on carbohydrate metabolism in (induced type two diabetic rats

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    Omayma A.R.

    2016-06-01

    streptozotocin-induced diabetic rats allover the periods of the experiments when compared with normal control group. The results of this study indicated that (GBE has potential benefits in diabetes treatment.

  2. A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome.

    Science.gov (United States)

    Zimbron, Jorge; Khandaker, Golam M; Toschi, Chiara; Jones, Peter B; Fernandez-Egea, Emilio

    2016-09-01

    Metabolic complications are commonly found in people treated with clozapine. Reviews on the management of this problem have generally drawn conclusions by grouping different types of studies involving patients treated with various different antipsychotics. We carried out a systematic review and meta-analysis of pharmacological and non-pharmacological treatments for clozapine-induced obesity or metabolic syndrome. Two researchers independently searched PubMed and Embase for randomised controlled trials (RCTs) of treatments for clozapine-induced obesity or metabolic syndrome. All other types of studies were excluded. We only included RCTs where more than 50% of participants were taking clozapine. We identified 15 RCTs. Effective pharmacological treatments for clozapine-induced obesity and metabolic syndrome include metformin, aripiprazole, and Orlistat (in men only). Meta-analysis of three studies showed a robust effect of metformin in reducing body mass index and waist circumference but no effects on blood glucose, triglyceride levels, or HDL levels. In addition, there is limited evidence for combined calorie restriction and exercise as a non-pharmacological alternative for the treatment of clozapine-induced obesity, but only in an in-patient setting. Rosiglitazone, topiramate, sibutramine, phenylpropanolamine, modafinil, and atomoxetine have not shown to be beneficial, despite reports of efficacy in other populations treated with different antipsychotics. We conclude that randomised-controlled trial data support the use of metformin, aripiprazole, and Orlistat (in men only) for treating clozapine-induced obesity. Calorie restriction in combination with an exercise programme may be effective as a non-pharmacological alternative. Findings from trials in different populations should not be extrapolated to people being treated with clozapine. PMID:27496573

  3. Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart.

    Science.gov (United States)

    Crewe, Clair; Kinter, Michael; Szweda, Luke I

    2013-01-01

    Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on

  4. Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart.

    Directory of Open Access Journals (Sweden)

    Clair Crewe

    Full Text Available Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance

  5. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

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    Cai Z

    2013-08-01

    Full Text Available Zhiyou Cai,1 Yong Yan,2 Yonglong Wang2 1Department of Neurology, the Lu’an Affiliated Hospital of Anhui Medical University, Lu’an People’s Hospital, Lu’an, Anhui Province, People’s Republic of China; 2Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, People’s Republic of China Background: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results: These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting

  6. Proteomic responses to lead-induced oxidative stress in Talinum triangulare Jacq. (Willd.) roots: identification of key biomarkers related to glutathione metabolisms.

    Science.gov (United States)

    Kumar, Abhay; Majeti, Narasimha Vara Prasad

    2014-01-01

    In this study, Talinum triangulare Jacq. (Willd.) treated with different lead (Pb) concentrations for 7 days has been investigated to understand the mechanisms of ascorbate-glutathione metabolisms in response to Pb-induced oxidative stress. Proteomic study was performed for control and 1.25 mM Pb-treated plants to examine the root protein dynamics in the presence of Pb. Results of our analysis showed that Pb treatment caused a decrease in non-protein thiols, reduced glutathione (GSH), total ascorbate, total glutathione, GSH/oxidized glutathione (GSSG) ratio, and activities of glutathione reductase and γ-glutamylcysteine synthetase. Conversely, cysteine and GSSG contents and glutathione-S-transferase activity was increased after Pb treatment. Fourier transform infrared spectroscopy confirmed our metabolic and proteomic studies and showed that amino, phenolic, and carboxylic acids as well as alcoholic, amide, and ester-containing biomolecules had key roles in detoxification of Pb/Pb-induced toxic metabolites. Proteomic analysis revealed an increase in relative abundance of 20 major proteins and 3 new proteins (appeared only in 1.25 mM Pb). Abundant proteins during 1.25 mM Pb stress conditions have given a very clear indication about their involvement in root architecture, energy metabolism, reactive oxygen species (ROS) detoxification, cell signaling, primary and secondary metabolisms, and molecular transport systems. Relative accumulation patterns of both common and newly identified proteins are highly correlated with our other morphological, physiological, and biochemical parameters. PMID:24705950

  7. Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

    2016-01-01

    Aging is the main risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition. PMID:27656136

  8. Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer’s Disease

    Science.gov (United States)

    Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

    2016-01-01

    Aging is the main risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition. PMID:27656136

  9. Sublethal Concentrations Of Antibiotics Cause Shift To Anaerobic Metabolism In Listeria Monocytogenes And Induce Phenotypes Linked To Antibiotic Tolerance

    DEFF Research Database (Denmark)

    Knudsen, Gitte Maegaard; Ng, Yin; Gram, Lone

    2015-01-01

    dehydrogenase gene lmo1634 and repression of alsA and lmo1992, which are involved in acetoin production leading to more ethanol and less acetoin production. This shift in central metabolism indicates a shift from aerobic to anaerobic metabolism, that could reduce oxidative stress and be a survival strategy...... investigation. The concentration of acetoin and ethanol are also currently under investigation. Conclusions: Consistent with other studies, we hypothesize that L. monocytogenes when exposed to antibiotics alters its metabolism from aerobic to anaerobic metabolism, and this could prepare the organism...

  10. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    International Nuclear Information System (INIS)

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  11. Postprandial de novo lipogenesis and metabolic changes induced by a high-carbohydrate, low-fat meal in lean and overweight men

    OpenAIRE

    I. Marques-Lopes; D. Ansorena; Astiasaran, I. (Iciar); L. Forga; J. A. Martinez

    2001-01-01

    BACKGROUND: Adjustments of carbohydrate intake and oxidation occur in both normal-weight and overweight individuals. Nevertheless, the contribution of carbohydrates to the accumulation of fat through either reduction of fat oxidation or stimulation of fat synthesis in obesity remains poorly investigated. OBJECTIVE: The objective of this study was to assess the postprandial metabolic changes and the fractional hepatic de novo lipogenesis (DNL) induced by a high-carbohydrate, low-fat...

  12. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

    Energy Technology Data Exchange (ETDEWEB)

    Kandasamy, Neelamegam; Ashokkumar, Natarajan, E-mail: npashokkumar1@gmail.com

    2014-09-01

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative

  13. Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Li, Ying; Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zheng, Hao; Yu, Wei; Chai, Hongyan [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA (United States); Guo, Austin M. [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yue, Jiang; Peng, Renxiu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

    2013-10-01

    Arachidonic acid (AA)-derived eicosanoids and its downstream pathways have been demonstrated to play crucial roles in growth control of breast cancer. Here, we demonstrate that isoliquiritigenin, a flavonoid phytoestrogen from licorice, induces growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. Isoliquiritigenin diminished cell viability, 5-bromo-2′-deoxyuridine (BrdU) incorporation, and clonogenic ability in both MCF-7 and MDA-MB-231cells, and induced apoptosis as evidenced by an analysis of cytoplasmic histone-associated DNA fragmentation, flow cytometry and hoechst staining. Furthermore, isoliquiritigenin inhibited mRNA expression of multiple forms of AA-metabolizing enzymes, including phospholipase A2 (PLA2), cyclooxygenases (COX)-2 and cytochrome P450 (CYP) 4A, and decreased secretion of their products, including prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B{sub 4} (LTB{sub 4}). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser{sup 241}), phospho-Akt (Thr{sup 308}), phospho-Bad (Ser{sup 136}), and Bcl-x{sub L} expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE{sub 2}, LTB{sub 4} and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably, isoliquiritigenin induced growth inhibition and apoptosis of MDA-MB-231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt (Thr{sup 308}). Collectively, these data suggest that isoliquiritigenin induces growth inhibition and apoptosis through downregulating AA metabolic

  14. Chronic Caloric Restriction and Exercise Improve Metabolic Conditions of Dietary-Induced Obese Mice in Autophagy Correlated Manner without Involving AMPK

    Directory of Open Access Journals (Sweden)

    Mingxia Cui

    2013-01-01

    Full Text Available Aim. To investigate the role of AMPK activation and autophagy in mediating the beneficial effects of exercise and caloric restriction in obesity. Methods. Dietary-induced obesity mice were made and divided into 5 groups; one additional group of normal mice serves as control. Mice in each group received different combinations of interventions including low fat diet, caloric restriction, and exercise. Then their metabolic conditions were assessed by measuring serum glucose and insulin, serum lipids, and liver function. AMPK phosphorylation and autophagy activity were detected by western blotting. Results. Obese mice models were successfully induced by high fat diet. Caloric restriction consistently improved the metabolic conditions of the obese mice, and the effects are more prominent than the mice that received only exercise. Also, caloric restriction, exercise, and low fat diet showed a synergistic effect in the improvement of metabolic conditions. Western blotting results showed that this improvement was not related with the activation of AMPK in liver, skeletal muscle, or heart but correlates well with the autophagy activity. Conclusion. Caloric restriction has more prominent beneficial effects than exercise in dietary-induced obese mice. These effects are correlated with the autophagy activity and may be independent of AMPK activation.

  15. Aging Increases Susceptibility to High Fat Diet-Induced Metabolic Syndrome in C57BL/6 Mice: Improvement in Glycemic and Lipid Profile after Antioxidant Therapy

    Directory of Open Access Journals (Sweden)

    Valéria Nunes-Souza

    2016-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD has been considered a novel component of the metabolic syndrome (MetS, with the oxidative stress participating in its progression. This study aimed to evaluate the metabolic profile in young and old mice with MetS, and the effects of apocynin and tempol on glycemic and lipid parameters. Young and old C57BL/6 mice with high fat diet- (HFD- induced MetS received apocynin and tempol 50 mg·kg−1/day in their drinking water for 10 weeks. After HFD, the young group showed elevated fasting glucose, worsened lipid profile in plasma, steatosis, and hepatic lipid peroxidation. Nevertheless, the old group presented significant increase in fasting insulin levels, insulin resistance, plasma and hepatic lipid peroxidation, and pronounced steatosis. The hepatic superoxide dismutase and catalase activity did not differ between the groups. Tempol and apocynin seemed to prevent hepatic lipid deposition in both groups. Furthermore, apocynin improved glucose tolerance and insulin sensitivity in old mice. In summary, old mice are more susceptible to HFD-induced metabolic changes than their young counterparts. Also, the antioxidant therapy improved insulin sensitivity and glucose tolerance, and in addition, apocynin seemed to prevent the HFD-induced hepatic fat deposition, suggesting an important role of oxidative stress in the induction of NAFLD.

  16. Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration.

    Science.gov (United States)

    He, Jiaojiao; Wang, Ke; Zheng, Ningning; Qiu, Yunping; Xie, Guoxiang; Su, Mingming; Jia, Wei; Li, Houkai

    2015-11-30

    Metformin is a widely used anti-diabetic drug with potential anti-tumor activity. However, little is known about its global metabolic and transcriptional impacts on tumor cells. In current study, we performed a metabolic profiling on human-derived colon cancer LoVo cells treated by 10 mM metformin for 8, 24 and 48 h. An obvious time-dependent metabolic alteration was observed from 8 to 48 h, prior to the reduction of cell viability. A total of 47, 45 and 66 differential metabolites were identified between control and metformin-treated cells at three time points. Most of the metabolites were up-regulated at 8 h, but down-regulated at 24 and 48 h by metformin. These metabolites were mainly involved in carbohydrates, lipids, amino acids, vitamins and nucleotides metabolism pathways. Meanwhile, the transcirptomic profile revealed 134 and 3061 differentially expressed genes at 8 and 24 h by metformin. In addition to the cancer signaling pathways, expression of genes involved in cell energy metabolism pathways was significantly altered, which were further validated with genes in glucose metabolism pathway. Altogether, our current data indicate that metformin suppressed the proliferation of LoVo cells, which may be due to the modulation on cell energy metabolism at both metabolic and transcriptional levels in a time-dependent way.

  17. The Role of Underlying Type 2 Diabetes Mellitus and Obesity in Ozone-Induced Pulmonary Injury and Metabolic Impairment

    Science.gov (United States)

    RATIONALE: A growing body of evidence indicates an association between air pollution exposure and metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). We have recently demonstrated that an acute exposure to ozone in metabolically normal rat strains produces h...

  18. Limb immobilization induces a coordinate down-regulation of mitochondrial and other metabolic pathways in men and women.

    Directory of Open Access Journals (Sweden)

    Arkan Abadi

    Full Text Available Advancements in animal models and cell culture techniques have been invaluable in the elucidation of the molecular mechanisms that regulate muscle atrophy. However, few studies have examined muscle atrophy in humans using modern experimental techniques. The purpose of this study was to examine changes in global gene transcription during immobilization-induced muscle atrophy in humans and then explore the effects of the most prominent transcriptional alterations on protein expression and function. Healthy men and women (N = 24 were subjected to two weeks of unilateral limb immobilization, with muscle biopsies obtained before, after 48 hours (48 H and 14 days (14 D of immobilization. Muscle cross sectional area (approximately 5% and strength (10-20% were significantly reduced in men and women (approximately 5% and 10-20%, respectively after 14 D of immobilization. Micro-array analyses of total RNA extracted from biopsy samples at 48 H and 14 D uncovered 575 and 3,128 probes, respectively, which were significantly altered during immobilization. As a group, genes involved in mitochondrial bioenergetics and carbohydrate metabolism were predominant features at both 48 H and 14 D, with genes involved in protein synthesis and degradation significantly down-regulated and up-regulated, respectively, at 14 D of muscle atrophy. There was also a significant decrease in the protein content of mitochondrial cytochrome c oxidase, and the enzyme activity of cytochrome c oxidase and citrate synthase after 14 D of immobilization. Furthermore, protein ubiquitination was significantly increased at 48 H but not 14 D of immobilization. These results suggest that transcriptional and post-transcriptional suppression of mitochondrial processes is sustained throughout 14 D of immobilization, while protein ubiquitination plays an early but transient role in muscle atrophy following short-term immobilization in humans.

  19. Nonesterified Fatty Acid-Induced Endoplasmic Reticulum Stress in Cattle Cumulus Oocyte Complexes Alters Cell Metabolism and Developmental Competence.

    Science.gov (United States)

    Sutton-McDowall, Melanie L; Wu, Linda L Y; Purdey, Malcolm; Abell, Andrew D; Goldys, Ewa M; MacMillan, Keith L; Thompson, Jeremy G; Robker, Rebecca L

    2016-01-01

    Reduced oocyte quality has been associated with poor fertility of high-perfo