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Sample records for acid suppression predict

  1. Chromatographic retention prediction and octanol-water partition coefficient determination of monobasic weak acidic compounds in ion-suppression reversed-phase liquid chromatography using acids as ion-suppressors.

    PubMed

    Ming, Xin; Han, Shu-ying; Qi, Zheng-chun; Sheng, Dong; Lian, Hong-zhen

    2009-08-15

    Although simple acids, replacing buffers, have been widely applied to suppress the ionization of weakly ionizable acidic analytes in reversed-phase liquid chromatography (RPLC), none of the previously reported works focused on the systematic studies about the retention behavior of the acidic solutes in this ion-suppression RPLC mode. The subject of this paper was therefore to investigate the retention behavior of monobasic weak acidic compounds using acetic, perchloric and phosphoric acids as the ion-suppressors. The apparent octanol-water partition coefficient (K" ow) was proposed to calibrate the octanol-water partition coefficient (K(ow)) of these weak acidic compounds, which resulted in a better linear correlation with log k(w), the logarithm of the hypothetical retention factor corresponding to neat aqueous fraction of hydroorganic mobile phase. This log K" ow-log k w linear correlation was successfully validated by the results of monocarboxylic acids and monohydrating phenols, and moreover by the results under diverse experimental conditions for the same solutes. This straightforward relationship not only can be used to effectively predict the retention values of weak acidic solutes combined with Snyder-Soczewinski equation, but also can offer a promising medium for directly measuring K(ow) data of these compounds via Collander equation. In addition, the influence of the different ion-suppressors on the retention of weak acidic compounds was also compared in this RPLC mode.

  2. Molecular Mechanisms for Sweet-suppressing Effect of Gymnemic Acids*

    PubMed Central

    Sanematsu, Keisuke; Kusakabe, Yuko; Shigemura, Noriatsu; Hirokawa, Takatsugu; Nakamura, Seiji; Imoto, Toshiaki; Ninomiya, Yuzo

    2014-01-01

    Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca2+]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3. PMID:25056955

  3. Molecular mechanisms for sweet-suppressing effect of gymnemic acids.

    PubMed

    Sanematsu, Keisuke; Kusakabe, Yuko; Shigemura, Noriatsu; Hirokawa, Takatsugu; Nakamura, Seiji; Imoto, Toshiaki; Ninomiya, Yuzo

    2014-09-12

    Gymnemic acids are triterpene glycosides that selectively suppress taste responses to various sweet substances in humans but not in mice. This sweet-suppressing effect of gymnemic acids is diminished by rinsing the tongue with γ-cyclodextrin (γ-CD). However, little is known about the molecular mechanisms underlying the sweet-suppressing effect of gymnemic acids and the interaction between gymnemic acids versus sweet taste receptor and/or γ-CD. To investigate whether gymnemic acids directly interact with human (h) sweet receptor hT1R2 + hT1R3, we used the sweet receptor T1R2 + T1R3 assay in transiently transfected HEK293 cells. Similar to previous studies in humans and mice, gymnemic acids (100 μg/ml) inhibited the [Ca(2+)]i responses to sweet compounds in HEK293 cells heterologously expressing hT1R2 + hT1R3 but not in those expressing the mouse (m) sweet receptor mT1R2 + mT1R3. The effect of gymnemic acids rapidly disappeared after rinsing the HEK293 cells with γ-CD. Using mixed species pairings of human and mouse sweet receptor subunits and chimeras, we determined that the transmembrane domain of hT1R3 was mainly required for the sweet-suppressing effect of gymnemic acids. Directed mutagenesis in the transmembrane domain of hT1R3 revealed that the interaction site for gymnemic acids shared the amino acid residues that determined the sensitivity to another sweet antagonist, lactisole. Glucuronic acid, which is the common structure of gymnemic acids, also reduced sensitivity to sweet compounds. In our models, gymnemic acids were predicted to dock to a binding pocket within the transmembrane domain of hT1R3. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Optimal Tuning for Disturbance Suppression Mechanism for Model Predictive Control

    NASA Astrophysics Data System (ADS)

    Tange, Yoshio; Nakazawa, Chikashi

    Disturbance suppression is one of most required performances in process control. We recently proposed a new disturbance suppression mechanism applicable for model predictive control in order to enhance disturbance suppression performance for ramp-like disturbances. The proposed method utilized the prediction error of controlled values and generates a disturbance compensation signal by a constant gain feedback. In this paper, we propose an improved version of the disturbance suppression mechanism by applying a low-pass filter and parameter tuning methods by which we can make the mechanism more tolerant to various disturbances such as ramp, step, and other supposable ones. We also show numerical simulation results with an oil distillation tower plant.

  5. Perceptual suppression of predicted natural images

    PubMed Central

    Denison, Rachel N.; Sheynin, Jacob; Silver, Michael A.

    2016-01-01

    Perception is shaped not only by current sensory inputs but also by expectations generated from past sensory experience. Humans viewing ambiguous stimuli in a stable visual environment are generally more likely to see the perceptual interpretation that matches their expectations, but it is less clear how expectations affect perception when the environment is changing predictably. We used statistical learning to teach observers arbitrary sequences of natural images and employed binocular rivalry to measure perceptual selection as a function of predictive context. In contrast to previous demonstrations of preferential selection of predicted images for conscious awareness, we found that recently acquired sequence predictions biased perceptual selection toward unexpected natural images and image categories. These perceptual biases were not associated with explicit recall of the learned image sequences. Our results show that exposure to arbitrary sequential structure in the environment impacts subsequent visual perceptual selection and awareness. Specifically, for natural image sequences, the visual system prioritizes what is surprising, or statistically informative, over what is expected, or statistically likely. PMID:27802512

  6. Weight Suppression Predicts Time to Remission from Bulimia Nervosa

    ERIC Educational Resources Information Center

    Lowe, Michael R.; Berner, Laura A.; Swanson, Sonja A.; Clark, Vicki L.; Eddy, Kamryn T.; Franko, Debra L.; Shaw, Jena A.; Ross, Stephanie; Herzog, David B.

    2011-01-01

    Objective: To investigate whether, at study entry, (a) weight suppression (WS), the difference between highest past adult weight and current weight, prospectively predicts time to first full remission from bulimia nervosa (BN) over a follow-up period of 8 years, and (b) weight change over time mediates the relationship between WS and time to first…

  7. Weight Suppression Predicts Time to Remission from Bulimia Nervosa

    ERIC Educational Resources Information Center

    Lowe, Michael R.; Berner, Laura A.; Swanson, Sonja A.; Clark, Vicki L.; Eddy, Kamryn T.; Franko, Debra L.; Shaw, Jena A.; Ross, Stephanie; Herzog, David B.

    2011-01-01

    Objective: To investigate whether, at study entry, (a) weight suppression (WS), the difference between highest past adult weight and current weight, prospectively predicts time to first full remission from bulimia nervosa (BN) over a follow-up period of 8 years, and (b) weight change over time mediates the relationship between WS and time to first…

  8. To dissociate or suppress? Predicting automatic vs. conscious cognitive avoidance.

    PubMed

    Hetzel-Riggin, Melanie D; Wilber, Emily L

    2010-01-01

    Cognitive avoidance is a common response to sexual assault and reminders of trauma, but there is a paucity of research regarding predictors of automatic and conscious cognitive avoidance in response to trauma-related stimuli. The present study examined whether posttraumatic stress disorder (PTSD) and depression symptoms, physiological responses, and subjective emotional responses predicted peritraumatic dissociation and thought suppression in a sample of 86 female sexual assault victims. Participants provided information about their current symptoms of PTSD and depression as well as their emotional reactions and physiological responses to hearing a personalized sexual assault narrative. PTSD and self-reported anger predicted thought suppression; peritraumatic dissociation was predicted by PTSD symptoms, changes in skin conductance, and self-reported arousal. Heart rate failed to predict either cognitive avoidance response. The results suggest that peritraumatic dissociation and thought suppression are associated with different physiological and emotional responses to trauma cues, perhaps because they tap different memory systems. Limitations and suggestions for future research are discussed.

  9. Perfluorooctanoic Acid Exposure Suppresses T-independent Antibody Responses

    EPA Science Inventory

    Exposure to  3.75mg/kg of perfluoroocatnoic acid (PFOA) for 15d suppresses T-dependent antibody responses (TDAR), suggesting that T helper cells and/or B cells/plasma cells may be impacted. This study evaluated effects of PFOA exposure on the T cell-independent antibody response...

  10. Perfluorooctanoic Acid Exposure Suppresses T-independent Antibody Responses

    EPA Science Inventory

    Exposure to  3.75mg/kg of perfluoroocatnoic acid (PFOA) for 15d suppresses T-dependent antibody responses (TDAR), suggesting that T helper cells and/or B cells/plasma cells may be impacted. This study evaluated effects of PFOA exposure on the T cell-independent antibody response...

  11. DST non-suppression predicts suicide after attempted suicide.

    PubMed

    Jokinen, Jussi; Carlborg, Andreas; Mårtensson, Björn; Forslund, Kaj; Nordström, Anna-Lena; Nordström, Peter

    2007-04-15

    Most prospective studies of HPA axis have found that non-suppressors in the dexamethasone suppression test (DST) are more likely to commit suicide during the follow-up. Attempted suicide is a strong clinical predictor of suicide. The aim of this study was to assess the predictive value of DST for suicide in a group of depressed inpatients with and without an index suicide attempt. Historical cohort of 382 psychiatric inpatients with mood disorder admitted to the department of Psychiatry at the Karolinska University Hospital between 1980 and 2000 were submitted to the DST and followed up for causes of death. During the follow-up (mean 18 years), 36 suicides (9.4%) occurred, 20 of these were non-suppressors and 16 were suppressors. There was no statistically significant difference in suicide risk between the suppressors and non-suppressors for the sample as a whole. An index suicide attempt predicted suicide. In suicide attempters with mood disorder, the non-suppressor status was significantly associated with suicide indicating that HPA axis hyperactivity is a risk factor for suicide in this group. The dexamethasone suppression test may be a useful predictor within this population.

  12. Acid suppressing therapy as a risk factor for Candida esophagitis.

    PubMed

    Daniell, H W

    2016-07-01

    Studies were reviewed from PubMed for risk factors for the development, recurrence, prevention and therapy of Candida esophagitis, and for mechanisms induced by acid-suppressing therapy potentially influencing these factors. Documented observations included greatly increased Candida populations in the mouth, esophagus, stomach, and upper small intestine induced by acid-suppressing therapy. Among patients without HIV disease, PPI consumers more frequently had developed Candida esophagitis than did non-consumers and had also developed its recurrences more frequently. Similar phenomena associated with H2 -blocker use were less intense, and the possibility of similar phenomena in patients with HIV disease apparently had not yet been examined in spite of their high frequency of this disorder. PPI-induced elimination of the gastric acid barrier is a major mechanism leading to oro-pharyngeal and esophageal candida colonization, while PPI-induced impairment of absorption of most orally administered antifungal agents may limit the prophylactic and therapeutic success of these agents. These observations suggest potential value in limiting PPI use in populations of patients with Candida infections including esophagitis, as well as in patients at risk for their development, and also suggest that post-PPI rebound acid hypersecretion may provide additional anti-Candida benefit. Studies designed to develop the risk-benefit ratios of PPI use in these patients deserve investigation with high priority appropriate for studies in patients with HIV disease. © 2015 International Society for Diseases of the Esophagus.

  13. Predicting Affective Information – An Evaluation of Repetition Suppression Effects

    PubMed Central

    Trapp, Sabrina; Kotz, Sonja A.

    2016-01-01

    Both theoretical proposals and empirical studies suggest that the brain interprets sensory input based on expectations to mitigate computational burden. However, as social beings, much of sensory input is affectively loaded – e.g., the smile of a partner, the critical voice of a boss, or the welcoming gesture of a friend. Given that affective information is highly complex and often ambiguous, building up expectations of upcoming affective sensory input may greatly contribute to its rapid and efficient processing. This review points to the role of affective information in the context of the ‘predictive brain’. It particularly focuses on repetition suppression (RS) effects that have recently been linked to prediction processes. The findings are interpreted as evidence for more pronounced prediction processes with affective material. Importantly, it is argued that bottom-up attention inflates the neural RS effect, and because affective stimuli tend to attract more bottom-up attention, it thereby particularly overshadows the magnitude of RS effects for this information. Finally, anxiety disorders, such as social phobia, are briefly discussed as manifestations of modulations in affective prediction. PMID:27667980

  14. Acid suppression and surgical therapy for Barrett's oesophagus.

    PubMed

    de Jonge, Pieter J F; Spaander, Manon C; Bruno, Marco J; Kuipers, Ernst J

    2015-02-01

    Gastro-oesophageal reflux disease is a common medical problem in developed countries, and is a risk factor for the development of Barrett's oesophagus and oesophageal adenocarcinoma. Both proton pump inhibitor therapy and antireflux surgery are effective at controlling endoscopic signs and symptoms of gastro-oesophageal reflux in patients with Barrett's oesophagus, but often fail to eliminate pathological oesophageal acid exposure. The current available studies strongly suggest that acid suppressive therapy, both pharmacological as well as surgical acid suppression, can reduce the risk the development and progression in patients with Barrett's oesophagus, but are not capable of complete prevention. No significant differences have been found between pharmacological and surgical therapy. For clinical practice, patients should be prescribed a proton pump inhibitor once daily as maintenance therapy, with the dose guided by symptoms. Antireflux surgery can be a good alternative to proton pump inhibitor therapy, but should be primarily offered to patients with symptomatic reflux, and not to asymptomatic patients with the rationale to protect against cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Effects of acid suppression on microbial flora of upper gut.

    PubMed

    Yeomans, N D; Brimblecombe, R W; Elder, J; Heatley, R V; Misiewicz, J J; Northfield, T C; Pottage, A

    1995-02-01

    Decreased acid secretion, due to therapy or disease, predisposes to increased bacterial counts in gastric juice. As bacterial numbers increase, the number of nitrate-reducing strains and the concentration of luminal nitrite usually also increase. However, there is controversy (mainly because of assay problems) about whether decreased acid increases generation of N-nitroso compounds: these may be produced by acid or by bacterial catalysis, and the relative contributions of each are still uncertain. Other potentially important factors include ascorbate secretion (can prevent nitrite conversion to nitroso compounds) and the particular spectrum of nitroso compounds produced. Nitrosation of several histamine H2-receptor antagonists has been demonstrated experimentally, but under conditions that are very unlikely to be encountered clinically. Some acid suppressant therapies have been claimed to aid eradication of Helicobacter pylori, but more work is needed to evaluate this. If ulcer treatment regimens do not also address eradication of H. pylori (when present), gastritis will progress, and the recently documented association between H. pylori and gastric carcinoma needs to be considered. Enteric flora probably also increase if acid secretion is markedly reduced: this does not appear to have nutritional consequences but probably reduces the resistance to occasional infections, of which cholera is the best documented.

  16. The Role of Acid Suppression in Barrett's Esophagus.

    PubMed

    Elias, Pooja S; Castell, Don O

    2017-05-01

    In recent years, proton pump inhibitors (PPIs) have come under great scrutiny due to possible adverse, long-term side effects. At the same time, Barrett's esophagus, a premalignant condition in the esophagus, continues to be a disease whose course is thought to be improved by the use of PPIs. We review the impact of proton pump therapy on the esophagus and on Barrett's mucosa. In analyzing changes on a cellular level, we explore the effect of mixed gastric refluxate and the complex cascade that ensues with esophageal exposure of these contents. Because the incidence of esophageal adenocarcinoma is on the rise, we explore other factors that may contribute to the progression of Barrett's from non-dysplastic mucosa to esophageal adenocarcinoma. By revisiting the need for adequate acid suppression in Barrett's and increasing our understanding of other possible factors that may have an effect of Barrett's progression, we hope to support our multifaceted approach to acid suppression in patients with Barrett's esophagus. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Eicosapentaenoic Acid Suppresses the Proliferation of Synoviocytes from Rheumatoid Arthritis

    PubMed Central

    Hamaguchi, Masahide; Kawahito, Yutaka; Omoto, Atsushi; Tsubouchi, Yasunori; Kohno, Masataka; Seno, Takahiro; Kadoya, Masatoshi; Yamamoto, Aihiro; Ishino, Hidetaka; Matsuyama, Masahide; Yoshimura, Rikio; Yoshikawa, Toshikazu

    2008-01-01

    Eicosapentaenoic acid (EPA) is essential for normal cell growth, and may play an important role in inflammatory and autoimmune disorders including rheumatoid arthritis. We investigate that EPA could suppress the proliferation of fibroblast like synoviocytes in vitro. We treated synoviocytes with 1 to 50 µM EPA and measured cell viabilities by the modified MTT assay. We sorted the number of them in sub G1 stage by fluorescence-activated cell sorting caliber. And we stained them by light green or Hoechst 33258, and investigate microscopic appearance. The cell viabilities were decreased at 30 µM, 40 µM, and 50 µM of EPA comparing to 0 µM of EPA. The half maximal concentration of synoviocytes inhibition was approximately 25 µM. At day 1 and day 3, cell number was also decreased at 50 µM EPA comparing to control. FACS caliber indicated the number of synoviocytes in sub G1 stage did not increase in each concentration of EPA. Hoechst staining indicated normal chromatin pattern and no change in a nuclear morphology both in EPA treated synoviocytes and in untreated synoviocytes. These findings suggest that EPA could suppress the proliferation of synoviocytes in vivo dose dependently and time dependently, however, the mechanism is not due to apoptosis. PMID:18818751

  18. Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression.

    PubMed

    Chang, Shy-Shin; Lai, Chih-Cheng; Lee, Meng-tse Gabriel; Lee, Yu-Chien; Tsai, Yi-Wen; Hsu, Wan-Ting; Lee, Chien-Chang

    2015-06-01

    The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case-control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30-90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95% CI: 1.90-4.04) and H2RAs was 2.62 (95% CI: 2.00-3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60-3.02) or H2RAs (aRR: 1.72, 95% CI: 1.25-2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95% CI: 2.08-5.05) and H2RAs (aRR 2.43; 95% CI 1.71-3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers.

  19. Anger suppression predicts pain, emotional, and cardiovascular responses to the cold pressor.

    PubMed

    Quartana, Phillip J; Bounds, Sara; Yoon, K Lira; Goodin, Burel R; Burns, John W

    2010-06-01

    Manipulated anger suppression has been shown to heighten pain and anger responses to pain. We examined whether individual differences in self-reported anger suppression predicted pain, anger, and blood pressure responses to acute pain. Healthy participants (N = 47) underwent an anger-provoking speech task followed by a cold pressor pain task. Participants reported their degree of suppression of thoughts and feelings related to the speech. Pain intensity ratings were obtained throughout the cold pressor. Self-reported anger, anxiety and positive emotion, as well as ratings of sensory, general distress, and anger-specific elements of pain were obtained following the cold pressor. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded throughout. Self-reported suppression predicted greater pain intensity ratings, perception of sensory and anger-specific elements of pain, and self-reported anger in response to the cold pressor. Associations between self-reported suppression and pain intensity and ratings of anger-specific elements of pain were statistically mediated by pain-induced changes in self-reported anger, whereas the effect of suppression on sensory pain ratings was not. Self-reported suppression was also correlated inversely with SBP responses to the cold pressor. Consistent with an ironic process model and prior studies involving experimental manipulation of suppression, self-reported suppression of anger predicted greater pain intensity and perception of the anger-specific element of pain. Findings also suggest that suppression might attenuate homeostatic pressor responses to acute pain.

  20. Can acid (pH) refluxes predict multichannel intraluminal impedance refluxes? A correlation study.

    PubMed

    Misra, Sudipta

    2010-04-01

    The present study aims to explore if and when acid (pH) refluxes can predict refluxes detected by multichannel intraluminal impedance (MII) studies. This correlation may indicate whether pH probe-only and MII-pH studies are interchangeable. Prospective observational cross sectional study of symptomatic children (below 18 years) who had MII-pH studies done for gastroesophageal reflux. Clinical data were extracted from patient records. Non-parametric tests, Pearson's rho and receiver operating characteristic (ROC) curves were used for data analysis. A total of 153 children were included in the study and 62% were on acid suppression. Indices for acid and MII refluxes correlated with each other only in those without acid suppression. This correlation was lost in children on acid suppression. There was no statistically significant difference in acid or MII reflux indices in children with or without acid suppression. Like acid reflux, indices for MII refluxes had good correlation with each other irrespective of acid suppression. Liquid and mixed MII refluxes showed excellent correlation with respective types of proximally migrating refluxes. The values for MII reflux indices derived from our patient population were in broad agreement with available pediatric and adult data. A pH probe-only study in patients without acid suppression may reflect both acid and volume (MII) reflux activities adequately and can substitute for MII-pH study. The observed excellent correlation between acid and MII refluxes with proximal migration may justify using pH probe-only studies for extra esophageal symptoms in patients without acid suppression.

  1. Weight Suppression Predicts Maintenance and Onset of Bulimic Syndromes at 10-Year Follow-up

    PubMed Central

    Keel, Pamela K.; Heatherton, Todd F.

    2010-01-01

    Conflicting results have emerged regarding the prognostic significance of weight suppression for maintenance of bulimic symptoms. This study examined whether the magnitude of weight suppression would predict bulimic syndrome maintenance and onset in college-based samples of men (n=369) and women (n=968) at 10-year follow-up. Data come from a longitudinal study of body weight and disordered eating with high retention (80%). Among those with a bulimic syndrome at baseline, greater weight suppression significantly predicted maintenance of the syndrome, and, among those without a bulimic syndrome at baseline, greater weight suppression predicted onset of a bulimic syndrome at 10-year follow-up in multivariate models that included baseline body mass index, diet frequency, and weight perception. Future research should address mechanisms that could account for the effects of weight suppression over a long duration of follow-up. PMID:20455599

  2. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.

    PubMed

    Jiao, Na; Baker, Susan S; Chapa-Rodriguez, Adrian; Liu, Wensheng; Nugent, Colleen A; Tsompana, Maria; Mastrandrea, Lucy; Buck, Michael J; Baker, Robert D; Genco, Robert J; Zhu, Ruixin; Zhu, Lixin

    2017-08-03

    Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na(+)-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome. © Article

  3. Suppression of Acid Sphingomyelinase Protects the Retina from Ischemic Injury

    PubMed Central

    Fan, Jie; Wu, Bill X.; Crosson, Craig E.

    2016-01-01

    Purpose Acid sphingomyelinase (ASMase) catalyzes the hydrolysis of sphingomyelin to ceramide and mediates multiple responses involved in inflammatory and apoptotic signaling. However, the role ASMase plays in ischemic retinal injury has not been investigated. The purpose of this study was to investigate how reduced ASMase expression impacts retinal ischemic injury. Methods Changes in ceramide levels and ASMase activity were determined by high performance liquid chromatography-tandem mass spectrometry analysis and ASMase activity. Retinal function and morphology were assessed by electroretinography (ERG) and morphometric analyses. Levels of TNF-α were determined by ELISA. Activation of p38 MAP kinase was assessed by Western blot analysis. Results In wild-type mice, ischemia produced a significant increase in retinal ASMase activity and ceramide levels. These increases were associated with functional deficits as measured by ERG analysis and significant structural degeneration in most retinal layers. In ASMase+/− mice, retinal ischemia did not significantly alter ASMase activity, and the rise in ceramide levels were significantly reduced compared to levels in retinas from wild-type mice. In ASMase+/− mice, functional and morphometric analyses of ischemic eyes revealed significantly less retinal degeneration than in injured retinas from wild-type mice. The ischemia-induced increase in retinal TNF-α levels was suppressed by the administration of the ASMase inhibitor desipramine, or by reducing ASMase expression. Conclusions Our results demonstrate that reducing ASMase expression provides partial protection from ischemic injury. Hence, the production of ceramide and subsequent mediators plays a role in the development of ischemic retinal injury. Modulating ASMase may present new opportunities for adjunctive therapies when treating retinal ischemic disorders. PMID:27571014

  4. Retinoic acid suppresses interleukin 6 production in normal human osteoblasts.

    PubMed

    Ahmed, N; Sammons, J; Khokher, M A; Hassan, H T

    2000-03-01

    Systemic long-term retinoid therapy for chronic skin diseases significantly reduced bone turnover markers within days and led to bone abnormalities. Retinoic acid (RA) plays a key role in the regulation of mouse bone cell proliferation, differentiation and functions. Meanwhile, there is little information of RA effect on human osteoblast and osteoclast cell development and function. Interleukin 6 (IL-6) is a pleiotropic cytokine with profound effects on bone metabolism. Thus, the present study examined the RA effect on cell differentiation, alkaline phosphatase and osteocalcin production as well as IL-6 production in normal human osteoblasts. The number of large differentiated osteoblast cells decreased in RA-treated cultures P<0.05. The production of bone specific markers, alkaline phosphatase and osteocalcin, was also reduced in RA-treated cultures. Normal human osteoblasts produced 31.0+/-4.8 pg IL-6 per ml in control cultures. Within 24 h, RA at all four concentrations reduced Il-6 production from normal human osteoblasts. The pharmacological concentration of 10(-5) M RA suppressed 90% of IL-6 production. The present study shows for the first time that RA profoundly inhibits IL-6 production in normal human osteoblasts within 24 h and in a dose-dependent manner. RA was shown previously to inhibit IL-6 production in several other normal and malignant human cell types. The associated decrease in osteoblast cell differentiation, alkaline phosphatase and osteocalcin production could result from the rapid RA-inhibition of IL-6 production. Thus, RA inhibition of IL-6 production in normal human osteoblasts may contribute to the bone abnormalities seen after systemic long-term retinoid therapy in some patients. Copyright 2000 Academic Press.

  5. Risk of Stroke-Associated Pneumonia With Acid-Suppressive Drugs

    PubMed Central

    Ho, Sai-Wai; Hsieh, Ming-Ju; Yang, Shun-Fa; Yeh, Ying-Tung; Wang, Yu-Hsun; Yeh, Chao-Bin

    2015-01-01

    Abstract Acid-suppressive drugs, including histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), are common medications used for treating upper gastrointestinal tract disorders. However, acid-suppressive drugs have been reported to increase the risk of pneumonia in numerous disease populations. However, the relationship between acid-suppressive drugs and stroke-associated pneumonia (SAP) remains controversial. The purpose of this study was to investigate the association between acid-suppressive drug usage and pneumonia among patients with stroke by using a nationwide data set. A population-based cohort study was conducted using a data set from the Taiwanese National Health Insurance Research Database. Data on patients with new-onset stroke from 2010 to 2011 were collected. Patients with and without acid-suppressive drug usage were followed up to identify the occurrence of any type of pneumonia. We estimated the adjusted hazard ratios (HRs) by using the Cox proportional hazards model. The study cohort comprised 7965 patients with new-onset stroke. The incidence of pneumonia was 6.9% (552/7965) and more than 40% (225/552) of patients developed pneumonia within 3 months after an acute stroke. Acid-suppressive drug usage was an independent risk factor of pneumonia. The adjusted HR for the risk of pneumonia in patients with new-onset stroke using acid-suppressive drugs was 1.44 (95% confidence interval [CI] = 1.18–1.75, P < 0.01). Only PPI usage increased risk of chronic SAP (adjusted HR = 1.46, 95% CI = 1.04–2.05). Acid-suppressive drug usage was associated with a slightly increased risk of SAP. Physicians should exercise caution when prescribing acid-suppressive drugs to patients with stroke, particularly at the chronic stage. PMID:26200649

  6. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    PubMed

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

  7. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling

    PubMed Central

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen

    2015-01-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease. PMID:26431088

  8. Prediction suppression in monkey inferotemporal cortex depends on the conditional probability between images.

    PubMed

    Ramachandran, Suchitra; Meyer, Travis; Olson, Carl R

    2016-01-01

    When monkeys view two images in fixed sequence repeatedly over days and weeks, neurons in area TE of the inferotemporal cortex come to exhibit prediction suppression. The trailing image elicits only a weak response when presented following the leading image that preceded it during training. Induction of prediction suppression might depend either on the contiguity of the images, as determined by their co-occurrence and captured in the measure of joint probability P(A,B), or on their contingency, as determined by their correlation and as captured in the measures of conditional probability P(A|B) and P(B|A). To distinguish between these possibilities, we measured prediction suppression after imposing training regimens that held P(A,B) constant but varied P(A|B) and P(B|A). We found that reducing either P(A|B) or P(B|A) during training attenuated prediction suppression as measured during subsequent testing. We conclude that prediction suppression depends on contingency, as embodied in the predictive relations between the images, and not just on contiguity, as embodied in their co-occurrence.

  9. Amino acids inhibit kynurenic acid formation via suppression of kynurenine uptake or kynurenic acid synthesis in rat brain in vitro.

    PubMed

    Sekine, Airi; Okamoto, Misaki; Kanatani, Yuka; Sano, Mitsue; Shibata, Katsumi; Fukuwatari, Tsutomu

    2015-01-01

    The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor at endogenous brain concentrations. Recent studies have suggested that increase of brain KYNA levels is involved in psychiatric disorders such as schizophrenia and depression. KYNA-producing enzymes have broad substrate specificity for amino acids, and brain uptake of kynurenine (KYN), the immediate precursor of KYNA, is via large neutral amino acid transporters (LAT). In the present study, to find out amino acids with the potential to suppress KYNA production, we comprehensively investigated the effects of proteinogenic amino acids on KYNA formation and KYN uptake in rat brain in vitro. Cortical slices of rat brain were incubated for 2 h in Krebs-Ringer buffer containing a physiological concentration of KYN with individual amino acids. Ten out of 19 amino acids (specifically, leucine, isoleucine, phenylalanine, methionine, tyrosine, alanine, cysteine, glutamine, glutamate, and aspartate) significantly reduced KYNA formation at 1 mmol/L. These amino acids showed inhibitory effects in a dose-dependent manner, and partially inhibited KYNA production at physiological concentrations. Leucine, isoleucine, methionine, phenylalanine, and tyrosine, all LAT substrates, also reduced tissue KYN concentrations in a dose-dependent manner, with their inhibitory rates for KYN uptake significantly correlated with KYNA formation. These results suggest that five LAT substrates inhibit KYNA formation via blockade of KYN transport, while the other amino acids act via blockade of the KYNA synthesis reaction in brain. Amino acids can be a good tool to modulate brain function by manipulation of KYNA formation in the brain. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with increased KYNA levels.

  10. Ultraviolet-irradiated urocanic acid suppresses delayed-type hypersensitivity to herpes simplex virus in mice

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.; Simpson, T.J.

    1986-11-01

    Ultraviolet radiation is known to induce a transient defect in epidermal antigen presentation which leads to the generation of antigen-specific suppression of the delayed-type hypersensitivity (DTH) response. The putative receptor in skin for the primary event in UV-suppression is urocanic acid (UCA) which may then interact locally, or systemically, with antigen presenting cells or initiate a cascade of events resulting in suppression. We present the first direct evidence that UCA, when irradiated with a dose (96 mJ/cm2) of UVB radiation known to suppress the DTH response to herpes simplex virus, type 1 (HSV-1) in mice, can induce suppression following epidermal application or s.c. injection of the irradiated substance. This suppression is transferable with nylon wool-passed spleen cells.

  11. Interfering ribonucleic acids that suppress expression of multiple unrelated genes

    PubMed Central

    Passioura, Toby; Gozar, Mary M; Goodchild, Amber; King, Andrew; Arndt, Greg M; Poidinger, Michael; Birkett, Donald J; Rivory, Laurent P

    2009-01-01

    Background Short interfering RNAs (siRNAs) have become the research tool of choice for gene suppression, with human clinical trials ongoing. The emphasis so far in siRNA therapeutics has been the design of one siRNA with complete complementarity to the intended target. However, there is a need for multi-targeting interfering RNA in diseases in which multiple gene products are of importance. We have investigated the possibility of using a single short synthetic duplex RNA to suppress the expression of VEGF-A and ICAM-1; genes implicated in the progression of ocular neovascular diseases such as diabetic retinopathy. Results Duplex RNA were designed to have incomplete complementarity with the 3'UTR sequences of both target genes. One such duplex, CODEMIR-1, was found to suppress VEGF and ICAM-1 by 90 and 60%, respectively in ARPE-19 cells at a transfected concentration of 40 ng/mL. Use of a cyan fusion reporter with target sites constructed in its 3'UTR demonstrated that the repression of VEGF and ICAM-1 by CODEMIR-1 was indeed due to interaction with the target sequence. An exhaustive analysis of sequence variants of CODEMIR-1 demonstrated a clear positive correlation between activity against VEGF (but not ICAM-1) and the length of the contiguous complementary region (from the 5' end of the guide strand). Various strategies, including the use of inosine bases at the sites of divergence of the target sequences were investigated. Conclusion Our work demonstrates the possibility of designing multitargeting dsRNA to suppress more than one disease-altering gene. This warrants further investigation as a possible therapeutic approach. PMID:19531249

  12. Prediction, Measurement, and Suppression of High Temperature Supersonic Jet Noise

    NASA Technical Reports Server (NTRS)

    Seiner, John M.; Bhat, T. R. S.; Jansen, Bernard J.

    1999-01-01

    The photograph in figure 1 displays a water cooled round convergent-divergent supersonic nozzle operating slightly overexpanded near 2460 F. The nozzle is designed to produce shock free flow near this temperature at Mach 2. The exit diameter of this nozzle is 3.5 inches. This nozzle is used in the present study to establish properties of the sound field associated with high temperature supersonic jets operating fully pressure balanced (i.e. shock free) and to evaluate capability of the compressible Rayleigh model to account for principle physical features of the observed sound emission. The experiment is conducted statically (i.e. M(sub f) = 0.) in the NASA/LaRC Jet Noise Laboratory. Both aerodynamic and acoustic measurements are obtained in this study along with numerical plume simulation and theoretical prediction of jet noise. Detailed results from this study are reported previously by Seiner, Ponton, Jansen, and Lagen.

  13. EMOTION REGULATION AND BRAIN PLASTICITY: EXPRESSIVE SUPPRESSION USE PREDICTS ANTERIOR INSULA VOLUME

    PubMed Central

    Giuliani, Nicole R.; Drabant, Emily M.; Bhatnagar, Roshni; Gross, James J.

    2011-01-01

    Expressive suppression is an emotion regulation strategy that requires interoceptive and emotional awareness. These processes both recruit the anterior insula. It is not known, however, whether increased use of expressive suppression is associated with increased anterior insula volume. In the present study, high-resolution anatomical MRI images were used to calculate insula volumes in a set of 50 healthy female subjects (mean 21.9 years) using both region of interest (ROI) and voxel-based morphometry (VBM) approaches. Participants also completed trait measures of expressive suppression usage, cognitive reappraisal usage, and negative emotional reactivity (the latter two served as control measures). As predicted, both ROI and VBM methods found that expressive suppression usage, but not negative affect and cognitive reappraisal, was positively related to anterior insula volume. These findings are consistent with the idea that trait patterns of emotion processing are related to brain structure. PMID:21704173

  14. The predictive value of the dexamethasone suppression test. A placebo-controlled study.

    PubMed

    Peselow, E D; Stanley, M; Filippi, A M; Barouche, F; Goodnick, P; Fieve, R R

    1989-11-01

    We evaluated the dexamethasone suppression test (DST) as a predictor of response to drugs and placebo in 105 patients, in a large double-blind placebo-controlled out-patient trial to determine the efficacy of paroxetine HCl, a selective serotonin reuptake inhibitor, compared with that of imipramine HCl and placebo. The presence of a positive or negative DST did not predict response to either paroxetine or imipramine. However, a positive DST predicted a poorer response to placebo: only 3 out of 18 patients who showed DST non-suppression responded to placebo, as opposed to 11 out of 21 who exhibited DST suppression (P less than 0.05). A positive DST was associated with a 61% response to drugs and a 16% response to placebo. This finding suggests that the presence of a positive DST implies the need for active somatic treatment.

  15. Suppression of adipose lipolysis by long-chain fatty acid analogs.

    PubMed

    Kalderon, Bella; Azazmeh, Narmen; Azulay, Nili; Vissler, Noam; Valitsky, Michael; Bar-Tana, Jacob

    2012-05-01

    Agonist-induced lipolysis of adipose fat is robustly inhibited by insulin or by feedback inhibition by the long-chain fatty acids (LCFA) produced during lipolysis. However, the mode of action of LCFA in suppressing adipose lipolysis is not clear. β,β'-Tetramethyl hexadecanedioic acid (Mββ/ EDICA16) is a synthetic LCFA that is neither esterified into lipids nor β-oxidized, and therefore, it was exploited for suppressing agonist-induced lipolysis in analogy to natural LCFA. Mββ is shown here to suppress isoproterenol-induced lipolysis in the rat in vivo as well as in 3T3-L1 adipocytes. Inhibition of isoproterenol-induced lipolysis is due to decrease in isoproterenol-induced cAMP with concomitant inhibition of the phosphorylation of hormone-sensitive lipase and perilipin by protein kinase A. Suppression of cellular cAMP levels is accounted for by inhibition of the adenylate cyclase due to suppression of Raf1 expression by Mββ-activated AMPK. Suppression of Raf1 is further complemented by induction of components of the unfolded-protein-response by Mββ. Our findings imply genuine inhibition of agonist-induced adipose lipolysis by LCFA, independent of their β-oxidation or reesterification. Mββ suppression of agonist-induced lipolysis and cellular cAMP levels independent of the insulin transduction pathway may indicate that synthetic LCFA could serve as insulin mimetics in the lipolysis context under conditions of insulin resistance.

  16. Novel features of early burst suppression predict outcome after birth asphyxia

    PubMed Central

    Iyer, Kartik K; Roberts, James A; Metsäranta, Marjo; Finnigan, Simon; Breakspear, Michael; Vanhatalo, Sampsa

    2014-01-01

    Burst suppression patterns in the electroencephalogram are a reliable marker of recent severe brain insult. Here we analyze statistical properties of bursts occurring in 20 electroencephalographic recordings acquired from hypothermic asphyxic newborns in the hours immediately following birth. We show that the distributions of burst area and duration in these acute data predict later clinical outcome in both structural neuroimaging and neurodevelopment. Our findings indicate the first early electroencephalographic metrics that offer outcome prediction in asphyxic neonates undergoing hypothermia treatment. PMID:25356399

  17. On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans.

    PubMed

    Carpentier, André C; Frisch, Frédérique; Cyr, Denis; Généreux, Philippe; Patterson, Bruce W; Giguère, Robert; Baillargeon, Jean-Patrice

    2005-11-01

    During the fasting state, insulin reduces nonesterified fatty acid (NEFA) appearance in the systemic circulation mostly by suppressing intracellular lipolysis in the adipose tissue. In the postprandial state, insulin may also control NEFA appearance through enhanced trapping into the adipose tissue of NEFA derived from intravascular triglyceride lipolysis. To determine the contribution of suppression of intracellular lipolysis in the modulation of plasma NEFA metabolism by insulin during enhanced intravascular triglyceride lipolysis, 10 healthy nonobese subjects underwent pancreatic clamps at fasting vs. high physiological insulin level with intravenous infusion of heparin plus Intralipid. Nicotinic acid was administered orally during the last 2 h of each 4-h clamp to inhibit intracellular lipolysis and assess insulin's effect on plasma NEFA metabolism independently of its effect on intracellular lipolysis. Stable isotope tracers of palmitate, acetate, and glycerol were used to assess plasma NEFA metabolism and total triglyceride lipolysis in each participant. The glycerol appearance rate was similar during fasting vs. high insulin level, but plasma NEFA levels were significantly lowered by insulin. Nicotinic acid significantly blunted the insulin-mediated suppression of plasma palmitate appearance and oxidation rates by approximately 60 and approximately 70%, respectively. In contrast, nicotinic acid did not affect the marked stimulation of palmitate clearance by insulin. Thus most of the insulin-mediated reduction of plasma NEFA appearance and oxidation can be explained by suppression of intracellular lipolysis during enhanced intravascular triglyceride lipolysis in healthy humans. Our results also suggest that insulin may affect plasma NEFA clearance independently of the suppression of intracellular lipolysis.

  18. Suppression in Bitterness Intensity of Bitter Basic Drug by Chlorogenic Acid.

    PubMed

    Shiraishi, Sayuko; Haraguchi, Tamami; Nakamura, Saki; Kojima, Honami; Kawasaki, Ikuo; Yoshida, Miyako; Uchida, Takahiro

    2017-01-01

    The purpose of the study was to evaluate suppression of the bitterness intensity of bitter basic drugs by chlorogenic acid (CGA) using the artificial taste sensor and human gustatory sensation testing and to investigate the mechanism underlying bitterness suppression using (1)H-NMR. Diphenhydramine hydrocholoride (DPH) was the bitter basic drug used in the study. Quinic acid (QNA) and caffeic acid (CFA) together form CGA. Although all three acids suppressed the bitterness intensity of DPH in a dose-dependent manner as determined by the taste sensor and in gustatory sensation tests, CFA was less effective than either CGA or QNA. Data from (1)H-NMR spectroscopic analysis of mixtures of the three acids with DPH suggest that the carboxyl group, which is present in both QNA and CGA but not CFA, interact with the amine group of DPH. This study showed that the bitterness intensity of DPH was suppressed by QNA and CGA through a direct electrostatic interaction with DPH as confirmed in (1)H-NMR spectroscopic analysis. CGA and QNA may therefore be useful bitterness-masking agents for the basic drug DPH.

  19. Ellagic acid suppresses lipid accumulation by suppressing early adipogenic events and cell cycle arrest.

    PubMed

    Woo, Mi-Seon; Choi, Hyeon-Son; Seo, Min-Jung; Jeon, Hui-Jeon; Lee, Boo-Yong

    2015-03-01

    Ellagic acid (EA) is a natural polyphenol found in various fruits and vegetables. In this study, we examined the inhibitory effect of EA on fat accumulation in 3T3-L1 cells during adipogenesis. Our data showed that EA reduced fat accumulation by down-regulating adipogenic markers such as peroxisome proliferator activated receptor γ (PPARγ) and the CCAAT/enhancer binding protein α (C/EBPα) at the mRNA and protein levels in a dose-dependent manner. We found that the decrease in adipogenic markers resulted from reduced expression of some early adipogenic transcription factors such as KLF4, KLF5, Krox20, and C/EBPβ within 24 h. Also, these inhibitions were correlated with down-regulation of TG synthetic enzymes, causing inhibition of triglyceride (TG) levels in 3T3-L1 cells investigated by ORO staining and in zebrafish investigated by TG assay. Additionally, the cell cycle analysis showed that EA inhibited cell cycle progression by arresting cells at the G0/G1 phase.

  20. Amino acid composition predicts prion activity.

    PubMed

    Afsar Minhas, Fayyaz Ul Amir; Ross, Eric D; Ben-Hur, Asa

    2017-04-10

    Many prion-forming proteins contain glutamine/asparagine (Q/N) rich domains, and there are conflicting opinions as to the role of primary sequence in their conversion to the prion form: is this phenomenon driven primarily by amino acid composition, or, as a recent computational analysis suggested, dependent on the presence of short sequence elements with high amyloid-forming potential. The argument for the importance of short sequence elements hinged on the relatively-high accuracy obtained using a method that utilizes a collection of length-six sequence elements with known amyloid-forming potential. We weigh in on this question and demonstrate that when those sequence elements are permuted, even higher accuracy is obtained; we also propose a novel multiple-instance machine learning method that uses sequence composition alone, and achieves better accuracy than all existing prion prediction approaches. While we expect there to be elements of primary sequence that affect the process, our experiments suggest that sequence composition alone is sufficient for predicting protein sequences that are likely to form prions. A web-server for the proposed method is available at http://faculty.pieas.edu.pk/fayyaz/prank.html, and the code for reproducing our experiments is available at http://doi.org/10.5281/zenodo.167136.

  1. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR

    PubMed Central

    Feldman, Rebecca; Martinez, Jesse D.

    2009-01-01

    Summary Ursodeoxycholic acid (UDCA) has been shown to prevent colon tumorigenesis in animal models and in humans. In vitro work indicates that this bile acid can suppress cell growth and mitogenic signaling suggesting that UDCA may be an anti-proliferative agent. However, the mechanism by which UDCA functions is unclear. Previously we showed that bile acids may alter cellular signaling by acting at the plasma membrane. Here we utilized EGFR as a model membrane receptor and examined the effects that UDCA has on its functioning. We found that UDCA promoted an interaction between EGFR and caveolin-1 and this interaction enhanced UDCA-mediated suppression of MAP kinase activity and cell growth . Importantly, UDCA treatment led to recruitment of the ubiquitin ligase, c-Cbl, to the membrane, ubiquitination of EGFR, and increased receptor degradation. Moreover, suppression of c-Cbl activity abrogated UDCA's growth suppression activities suggesting that receptor ubiquitination plays an important role in UDCA's biological activities. Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation. PMID:19446582

  2. Individual Differences in Spontaneous Expressive Suppression Predict Amygdala Responses to Fearful Stimuli: The Role of Suppression Priming

    PubMed Central

    Chen, Shengdong; Deng, Zhongyan; Xu, Yin; Long, Quanshan; Yang, Jiemin; Yuan, Jiajin

    2017-01-01

    Though the spontaneous emotion regulation has received long discussions, few studies have explored the regulatory effects of spontaneous expressive suppression in neural activations, especially in collectivistic cultural context. The functional magnetic resonance imaging (fMRI) study aimed to examine whether individual differences in the tendency to use suppression are correlated with amygdala responses to negative situations when individuals are unconsciously primed with expressive suppression. Twenty-three healthy Chinese undergraduates completed an fMRI paradigm involving fear processing, and a synonym matching task was added to prime participants with the unconscious (automatic) expressive suppression goal. Participants completed measures of typical emotion regulation use (reappraisal and suppression), trait anxiety, and neuroticism. Results indicated that only in emotion suppression prime condition, greater use of suppression in everyday life was related to decreased amygdala activity. These associations were not attributable to variation in trait anxiety, neuroticism, or the habitual use of reappraisal. These findings suggest that in collectivistic cultural settings, individual differences in expressive suppression do not alter fear-related neural activation during suppression-irrelevant context. However, unconscious suppression priming facilitates the manifestation of individual differences in the neural consequence of expressive suppression, as reflected by the priming-specific decrease of emotional subcortical activations with more use of expressive suppression. PMID:28197108

  3. The dexamethasone suppression test (DST) in predicting response to desipramine and amitriptyline in depressed outpatients.

    PubMed

    Peselow, E D; Goldring, N; Stanley, M; Barouche, F; Fieve, R R

    1986-01-01

    The predictive value of the dexamethasone suppression test (DST) was evaluated in two consecutive clinical trials involving 99 individuals treated with amitriptyline or desipramine. Following one week observation, and following one week on low-dose desipramine or amitriptyline (50 mg), all patients who remained depressed (Hamilton score 16 or greater) were given a full clinical trial of either desipramine or amitriptyline (150-300 mg/day) over a minimum 3-5 week period. In all, 68 patients required this trial, 31 receiving amitriptyline and 37 receiving desipramine. For these patients there was no relationship between DST suppression/non-suppression vs clinical response to either desipramine or amitriptyline. There was a non-significant trend for suppressors (negative DST) to respond either spontaneously or to low-dose desipramine or amitriptyline as opposed to non-suppressors (positive DST).

  4. DETERMINATION OF CARBOXYLIC ACIDS BY ION-EXCLUSION CHROMATOGRAPHY WITH NON-SUPPRESSED CONDUCTIVITY AND OPTICAL DETECTORS

    EPA Science Inventory

    Determination of carboxylic acids using non-suppressed conductivity and UV detections is described. The background conductance of 1-octanesulfonic acid, hexane sulfonic acid and sulfuric acid at varying concentrations was determined. Using 0.2 mM 1-octanesulfonic acid as a mobile...

  5. DETERMINATION OF CARBOXYLIC ACIDS BY ION-EXCLUSION CHROMATOGRAPHY WITH NON-SUPPRESSED CONDUCTIVITY AND OPTICAL DETECTORS

    EPA Science Inventory

    Determination of carboxylic acids using non-suppressed conductivity and UV detections is described. The background conductance of 1-octanesulfonic acid, hexane sulfonic acid and sulfuric acid at varying concentrations was determined. Using 0.2 mM 1-octanesulfonic acid as a mobile...

  6. Evidence-based medicine as it applies to acid suppression in the hospitalized patient.

    PubMed

    Cash, Brooks D

    2002-06-01

    An evidence-based-medicine approach may be applied to studies in the medical literature to help physicians make sound judgments about efficacy and safety data and to improve clinical decision making. To assess the role of gastric acid suppression in the prevention of stress ulcer bleeding and in the management of upper gastrointestinal bleeding after successful hemostasis of bleeding peptic ulcer disease, the following questions should be addressed: Is it possible to identify risk factors for clinically important bleeding in critically ill patients? Can intravenous acid suppression prevent stress ulcer-related bleeding or prevent rebleeding in peptic ulcers after successful hemostasis? What is the most effective method of acid suppression for these disorders? An evidence-based-medicine review of published trials yields sufficient evidence to support the use of prophylactic acid suppression in critically ill patients with coagulopathy or in those who are receiving prolonged mechanical ventilation. Not enough data have accumulated to prove the superiority of intravenous proton pump inhibitors to intravenous histamine-2-receptor antagonists for prophylaxis of clinically important stress ulcer bleeding. With respect to acute gastrointestinal bleeding, however, two well-conducted trials indicate that an intravenous proton pump inhibitor is significantly more effective than an intravenous histamine-2-receptor antagonist or placebo in reducing the rate of rebleeding after hemostasis in patients with bleeding peptic ulcer. Analysis of the data from both trials shows that only five to six patients would need to receive an intravenous proton pump inhibitor to avoid one episode of rebleeding.

  7. DIBROMOACETIC ACID ATTENUATES A DIMETHYLDITHIOCARBAMATE-INDUCED SUPPRESSION OF THE RAT LH SURGE

    EPA Science Inventory

    DIBROMOACETIC ACID ATTENUATES A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LH SURGE IN THE RAT. Jerome M. Goldman, Ashley S. Murr, Angela R. Buckelew, W. Keith McElroy and Janet M. Ferrell. Repro. Toxicol. Div., NHEERL, ORD, US EPA, RTP, NC

    At elevated concentrations, the ...

  8. Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrow-derived macrophages

    USDA-ARS?s Scientific Manuscript database

    Individuals with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease (CVD), possibly associated with elevated plasma free fatty acid concentrations. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage chole...

  9. Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5.

    PubMed

    Levi, Liraz; Wang, Zeneng; Doud, Mary Kathryn; Hazen, Stanley L; Noy, Noa

    2015-11-23

    Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5, which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting the activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer.

  10. Saturated fatty-acids regulate retinoic acid signaling and suppress tumorigenesis by targeting fatty-acid-binding protein 5

    PubMed Central

    Levi, Liraz; Wang, Zeneng; Doud, Mary Kathryn; Hazen, Stanley L.; Noy, Noa

    2015-01-01

    Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes, and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARβ/δ. The data indicate that these activities of LCFA are mediated by FABP5 which delivers ligands from the cytosol to nuclear PPARβ/δ. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARβ/δ pathway. We show further that, by concomitantly promoting activation of RAR and inhibiting the activation of PPARβ/δ, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer. PMID:26592976

  11. Predictive factors for the suppression of fusarium wilt of tomato in plant growth media.

    PubMed

    Borrero, Celia; Trillas, M Isabel; Ordovás, José; Tello, Julio C; Avilés, Manuel

    2004-10-01

    ABSTRACT Fusarium wilts are economically important diseases for which there are no effective chemical control measures. However, biological control and fertility management are becoming efficient alternatives for controlling this disease. Growth media formulated with composts that are able to suppress Fusarium wilt of tomato provide a control system that integrates both strategies. The aim of this study was to predict Fusarium wilt suppression of growth media using abiotic and biotic variables. Grape marc compost was the most effective medium used to suppress Fusarium wilt. Cork compost was intermediate, and light peat and expanded vermiculite were the most conducive growth media. The growth media evaluated were in a pH range of 6.26 to 7.97. Both composts had high beta-glucosidase activity. When pH and beta-glucosidase activity were taken into account as predictive variables, more than 91% of the variation in severity of Fusarium wilt was explained. This relationship illustrates the effect of nutrient availability and the degree of microbiostasis, two key factors in this pathosystem. Microbial populations involved in suppressiveness were cellulolytic and oligotrophic actinomycetes, fungi, and the ratios cellulolytic actinomycetes/cellulolytic bacteria, oligotrophic bacteria/copiotrophic bacteria, and oligotrophic actinomycetes/oligotrophic bacteria. Based on community level physiological profiles, different community structures were evident among growth media evaluated.

  12. Suppression of Striatal Prediction Errors by the Prefrontal Cortex in Placebo Hypoalgesia.

    PubMed

    Schenk, Lieven A; Sprenger, Christian; Onat, Selim; Colloca, Luana; Büchel, Christian

    2017-10-04

    Classical learning theories predict extinction after the discontinuation of reinforcement through prediction errors. However, placebo hypoalgesia, although mediated by associative learning, has been shown to be resistant to extinction. We tested the hypothesis that this is mediated by the suppression of prediction error processing through the prefrontal cortex (PFC). We compared pain modulation through treatment cues (placebo hypoalgesia, treatment context) with pain modulation through stimulus intensity cues (stimulus context) during functional magnetic resonance imaging in 48 male and female healthy volunteers. During acquisition, our data show that expectations are correctly learned and that this is associated with prediction error signals in the ventral striatum (VS) in both contexts. However, in the nonreinforced test phase, pain modulation and expectations of pain relief persisted to a larger degree in the treatment context, indicating that the expectations were not correctly updated in the treatment context. Consistently, we observed significantly stronger neural prediction error signals in the VS in the stimulus context compared with the treatment context. A connectivity analysis revealed negative coupling between the anterior PFC and the VS in the treatment context, suggesting that the PFC can suppress the expression of prediction errors in the VS. Consistent with this, a participant's conceptual views and beliefs about treatments influenced the pain modulation only in the treatment context. Our results indicate that in placebo hypoalgesia contextual treatment information engages prefrontal conceptual processes, which can suppress prediction error processing in the VS and lead to reduced updating of treatment expectancies, resulting in less extinction of placebo hypoalgesia.SIGNIFICANCE STATEMENT In aversive and appetitive reinforcement learning, learned effects show extinction when reinforcement is discontinued. This is thought to be mediated by

  13. Selective enhancement and suppression of frog gustatory responses to amino acids

    PubMed Central

    1981-01-01

    Properties of the receptor sites for L-amino acids in taste cells of the bullfrog (Rana catesbeiana) were examined by measuring the neural activities of the glossopharyngeal nerve under various conditions. (a) The frogs responded to 12 amino acids, but the responses to the amino acids varied with individual frogs under natural conditions. The frog tongues, however, exhibited similar responses after an alkaline treatment that removes Ca2+ from the tissue. The variation in the responses under natural conditions was apparently due to the variation in the amount of Ca2+ bound to the receptor membrane. (b) The responses to hydrophilic L-amino acids (glycine, L-alanine, L-serine, L- threonine, L-cysteine, and L-proline) were of a tonic type, but those to hydrophobic L-amino acids (L-valine, L-leucine, L-isoleucine, L- methionine, L-phenylalanine, and L-tyrptophan) were usually composed of both phasic and tonic components. (c) The properties of the tonic component were quite different from those of the phasic component: the tonic component was largely enhanced by the alkaline treatment and suppressed by the acidic treatment that increases binding of Ca2+ to the tissue. Also, the tonic component was suppressed by the presence of low concentrations of salts, or the action of pronase E, whereas the phasic component was unchanged under these conditions. These properties of the phasic component were quite similar to those of the response to hydrophobic substances such as quinine. These results suggest that the hydrophilic L-amino acids stimulate receptor protein(s) and that the hydrophobic L-amino acids stimulate both the receptor protein and a receptor site similar to that for quinine. (d) On the basis of the suppression of the responses to amino acids by salts, the mechanism of generation of the receptor potential is discussed. PMID:6972437

  14. Citric Acid Suppresses the Bitter Taste of Olopatadine Hydrochloride Orally Disintegrating Tablets.

    PubMed

    Sotoyama, Mai; Uchida, Shinya; Tanaka, Shimako; Hakamata, Akio; Odagiri, Keiichi; Inui, Naoki; Watanabe, Hiroshi; Namiki, Noriyuki

    2017-01-01

    Orally disintegrating tablets (ODTs) are formulated to disintegrate upon contact with saliva, allowing administration without water. Olopatadine hydrochloride, a second-generation antihistamine, is widely used for treating allergic rhinitis. However, it has a bitter taste; therefore, the development of taste-masked olopatadine ODTs is essential. Some studies have suggested that citric acid could suppress the bitterness of drugs. However, these experiments were performed using solutions, and the taste-masking effect of citric acid on ODTs has not been evaluated using human gustatory sensation tests. Thus, this study evaluated citric acid's taste-masking effect on olopatadine ODTs. Six types of olopatadine ODTs containing 0-10% citric acid were prepared and subjected to gustatory sensation tests that were scored using the visual analog scale. The bitterness and overall palatability of olopatadine ODTs during disintegration in the mouth and after spitting out were evaluated in 11 healthy volunteers (age: 22.8±2.2 years). The hardness of the ODTs was >50 N. Disintegration time and dissolution did not differ among the different ODTs. The results of the gustatory sensation tests suggest that citric acid could suppress the bitterness of olopatadine ODTs in a dose-dependent manner. Olopatadine ODTs with a high content of citric acid (5-10%) showed poorer overall palatability than that of those without citric acid despite the bitterness suppression. ODTs containing 2.5% citric acid, yogurt flavoring, and aspartame were the most suitable formulations since they showed low bitterness and good overall palatability. Thus, citric acid is an effective bitterness-masking option for ODTs.

  15. Long-term suppression of wetland methane flux following a pulse of simulated acid rain

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy; Blake, Stephen

    2005-06-01

    Wetlands are a potent source of the radiatively important gas methane (CH4). Recent findings have demonstrated that sulfate (SO42-) deposition via acid rain suppresses CH4 emissions by stimulating competitive exclusion of methanogens by sulfate-reducing microbial populations. Here we report data from a field experiment showing that a finite pulse of simulated acid rain SO42- deposition, as would be expected from a large Icelandic volcanic eruption, continues to suppress CH4 emissions from wetlands long after the pollution event has ceased. Our analysis of the stoichiometries suggests that 5 years is a minimum CH4 emission recovery period, with 10 years being a reasonable upper limit. Our findings highlight the long-term impact of acid rain on biospheric output of CH4 which, for discrete polluting events such as volcanic eruptions, outlives the relatively short-term SO42- aerosol radiative cooling effect.

  16. Effects of pirenzepine on omeprazole-induced hypergastrinemia and acid suppression in peptic ulcer patients.

    PubMed

    Tari, A; Hamada, M; Kamiyasu, T; Fukino, Y; Sumii, M; Haruma, K; Sumii, K; Inoue, M; Kajiyama, G

    1996-04-01

    Omeprazole effectively suppresses acid secretion, resulting in the long-term elevation of intragastric pH and serum gastrin level. Pirenzepine has been reported to inhibit gastrin secretion. This study was carried out to examine the effects of additional pirenzepine treatment on the hypergastrinemia and gastric acid suppression induced by omeprazole. Concentrations of serum gastrin and plasma somatostatin were measured in 28 peptic ulcer patients before treatment, after omeprazole treatment (20 mg/day) for 2 weeks, and after omeprazole and pirenzepine (100 mg/day) treatment for 2 weeks. The acid inhibitory effect of pirenzepine treatment in addition to omeprazole was evaluated by 24-h intragastric pH measurement in six healthy volunteers. Serum gastrin level was increased significantly, to 2.4-fold the pretreatment level, by omeprazole treatment. Additional treatment with pirenzepine suppressed serum gastrin level to 0.6-fold the omeprazole-treatment level. The serum somatostatin level was not altered significantly either by omeprazole treatment or by omeprazole and pirenzepine treatment. In healthy volunteers whose pH 3 holding time on 24-h intragastric pH monitoring was 70% by omeprazole treatment, omeprazole and pirenzepine treatment markedly increased the pH 3 holding time, to 89%. These findings suggest that pirenzepine is useful in reducing the undesirable effects of omeprazole-induced hypergastrinemia, i.e., the excessive trophic effect of omeprazole on the acid-secreting part of the stomach and the overstimulation of acid secretion. The additional pirenzepine treatment is also effective in suppressing acid secretion.

  17. Harmonic suppression and delay compensation for inverters via variable horizon nonlinear model predictive control

    NASA Astrophysics Data System (ADS)

    Mirzaeva, G.; Goodwin, G. C.

    2015-07-01

    Inverters play a central role in modern society including renewable energy integration and motor drives. Due to the inherent switched nature of the inverter waveforms harmonic distortion is an issue. Additionally, the switching patterns are perturbed by unavoidable switching delays. Amongst those, nonlinear and load-dependent switching delays (known as inverter 'dead-time delays') are the most difficult to compensate. In this paper, we propose a new approach to delay compensation and harmonic suppression in inverter voltage. The proposed approach is based on variable prediction horizon nonlinear model predictive control.

  18. Evaporation suppression from water reservoirs using floating covers: Lab scale observations and model predictions

    NASA Astrophysics Data System (ADS)

    Or, D.; Lehmann, P.; Aminzadeh, M.; Sommer, M.; Wey, H.; Wunderli, H.; Breitenstein, D.

    2016-12-01

    The competition over dwindling fresh water resources is expected to intensify with projected increase in human population in arid regions, expansion of irrigated land and changes in climate and drought patterns. The volume of water stored in reservoirs would also increase to mitigate seasonal shortages due to rainfall variability and to meet irrigation water needs. By some estimates up to half of the stored water is lost to evaporation thereby exacerbating the water scarcity problem. Recently, there is an upsurge in the use of self-assembling floating covers to suppress evaporation, yet the design, and implementation remain largely empirical. Studies have shown that evaporation suppression is highly nonlinear, as also known from a century of research on gas exchange from plant leaves (that often evaporate as free water surfaces through stomata that are only 1% of leaf area). We report a systematic evaluation of different cover types and external drivers (radiation, wind, wind+radiation) on evaporation suppression and energy balance of a 1.4 m2 basin placed in a wind-tunnel. Surprisingly, evaporation suppression by black and white floating covers (balls and plates) were similar despite significantly different energy balance regimes over the cover surfaces. Moreover, the evaporation suppression efficiency was a simple function of the uncovered area (square root of the uncovered fraction) with linear relations with the covered area in some cases. The thermally decoupled floating covers offer an efficient solution to the evaporation suppression with limited influence of the surface energy balance (water temperature for black and white covers was similar and remained nearly constant). The results will be linked with a predictive evaporation-energy balance model and issues of spatial scales and long exposure times will be studied.

  19. Malonic acid suppresses mucin-type O-glycan degradation during hydrazine treatment of glycoproteins.

    PubMed

    Goso, Yukinobu

    2016-03-01

    Hydrazine treatment is frequently used for releasing mucin-type O-glycans (O-glycans) from glycoproteins because the method provides O-glycans that retain a reducible GalNAc at their reducing end, which is available for fluorescent labeling. However, many O-glycans are degraded by "peeling" during this treatment. In the current study, it was found that malonic acid suppressed O-glycan degradation during hydrazine treatment of bovine fetuin or porcine gastric mucin in both the gas and liquid phases. This is paradoxical because the release of O-glycans from glycoproteins occurs under alkaline conditions. However, malonic acid seems to prevent the degradation through its acidic property given that other weak acids also prevented the degradation. Accordingly, disodium malonate did not suppress O-glycan degradation. Application of this method to rat gastric mucin demonstrated that the majority of the major O-glycans obtained in the presence of malonic acid were intact, whereas those obtained in the absence of malonic acid were degraded. These results suggest that hydrazine treatment in the presence of malonic acid would allow glycomic analysis of native mucin glycoproteins.

  20. Predicting folic acid intake among college students.

    PubMed

    Lane, Susan H; Hines, Annette; Krowchuk, Heidi

    2015-01-01

    Annually in the United States, approximately 3,000 babies are born with neural tube defects (NTDs). Folic acid supplementation can reduce NTDs by 50% to 70%. Despite recommendations for folic acid intake, only 30% of women ages 18 to 24 report folic acid supplementation and 6% have knowledge of when to take folic acid. There is little information regarding lifestyle factors that correlate with consuming folic acid. The purpose was to describe folic acid consumption among college students; and explore the relationship between folic acid intake and the variables of: age, gender, year in college, alcohol and tobacco use, and vitamin supplement intake. This was a descriptive study with secondary analysis of data from 1,921 college-aged student participants in North Carolina who took part in a pretest/posttest-designed intervention to increase folic acid consumption and knowledge. Surveys included demographic, lifestyle, folic acid knowledge, and consumption questions adapted from the Centers for Disease Control and Prevention questionnaire. Quantitative analyses included descriptive statistics and logistic regression. Of the 1,921 college students, 83.3% reported taking a vitamin supplement, but only 47.6% stated that the vitamin contained folic acid. A relationship was found between age, year in school, gender, and vitamin intake. Lifestyle variables were not significant predictors of folic acid consumption. Identification of variables associated with folic acid intake, marketing, and education can be focused to increase supplementation levels, and ultimately reduce the number of NTDs.

  1. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1

    PubMed Central

    Li, Xin; Fan, Shengjun; Pan, Xueyang; Xiaokaiti, Yilixiati; Duan, Jianhui; Shi, Yundi; Pan, Yan; Tie, Lu; Wang, Xin; Li, Yuhua; Li, Xuejun

    2016-01-01

    Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer. PMID:27863391

  2. Nordihydroguaiaretic acid impairs prostate cancer cell migration and tumor metastasis by suppressing neuropilin 1.

    PubMed

    Li, Xin; Fan, Shengjun; Pan, Xueyang; Xiaokaiti, Yilixiati; Duan, Jianhui; Shi, Yundi; Pan, Yan; Tie, Lu; Wang, Xin; Li, Yuhua; Li, Xuejun

    2016-12-27

    Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.

  3. Prediction of the Seizure Suppression Effect by Electrical Stimulation via a Computational Modeling Approach

    PubMed Central

    Ahn, Sora; Jo, Sumin; Jun, Sang Beom; Lee, Hyang Woon; Lee, Seungjun

    2017-01-01

    In this paper, we identified factors that can affect seizure suppression via electrical stimulation by an integrative study based on experimental and computational approach. Preferentially, we analyzed the characteristics of seizure-like events (SLEs) using our previous in vitro experimental data. The results were analyzed in two groups classified according to the size of the effective region, in which the SLE was able to be completely suppressed by local stimulation. However, no significant differences were found between these two groups in terms of signal features or propagation characteristics (i.e., propagation delays, frequency spectrum, and phase synchrony). Thus, we further investigated important factors using a computational model that was capable of evaluating specific influences on effective region size. In the proposed model, signal transmission between neurons was based on two different mechanisms: synaptic transmission and the electrical field effect. We were able to induce SLEs having similar characteristics with differentially weighted adjustments for the two transmission methods in various noise environments. Although the SLEs had similar characteristics, their suppression effects differed. First of all, the suppression effect occurred only locally where directly received the stimulation effect in the high noise environment, but it occurred in the entire network in the low noise environment. Interestingly, in the same noise environment, the suppression effect was different depending on SLE propagation mechanism; only a local suppression effect was observed when the influence of the electrical field transmission was very weak, whereas a global effect was observed with a stronger electrical field effect. These results indicate that neuronal activities synchronized by a strong electrical field effect respond more sensitively to partial changes in the entire network. In addition, the proposed model was able to predict that stimulation of a seizure focus

  4. Improved NASA-ANOPP Noise Prediction Computer Code for Advanced Subsonic Propulsion Systems. Volume 2; Fan Suppression Model Development

    NASA Technical Reports Server (NTRS)

    Kontos, Karen B.; Kraft, Robert E.; Gliebe, Philip R.

    1996-01-01

    The Aircraft Noise Predication Program (ANOPP) is an industry-wide tool used to predict turbofan engine flyover noise in system noise optimization studies. Its goal is to provide the best currently available methods for source noise prediction. As part of a program to improve the Heidmann fan noise model, models for fan inlet and fan exhaust noise suppression estimation that are based on simple engine and acoustic geometry inputs have been developed. The models can be used to predict sound power level suppression and sound pressure level suppression at a position specified relative to the engine inlet.

  5. Insulin Acutely Inhibits Intestinal Lipoprotein Secretion in Humans in Part by Suppressing Plasma Free Fatty Acids

    PubMed Central

    Pavlic, Mirjana; Xiao, Changting; Szeto, Linda; Patterson, Bruce W.; Lewis, Gary F.

    2010-01-01

    OBJECTIVE Intestinal lipoprotein production has recently been shown to be increased in insulin resistance, but it is not known whether it is regulated by insulin in humans. Here, we investigated the effect of acute hyperinsulinemia on intestinal (and hepatic) lipoprotein production in six healthy men in the presence and absence of concomitant suppression of plasma free fatty acids (FFAs). RESEARCH DESIGN AND METHODS Each subject underwent the following three lipoprotein turnover studies, in random order, 4–6 weeks apart: 1) insulin and glucose infusion (euglycemic-hyperinsulinemic clamp) to induce hyperinsulinemia, 2) insulin and glucose infusion plus Intralipid and heparin infusion to prevent the insulin-induced suppression of plasma FFAs, and 3) saline control. RESULTS VLDL1 and VLDL2-apoB48 and -apoB100 production rates were suppressed by 47–62% by insulin, with no change in clearance. When the decline in FFAs was prevented by concomitant infusion of Intralipid and heparin, the production rates of VLDL1 and VLDL2-apoB48 and -apoB100 were intermediate between insulin and glucose infusion and saline control. CONCLUSIONS This is the first demonstration in humans that intestinal apoB48-containing lipoprotein production is acutely suppressed by insulin, which may involve insulin's direct effects and insulin-mediated suppression of circulating FFAs. PMID:20028946

  6. Suppression of Progesterone-enhanced Hyperactivation in Hamster Spermatozoa by γ-aminobutyric Acid

    PubMed Central

    KON, Hiroe; TAKEI, Gen L.; FUJINOKI, Masakatsu; SHINODA, Motoo

    2014-01-01

    It has been recently shown that mammalian spermatozoa were hyperactivated by steroids, amines and amino acids. In the present study, we investigated whether hyperactivation of hamster sperm is regulated by progesterone (P) and γ-aminobutyric acid (GABA). Although sperm hyperactivation was enhanced by P, GABA significantly suppressed P-enhanced hyperactivation in a dose-dependent manner. Suppression of P-enhanced hyperactivation by GABA was significantly inhibited by an antagonist of the GABAA receptor (bicuculline). Moreover, P bound to the sperm head, and this binding was decreased by GABA. Because the concentrations of GABA and P change in association with the estrous cycle, these results suggest that GABA and P competitively regulate the enhancement of hyperactivation through the GABAA receptor. PMID:24614320

  7. Acid Treatment Enables Suppression of Electron-Hole Recombination in Hematite for Photoelectrochemical Water Splitting.

    PubMed

    Yang, Yi; Forster, Mark; Ling, Yichuan; Wang, Gongming; Zhai, Teng; Tong, Yexiang; Cowan, Alexander J; Li, Yat

    2016-03-01

    We report a strategy for efficient suppression of electron-hole recombination in hematite photoanodes. Acid-treated hematite showed a substantially enhanced photocurrent density compared to untreated samples. Electrochemical impedance spectroscopy studies revealed that the enhanced photocurrent is partly due to improved efficiency of charge separation. Transient absorption spectroscopic studies coupled to electrochemical measurements indicate that, in addition to improved bulk electrochemical properties, acid-treated hematite has significantly decreased surface electron-hole recombination losses owing to a greater yield of the trapped photoelectrons being extracted to the external circuit.

  8. Efficacy of acid suppression therapy in gastroesophageal reflux disease-related chronic laryngitis

    PubMed Central

    Yang, Yue; Wu, Haitao; Zhou, Jian

    2016-01-01

    Abstract Background: This research aims to assess the response to acid suppression therapy in gastroesophageal reflux disease (GERD)-related chronic laryngitis (CL). Methods: Data were extracted from Web of Knowledge, Embase, and PubMed for English language article published up to March 2016. Pooled overall response rate (ORR) rates were evaluated to determine acid suppression treatment efficacy. Random effects model was used with standard approaches to sensitivity analysis, quality assessment, heterogeneity, and exploration of publication bias. Results: Pooled data from 21 reports (N = 2864, antireflux medicine: 2741; antireflux surgery: 123, study duration 4–108 week) were analyzed. With the random-effect model, the ORR was 66% (95% confidence interval [CI] 54%–78%). The ORRs were 80% for antireflux surgery (95% CI 67%–93%, 3 studies, 123 patients), whereas 64% for antireflux medicine (95% CI 50%–77%, 18 studies, 2741 patients), and the ORR was 70% (95% CI 55%–85%, 15 reports, 2731 patients) for >8 weeks’ therapy duration, whereas 57% (95% CI 48%–65%, 6 reports, 133 patients) for ≤8 weeks’ duration of therapy. Conclusions: Acid suppression seems to be an effective therapy for GERD-related CL. There was an increase in effect among patients with surgery therapeutic method and longer therapy duration. PMID:27749540

  9. Acid-suppressing therapies and subsite-specific risk of stomach cancer.

    PubMed

    Wennerström, E Christina M; Simonsen, Jacob; Camargo, M Constanza; Rabkin, Charles S

    2017-04-25

    Associations of stomach cancer risk with histamine type-2 receptor antagonists (H2RA) and proton-pump inhibitors (PPI) are controversial. We hypothesised that proximal extension of Helicobacter pylori infection from acid suppression would disproportionately increase cancers at proximal subsites. A total of 1 563 860 individuals in the Danish Prescription Drug Registry first prescribed acid-suppressive drugs 1995-2011 were matched to unexposed population-based controls. Hazard ratios (HR) were calculated by Cox proportional hazard regression for stomach cancers diagnosed more than one year after first prescription. There were 703 stomach cancers among H2RA-exposed individuals and 1347 among PPI-exposed. Restricted to individuals with five or more prescriptions, subsite-specific HRs for H2RA and PPI were 4.1 and 6.4 for proximal subsites vs 8.0 and 10.3 for distal subsites, respectively. Moderate exposures to acid-suppressive drugs did not favour proximal tumour localisation. Given confounding by indication, these findings do not resolve potential contribution to gastric carcinogenesis overall.

  10. Risk of Stroke-Associated Pneumonia With Acid-Suppressive Drugs: A Population-Based Cohort Study.

    PubMed

    Ho, Sai-Wai; Hsieh, Ming-Ju; Yang, Shun-Fa; Yeh, Ying-Tung; Wang, Yu-Hsun; Yeh, Chao-Bin

    2015-07-01

    Acid-suppressive drugs, including histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), are common medications used for treating upper gastrointestinal tract disorders. However, acid-suppressive drugs have been reported to increase the risk of pneumonia in numerous disease populations. However, the relationship between acid-suppressive drugs and stroke-associated pneumonia (SAP) remains controversial. The purpose of this study was to investigate the association between acid-suppressive drug usage and pneumonia among patients with stroke by using a nationwide data set. A population-based cohort study was conducted using a data set from the Taiwanese National Health Insurance Research Database. Data on patients with new-onset stroke from 2010 to 2011 were collected. Patients with and without acid-suppressive drug usage were followed up to identify the occurrence of any type of pneumonia. We estimated the adjusted hazard ratios (HRs) by using the Cox proportional hazards model. The study cohort comprised 7965 patients with new-onset stroke. The incidence of pneumonia was 6.9% (552/7965) and more than 40% (225/552) of patients developed pneumonia within 3 months after an acute stroke. Acid-suppressive drug usage was an independent risk factor of pneumonia. The adjusted HR for the risk of pneumonia in patients with new-onset stroke using acid-suppressive drugs was 1.44 (95% confidence interval [CI] = 1.18-1.75, P < 0.01). Only PPI usage increased risk of chronic SAP (adjusted HR = 1.46, 95% CI = 1.04-2.05). Acid-suppressive drug usage was associated with a slightly increased risk of SAP. Physicians should exercise caution when prescribing acid-suppressive drugs to patients with stroke, particularly at the chronic stage.

  11. Synthesized enone fatty acids resembling metabolites from gut microbiota suppress macrophage-mediated inflammation in adipocytes.

    PubMed

    Yang, Ha-Eun; Li, Yongjia; Nishimura, Akira; Jheng, Huei-Fen; Yuliana, Ana; Kitano-Ohue, Ryuji; Nomura, Wataru; Takahashi, Nobuyuki; Kim, Chu-Sook; Yu, Rina; Kitamura, Nahoko; Park, Si-Bum; Kishino, Shigenobu; Ogawa, Jun; Kawada, Teruo; Goto, Tsuyoshi

    2017-10-01

    Recent reports indicate that gut microbiota and their metabolites may regulate host inflammatory conditions, including the chronic inflammation of obese adipose tissues. In this study, we investigated whether specific synthesized fatty acids, identical to the metabolites generated by gut microbiota, act as anti-inflammatory factors in obesity-induced inflammation. We first used lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages to examine the anti-inflammatory effect of fatty acids synthesized to resemble representative polyunsaturated fatty acid metabolites from gut microbiota. Fatty acids containing an enone structure showed the most potent anti-inflammatory activity. Enone fatty acids also displayed anti-inflammatory effects on macrophages cocultured with hypertrophied 3T3-L1 or immortalized primary adipocytes; and macrophages stimulated with 3T3-L1 adipocyte conditioned medium. Consistently, the beneficial outcome was revealed in the case of LPS- and obesity-induced inflammatory cytokine stimulation in ex vivo adipose tissues. Furthermore, these fatty acids recovered the suppression of β-adrenergic receptor-stimulated uncoupling protein 1 expression and secretion of adiponectin in C3H10T1/2 and 3T3-L1 adipocytes, respectively, under inflammatory conditions, suggesting that enone fatty acids can ameliorate dysfunctions of adipocytes induced by inflammation. These findings indicate that synthesized enone fatty acids show potent anti-inflammatory effects, leading to the improvement of inflammation-induced dysfunctions in adipocytes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Hair Concentrations of Antiretrovirals Predict Viral Suppression in HIV-Infected Pregnant and Breastfeeding Ugandan Women

    PubMed Central

    KOSS, Catherine A.; NATUREEBA, Paul; MWESIGWA, Julia; COHAN, Deborah; NZARUBARA, Bridget; BACCHETTI, Peter; HORNG, Howard; CLARK, Tamara D.; PLENTY, Albert; RUEL, Theodore D.; ACHAN, Jane; CHARLEBOIS, Edwin D.; KAMYA, Moses R.; HAVLIR, Diane V.; GANDHI, Monica

    2015-01-01

    Objective Hair concentrations are a non-invasive measure of cumulative antiretroviral (ARV) exposure and the strongest predictor of viral suppression in large cohorts of non-pregnant patients. We examined hair concentrations of ARVs in relation to virologic outcomes in pregnant and breastfeeding women for the first time. Design/Methods The PROMOTE trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12–28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30–34 weeks gestation and 10–25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ≤400 copies/ml) at delivery and 24 weeks postpartum. Results Among 325 women, median CD4 cell count was 366 cells/mm3 (IQR 270–488) at ART initiation. Mean self-reported 3-day adherence was >97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, ARV hair concentrations were the strongest predictors of viral suppression at delivery (efavirenz: aOR 1.86 per doubling in concentration, 95% CI 1.14–3.1, P=0.013; lopinavir: aOR 1.90, 95% CI 1.33–2.7, P=0.0004) and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22–2.7, P=0.003; lopinavir: aOR 1.53, 95% CI: 1.05–2.2, P=0.026). Conclusions ARV hair concentrations represent an innovative tool that strongly predicts viral suppression among HIV-infected childbearing women during the critical periods of delivery and breastfeeding. PMID:25985404

  13. γ-Aminobutyric acid suppresses enhancement of hamster sperm hyperactivation by 5-hydroxytryptamine

    PubMed Central

    FUJINOKI, Masakatsu; TAKEI, Gen L.

    2016-01-01

    Sperm hyperactivation is regulated by hormones present in the oviduct. In hamsters, 5-hydroxytryptamine (5HT) enhances hyperactivation associated with the 5HT2 receptor and 5HT4 receptor, while 17β-estradiol (E2) and γ-aminobutyric acid (GABA) suppress the association of the estrogen receptor and GABAA receptor, respectively. In the present study, we examined the regulatory interactions among 5HT, GABA, and E2 in the regulation of hamster sperm hyperactivation. When sperm were exposed to E2 prior to 5HT exposure, E2 did not affect 5HT-enhanced hyperactivation. In contrast, GABA partially suppressed 5HT-enhanced hyperactivation when sperm were exposed to GABA prior to 5HT. GABA suppressed 5HT-enhanced hyperactivation associated with the 5HT2 receptor although it did not suppress 5HT-enhanced hyperactivation associated with the 5HT4 receptor. These results demonstrate that hamster sperm hyperactivation is regulated by an interaction between the 5HT2 receptor-mediated action of 5HT and GABA. PMID:27773888

  14. Does adolescent alcohol and marijuana use predict suppressed growth in psychosocial maturity among male juvenile offenders?

    PubMed Central

    Chassin, Laurie; Dmitrieva, Julia; Modecki, Kathryn; Steinberg, Laurence; Cauffman, Elizabeth; Piquero, Alex R.; Knight, George P.; Losoya, Sandra H.

    2009-01-01

    Multiple theories suggest mechanisms by which the use of alcohol and drugs during adolescence could dampen growth in psychosocial maturity. However, scant empirical evidence exists to support this proposition. The current study tested whether alcohol and marijuana use predicted suppressed growth in psychosocial maturity among a sample of male serious juvenile offenders (n = 1,170) who were followed from ages 15 to 21. Alcohol and marijuana use prospectively predicted lower maturity six months later. Moreover, boys with the greatest increases in marijuana use showed the smallest increases in psychosocial maturity. Finally, heterogeneity in the form of age-related alcohol and marijuana trajectories was related to growth in maturity, such that only boys who decreased their alcohol and marijuana use significantly increased in psychosocial maturity. Taken together, these findings suggest that patterns of elevated alcohol and marijuana use in adolescence may suppress age-typical growth in psychosocial maturity from adolescence to young adulthood, but that effects are not necessarily permanent, because decreasing use is associated with increases in maturity. PMID:20307112

  15. Tumor growth suppression by alpha-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via lipid peroxidation.

    PubMed

    Tsuzuki, Tsuyoshi; Tokuyama, Yoshiko; Igarashi, Miki; Miyazawa, Teruo

    2004-08-01

    We have previously shown that conjugated linolenic acids (CLnA) prepared by alkaline isomerization have a stronger antitumor effect than conjugated linoleic acids (CLA). In this study we have compared the suppressive effect on tumor growth of alpha-eleostearic acid (alpha-ESA, 9Z11E13E-18:3) with those of the CLA isomers 9Z11E-CLA and 10E12Z-CLA, using nude mice into which DLD-1 human colon cancer cells were transplanted. The results showed that alpha-ESA, which is a CLnA that can be prepared from natural sources in bulk, had a stronger antitumor effect than CLA. DNA fragmentation was enhanced and lipid peroxidation was increased in tumor tissues of the alpha-ESA-fed mice, which suggested that alpha-ESA induced apoptosis via lipid peroxidation. Furthermore, treatment of DLD-1 cells with alpha-ESA, 9Z11E-CLA and 10E12Z-CLA confirmed that alpha-ESA had a stronger antitumor effect than CLA in cultured cell lines. The induction of apoptosis by alpha-ESA was consistent with enhanced DNA fragmentation, increased caspase activity and increased expression of caspase mRNA following alpha-ESA treatment. Addition of alpha-tocopherol, an antioxidant, suppressed oxidative stress and apoptosis, suggesting that these effects were associated with lipid peroxidation.

  16. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer.

    PubMed

    Pollard, Harvey B; Levine, Mark A; Eidelman, Ofer; Pollard, Morris

    2010-01-01

    The aim of this study was to test for the influence of ascorbic acid on tumorigenicity and metastases of implanted PAIII prostate cancer adenocarcinoma cells in syngeneic LW rats. Hormone-refractory prostate cancer PAIII cells were implanted subcutaneously into immunologically intact, Lobund-Wistar (LW) rats. Intraperitoneal pharmacological doses of ascorbic acid were administered each day for the ensuing 30 days. On the 40th day, animals were sacrificed. Local tumor weights were measured, and metastases were counted. At the end of the 40 day experimental period, the primary tumors were found to be significantly reduced in weight (p=0.026). In addition, sub-pleural lung metastases were even more profoundly reduced in number and size (p=0.009). Grossly enlarged ipsilateral lymph node metastases declined from 7 of 15 rats to 1 of 15 rats. Pharmacological doses of ascorbic acid suppress tumor growth and metastases in hormone-refractory prostate cancer.

  17. Use of lanthanum and sulphuric acid to suppress interferences in the flame photometric determination of calcium m soil extracts.

    PubMed

    Evans, C C; Grimshaw, H M

    1968-04-01

    Interference by iron, aluminium and phosphate in the flame photometric determination of calcium in soil extracts is not fully suppressed by lanthanum unless dilute sulphuric acid is also present. The investigation was restricted to the oxy-acetylene flame.

  18. Induction of Glycosphingolipid GM3 Expression by Valproic Acid Suppresses Cancer Cell Growth.

    PubMed

    Kawashima, Nagako; Nishimiya, Yoshiyuki; Takahata, Shouta; Nakayama, Ken-Ichi

    2016-10-07

    Glycosphingolipid GM3, a known suppressor of epidermal growth factor receptor (EGFR) phosphorylation, inhibits cell proliferation. Valproic acid, conversely, is known as an up-regulator of GM3 synthase gene (ST3GAL5). To test the possibility that valproic acid could inhibit EGFR phosphorylation by increasing the level of GM3 in cells, we treated A431 epidermoid carcinoma cells with valproic acid and found that valproic acid treatment caused an about 6-fold increase in the GM3 level but only a marginal increase in the GM2 level in these cells and that the observed increase in GM3 level was valproic acid dose-dependent. Consistent with this observation, valproic acid treatment induced GM3 synthase gene expression by about 8-fold. Furthermore, phosphorylation of EGFR was reduced, and cell proliferation was inhibited following valproic acid treatment. Consistent with these results, transient expression of GM3 synthase gene in A431 cells also increased cellular level of GM3, reduced phosphorylation of EGFR, and inhibited cell proliferation. Treatment with l-phenyl-2-decanoylamino-3-morpholino-l-propanol, an inhibitor of glucosylceramide synthesis, decreased the cellular level of GM3 and reduced the inhibitory effects of valproic acid on EGFR phosphorylation and cell proliferation. These results suggested that induction of GM3 synthesis was enough to inhibit proliferation of cancer cells by suppressing EGFR activity. Valproic acid treatment similarly increased the GM3 level and reduced phosphorylation of EGFR in U87MG glioma cells and inhibited their proliferation. These results suggested that up-regulators of GM3 synthase gene, such as valproic acid, are potential suppressors of cancer cell proliferation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Acid mine drainage prediction and remediation

    SciTech Connect

    Robb, G.; Robinson, J.

    1996-12-31

    The use of constructed wetlands for treatment of acid mine drainage is discussed in the article. Drainage characteristics and mine water flow rate are identified as important predictors of remediation success. Aerobic and anaerobic chemical reaction processes are described. Problems and potential uses of wetlands are briefly described.

  20. Hyaluronic Acid Oligosaccharides Suppress TLR3-Dependent Cytokine Expression in a TLR4-Dependent Manner

    PubMed Central

    Gallo, Richard L.

    2013-01-01

    The release of endogenous molecules from the skin after injury has been proposed to influence inflammation. Recent studies have found that pro-inflammatory signals can be generated by damaged endogenous self-RNA, and this event is detected by TLR3. Conversely, release of endogenous fragments of hyaluronic acid (HA) after injury has been proposed to inhibit LPS induced inflammation driven by TLR4. In this study we investigated if HA oligomers could also influence inflammation mediated by TLR3. A tetramer form of HA (oligo-HA) was added to MH-S cells (mouse alveolar macrophage cell line) that were then activated by poly(I:C). ELISA analysis of culture supernatants showed that the presence of oligo-HA suppressed the poly(I:C) induced release of IL-6 and TNFα. IL-6 mRNA expression was also suppressed as measured by quantitative RT-PCR. To determine the mechanism of action for oligo-HA to inhibit poly(I:C), macrophages derived from wild-type (WT), Tlr2−/− or Tlr4−/− mice were treated with oligo-HA and poly(I:C). Similar to WT cells, Tlr2−/− macrophages were inhibited by oligo-HA and retained suppression of cytokine release. In contrast, Tlr4−/− macrophages lost the capacity to be suppressed by oligo-HA. An increase in Traf1 (TLR negative regulator) mRNA was observed after oligo-HA treatment of WT but not in Tlr4−/− macrophages, and oligo-HA did not suppress cytokine responsiveness in Traf1−/− macrophages. These results show that oligo-HA acts through TLR4 and TRAF1 to inhibit TLR3-dependent inflammation. This observation illustrates the complex immunomodulatory action of endogenous products released after injury. PMID:24058413

  1. Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats.

    PubMed

    Exposto, C R; Oz, U; Callard, J S; Allen, M J; Khurana, H; Atri, A D'; Mo, X; Fernandez, S A; Tatakis, D N; Edmonds, K; Westgate, P M; Huja, S S

    2017-06-01

    To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (P<.05), but its effect was not significant at the periosteal surfaces of both jaws. BV for the healing sockets of ZOL treated animals was not significantly different (P=.07) compared to the saline group. ZOL suppressive effect was higher in the tibia compared to the jaws. ZOL severely suppresses coupled remodelling in the tibia, and the suppression of bone formation in the modelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. The suppression of enhanced bitterness intensity of macrolide dry syrup mixed with an acidic powder.

    PubMed

    Ishizaka, Toshihiko; Okada, Sachie; Takemoto, Eri; Tokuyama, Emi; Tsuji, Eriko; Mukai, Junji; Uchida, Takahiro

    2007-10-01

    The aim of the present study was to identify a medicine which strongly enhanced the bitterness of clarithromycin dry syrup (CAMD) when administered concomitantly and to develop a method to suppress this enhanced bitterness. The bitterness enhancement was evaluated not only by gustatory sensation tests but also using pH and taste sensor measurements of the mixed sample. A remarkable bitterness enhancement was found when CAMD was mixed with the acidic powder L-carbocysteine. The acidic pH (pH 3.40) of the suspension made from these two preparations, seemed to be due to enhanced release of clarithromycin caused by the dissolution of the alkaline polymer film-coating. Several methods for preventing this bitterness enhancement were investigated. Neither increasing the volume of water taken with the mixture, nor changing the ratio of CAMD:L-carbocysteine in the mixture, were effective in reducing the bitterness intensity of the CAMD/L-carbocysteine mixture. The best way to achieve taste masking was to first administer CAMD mixed with chocolate jelly, which has a neutral pH, followed by the L-carbocysteine suspension. Similar results were obtained for the bitterness suppression of azithromycin fine granules with L-carbocysteine. The chocolate jelly will be useful for taste masking of bitter macrolide drug formulations, when they need to be administered together with acidic drug formulations.

  3. Response of Chronic Cough to Acid-Suppressive Therapy in Patients With Gastroesophageal Reflux Disease

    PubMed Central

    Howden, Colin W.; Hughes, Nesta; Molloy-Bland, Michael

    2013-01-01

    Background: Epidemiologic and physiologic studies suggest an association between gastroesophageal reflux disease (GERD) and chronic cough. However, the benefit of antireflux therapy for chronic cough remains unclear, with most relevant trials reporting negative findings. This systematic review aimed to reevaluate the response of chronic cough to antireflux therapy in trials that allowed us to distinguish patients with or without objective evidence of GERD. Methods: PubMed and Embase systematic searches identified clinical trials reporting cough response to antireflux therapy. Datasets were derived from trials that used pH-metry to characterize patients with chronic cough. Results: Nine randomized controlled trials of varied design that treated patients with acid suppression were identified (eight used proton pump inhibitors [PPIs], one used ranitidine). Datasets from two crossover studies showed that PPIs significantly improved cough relative to placebo, albeit only in the arm receiving placebo first. Therapeutic gain in seven datasets was greater in patients with pathologic esophageal acid exposure (range, 12.5%-35.8%) than in those without (range, 0.0%-8.6%), with no overlap between groups. Conclusions: A therapeutic benefit for acid-suppressive therapy in patients with chronic cough cannot be dismissed. However, evidence suggests that rigorous patient selection is necessary to identify patient populations likely to be responsive, using physiologically timed cough events during reflux testing, minimal patient exclusion because of presumptive alternative diagnoses, and appropriate power to detect a modest therapeutic gain. Only then can we hope to resolve this vexing clinical management problem. PMID:23117307

  4. Suppression of DS1 phosphatidic acid phosphatase confirms resistance to Ralstonia solanacearum in Nicotiana benthamiana.

    PubMed

    Nakano, Masahito; Nishihara, Masahiro; Yoshioka, Hirofumi; Takahashi, Hirotaka; Sawasaki, Tatsuya; Ohnishi, Kouhei; Hikichi, Yasufumi; Kiba, Akinori

    2013-01-01

    Nicotianabenthamiana is susceptible to Ralstonia solanacearum. To analyze molecular mechanisms for disease susceptibility, we screened a gene-silenced plant showing resistance to R. solanacearum, designated as DS1 (Disease suppression 1). The deduced amino acid sequence of DS1 cDNA encoded a phosphatidic acid phosphatase (PAP) 2. DS1 expression was induced by infection with a virulent strain of R. solanacearum in an hrp-gene-dependent manner. DS1 rescued growth defects of the temperature-sensitive ∆lpp1∆dpp1∆pah1 mutant yeast. Recombinant DS1 protein showed Mg(2+)-independent PAP activity. DS1 plants showed reduced PAP activity and increased phosphatidic acid (PA) content. After inoculation with R. solanacearum, DS1 plants showed accelerated cell death, over-accumulation of reactive oxygen species (ROS), and hyper-induction of PR-4 expression. In contrast, DS1-overexpressing tobacco plants showed reduced PA content, greater susceptibility to R. solanacearum, and reduced ROS production and PR-4 expression. The DS1 phenotype was partially compromised in the plants in which both DS1 and NbCoi1 or DS1 and NbrbohB were silenced. These results show that DS1 PAP may affect plant immune responses related to ROS and JA cascades via regulation of PA levels. Suppression of DS1 function or DS1 expression could rapidly activate plant defenses to achieve effective resistance against Ralstonia solanacearum.

  5. Suppression of DS1 Phosphatidic Acid Phosphatase Confirms Resistance to Ralstonia solanacearum in Nicotiana benthamiana

    PubMed Central

    Nakano, Masahito; Nishihara, Masahiro; Yoshioka, Hirofumi; Takahashi, Hirotaka; Sawasaki, Tatsuya; Ohnishi, Kouhei; Hikichi, Yasufumi; Kiba, Akinori

    2013-01-01

    Nicotianabenthamiana is susceptible to Ralstonia solanacearum. To analyze molecular mechanisms for disease susceptibility, we screened a gene-silenced plant showing resistance to R. solanacearum, designated as DS1 (Disease suppression 1). The deduced amino acid sequence of DS1 cDNA encoded a phosphatidic acid phosphatase (PAP) 2. DS1 expression was induced by infection with a virulent strain of R. solanacearum in an hrp-gene-dependent manner. DS1 rescued growth defects of the temperature-sensitive ∆lpp1∆dpp1∆pah1 mutant yeast. Recombinant DS1 protein showed Mg2+-independent PAP activity. DS1 plants showed reduced PAP activity and increased phosphatidic acid (PA) content. After inoculation with R. solanacearum, DS1 plants showed accelerated cell death, over-accumulation of reactive oxygen species (ROS), and hyper-induction of PR-4 expression. In contrast, DS1-overexpressing tobacco plants showed reduced PA content, greater susceptibility to R. solanacearum, and reduced ROS production and PR-4 expression. The DS1 phenotype was partially compromised in the plants in which both DS1 and NbCoi1 or DS1 and NbrbohB were silenced. These results show that DS1 PAP may affect plant immune responses related to ROS and JA cascades via regulation of PA levels. Suppression of DS1 function or DS1 expression could rapidly activate plant defenses to achieve effective resistance against Ralstonia solanacearum. PMID:24073238

  6. Reduced hepatic triglyceride secretion in rats fed docosahexaenoic acid-rich fish oil suppresses postprandial hypertriglyceridemia.

    PubMed

    Ikeda, I; Kumamaru, J; Nakatani, N; Sakono, M; Murota, I; Imaizumi, K

    2001-04-01

    To evaluate the mechanisms of suppression of postprandial hypertriglyceridemia by fish oil rich in docosahexaenoic acid, the effect on the intestinal absorption of triglyceride, activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) and metabolism of chylomicrons (CM) and CM remnants were compared with that of safflower oil in Sprague-Dawley rats in a series of studies. The feeding of fish oil for 3 wk suppressed postprandial hypertriglyceridemia (study 1). Dietary fish oil did not alter the rate of lymphatic absorption of triglyceride (study 2). The activities of LPL and HTGL were measured at 5 h after the beginning of feeding, when serum triglyceride concentrations were highest in both dietary groups. The activities of LPL in adipose tissue and heart were greater (P < 0.05) and those of HTGL were lower (P < 0.05) in the rats fed fish oil (study 3). In contrast, there were no differences in the activities of LPL and HTGL in postheparin plasma between the fish and safflower oil groups (study 4). The clearance rates of CM and CM remnants were measured by injecting intravenously CM collected from rats fed safflower or fish oils with [14C]triolein and [3H]cholesterol (study 5). Dietary oil did not influence the half-lives of CM or CM remnants. The secretion of triglyceride from the liver of rats injected with Triton WR-1339 was lower (P < 0.05) in the rats fed docosahexaenoic acid, a major component of fish oil, than those fed linoleic acid, a major component of safflower oil (study 6). These observations strongly support the hypothesis that in rats, the principal cause of the suppression of postprandial hypertriglyceridemia by fish oil is the depression of triglyceride secretion from the liver.

  7. Effect of gastric acid suppressants and prokinetics on peritoneal dialysis-related peritonitis

    PubMed Central

    Kwon, Ji Eun; Koh, Seong-Joon; Chun, Jaeyoung; Kim, Ji Won; Kim, Byeong Gwan; Lee, Kook Lae; Im, Jong Pil; Kim, Joo Sung; Jung, Hyun Chae

    2014-01-01

    AIM: To investigate the effect of gastric acid suppressants and prokinetics on peritonitis development in peritoneal dialysis (PD) patients. METHODS: This was a single-center, retrospective study. The medical records of 398 PD patients were collected from January 2000 to September 2012 and analyzed to compare patients with at least one episode of peritonitis (peritonitis group, group A) to patients who never had peritonitis (no peritonitis group, group B). All peritonitis episodes were analyzed to compare peritonitis caused by enteric organisms and peritonitis caused by non-enteric organisms. RESULTS: Among the 120 patients who met the inclusion criteria, 61 patients had at least one episode of peritonitis and 59 patients never experienced peritonitis. Twenty-four of 61 patients (39.3%) in group A and 15 of 59 patients (25.4%) in group B used gastric acid suppressants. Only the use of H2-blocker (H2B) was associated with an increased risk of PD-related peritonitis; the use of proton pump inhibitors, other antacids, and prokinetics was not found to be a significant risk factor for PD-related peritonitis. A total of 81 episodes of peritonitis were divided into enteric peritonitis (EP) or non-enteric peritonitis, depending on the causative organism, and gastric acid suppressants and prokinetics did not increase the risk of EP in PD patients. CONCLUSION: The use of H2B showed a trend for an increased risk of overall PD-related peritonitis, although further studies are required to clarify the effects of drugs on PD-related peritonitis. PMID:25057226

  8. Poor outcome prediction by burst suppression ratio in adults with post-anoxic coma without hypothermia.

    PubMed

    Yang, Qinglin; Su, Yingying; Hussain, Mohammed; Chen, Weibi; Ye, Hong; Gao, Daiquan; Tian, Fei

    2014-05-01

    Burst suppression ratio (BSR) is a quantitative electroencephalography (qEEG) parameter. The purpose of our study was to compare the accuracy of BSR when compared to other EEG parameters in predicting poor outcomes in adults who sustained post-anoxic coma while not being subjected to therapeutic hypothermia. EEG was registered and recorded at least once within 7 days of post-anoxic coma onset. Electrodes were placed according to the international 10-20 system, using a 16-channel layout. Each EEG expert scored raw EEG using a grading scale adapted from Young and scored amplitude-integrated electroencephalography tracings, in addition to obtaining qEEG parameters defined as BSR with a defined threshold. Glasgow outcome scales of 1 and 2 at 3 months, determined by two blinded neurologists, were defined as poor outcome. Sixty patients with Glasgow coma scale score of 8 or less after anoxic accident were included. The sensitivity (97.1%), specificity (73.3%), positive predictive value (82.5%), and negative prediction value (95.0%) of BSR in predicting poor outcome were higher than other EEG variables. BSR1 and BSR2 were reliable in predicting death (area under the curve > 0.8, P < 0.05), with the respective cutoff points being 39.8% and 61.6%. BSR1 was reliable in predicting poor outcome (area under the curve  =  0.820, P < 0.05) with a cutoff point of 23.9%. BSR1 was also an independent predictor of increased risk of death (odds ratio  =  1.042, 95% confidence intervals: 1.012-1.073, P  =  0.006). BSR may be a better predictor in prognosticating poor outcomes in patients with post-anoxic coma who do not undergo therapeutic hypothermia when compared to other qEEG parameters.

  9. SNR Loss: A new objective measure for predicting speech intelligibility of noise-suppressed speech

    PubMed Central

    Ma, Jianfen; Loizou, Philipos C.

    2010-01-01

    Most of the existing intelligibility measures do not account for the distortions present in processed speech, such as those introduced by speech-enhancement algorithms. In the present study, we propose three new objective measures that can be used for prediction of intelligibility of processed (e.g., via an enhancement algorithm) speech in noisy conditions. All three measures use a critical-band spectral representation of the clean and noise-suppressed signals and are based on the measurement of the SNR loss incurred in each critical band after the corrupted signal goes through a speech enhancement algorithm. The proposed measures are flexible in that they can provide different weights to the two types of spectral distortions introduced by enhancement algorithms, namely spectral attenuation and spectral amplification distortions. The proposed measures were evaluated with intelligibility scores obtained by normal-hearing listeners in 72 noisy conditions involving noise-suppressed speech (consonants and sentences) corrupted by four different maskers (car, babble, train and street interferences). Highest correlation (r=−0.85) with sentence recognition scores was obtained using a variant of the SNR loss measure that only included vowel/consonant transitions and weak consonant information. High correlation was maintained for all noise types, with a maximum correlation (r=−0.88) achieved in street noise conditions. PMID:21503274

  10. Phytic acid suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum.

    PubMed

    Obata, Toshio

    2003-07-18

    The present study examined the antioxidant effect of phytic acid on iron (II)-enhanced hydroxyl radical (*OH) generation induced by 1-methyl-4-phenylpyridinium ion (MPP(+)) in the extracellular fluid of rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Phytic acid (100 microM) did not significantly decrease the levels of MPP(+)-induced *OH formation trapped as 2,3-DHBA. To confirm the generation of *OH by the Fenton-type reaction, iron (II) was infused through a microdialysis probe. Introduction of iron (II) (10 microM) enhanced MPP(+) induced *OH generation. However, phytic acid significantly suppressed iron (II)-enhanced *OH formation after MPP(+) treatment (n=6, P<0.05). These results suggest that the antiradical effect of phytic acid occurs by chelating iron required for the MPP(+)-enhanced *OH generation via the Fenton-type reaction.

  11. Suppression of fat deposition in broiler chickens by (-)-hydroxycitric acid supplementation: A proteomics perspective

    PubMed Central

    Peng, Mengling; Han, Jing; Li, Longlong; Ma, Haitian

    2016-01-01

    (-)-Hydroxycitric acid (HCA) suppresses fatty acid synthesis in animals, but its biochemical mechanism in poultry is unclear. This study identified the key proteins associated with fat metabolism and elucidated the biochemical mechanism of (-)-HCA in broiler chickens. Four groups (n = 30 each) received a diet supplemented with 0, 1000, 2000 or 3000 mg/kg (-)-HCA for 4 weeks. Of the differentially expressed liver proteins, 40 and 26 were identified in the mitochondrial and cytoplasm respectively. Pyruvate dehydrogenase E1 components (PDHA1 and PDHB), dihydrolipoyl dehydrogenase (DLD), aconitase (ACO2), a-ketoglutarate dehydrogenase complex (DLST), enoyl-CoA hydratase (ECHS1) and phosphoglycerate kinase (PGK) were upregulated, while NADP-dependent malic enzyme (ME1) was downregulated. Biological network analysis showed that the identified proteins were involved in glycometabolism and lipid metabolism, whereas PDHA1, PDHB, ECHS1, and ME1 were identified in the canonical pathway by Ingenuity Pathway Analysis. The data indicated that (-)-HCA inhibited fatty acid synthesis by reducing the acetyl-CoA supply, via promotion of the tricarboxylic acid cycle (upregulation of PDHA1, PDHB, ACO2, and DLST expression) and inhibition of ME1 expression. Moreover, (-)-HCA promoted fatty acid beta-oxidation by upregulating ECHS1 expression. These results reflect a biochemically relevant mechanism of fat reduction by (-)-HCA in broiler chickens. PMID:27586962

  12. Suppression of rice methane emission by sulfate deposition in simulated acid rain

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy B.; Howell, Graham; Jenkins, Meaghan E.

    2008-09-01

    Sulfate in acid rain is known to suppress methane (CH4) emissions from natural freshwater wetlands. Here we examine the possibility that CH4 emissions from rice agriculture may be similarly affected by acid rain, a major and increasing pollution problem in Asia. Our findings suggest that acid rain rates of SO42- deposition may help to reduce CH4 emissions from rice agriculture. Emissions from rice plants treated with simulated acid rain at levels of SO42- consistent with the range of deposition in Asia were reduced by 24% during the grain filling and ripening stage of the rice season which accounts for 50% of the overall CH4 that is normally emitted in a rice season. A single application of SO42- at a comparable level reduced CH4 emission by 43%. We hypothesize that the reduction in CH4 emission may be due to a combination of effects. The first mechanism is that the low rates of SO42- may be sufficient to boost yields of rice and, in so doing, may cause a reduction in root exudates to the rhizosphere, a key substrate source for methanogenesis. Decreasing a major substrate source for methanogens is also likely to intensify competition with sulfate-reducing microorganisms for whom prior SO42- limitation had been lifted by the simulated acid rain S deposition.

  13. [Regulation effect of exogenous salicylic acid on weed suppression and molecular physiological characteristics of allelopathic rice].

    PubMed

    Qiu, Long; Wang, Hai-Bin; Xiong, Jun; Fang, Chang-Xun; Wu, Wen-Xiang; He, Hai-Bin; Lin, Wen-Xiong

    2008-02-01

    To investigate the feasibility of using exogenous salicylic acid (SA) to regulate the allelopathic weed suppression of rice, this paper studied the effects of different concentrations exogenous SA on the weed-suppression and physiological-biochemical characteristics of allelopathic rice PI312777, and the relative expression quantity of gene ZB8 in the rice by real time quantitative RT-PCR (FQ-PCR). The results showed that exogenous SA induced the enhancement of the allelopathic potential of donor rice in suppressing target weed plants, and this inducing effect was SA dose and treatment time dependent. After foliar spraying SA, the inhibitory effect of PI312777 on barnyardgrass increased significantly, and the root vigor and superoxide dismutase (SOD) and peroxidase (POD) activities of PI312777 increased, while its catalase (CAT) activity decreased. The reverse was true for the target weed barnyardgrass. At the same time, the phenylalanine ammonialyase (PAL) activity of PI312777 increased significantly, leading to an increase of the total content of phenols. Among the test concentrations of SA, 0.2 mmol x L(-1) had the best inducing effect, under which, the relative expression quantity of ZB8 increased first and decreased then, with a peak at 24 hours after treatment.

  14. 1. Appetite suppressant activity of supplemental dietary amino acids and subsequent compensatory growth of broilers.

    PubMed

    Acar, N; Patterson, P H; Barbato, G F

    2001-08-01

    This study was conducted to take advantage of the appetite-suppressant effect of excessive dietary amino acids in reducing feed intake and, in turn, restricting the early rapid growth of broilers to minimize metabolic disorders. Dietary amino acids were supplemented to a basal diet to yield a total of 1.57, 2.57, and 3.57% His; 2.7, 4.3, and 5.9% Lys; 1.36, 2.16, and 2.96% Met; 2.8, 3.8, and 4.8% Thr; and 1.27, 2.27, and 3.27% Trp and were fed to 408 chicks from 4 to 11 d of age. Fifteen dietary treatments of His, Lys, Met, Thr, and Trp were compared to the basal diet. Feed consumption was measured daily. Body weight measurements were taken at 0, 4, 7, 11, 14, and 21 d. At 21 d, pectoralis major and minor muscles, liver, and abdominal fat pad were weighed. High levels of Met and His caused the greatest depression in appetite from 4 to 11 d, and Thr, Trp, and Lys were found to be less potent. The exponential growth rate (EGR) of birds from 4 to 11 d of age was significantly reduced by the intermediate and high levels of the amino acid supplementation. From 11 to 14 d, EGR was greatest with high levels of Met or Trp, indicating more potential compensatory growth realized with these treatments. The high level of His decreased the percentage of pectoralis minor muscle yield, whereas the high level of Lys and Met increased the percentage of liver compared to those fed the basal diet. These results indicate that it is possible to use excessive individual amino acids in diets to suppress the appetite and early rapid growth to alleviate or minimize metabolic disorders.

  15. Phytic acid suppresses ischemia-induced hydroxyl radical generation in rat myocardium.

    PubMed

    Obata, Toshio; Nakashima, Michiko

    2016-03-05

    The present study examined whether ischemia-reperfusion-induced hydroxyl radical (·OH) generation was attenuated by myo-inositol hexaphosphoric acid (phytic acid). A flexibly mounted microdialysis technique was used to detect the generation of ·OH in in vivo rat hearts. To measure the level of ·OH, sodium salicylate in Ringer's solution (0.5mM or 0.5 nmol/μl/min) was infused directly through a microdialysis probe to detect the generation of ·OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). To confirm the generation of ·OH by Fenton-type reaction, iron(II) was infused through a microdialysis probe. A positive linear correlation between iron(II) and the formation of 2,3-DHBA (R(2)=0.983) was observed. However, the level of 2,3-DHBA in norepinephrine (100 μM) plus phytic acid (100 μM) treated group were significantly lower than those observed in norepinephrine-only-treated group (n=6, *p<0.05). To examine the effect of phytic acid on ischemia-reperfusion-induced ·OH generation, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, the normal elevation of 2,3-DHBA in the heart dialysate was not observed in animals pretreated with phytic acid. These results suggest that phytic acid is associated with antioxidant effect due to the suppression of iron-induced ·OH generation.

  16. Simultaneous determination of trace oxyhalides and haloacetic acids using suppressed ion chromatography-electrospray mass spectrometry.

    PubMed

    Barron, Leon; Paull, Brett

    2006-05-15

    A new analytical procedure for the simultaneous determination of trace oxyhalides and haloacetic acids (HAs) in drinking water and aqueous soil extracts is described. The method uses micro-bore ion chromatography (IC) coupled with suppressed conductivity (SC) and electrospray ionization mass spectrometric detection (ESI-MS). The IC-SC-ESI-MS system included a secondary flow of 100% MeOH, which was added to the column eluate (post-suppressor) and resulted in a significant increase in sensitivity for all analytes. All ESI-MS parameters were optimized for HA analysis and sensitivity quantitatively compared to suppressed conductivity. Full analytical performance characteristics for the developed method are presented for monochloro-, monobromo-, dichloro-, dibromo-, trichloro-, bromochloro, chlorodifluoro-, trifluoro-, dichlorobromo- and dibromochloroacetic acid, as well as the oxyhalides iodate, bromate, chlorate and perchlorate. In the case of the HAs, an optimised 25-fold SPE preconcentration method meant all analytes could be readily detected well below the USEPA 60mug/L regulatory limit using conductivity and/or ESI-MS. The IC-ESI-MS method was applied to the determination of oxyhalides and HAs in both soil extracts and drinking water samples. Soil samples were extracted using ultra pure water with subsequent determination of perchlorate at 1.68mug/g of soil. A drinking water sample containing HAs was preconcentrated using LiChrolut EN solid phase extraction cartridges with subsequent sulphate and chloride removal. Total HAs were determined at 13mug/L.

  17. The Ketogenic Diet Suppresses the Cathepsin E Expression Induced by Kainic Acid in the Rat Brain

    PubMed Central

    Jeong, Hyun Jeong; Kim, Hojeong; Kim, Yoon-Kyoung; Park, Sang-Kyu; Kang, Dong-Won

    2010-01-01

    Purpose The ketogenic diet has long been used to treat epilepsy, but its mechanism is not yet clearly understood. To explore the potential mechanism, we analyzed the changes in gene expression induced by the ketogenic diet in the rat kainic acid (KA) epilepsy model. Materials and Methods KA-administered rats were fed the ketogenic diet or a normal diet for 4 weeks, and microarray analysis was performed with their brain tissues. The effects of the ketogenic diet on cathepsin E messenger ribonucleic acid (mRNA) expression were analyzed in KA-administered and normal saline-administered groups with semi-quantitative and real-time reverse transcription polymerase chain reaction (RT-PCR). Brain tissues were dissected into 8 regions to compare differential effects of the ketogenic diet on cathepsin E mRNA expression. Immunohistochemistry with an anti-cathepsin E antibody was performed on slides of hippocampus obtained from whole brain paraffin blocks. Results The microarray data and subsequent RT-PCR experiments showed that KA increased the mRNA expression of cathepsin E, known to be related to neuronal cell death, in most brain areas except the brain stem, and these increases of cathepsin E mRNA expression were suppressed by the ketogenic diet. The expression of cathepsin E mRNA in the control group, however, was not significantly affected by the ketogenic diet. The change in cathepsin E mRNA expression was greatest in the hippocampus. The protein level of cathepsin E in the hippocampus of KA-administered rat was elevated in immunohistochemistry and the ketogenic diet suppressed this increase. Conclusion Our results showed that KA administration increased cathepsin E expression in the rat brain and its increase was suppressed by the ketogenic diet. PMID:20635438

  18. Silverleaf whitefly induces salicylic acid defenses and suppresses effectual jasmonic acid defenses.

    PubMed

    Zarate, Sonia I; Kempema, Louisa A; Walling, Linda L

    2007-02-01

    The basal defenses important in curtailing the development of the phloem-feeding silverleaf whitefly (Bemisia tabaci type B; SLWF) on Arabidopsis (Arabidopsis thaliana) were investigated. Sentinel defense gene RNAs were monitored in SLWF-infested and control plants. Salicylic acid (SA)-responsive gene transcripts accumulated locally (PR1, BGL2, PR5, SID2, EDS5, PAD4) and systemically (PR1, BGL2, PR5) during SLWF nymph feeding. In contrast, jasmonic acid (JA)- and ethylene-dependent RNAs (PDF1.2, VSP1, HEL, THI2.1, FAD3, ERS1, ERF1) were repressed or not modulated in SLWF-infested leaves. To test for a role of SA and JA pathways in basal defense, SLWF development on mutant and transgenic lines that constitutively activate or impair defense pathways was determined. By monitoring the percentage of SLWF nymphs in each instar, we show that mutants that activate SA defenses (cim10) or impair JA defenses (coi1) accelerated SLWF nymphal development. Reciprocally, mutants that activate JA defenses (cev1) or impair SA defenses (npr1, NahG) slowed SLWF nymphal development. Furthermore, when npr1 plants, which do not activate downstream SA defenses, were treated with methyl jasmonate, a dramatic delay in nymph development was observed. Collectively, these results showed that SLWF-repressed, JA-regulated defenses were associated with basal defense to the SLWF.

  19. Disproportionation Kinetics of Hypoiodous Acid As Catalyzed and Suppressed by Acetic Acid-Acetate Buffer.

    PubMed

    Urbansky, Edward T.; Cooper, Brian T.; Margerum, Dale W.

    1997-03-26

    The kinetics of the disproportionation of hypoiodous acid to give iodine and iodate ion (5HOI right harpoon over left harpoon 2I(2) + IO(3)(-) + H(+) + 2H(2)O) are investigated in aqueous acetic acid-sodium acetate buffer. The rate of iodine formation is followed photometrically at -log [H(+)] = 3.50, 4.00, 4.50, and 5.00, &mgr; = 0.50 M (NaClO(4)), and 25.0 degrees C. Both catalytic and inhibitory buffer effects are observed. The first process is proposed to be a disproportionation of iodine(I) to give HOIO and I(-); the iodide then reacts with HOI to give I(2). The reactive species (acetato-O)iodine(I), CH(3)CO(2)I, is postulated to increase the rate by assisting in the formation of I(2)O, a steady-state species that hydrolyzes to give HOIO and I(2). Inhibition is postulated to result from the formation of the stable ion bis(acetato-O)iodate(I), (CH(3)CO(2))(2)I(-), as buffer concentration is increased. This species is observed spectrophotometrically with a UV absorption shoulder (lambda = 266 nm; epsilon = 530 M(-)(1) cm(-)(1)). The second process is proposed to be a disproportionation of HOIO to give IO(3)(-) and I(2). Above 1 M total buffer, the reaction becomes reversible with less than 90% I(2) formation. Rate and equilibrium constants are resolved and reported for the proposed mechanism.

  20. Silverleaf Whitefly Induces Salicylic Acid Defenses and Suppresses Effectual Jasmonic Acid Defenses1[W][OA

    PubMed Central

    Zarate, Sonia I.; Kempema, Louisa A.; Walling, Linda L.

    2007-01-01

    The basal defenses important in curtailing the development of the phloem-feeding silverleaf whitefly (Bemisia tabaci type B; SLWF) on Arabidopsis (Arabidopsis thaliana) were investigated. Sentinel defense gene RNAs were monitored in SLWF-infested and control plants. Salicylic acid (SA)-responsive gene transcripts accumulated locally (PR1, BGL2, PR5, SID2, EDS5, PAD4) and systemically (PR1, BGL2, PR5) during SLWF nymph feeding. In contrast, jasmonic acid (JA)- and ethylene-dependent RNAs (PDF1.2, VSP1, HEL, THI2.1, FAD3, ERS1, ERF1) were repressed or not modulated in SLWF-infested leaves. To test for a role of SA and JA pathways in basal defense, SLWF development on mutant and transgenic lines that constitutively activate or impair defense pathways was determined. By monitoring the percentage of SLWF nymphs in each instar, we show that mutants that activate SA defenses (cim10) or impair JA defenses (coi1) accelerated SLWF nymphal development. Reciprocally, mutants that activate JA defenses (cev1) or impair SA defenses (npr1, NahG) slowed SLWF nymphal development. Furthermore, when npr1 plants, which do not activate downstream SA defenses, were treated with methyl jasmonate, a dramatic delay in nymph development was observed. Collectively, these results showed that SLWF-repressed, JA-regulated defenses were associated with basal defense to the SLWF. PMID:17189328

  1. Uric acid excretion predicts increased aggression in urban adolescents.

    PubMed

    Mrug, Sylvie; Mrug, Michal

    2016-09-01

    Elevated levels of uric acid have been linked with impulsive and disinhibited behavior in clinical and community populations of adults, but no studies have examined uric acid in relation to adolescent aggression. This study examined the prospective role of uric acid in aggressive behavior among urban, low income adolescents, and whether this relationship varies by gender. A total of 84 adolescents (M age 13.36years; 50% male; 95% African American) self-reported on their physical aggression at baseline and 1.5years later. At baseline, the youth also completed a 12-h (overnight) urine collection at home which was used to measure uric acid excretion. After adjusting for baseline aggression and age, greater uric acid excretion predicted more frequent aggressive behavior at follow up, with no significant gender differences. The results suggest that lowering uric acid levels may help reduce youth aggression. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. New approaches to toxicity: a seven-gas predictive model and toxicant suppressants.

    PubMed

    Levin, B C

    1997-11-01

    Two new research approaches in combustion toxicology are: 1. the prediction of smoke toxicity from mathematical equations, which are empirically derived from, experiments on the toxicological interactions of complex fire gas mixtures and 2. the use of toxicant suppressants in materials or products to prevent the formation of toxic combustion products. The predictive approach consists of burning materials using a bench-scale method that simulates realistic fire conditions, measuring the concentrations of the primary fire gases--CO, CO2, low O2, HCN, HCl, HBr, and NO2--and predicting the toxicity of the smoke using either the 6- or 7-gas N-Gas Model. These models are based on the results of toxicological studies of these primary gases as individual gases and as complex mixtures. The predicted toxic potency is checked with a small number of animal (Fischer 344 male rats) tests to assure that an unanticipated toxic gas is not generated or an unexpected synergistic or antagonistic effect has not occurred. The results indicate if the smoke from a material or product is extremely toxic (based on mass consumed at the predicted toxic level) or unusually toxic (based on the gases deemed responsible). The predictions based on bench-scale laboratory tests have been validated with full-scale room burns of a limited number of materials of widely differing characteristics chosen to challenge the system. The advantages of this new approach are 1. the number of test animals is minimized by predicting the toxic potency from the chemical analysis of the smoke, 2. smoke may be produced under conditions that simulate the fire scenario of concern, 3. fewer tests are needed, thereby reducing the overall cost of the testing and 4, information is obtained on both the toxic potency of the smoke and the responsible gases. The N-Gas Models have been developed into the N-Gas Method (described in this paper) and these results have been used in computations of fire hazard. The 6-Gas Model is now

  3. Finite element based model predictive control for active vibration suppression of a one-link flexible manipulator.

    PubMed

    Dubay, Rickey; Hassan, Marwan; Li, Chunying; Charest, Meaghan

    2014-09-01

    This paper presents a unique approach for active vibration control of a one-link flexible manipulator. The method combines a finite element model of the manipulator and an advanced model predictive controller to suppress vibration at its tip. This hybrid methodology improves significantly over the standard application of a predictive controller for vibration control. The finite element model used in place of standard modelling in the control algorithm provides a more accurate prediction of dynamic behavior, resulting in enhanced control. Closed loop control experiments were performed using the flexible manipulator, instrumented with strain gauges and piezoelectric actuators. In all instances, experimental and simulation results demonstrate that the finite element based predictive controller provides improved active vibration suppression in comparison with using a standard predictive control strategy. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

  4. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation.

    PubMed

    Kondo, Tomoo; Kishi, Mikiya; Fushimi, Takashi; Kaga, Takayuki

    2009-07-08

    We investigated the effect of acetic acid (AcOH) on the prevention of obesity in high-fat-fed mice. The mice were intragastrically administrated with water or 0.3 or 1.5% AcOH for 6 weeks. AcOH administration inhibited the accumulation of body fat and hepatic lipids without changing food consumption or skeletal muscle weight. Significant increases were observed in the expressions of genes for peroxisome-proliferator-activated receptor alpha (PPARalpha) and for fatty-acid-oxidation- and thermogenesis-related proteins: acetyl-CoA oxidase (ACO), carnitine palmitoyl transferase-1 (CPT-1), and uncoupling protein-2 (UCP-2), in the liver of the AcOH-treatment groups. PPARalpha, ACO, CPT-1, and UCP-2 gene expressions were increased in vitro by acetate addition to HepG2 cells. However, the effects were not observed in cells depleted of alpha2 5'-AMP-activated protein kinase (AMPK) by siRNA. In conclusion, AcOH suppresses accumulation of body fat and liver lipids by upregulation of genes for PPARalpha and fatty-acid-oxidation-related proteins by alpha2 AMPK mediation in the liver.

  5. Valproic acid suppresses collagen by selective regulation of Smads in conjunctival fibrosis.

    PubMed

    Seet, Li-Fong; Toh, Li Zhen; Finger, Sharon N; Chu, Stephanie W L; Stefanovic, Branko; Wong, Tina T

    2016-03-01

    Overproduction of type I collagen is associated with a wide range of fibrotic diseases as well as surgical failure such as in glaucoma filtration surgery (GFS). Its modulation is therefore of clinical importance. Valproic acid (VPA) is known to reduce collagen in a variety of tissues with unclear mechanism of action. In this report, we demonstrate that VPA inhibited collagen production in both conjunctival fibroblasts and the mouse model of GFS. In fibroblasts, VPA decreased type I collagen expression which intensified with longer drug exposure and suppressed steady-state type I collagen promoter activity. Moreover, VPA decreased Smad2, Smad3 and Smad4 but increased Smad6 expression with a similar intensity-exposure profile. Reduction of Smad3 using small hairpin RNA and/or overexpression of Smad6 resulted in decreased collagen expression which was exacerbated when VPA was simultaneously present. Furthermore, fibrogenic TGF-β2 failed to induce collagen when VPA was present, as opposed to the myofibroblast markers, beta-actin, alpha-smooth muscle actin and tenascin-C, which were elevated by TGF-β2. VPA suppressed p3TP-Lux luciferase activity and selectively rescued Smad6 expression from suppression by TGF-β2. Notably, SMAD6 overexpression reduced the effectiveness of TGF-β2 in inducing collagen expression. In corroboration, VPA inhibited type I collagen but increased Smad6 expression in the late phase of wound healing in the mouse model of GFS. Taken together, our data indicate that VPA has the capacity to effectively suppress both steady-state and fibrogenic activation of type I collagen expression by modulating Smad expression. Hence, VPA is potentially applicable as an anti-fibrotic therapeutic by targeting collagen. Key message: • VPA modulates type I collagen expression via members of the Smad family. • VPA suppresses Smad2, Smad3 and Smad4 but upregulates Smad6. • Smad3 and Smad6 are involved in VPA regulation of steady-state collagen expression.

  6. Inter-domain linker prediction using amino acid compositional index.

    PubMed

    Shatnawi, Maad; Zaki, Nazar

    2015-04-01

    Protein chains are generally long and consist of multiple domains. Domains are distinct structural units of a protein that can evolve and function independently. The accurate and reliable prediction of protein domain linkers and boundaries is often considered to be the initial step of protein tertiary structure and function predictions. In this paper, we introduce CISA as a method for predicting inter-domain linker regions solely from the amino acid sequence information. The method first computes the amino acid compositional index from the protein sequence dataset of domain-linker segments and the amino acid composition. A preference profile is then generated by calculating the average compositional index values along the amino acid sequence using a sliding window. Finally, the protein sequence is segmented into intervals and a simulated annealing algorithm is employed to enhance the prediction by finding the optimal threshold value for each segment that separates domains from inter-domain linkers. The method was tested on two standard protein datasets and showed considerable improvement over the state-of-the-art domain linker prediction methods. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats.

    PubMed

    Xu, J; Nakamura, M T; Cho, H P; Clarke, S D

    1999-08-13

    Polyunsaturated fatty acids (PUFA) coordinately suppress the transcription of a wide array of hepatic lipogenic genes including fatty acid synthase (FAS) and acetyl-CoA carboxylase. Interestingly, the over-expression of sterol regulatory element binding protein-1 (SREBP-1) induces the expression of all of the enzymes suppressed by PUFA. This observation led us to hypothesize that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1. Our initial studies revealed that the SREBP-1 and FAS mRNA contents of HepG2 cells were reduced by 20:4(n-6) in a dose-dependent manner (i.e. EC(50) approximately 10 microM), whereas 18:1(n-9) had no effect. Similarly, supplementing a fat-free, high glucose diet with oils rich in (n-6) or (n-3) PUFA reduced the hepatic content of precursor and nuclear SREBP-1 60 and 85%, respectively; however, PUFA had no effect on the nuclear content of upstream stimulatory factor (USF)-1. The PUFA-dependent decrease in nuclear content of mature SREBP-1 was paralleled by a 70-90% suppression in FAS gene transcription. In contrast, dietary 18:1(n-9), i.e. triolein, had no inhibitory influence on the expression of SREBP-1 or FAS. The decrease in hepatic expression of SREBP-1 and FAS associated with PUFA ingestion was mimicked by supplementing the fat-free diet with the PPARalpha-activator, WY 14, 643. Interestingly, nuclear run-on assays revealed that changes in SREBP-1 mRNA abundance were not accompanied by changes in SREBP-1 gene transcription. These results support the concept that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1 and that the PUFA regulation of SREBP-1 appears to occur at the post-transcriptional level.

  8. Polyunsaturated fatty acid supplementation reverses cystic fibrosis-related fatty acid abnormalities in CFTR-/- mice by suppressing fatty acid desaturases.

    PubMed

    Njoroge, Sarah W; Laposata, Michael; Boyd, Kelli L; Seegmiller, Adam C

    2015-01-01

    Cystic fibrosis patients and model systems exhibit consistent abnormalities in metabolism of polyunsaturated fatty acids that appear to play a role in disease pathophysiology. Recent in vitro studies have suggested that these changes are due to overexpression of fatty acid desaturases that can be reversed by supplementation with the long-chain polyunsaturated fatty acids docosahexaenoate and eicosapentaenoate. However, these findings have not been tested in vivo. The current study aimed to test these results in an in vivo model system, the CFTR(-/-) knockout mouse. When compared with wild-type mice, the knockout mice exhibited fatty acid abnormalities similar to those seen in cystic fibrosis patients and other model systems. The abnormalities were confined to lung, ileum and pancreas, tissues that are affected by the disease. Similar to in vitro models, these fatty acid changes correlated with increased expression of Δ5- and Δ6-desaturases and elongase 5. Dietary supplementation with high-dose free docosahexaenoate or a combination of lower-dose docosahexaenoate and eicosapentaenoate in triglyceride form corrected the fatty acid abnormalities and reduced expression of the desaturase and elongase genes in the ileum and liver of knockout mice. Only the high-dose docosahexaenoate reduced histologic evidence of disease, reducing mucus accumulation in ileal sections. These results provide in vivo support for the hypothesis that fatty acid abnormalities in cystic fibrosis result from abnormal expression and activity of metabolic enzymes in affected cell types. They further demonstrate that these changes can be reversed by dietary n-3 fatty acid supplementation, highlighting the potential therapeutic benefit for cystic fibrosis patients.

  9. Ingestion of theanine, an amino acid in tea, suppresses psychosocial stress in mice.

    PubMed

    Unno, Keiko; Iguchi, Kazuaki; Tanida, Naoki; Fujitani, Keisuke; Takamori, Nina; Yamamoto, Hiroyuki; Ishii, Naoto; Nagano, Hiroko; Nagashima, Takashi; Hara, Ayane; Shimoi, Kayoko; Hoshino, Minoru

    2013-01-01

    The antistress effect of theanine (γ-glutamylethylamide), an amino acid in tea, was investigated using mice that were psychosocially stressed from a conflict among male mice in conditions of confrontational housing. Two male mice were housed in the same cage separated by a partition to establish a territorial imperative. When the partition was removed, the mice were co-housed confrontationally. As a marker for the stress response, changes in the adrenal gland were studied in comparison to group-housed control mice (six mice in a cage). Significant adrenal hypertrophy was observed in mice during confrontational housing, which was developed within 24 h and persisted for at least 1 week. The size of cells in the zona fasciculata of the adrenal gland, from which glucocorticoid is mainly secreted, increased (∼1.11-fold) in mice during confrontational housing, which was accompanied by a flattened diurnal rhythm of corticosterone and ACTH in blood. The ingestion of theanine (>5 μg ml(-1)) prior to confrontational housing significantly suppressed adrenal hypertrophy. An antidepressant, paroxetin, suppressed adrenal hypertrophy in a similar manner in mice during confrontational housing. In mice that ingested theanine, behavioural depression was also suppressed, and a diurnal rhythm of corticosterone and ACTH was observed, even in mice that were undergoing confrontational housing. Furthermore, the daily dose of theanine (40 μg ml(-1)) blocked the counteracting effects of caffeine (30 μg ml(-1)) and catechin (200 μg ml(-1)). The present study demonstrated that theanine prevents and relieves psychosocial stress through the modulation of hypothalamic-pituitary-adrenal axis activity.

  10. Climate dependency of tree growth suppressed by acid deposition effects on soils in Northwest Russia

    USGS Publications Warehouse

    Lawrence, G.B.; Lapenis, A.G.; Berggren, D.; Aparin, B.F.; Smith, K.T.; Shortle, W.C.; Bailey, S.W.; Varlyguin, D.L.; Babikov, B.

    2005-01-01

    Increased tree growth in temperate and boreal forests has been proposed as a direct consequence of a warming climate. Acid deposition effects on nutrient availability may influence the climate dependency of tree growth, however. This study presents an analysis of archived soil samples that has enabled changes in soil chemistry to be tracked with patterns of tree growth through the 20th century. Soil samples collected in 1926, 1964, and 2001, near St. Petersburg, Russia, showed that acid deposition was likely to have decreased root-available concentrations of Ca (an essential element) and increased root-available concentrations of Al (an inhibitor of Ca uptake). These soil changes coincided with decreased diameter growth and a suppression of climate-tree growth relationships in Norway spruce. Expected increases in tree growth from climate warming may be limited by decreased soil fertility in regions of northern and eastern Europe, and eastern North America, where Ca availability has been reduced by acidic deposition. ?? 2005 American Chemical Society.

  11. Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1

    PubMed Central

    Nishioka, N; Matsuoka, T; Yashiro, M; Hirakawa, K; Olden, K; Roberts, J D

    2011-01-01

    Background: The intake of dietary fatty acids is highly correlated with the risk of various cancers. Linoleic acid (LA) is the most abundant polyunsaturated fat in the western diet, but the mechanism(s) by fatty acids such as LA modulate cancer cells is unclear. In this study, we examined the role of LA in various steps in gastric cancer progression. Methods: The difference in gene expression between LA-treated and untreated OCUM-2MD3 gastric carcinoma cells was examined by mRNA differential display. The involvement of candidate genes was examined by oligo- and plasmid-mediated RNA interference. Biological functions of several of these genes were examined using in vitro assays for invasion, angiogenesis, apoptosis, cell viability, and matrix digestion. Angiogenesis in vivo was measured by CD-31 immunohistochemistry and microvessel density scoring. Results: LA enhanced the plasminogen activator inhibitor 1 (PAI-1) mRNA and protein expression, which are controlled by PAI-1 mRNA-binding protein. LA-stimulated invasion depended on PAI-1. LA also enhanced angiogenesis by suppression of angiostatin, also through PAI-1. LA did not alter cell growth in culture, but increased dietary LA-enhanced tumour growth in an animal model. Conclusion: Our findings suggest that dietary LA impacts multiple steps in cancer invasion and angiogenesis, and that reducing LA in the diet may help slow cancer progression. PMID:22015554

  12. Omega-3 Polyunsaturated Fatty Acids Attenuate Fibroblast Activation and Kidney Fibrosis Involving MTORC2 Signaling Suppression.

    PubMed

    Zeng, Zhifeng; Yang, Haiyuan; Wang, Ying; Ren, Jiafa; Dai, Yifan; Dai, Chunsun

    2017-04-10

    Epidemiologic studies showed the correlation between the deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and the progression of chronic kidney diseases (CKD), however, the role and mechanisms for n-3 PUFAs in protecting against kidney fibrosis remain obscure. In this study, NRK-49F cells, a rat kidney interstitial fibroblast cell line, were stimulated with TGFβ1. A Caenorhabditis elegans fat-1 transgenic mouse model in which n-3 PUFAs are endogenously produced from n-6 PUFAs owing to the expression of n-3 fatty acid desaturase were deployed. Docosahexaenoic acid (DHA), one member of n-3 PUFAs family, could suppress TGFβ1-induced fibroblast activation at a dose and time dependent manner. Additionally, DHA could largely inhibit TGFβ1-stimulated Akt but not S6 or Smad3 phosphorylation at a time dependent manner. To decipher the role for n-3 PUFAs in protecting against kidney fibrosis, fat-1 transgenic mice were operated with unilateral ureter obstruction (UUO). Compared to the wild types, fat-1 transgenics developed much less kidney fibrosis and inflammatory cell accumulation accompanied by less p-Akt (Ser473), p-Akt (Thr308), p-S6 and p-Smad3 in kidney tissues at day 7 after UUO. Thus, n-3 PUFAs can attenuate fibroblast activation and kidney fibrosis, which may be associated with the inhibition of mTORC2 signaling.

  13. Effective gastric acid suppression after oral administration of enteric-coated omeprazole granules.

    PubMed

    Mohiuddin, M A; Pursnani, K G; Katzka, D A; Gideon, R M; Castell, J A; Castell, D O

    1997-04-01

    Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsule containing enteric-coated granules that release the drug in alkaline medium. In clinical situations where patients are unable to take the capsule orally, the optimum means of administration is uncertain. Eleven normal volunteers were given omeprazole 20 mg every day for one week before breakfast in random order as either a 20-mg capsule with water or free enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzer antacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hr intragastric pH study was performed following omeprazole 20 mg and standard breakfast. The median percentage of time of gastric acid pH > 4 after an omeprazole capsule was 68.5 (25-100); after granules with orange juice 59 (43-100); after granules in Alka-Seltzer solution 63 (31-100), and after granules in apple sauce 65 (30-99), with no significant differences (ANOVA). The time for the gastric pH to reach <4' after having been above was also similar for all four regimens (ANOVA). Omeprazole granules administered orally in a variety of ways achieve gastric acid suppression as effectively as the intact capsule.

  14. Omega-3 Polyunsaturated Fatty Acids Attenuate Fibroblast Activation and Kidney Fibrosis Involving MTORC2 Signaling Suppression

    PubMed Central

    Zeng, Zhifeng; Yang, Haiyuan; Wang, Ying; Ren, Jiafa; Dai, Yifan; Dai, Chunsun

    2017-01-01

    Epidemiologic studies showed the correlation between the deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and the progression of chronic kidney diseases (CKD), however, the role and mechanisms for n-3 PUFAs in protecting against kidney fibrosis remain obscure. In this study, NRK-49F cells, a rat kidney interstitial fibroblast cell line, were stimulated with TGFβ1. A Caenorhabditis elegans fat-1 transgenic mouse model in which n-3 PUFAs are endogenously produced from n-6 PUFAs owing to the expression of n-3 fatty acid desaturase were deployed. Docosahexaenoic acid (DHA), one member of n-3 PUFAs family, could suppress TGFβ1-induced fibroblast activation at a dose and time dependent manner. Additionally, DHA could largely inhibit TGFβ1-stimulated Akt but not S6 or Smad3 phosphorylation at a time dependent manner. To decipher the role for n-3 PUFAs in protecting against kidney fibrosis, fat-1 transgenic mice were operated with unilateral ureter obstruction (UUO). Compared to the wild types, fat-1 transgenics developed much less kidney fibrosis and inflammatory cell accumulation accompanied by less p-Akt (Ser473), p-Akt (Thr308), p-S6 and p-Smad3 in kidney tissues at day 7 after UUO. Thus, n-3 PUFAs can attenuate fibroblast activation and kidney fibrosis, which may be associated with the inhibition of mTORC2 signaling. PMID:28393852

  15. Inhibition of Large Neutral Amino Acid Transporters Suppresses Kynurenic Acid Production Via Inhibition of Kynurenine Uptake in Rodent Brain.

    PubMed

    Sekine, Airi; Kuroki, Yusuke; Urata, Tomomi; Mori, Noriyuki; Fukuwatari, Tsutomu

    2016-09-01

    The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor and N-methyl-D-aspartic acid receptor at endogenous brain concentrations. Recent studies have suggested that increases of brain KYNA levels are involved in psychiatric disorders such as schizophrenia and depression, and regulation of KYNA production has become a new target for treatment of these diseases. Kynurenine (KYN), the immediate precursor of KYNA, is transported into astrocytes via large neutral amino acid transporters (LATs). In the present study, the effect of LATs regulation on KYN uptake and KYNA production was investigated in vitro and in vivo using an LATs inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). In the in vitro study, cortical slices of rat brain were incubated with a physiological concentration of KYN and 3 µmol/L-3 mmol/L BCH. BCH inhibited KYNA production and KYN uptake in a dose-dependent manner, and their IC50 values were 90.7 and 97.4 µmol/L, respectively. In the in vivo study, mice were administered KYN (50 mg/kg BW) orally and BCH (200 mg/kg BW) intravenously. Administration of KYN increased brain KYN and KYNA levels compared with the mice treated with vehicle, whereas additional administration of BCH suppressed KYN-induced elevations in KYN and KYNA levels to 50 and 70 % in the brain. These results suggest that inhibition of LATs prevented the increase of KYNA production via blockade of KYN uptake in the brain in vitro and in vivo. LATs can be a target to modulate brain function by regulation of KYNA production in the brain.

  16. Docosahexaenoic acid suppresses breast cancer cell metastasis by targeting matrix-metalloproteinases

    PubMed Central

    Shin, Soyeon; Kim, Soyeon; Heo, Jun-Young; Kweon, Gi-Ryang; Wu, Tong; Park, Jong-Il; Lim, Kyu

    2016-01-01

    Breast cancer is one of the most prevalent cancers in women, and nearly half of breast cancer patients develop distant metastatic disease after therapy. Despite the significant advances that have been achieved in understanding breast cancer metastasis in the past decades, metastatic cancer is still hard to cure. Here, we demonstrated an anti-cancer mechanism of docosahexaenoic acid (DHA) that suppressed lung metastasis in breast cancer. DHA could inhibit proliferation and invasion of breast cancer cells in vitro, and this was mainly through blocking Cox-2-PGE2-NF-κB-MMPs cascades. DHA treatment significantly decreased Cox-2 and NF-κB expression as well as nuclear translocation of NF-κB in MDA-MB-231 cells. In addition, DHA also reduced NF-κB binding to DNA which may lead to inactivation of MMPs. Moreover, in vivo studies using Fat-1 transgenic mice showed remarkable decrease of tumor growth and metastasis to EO771 cells to lung in DHA-rich environment. In conclusion, DHA attenuated breast cancer progression and lung metastasis in part through suppressing MMPs, and these findings suggest chemoprevention and potential therapeutic strategy to overcome malignant breast cancer. PMID:27363023

  17. Suppression of autophagy by mycophenolic acid contributes to inhibition of HCV replication in human hepatoma cells

    PubMed Central

    Fang, Shoucai; Su, Jinming; Liang, Bingyu; Li, Xu; Li, Yu; Jiang, Junjun; Huang, Jiegang; Zhou, Bo; Ning, Chuanyi; Li, Jieliang; Ho, Wenzhe; Li, Yiping; Chen, Hui; Liang, Hao; Ye, Li

    2017-01-01

    Previous studies have shown that mycophenolic acid (MPA) has an anti-HCV activity. However, the mechanism of MPA-mediated inhibition of HCV replication remains to be determined. This study investigated whether MPA has an effect on autophagy, a cellular machinery required for HCV replication, thereby, inhibits HCV replication in Huh7 cells. MPA treatment of Huh7 cells could suppress autophagy, evidenced by decreased LC3B-II level and conversion of LC3B-I to LC3B-II, decreased autophagosome formation, and increased p62 level compared to MPA-untreated cells. Tunicamycin treatment or HCV infection could induce cellular autophagy, however, MPA also exhibited its inhibitory effect on tunicamycin- or HCV infection-induced autophagy. The expression of three autophagy-related genes, Atg3, Atg5, and Atg7 were identified to be inhibited by MPA treatment. Over-expression of these genes could partly recover HCV replication inhibited by MPA; however, silencing their expression by siRNAs could enhance the inhibitory effect of MPA on HCV. Collectively, these results reveal that suppression of autophagy by MPA plays a role in its anti-HCV activity. Down-regulating the expression of three autophagy-related genes by MPA involves in its antiviral mechanism. PMID:28276509

  18. Oleanolic acid suppresses aerobic glycolysis in cancer cells by switching pyruvate kinase type M isoforms.

    PubMed

    Liu, Jia; Wu, Ning; Ma, Leina; Liu, Ming; Liu, Ge; Zhang, Yuyan; Lin, Xiukun

    2014-01-01

    Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.

  19. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis

    PubMed Central

    2012-01-01

    Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis. PMID:22676575

  20. Interleukin-1 family members are enhanced in psoriasis and suppressed by vitamin D and retinoic acid.

    PubMed

    Balato, Anna; Schiattarella, Maria; Lembo, Serena; Mattii, Martina; Prevete, Nella; Balato, Nicola; Ayala, Fabio

    2013-04-01

    Interleukin (IL)-1 family comprise 11 members that play an important role in immune regulation and inflammatory process. Retinoids exert complex effects on the immune system, having anti-inflammatory effects in chronic dermatological diseases. Vitamin D (vitD) and analogs have been shown to suppress TNF-α-induced IL-1α in human keratinocytes (KCs). In the present study, we investigated IL-1 family members in psoriasis and the effects of vitD and retinoic acid (RA) on these members. We analyzed IL-1 family members gene expression in psoriatic skin and in ex vivo skin organ culture exposed to TNF-α, IL-17 or broadband UVB; afterwards, treatment with vitD or RA was performed and IL-1 family members mRNA was evaluated. Similarly, KCs were stimulated with IL-17 and subsequently treated with vitD. IL-1 family members were enhanced in psoriatic skin and in ex vivo skin organ cultures after pro-inflammatory stimuli (TNF-α, IL-17 and UVB). RA and vitD were able to suppress this enhancement.

  1. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis.

    PubMed

    Biswas, Sangita; Benedict, Stephen H; Lynch, Sharon G; LeVine, Steven M

    2012-06-07

    Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis.

  2. Prunella vulgaris extract and rosmarinic acid suppress lipopolysaccharide-induced alteration in human gingival fibroblasts.

    PubMed

    Zdarilová, A; Svobodová, A; Simánek, V; Ulrichová, J

    2009-04-01

    Periodontitis is a chronic disease associated with inflammation of the tooth-supporting tissues. The inflammation is initiated by a group of gram-negative anaerobic bacteria. These express a number of irritating factors including a lipopolysaccharide (LPS), which plays a key role in periodontal disease development. Plant extracts with anti-inflammatory and anti-microbial properties have been shown to inhibit bacterial plaque formation and thus prevent chronic gingivitis. In this study we tested effects of Prunella vulgaris L. extract (PVE; 5, 10, 25microg/ml) and its component rosmarinic acid (RA; 1microg/ml) on LPS-induced oxidative damage and inflammation in human gingival fibroblasts. PVE and RA reduced reactive oxygen species (ROS) production, intracellular glutathione (GSH) depletion as well as lipid peroxidation in LPS-treated cells. Treatment with PVE and RA also inhibited LPS-induced up-regulation of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and suppressed expression of inducible nitric oxide synthase (iNOS). The results indicate that PVE and RA are able to suppress LPS-induced biological changes in gingival fibroblasts. The effects of PVE and RA are presumably linked to their anti-inflammatory activities and thus use of PVE and RA may be relevant in modulating the inflammation process, including periodontal disease.

  3. Fatal spontaneous Clostridium septicum gas gangrene: a possible association with iatrogenic gastric acid suppression.

    PubMed

    Wu, Yiru E; Baras, Alexander; Cornish, Toby; Riedel, Stefan; Burton, Elizabeth C

    2014-06-01

    The long-term use of proton pump inhibitors has been linked to an increased risk for the development of gastric polyps, hip fractures, pneumonia, and Clostridium difficile colitis. There is evidence that chronic acid suppression from long-term use of proton pump inhibitors poses some risk for the development of C difficile-associated diarrhea by decreasing the elimination of pathogenic microbes before reaching the lower gastrointestinal tract. Here we present a case of a 51-year-old woman with a recent history of abdominal pain and fever who presented to the emergency department with rapidly progressive spontaneous necrotizing fasciitis and gas gangrene and died within hours of presentation. Postmortem examination confirmed spreading tissue gas gangrene and myonecrosis. In addition, multiple intestinal ulcers containing Clostridium septicum were present at autopsy. This case illustrates a possible association between proton pump inhibitor therapy and fatal C septicum infection.

  4. 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

    PubMed Central

    Crandall, James; Sakai, Yasuo; Zhang, Jinghua; Koul, Omanand; Mineur, Yann; Crusio, Wim E.; McCaffery, Peter

    2004-01-01

    The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA. PMID:15051884

  5. 13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice.

    PubMed

    Crandall, James; Sakai, Yasuo; Zhang, Jinghua; Koul, Omanand; Mineur, Yann; Crusio, Wim E; McCaffery, Peter

    2004-04-06

    The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.

  6. Determination of chloroacetic acids in drinking water using suppressed ion chromatography with solid-phase extraction.

    PubMed

    Yoshikawa, Kenji; Soda, Yuko; Sakuragawa, Akio

    2009-12-01

    Suppressed ion chromatography with a conductivity detector was developed for the determination of trace amounts of underivatized chloroacetic acids (CAAs). When sodium carbonate and methanol were used as a mobile phase, the simultaneous determination of each CAA took approximately 25 min. The linearity, reproducibility and detection limits were determined for the proposed method. For the solid-phase extraction step, the effects of the pH of the sample solution, sample volume and the eluting agent were tested. Under the optimized extracting conditions, the average recoveries for CAAs spiked in tap water were 83-107%, with an optimal preconcentration factor of 20. The reproducibility of recovery rate for CAAs was 1.2-3.8%, based upon 6 repetitions of the recovery experiments.

  7. Interactions between cranberries and fungi: the proposed function of organic acids in virulence suppression of fruit rot fungi.

    PubMed

    Tadych, Mariusz; Vorsa, Nicholi; Wang, Yifei; Bergen, Marshall S; Johnson-Cicalese, Jennifer; Polashock, James J; White, James F

    2015-01-01

    Cranberry fruit are a rich source of bioactive compounds that may function as constitutive or inducible barriers against rot-inducing fungi. The content and composition of these compounds change as the season progresses. Several necrotrophic fungi cause cranberry fruit rot disease complex. These fungi remain mostly asymptomatic until the fruit begins to mature in late August. Temporal fluctuations and quantitative differences in selected organic acid profiles between fruit of six cranberry genotypes during the growing season were observed. The concentration of benzoic acid in fruit increased while quinic acid decreased throughout fruit development. In general, more rot-resistant genotypes (RR) showed higher levels of benzoic acid early in fruit development and more gradual decline in quinic acid levels than that observed in the more rot-susceptible genotypes. We evaluated antifungal activities of selected cranberry constituents and found that most bioactive compounds either had no effects or stimulated growth or reactive oxygen species (ROS) secretion of four tested cranberry fruit rot fungi, while benzoic acid and quinic acid reduced growth and suppressed secretion of ROS by these fungi. We propose that variation in the levels of ROS suppressive compounds, such as benzoic and quinic acids, may influence virulence by the fruit rot fungi. Selection for crops that maintain high levels of virulence suppressive compounds could yield new disease resistant varieties. This could represent a new strategy for control of disease caused by necrotrophic pathogens that exhibit a latent or endophytic phase.

  8. Interactions between cranberries and fungi: the proposed function of organic acids in virulence suppression of fruit rot fungi

    PubMed Central

    Tadych, Mariusz; Vorsa, Nicholi; Wang, Yifei; Bergen, Marshall S.; Johnson-Cicalese, Jennifer; Polashock, James J.; White, James F.

    2015-01-01

    Cranberry fruit are a rich source of bioactive compounds that may function as constitutive or inducible barriers against rot-inducing fungi. The content and composition of these compounds change as the season progresses. Several necrotrophic fungi cause cranberry fruit rot disease complex. These fungi remain mostly asymptomatic until the fruit begins to mature in late August. Temporal fluctuations and quantitative differences in selected organic acid profiles between fruit of six cranberry genotypes during the growing season were observed. The concentration of benzoic acid in fruit increased while quinic acid decreased throughout fruit development. In general, more rot-resistant genotypes (RR) showed higher levels of benzoic acid early in fruit development and more gradual decline in quinic acid levels than that observed in the more rot-susceptible genotypes. We evaluated antifungal activities of selected cranberry constituents and found that most bioactive compounds either had no effects or stimulated growth or reactive oxygen species (ROS) secretion of four tested cranberry fruit rot fungi, while benzoic acid and quinic acid reduced growth and suppressed secretion of ROS by these fungi. We propose that variation in the levels of ROS suppressive compounds, such as benzoic and quinic acids, may influence virulence by the fruit rot fungi. Selection for crops that maintain high levels of virulence suppressive compounds could yield new disease resistant varieties. This could represent a new strategy for control of disease caused by necrotrophic pathogens that exhibit a latent or endophytic phase. PMID:26322038

  9. The ω-3 Polyunsaturated Fatty Acid, Eicosapentaenoic Acid, Attenuates Abdominal Aortic Aneurysm Development via Suppression of Tissue Remodeling

    PubMed Central

    Wang, Jack H.; Eguchi, Kosei; Matsumoto, Sahohime; Fujiu, Katsuhito; Komuro, Issei; Nagai, Ryozo; Manabe, Ichiro

    2014-01-01

    Abdominal aortic aneurysm (AAA) is a prevalent vascular disease that can progressively enlarge and rupture with a high rate of mortality. Inflammation and active remodeling of the aortic wall have been suggested to be critical in its pathogenesis. Meanwhile, ω-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) are known to reduce cardiovascular events, but its role in AAA management remains unclear. Here, we show that EPA can attenuate murine CaCl2-induced AAA formation. Aortas from BALB/c mice fed an EPA-diet appeared less inflamed, were significantly smaller in diameter compared to those from control-diet-fed mice, and had relative preservation of aortic elastic lamina. Interestingly, CT imaging also revealed markedly reduced calcification of the aortas after EPA treatment. Mechanistically, MMP2, MMP9, and TNFSF11 levels in the aortas were reduced after EPA treatment. Consistent with this finding, RAW264.7 macrophages treated with EPA showed attenuated Mmp9 levels after TNF-α simulation. These results demonstrate a novel role of EPA in attenuating AAA formation via the suppression of critical remodeling pathways in the pathogenesis of AAAs, and raise the possibility of using EPA for AAA prevention in the clinical setting. PMID:24798452

  10. Omega-3 Fatty Acids and a Novel Mammary Derived Growth Inhibitor Fatty Acid Binding Protein MRG in Suppression of Mammary Tumor

    DTIC Science & Technology

    2003-07-01

    suppressing effect of n-3 fatty acid DHA on mammary tumors. MRG induces differentiation of mammary epithelial cells in vitro and its expression is...expression of MRG also increased milk protein beta-casein expression in the gland. Treatment of human breast cancer cells with w-3 PUFA DHA resulted...differentiating effect of pregnancy on breast epithelial cells and may play a major role in w-3 PUFA -mediated tumor suppression.

  11. Cholera Toxin B Subunit Linked to Glutamic Acid Decarboxylase Suppresses Dendritic Cell Maturation and Function

    PubMed Central

    Odumosu, Oludare; Nicholas, Dequina; Payne, Kimberly; Langridge, William

    2012-01-01

    Dendritic cells are the largest population of antigen presenting cells in the body. One of their main functions is to regulate the delicate balance between immunity and tolerance responsible for maintenance of immunological homeostasis. Disruption of this delicate balance often results in chronic inflammation responsible for initiation of organ specific autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type I diabetes. The cholera toxin B subunit (CTB) is a weak mucosal adjuvant known for its ability to stimulate immunity to antigenic proteins. However, conjugation of CTB to many autoantigens can induce immunological tolerance resulting in suppression of autoimmunity. In this study, we examined whether linkage of CTB to a 5 kDa C-terminal protein fragment of the major diabetes autoantigen glutamic acid decarboxylase (GAD35), can block dendritic cell (DC) functions such as biosynthesis of co-stimulatory factor proteins CD86, CD83, CD80 and CD40 and secretion of inflammatory cytokines. The results of human umbilical cord blood monocyte-derived DC - GAD35 autoantigen incubation experiments showed that inoculation of immature DCs (iDCs), with CTB-GAD35 protein dramatically suppressed levels of CD86, CD83, CD80 and CD40 co-stimulatory factor protein biosynthesis in comparison with GAD35 alone inoculated iDCs. Surprisingly, incubation of iDCs in the presence of the CTB-autoantigen and the strong immunostimulatory molecules PMA and Ionomycin revealed that CTB-GAD35 was capable of arresting PMA + Ionomycin induced DC maturation. Consistant with this finding, CTB-GAD35 mediated suppression of DC maturation was accompanied by a dramatic decrease in the secretion of the pro-inflammatory cytokines IL-12/23p40 and IL-6 and a significant increase in secretion of the immunosuppressive cytokine IL-10. Taken together, our experimental data suggest that linkage of the weak adjuvant CTB to the dominant type 1 diabetes autoantigen GAD strongly inhibits DC

  12. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways.

    PubMed

    Lin, Jiumao; Chen, Youqin; Wei, Lihui; Hong, Zhenfeng; Sferra, Thomas J; Peng, Jun

    2013-11-01

    Angiogenesis plays a critical role in the development of solid tumors by supplying nutrients and oxygen to support continuous growth of tumor as well as providing an avenue for hematogenous metastasis. Tumor angiogenesis is highly regulated by multiple intracellular signaling transduction cascades such as Hedgehog, STAT3, Akt and p70S6K pathways that are known to malfunction in many types of cancer including colorectal cancer (CRC). Therefore, suppression of tumor angiogenesis through targeting these signaling pathways has become a promising strategy for cancer chemotherapy. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used in China for the clinical treatment of various types of cancer. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its anti-angiogenic activity are not well understood. To further elucidate the mechanism(s) of the tumorcidal activity of UA, using a CRC mouse xenograft model, chick embryo chorioallantoic membrane (CAM) model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the efficacy of UA against tumor growth and angiogenesis in vivo and in vitro and investigated the underlying molecular mechanisms. We found that administration of UA significantly inhibited tumor volume but had no effect on body weight changes in CRC mice, suggesting that UA can suppress colon cancer growth in vivo without noticeable signs of toxicity. In addition, UA treatment reduced intratumoral microvessel density (MVD) in CRC mice, decreased the total number of blood vessels in the CAM model, and dose and time-dependently inhibited the proliferation, migration and tube formation of HUVECs, demonstrating UA's antitumor angiogenesis in vivo and in vitro. Moreover, UA treatment inhibited the expression of critical angiogenic factors, such as VEGF-A and bFGF. Furthermore, UA suppressed the

  13. Computer analysis and structure prediction of nucleic acids and proteins.

    PubMed Central

    Kanehisa, M; Klein, P; Greif, P; DeLisi, C

    1984-01-01

    We have developed an integrated computer system for analysis of nucleic acid and protein sequences, which consists of sequence and structure databases, a relational database, and software for structural analysis. The system is potentially applicable to a number of problems in structural biology including predictive classification of the function and location of oncogene products. PMID:6546426

  14. Predicting nucleic acid binding interfaces from structural models of proteins

    PubMed Central

    Dror, Iris; Shazman, Shula; Mukherjee, Srayanta; Zhang, Yang; Glaser, Fabian; Mandel-Gutfreund, Yael

    2011-01-01

    The function of DNA- and RNA-binding proteins can be inferred from the characterization and accurate prediction of their binding interfaces. However the main pitfall of various structure-based methods for predicting nucleic acid binding function is that they are all limited to a relatively small number of proteins for which high-resolution three dimensional structures are available. In this study, we developed a pipeline for extracting functional electrostatic patches from surfaces of protein structural models, obtained using the I-TASSER protein structure predictor. The largest positive patches are extracted from the protein surface using the patchfinder algorithm. We show that functional electrostatic patches extracted from an ensemble of structural models highly overlap the patches extracted from high-resolution structures. Furthermore, by testing our pipeline on a set of 55 known nucleic acid binding proteins for which I-TASSER produces high-quality models, we show that the method accurately identifies the nucleic acids binding interface on structural models of proteins. Employing a combined patch approach we show that patches extracted from an ensemble of models better predicts the real nucleic acid binding interfaces compared to patches extracted from independent models. Overall, these results suggest that combining information from a collection of low-resolution structural models could be a valuable approach for functional annotation. We suggest that our method will be further applicable for predicting other functional surfaces of proteins with unknown structure. PMID:22086767

  15. Predicting nucleic acid binding interfaces from structural models of proteins.

    PubMed

    Dror, Iris; Shazman, Shula; Mukherjee, Srayanta; Zhang, Yang; Glaser, Fabian; Mandel-Gutfreund, Yael

    2012-02-01

    The function of DNA- and RNA-binding proteins can be inferred from the characterization and accurate prediction of their binding interfaces. However, the main pitfall of various structure-based methods for predicting nucleic acid binding function is that they are all limited to a relatively small number of proteins for which high-resolution three-dimensional structures are available. In this study, we developed a pipeline for extracting functional electrostatic patches from surfaces of protein structural models, obtained using the I-TASSER protein structure predictor. The largest positive patches are extracted from the protein surface using the patchfinder algorithm. We show that functional electrostatic patches extracted from an ensemble of structural models highly overlap the patches extracted from high-resolution structures. Furthermore, by testing our pipeline on a set of 55 known nucleic acid binding proteins for which I-TASSER produces high-quality models, we show that the method accurately identifies the nucleic acids binding interface on structural models of proteins. Employing a combined patch approach we show that patches extracted from an ensemble of models better predicts the real nucleic acid binding interfaces compared with patches extracted from independent models. Overall, these results suggest that combining information from a collection of low-resolution structural models could be a valuable approach for functional annotation. We suggest that our method will be further applicable for predicting other functional surfaces of proteins with unknown structure. Copyright © 2011 Wiley Periodicals, Inc.

  16. Urinary intestinal fatty acid binding protein predicts necrotizing enterocolitis.

    PubMed

    Gregory, Katherine E; Winston, Abigail B; Yamamoto, Hidemi S; Dawood, Hassan Y; Fashemi, Titilayo; Fichorova, Raina N; Van Marter, Linda J

    2014-06-01

    Necrotizing enterocolitis, characterized by sudden onset and rapid progression, remains the most significant gastrointestinal disorder among premature infants. In seeking a predictive biomarker, we found intestinal fatty acid binding protein, an indicator of enterocyte damage, was substantially increased within three and seven days before the diagnosis of necrotizing enterocolitis.

  17. Trait self-consciousness predicts amygdala activation and its functional brain connectivity during emotional suppression: an fMRI analysis.

    PubMed

    Chen, Shengdong; Chen, Changming; Yang, Jiemin; Yuan, Jiajin

    2017-03-08

    The present functional magnetic resonance imaging study investigated how trait neuroticism and its heterogeneous subdimensions are related to the emotional consequences and neural underpinnings of emotion regulation. Two levels of neuroticism assessments were conducted with 47 female subjects, who were required to attend to, suppress emotion displays to, or cognitively reappraise the meanings of negative images. The results showed reduced emotional experience and bilateral amygdala activation during reappraisal, and this regulation effect is unaffected by individual differences in neuroticism and its subdimensions. By contrast, the emotion downregulation effect of suppression in the right amygdala is compromised with increasing self-consciousness but not overall neuroticism dimension. This association holds robust after controlling the potential contribution of habitual suppression. Moreover, the psychophysiological interaction (PPI) analysis revealed that self-consciousness predicts weaker functional coupling of the right amygdala to supplementary motor area and putamen during expressive suppression, two regions mediating the control and execution of motor actions. These findings suggest that self-consciousness predicts increased difficulty in emotional regulation using expressive suppression; and that the heterogeneous nature of trait neuroticism needs to be considered in exploring the association of neuroticism and emotion regulation.

  18. Choice is good, but relevance is excellent: autonomy-enhancing and suppressing teacher behaviours predicting students' engagement in schoolwork.

    PubMed

    Assor, Avi; Kaplan, Haya; Roth, Guy

    2002-06-01

    This article examines two questions concerning teacher-behaviours that are characterised in Self-Determination Theory (Ryan & Deci, 2000) as autonomy-supportive or suppressive: (1) Can children differentiate among various types of autonomy-enhancing and suppressing teacher behaviours? (2) Which of those types of behaviour are particularly important in predicting feelings toward and engagement in schoolwork? It was hypothesised that teacher behaviours that help students to understand the relevance of schoolwork for their personal interests and goals are particularly important predictors of engagement in schoolwork. Israeli students in grades 3-5 (N = 498) and in grades 6-8 (N = 364) completed questionnaires assessing the variables of interest. Smallest Space Analyses indicated that both children and early adolescents can differentiate among three types of autonomy enhancing teacher behaviours - fostering relevance, allowing criticism, and providing choice - and three types of autonomy suppressing teacher behaviours - suppressing criticism, intruding, and forcing unmeaningful acts. Regression analyses supported the hypothesis concerning the importance of teacher behaviours that clarify the personal relevance of schoolwork. Among the autonomy-suppressing behaviours, 'Criticism-suppression' was the best predictor of feelings and engagement. The findings underscore the active and empathic nature of teachers' role in supporting students' autonomy, and suggest that autonomy-support is important not only for early adolescents but also for children. Discussion of potential determinants of the relative importance of various autonomy-affecting teacher actions suggests that provision of choice should not always be viewed as a major indicator of autonomy support.

  19. Radiation-induced neoplastic transformation of C3H10T1/2 cells is suppressed by ascorbic acid

    SciTech Connect

    Yasukawa, M.; Terasima, T.; Seki, M. )

    1989-12-01

    X-ray induced transformation of C3H10T1/2 cells was suppressed in a concentration-dependent manner by administration of ascorbic acid after irradiation (0.1-20 micrograms/ml for the first week) in the culture medium. The dose-response curve was shifted about 60% downward and was slightly steeper in the presence of ascorbic acid (5 micrograms/ml for the first week) than in its absence. The 1-week treatment procedure revealed that cells initiated by radiation remained susceptible to ascorbic acid until the time of morphological phenotype expression. The neoplastically transformed phenotype expressed after incubation for 8 weeks could no longer be suppressed by ascorbic acid even after culture transfer. Similarly, the neoplastically transformed phenotype suppressed for 8 weeks by ascorbic acid treatment was not subsequently expressed in the absence of ascorbic acid. On the basis of the oxygen-detoxifying nature of ascorbic acid, we postulated that expression of the neoplastically transformed phenotype is promoted by reactive oxygen species and peroxy radicals generated in cells during the whole assay period. The data may be useful as a guide for chemopreventive efforts against radiation carcinogenesis.

  20. Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid, a Farnesoid X Receptor Antagonist.

    PubMed

    Fujita, Kyosuke; Iguchi, Yusuke; Une, Mizuho; Watanabe, Shiro

    2017-03-17

    The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver.

  1. Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis

    PubMed Central

    Han, Suxia; Lei, Jianjun; Xu, Qinhong; Chen, Xin; Jiang, Zhengdong; Nan, Ligang; Li, Jiahui; Chen, Ke; Han, Liang; Wang, Zheng; Li, Xuqi; Wu, Erxi; Huo, Xiongwei

    2015-01-01

    Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis. PMID:25895130

  2. Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid.

    PubMed

    Zurier, Robert B; Rossetti, Ronald G; Burstein, Sumner H; Bidinger, Bonnie

    2003-02-15

    Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, reduces joint tissue damage in rats with adjuvant arthritis. Because interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are central to the progression of inflammation and joint tissue injury in patients with rheumatoid arthritis, we investigated human monocyte IL-1beta and TNFalpha responses after the addition of AjA to cells in vitro. Peripheral blood and synovial fluid monocytes (PBM and SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AjA (0-30 microM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for mRNA, and supernatants were collected for cytokine assay. Addition of AjA to PBM and SFM in vitro reduced both steady-state levels of IL-1beta mRNA and secretion of IL-1beta in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 microM AjA (P<0.05 vs untreated controls, N=7). AjA did not influence TNFalpha gene expression in or secretion from PBM. Reduction of IL-1beta by AjA may help explain the therapeutic effects of AjA in the animal model of arthritis. Development of nonpsychoactive therapeutically useful synthetic analogs of Cannabis constituents, such as AjA, may help resolve the ongoing debate about the use of marijuana as medicine.

  3. Complicated Clostridium difficile colitis in children with cystic fibrosis: association with gastric acid suppression?

    PubMed

    Com, G; Cetin, N; O'Brien, C E

    2014-01-01

    Patients with cystic fibrosis (CF) have several risk factors for Clostridium difficile colonization such as frequent hospitalization and exposure to a broad array of antibiotics utilized for the control, eradication, and prophylaxis of respiratory pathogens. However, despite this high rate of colonization, the occurrence of C. difficile infection (CDI) in CF is rare. We report three children with CF who presented with severe community-associated CDI. All three children had complicated courses and one died. These children were in good health without significant morbidities, and were not frequently hospitalized nor did they receive frequent antibiotic courses. The occurrence of 3 severe cases within a 15-month period prompted us to report these cases and review the literature in regard to CDI. We reviewed the CF GI tract as possible risk factors for a high rate of C. difficile colonization in individuals with CF. Since a high percentage of individuals with CF are on gastric acid blocking agents, we also focused on gastric acid suppression as a potential risk factor for CDI. © 2013. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. All rights reserved.

  4. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

    PubMed

    Kim, Seung-Tae; Doo, Ah-Reum; Kim, Seung-Nam; Kim, Song-Yi; Kim, Yoon Young; Kim, Jang-Hyun; Lee, Hyejung; Yin, Chang Shik; Park, Hi-Joon

    2012-09-01

    The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1β mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

  5. Predator evasion in zooplankton is suppressed by polyunsaturated fatty acid limitation.

    PubMed

    Brzeziński, Tomasz; von Elert, Eric

    2015-11-01

    Herbivorous zooplankton avoid size-selective predation by vertical migration to a deep, cold water refuge. Adaptation to low temperatures in planktonic poikilotherms depends on essential dietary lipids; the availability of these lipids often limits growth and reproduction of zooplankton. We hypothesized that limitation by essential lipids may affect habitat preferences and predator avoidance behavior in planktonic poikilotherms. We used a liposome supplementation technique to enrich the green alga Scenedesmus obliquus and the cyanobacterium Synecchococcus elongatus with the essential lipids, cholesterol and eicosapentaenoic acid (EPA), and an indoor system with a stratified water-column (plankton organ) to test whether the absence of these selected dietary lipids constrains predator avoidance (habitat preferences) in four species of the key-stone pelagic freshwater grazer Daphnia. We found that the capability of avoiding fish predation through habitat shift to the deeper and colder environment was suppressed in Daphnia unless the diet was supplemented with EPA; however, the availability of cholesterol did not affect habitat preferences of the tested taxa. Thus, their ability to access a predator-free refuge and the outcome of predator-prey interactions depends upon food quality (i.e. the availability of an essential fatty acid). Our results suggest that biochemical food quality limitation, a bottom-up factor, may affect the top-down control of herbivorous zooplankton.

  6. Suppression of rat hepatic fatty acid synthase and S14 gene transcription by dietary polyunsaturated fat.

    PubMed

    Blake, W L; Clarke, S D

    1990-12-01

    The objective of this research was to determine whether dietary polyunsaturated fatty acids suppress hepatic fatty acid synthase (FAS) mRNA levels by altering FAS gene transcription. Male Sprague-Dawley rats were meal-fed for 10 d a high glucose diet supplemented with 20% digestible energy as menhaden oil or tripalmitin. The transcription rate for FAS was determined by nuclear run-on analysis in hepatic nuclei isolated from rats 2 h postmeal. The values for transcription rates of FAS and S14 (a putative lipogenic protein) in rats fed menhaden oil were only 6 and 21%, respectively, of the rates in rats fed the tripalmitin diet (p less than 0.02). Gene transcription for beta-actin and phosphoenolpyruvate carboxykinase did not differ between treatments. The reduction in hepatic FAS mRNA levels caused by dietary polyunsaturated fats appears to be caused primarily by an inhibition of FAS transcription. The control of transcription by polyunsaturated fats appears not to be mediated by cAMP because the transcription rate for phosphoenolpyruvate carboxykinase (whose gene is very sensitive to cAMP stimulation) was unaffected by the source of dietary fat.

  7. Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α-Dependent miR-155 Suppression.

    PubMed

    Abebayehu, Daniel; Spence, Andrew J; Qayum, Amina Abdul; Taruselli, Marcela T; McLeod, Jamie J A; Caslin, Heather L; Chumanevich, Alena P; Kolawole, Elizabeth Motunrayo; Paranjape, Anuya; Baker, Bianca; Ndaw, Victor S; Barnstein, Brian O; Oskeritzian, Carole A; Sell, Scott A; Ryan, John J

    2016-10-01

    Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TGF-β-activated kinase-1, JNK, ERK, and NF-κB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to hypoxia-inducible factor (HIF)-1α, which was enhanced in bone marrow-derived mast cells treated with LA. Because HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and miR-155-3p species were measured. In fact, LA selectively suppressed miR-155-5p in an HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, because LA injected i.p. into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation. Copyright © 2016 by The American Association of Immunologists, Inc.

  8. The Pseudomonas syringae pv. tomato type III effector HopM1 suppresses Arabidopsis defenses independent of suppressing salicylic acid signaling and of targeting AtMIN7.

    PubMed

    Gangadharan, Anju; Sreerekha, Mysore-Venkatarau; Whitehill, Justin; Ham, Jong Hyun; Mackey, David

    2013-01-01

    Pseudomonas syringae pv tomato strain DC3000 (Pto) delivers several effector proteins promoting virulence, including HopM1, into plant cells via type III secretion. HopM1 contributes to full virulence of Pto by inducing degradation of Arabidopsis proteins, including AtMIN7, an ADP ribosylation factor-guanine nucleotide exchange factor. Pseudomonas syringae pv phaseolicola strain NPS3121 (Pph) lacks a functional HopM1 and elicits robust defenses in Arabidopsis thaliana, including accumulation of pathogenesis related 1 (PR-1) protein and deposition of callose-containing cell wall fortifications. We have examined the effects of heterologously expressed HopM1Pto on Pph-induced defenses. HopM1 suppresses Pph-induced PR-1 expression, a widely used marker for salicylic acid (SA) signaling and systemic acquired resistance. Surprisingly, HopM1 reduces PR-1 expression without affecting SA accumulation and also suppresses the low levels of PR-1 expression apparent in SA-signaling deficient plants. Further, HopM1 enhances the growth of Pto in SA-signaling deficient plants. AtMIN7 contributes to Pph-induced PR-1 expression. However, HopM1 fails to degrade AtMIN7 during Pph infection and suppresses Pph-induced PR-1 expression and callose deposition in wild-type and atmin7 plants. We also show that the HopM1-mediated suppression of PR-1 expression is not observed in plants lacking the TGA transcription factor, TGA3. Our data indicate that HopM1 promotes bacterial virulence independent of suppressing SA-signaling and links TGA3, AtMIN7, and other HopM1 targets to pathways distinct from the canonical SA-signaling pathway contributing to PR-1 expression and callose deposition. Thus, efforts to understand this key effector must consider multiple targets and unexpected outputs of its action.

  9. The Pseudomonas syringae pv. tomato Type III Effector HopM1 Suppresses Arabidopsis Defenses Independent of Suppressing Salicylic Acid Signaling and of Targeting AtMIN7

    PubMed Central

    Gangadharan, Anju; Sreerekha, Mysore-Venkatarau; Whitehill, Justin; Ham, Jong Hyun; Mackey, David

    2013-01-01

    Pseudomonas syringae pv tomato strain DC3000 (Pto) delivers several effector proteins promoting virulence, including HopM1, into plant cells via type III secretion. HopM1 contributes to full virulence of Pto by inducing degradation of Arabidopsis proteins, including AtMIN7, an ADP ribosylation factor-guanine nucleotide exchange factor. Pseudomonas syringae pv phaseolicola strain NPS3121 (Pph) lacks a functional HopM1 and elicits robust defenses in Arabidopsis thaliana, including accumulation of pathogenesis related 1 (PR-1) protein and deposition of callose-containing cell wall fortifications. We have examined the effects of heterologously expressed HopM1Pto on Pph-induced defenses. HopM1 suppresses Pph-induced PR-1 expression, a widely used marker for salicylic acid (SA) signaling and systemic acquired resistance. Surprisingly, HopM1 reduces PR-1 expression without affecting SA accumulation and also suppresses the low levels of PR-1 expression apparent in SA-signaling deficient plants. Further, HopM1 enhances the growth of Pto in SA-signaling deficient plants. AtMIN7 contributes to Pph-induced PR-1 expression. However, HopM1 fails to degrade AtMIN7 during Pph infection and suppresses Pph-induced PR-1 expression and callose deposition in wild-type and atmin7 plants. We also show that the HopM1-mediated suppression of PR-1 expression is not observed in plants lacking the TGA transcription factor, TGA3. Our data indicate that HopM1 promotes bacterial virulence independent of suppressing SA-signaling and links TGA3, AtMIN7, and other HopM1 targets to pathways distinct from the canonical SA-signaling pathway contributing to PR-1 expression and callose deposition. Thus, efforts to understand this key effector must consider multiple targets and unexpected outputs of its action. PMID:24324742

  10. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

    PubMed Central

    Rossi, A; Pergola, C; Koeberle, A; Hoffmann, M; Dehm, F; Bramanti, P; Cuzzocrea, S; Werz, O; Sautebin, L

    2010-01-01

    BACKGROUND AND PURPOSE Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo. EXPERIMENTAL APPROACH Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model. KEY RESULTS Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes. CONCLUSIONS AND IMPLICATION Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed. PMID:20880396

  11. Salidroside protects against kainic acid-induced status epilepticus via suppressing oxidative stress.

    PubMed

    Si, Pei-Pei; Zhen, Jun-Li; Cai, Yun-Lei; Wang, Wen-Jing; Wang, Wei-Ping

    2016-04-08

    There are numerous mechanisms by which the brain generates seizures. It is well known that oxidative stress plays a pivotal role in status epilepticus (SE). Salidroside (SDS) extracted from Rhodiola rosea L. shows multiple bioactive properties, such as neuroprotection and antioxidant activity in vitro and in vivo. This study explored the role of SDS in kainic acid (KA)-induced SE and investigated the underlying mechanism. Latency to SE increased in the SDS-pretreated mice compared to the KA group, while the percentage of incidence of SE was significantly reduced. These results suggested that pretreatment with SDS not only delayed SE, but it also decreased the incidence of SE induced by KA. KA increased MDA level and reduced the production of SOD and GSH at multiple timepoints after KA administration. SDS inhibited the change of MDA, SOD and GSH induced by KA prior to SE onset, indicating that SDS protects against KA-induced SE via suppressing oxidative stress. Based on these results, we investigated the possible molecular mechanism of SDS. Pretreatment with SDS reversed the KA-induced decrease in AMP-activated protein kinase (AMPK); increased the sirtuin 1 (SIRT1) deacetylase activity in KA-treated mice, which had no demonstrable effect on SIRT1 mRNA and protein; and suppressed the KA-induced increase in Ace-FoxO1. These results showed that AMPK/SIRT1/FoxO1 signaling is possibly the molecular mechanism of neuroprotection by SDS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Salvianolic acid B suppresses maturation of human monocyte-derived dendritic cells by activating PPARγ

    PubMed Central

    Sun, Aijun; Liu, Hongying; Wang, Shijun; Shi, Dazhuo; Xu, Lei; Cheng, Yong; Wang, Keqiang; Chen, Keji; Zou, Yunzeng; Ge, Junbo

    2011-01-01

    BACKGROUND AND PURPOSE Salvianolic acid B (Sal B), a water-soluble antioxidant derived from a Chinese medicinal herb, is known to be effective in the prevention of atherosclerosis. Here, we tested the hypothesis that the anti-atherosclerotic effect of Sal B might be mediated by suppressing maturation of human monocyte-derived dendritic cells (h-monDC). EXPERIMENTAL APPROACH h-monDC were derived by incubating purified human monocytes with GM-CSF and IL-4. h-monDC were pre-incubated with or without Sal B and stimulated by oxidized low-density lipoprotein (ox-LDL) in the presence or absence of PPARγ siRNA. Expression of h-monDC membrane molecules (CD40, CD86, CD1a, HLA-DR) were analysed by FACS, cytokines were measured by elisa and the TLR4-associated signalling pathway was determined by Western blotting. KEY RESULTS Ox-LDL promoted h-monDC maturation, stimulated CD40, CD86, CD1a, HLA-DR expression and IL-12, IL-10, TNF-α production; and up-regulated TLR4 signalling. These effects were inhibited by Sal B. Sal B also triggered PPARγ activation and promoted PPARγ nuclear translocation, attenuated ox-LDL-induced up-regulation of TLR4 and myeloid differentiation primary-response protein 88 and inhibited the downstream p38-MAPK signalling cascade. Knocking down PPARγ with the corresponding siRNA blocked these effects of Sal B. CONCLUSIONS AND IMPLICATIONS Our data suggested that Sal B effectively suppressed maturation of h-monDC induced by ox-LDL through PPARγ activation. PMID:21649636

  13. Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep.

    PubMed

    Brown, Laura D; Kohn, Jaden R; Rozance, Paul J; Hay, William W; Wesolowski, Stephanie R

    2017-05-01

    Acute amino acid (AA) infusion increases AA oxidation rates in normal late gestation fetal sheep. Because the fetal oxygen consumption rate does not change with increased AA oxidation, we hypothesized that AA infusion would suppress glucose oxidation pathways and that the additional carbon supply from AA would activate hepatic glucose production. To test this, late gestation fetal sheep were infused intravenously for 3 h with saline or exogenous AA (AA). Glucose tracer metabolic studies were performed and skeletal muscle and liver tissues samples were collected. AA infusion increased fetal arterial plasma branched chain AA, cortisol, and glucagon concentrations. Fetal glucose utilization rates were similar between basal and AA periods, yet the fraction of glucose oxidized and the glucose oxidation rate were decreased by 40% in the AA period. AA infusion increased expression of PDK4, an inhibitor of glucose oxidation, nearly twofold in muscle and liver. In liver, AA infusion tended to increase PCK1 gluconeogenic gene and PCK1 correlated with plasma cortisol concentrations. AA infusion also increased liver mRNA expression of the lactate transporter gene (MCT1), protein expression of GLUT2 and LDHA, and phosphorylation of AMPK, 4EBP1, and S6 proteins. In isolated fetal hepatocytes, AA supplementation increased glucose production and PCK1, LDHA, and MCT1 gene expression. These results demonstrate that AA infusion into fetal sheep competitively suppresses glucose oxidation and potentiates hepatic glucose production. These metabolic patterns support flexibility in fetal metabolism in response to increased nutrient substrate supply while maintaining a relatively stable rate of oxidative metabolism. Copyright © 2017 the American Physiological Society.

  14. Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro.

    PubMed

    Maier, Elisabeth; Kurz, Katharina; Jenny, Marcel; Schennach, Harald; Ueberall, Florian; Fuchs, Dietmar

    2010-07-01

    Food preservatives sodium benzoate and propionic acid and colorant curcumin are demonstrated to suppress in a dose-dependent manner Th1-type immune response in human peripheral blood mononuclear cells (PBMC) in vitro. Results show an anti-inflammatory property of compounds which however could shift the Th1-Th2-type immune balance towards Th2-type immunity.

  15. Crystal methamphetamine injection predicts slower HIV RNA suppression among injection drug users.

    PubMed

    Fairbairn, Nadia; Kerr, Thomas; Milloy, M-J; Zhang, Ruth; Montaner, Julio; Wood, Evan

    2011-07-01

    We examined the impact of crystal methamphetamine injection on HIV RNA suppression among a prospective cohort of HIV-positive injection drug users initiating antiretroviral therapy. A multivariate Cox regression analysis found crystal methamphetamine injection to be negatively associated with viral load suppression (RH=0.63 [95% CI: 0.40-0.98]; p=0.039). This study is the first to our knowledge to demonstrate an association between crystal methamphetamine use and HIV RNA suppression. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Retrospective analysis of the effect of acid-suppressant therapy on clinicopathologic parameters of cats with chronic kidney disease.

    PubMed

    Gould, Emily; Klos, Jacob; Price, Josh; Harris, Tonya; Vaden, Shelly; Tolbert, M Katherine

    2017-07-01

    Objectives To retrospectively evaluate the effects of acid-suppressant therapy in a population of cats with chronic kidney disease (CKD). The study objectives were to evaluate the effects of acid-suppressant therapy on clinicopathologic variables and progression of CKD over time. Methods The databases of two institutions were searched over an 11 year time span for cats fitting inclusion criteria for CKD. A total of 89 cats met the criteria for inclusion and were grouped according to either early (ie, stages 1-2) or advanced (ie, stages 3-4) CKD. Variables were statistically analyzed before and after treatment with either: (1) proton pump inhibitors (PPIs; n = 17), (2) histamine-2 receptor antagonists (H2RAs; n = 30), (3) combined acid-suppressant therapy (PPI + H2RA; n = 6) or (4) no acid-suppressant therapy (n = 36). Shapiro-Wilk testing and Q-Q plots were used to assess normality and variance, respectively. A complete randomized design with a mixed-effects repeated measures ANOVA was used to evaluate for differences in stage, treatment and time, as well as the interaction between these effects. Results A significant increase in blood creatinine concentration was found over time independent of severity of CKD and treatment group ( P = 0.0087). A significant increase in blood sodium concentration (change of 3.12 mmol/l) was found independent of stage in cats receiving PPI therapy ( P = 0.0109). A significant decrease in total blood magnesium (change of 0.15 mmol/l) was detected in two cats with early CKD receiving combined acid suppressants ( P = 0.0025). Conclusions and relevance Results of this retrospective study suggest that cats with CKD receiving PPI therapy may develop alterations in blood sodium concentrations but do not experience more rapid progression of CKD.

  17. The Role of Adjuvant Acid Suppression on the Outcomes of Bleeding Esophageal Varices after Endoscopic Variceal Ligation

    PubMed Central

    Wu, Cheng-Kun; Liang, Chih-Ming; Hsu, Chien-Ning; Hung, Tsung-Hsing; Yuan, Lan-Ting; Nguang, Seng-Howe; Wang, Jiunn-Wei; Tseng, Kuo-Lun; Ku, Ming-Kun; Yang, Shih-Cheng; Tai, Wei-Chen; Shih, Chih-Wei; Hsu, Pin-I; Wu, Deng-Chyang; Chuah, Seng-Kee

    2017-01-01

    The impact of adjuvant acid suppression via proton pump inhibitors or histamine-2 receptor antagonists after endoscopic variceal ligation remains uncertain. We therefore aimed to evaluate the effect of adjuvant acid suppression on the rebleeding and mortality rates in patients who received endoscopic variceal ligation and vasoconstrictor therapy for bleeding esophageal varices. Data from 1997 to 2011 were extracted from the National Health Insurance Research Database in Taiwan. A total of 1576 cirrhotic patients aged > 18 years with a primary diagnosis of acute esophageal variceal bleeding who received endoscopic variceal ligation therapy were screened. After strict exclusion, 637 patients were recruited. The exclusion criteria included patients with gastric variceal bleeding, failure in the control of bleeding, mortality within 12 hours, and history of hepatocellular carcinoma or gastric cancer. Patients were divided into two groups: the vasoconstrictors group (n = 126) and vasoconstrictors plus acid suppression group (n = 511). We observed that the rebleeding and mortality rates were not significantly different between 2 groups during hospitalization and the 15-year follow-up period after discharge. A Charlson score ≥3 (odds ratio: 2.42, 95% confidence interval: 1.55 ~3.79, P = 0.0001), presence of hepatitis C virus (odds ratio: 1.70, 95% confidence interval: 1.15 ~2.52, P = 0.0085), and cirrhosis (odds ratio: 1.69, 95% confidence interval: 1.08 ~2.66, P = 0.0229) were the independent risk factors of mortality after discharge. In conclusion, the results of the current study suggest that adjuvant acid suppression prescription to patients who received endoscopic variceal ligation and vasoconstrictor therapy for bleeding esophageal varices may not change the rebleeding and mortality outcomes compared to that for those who received endoscopic variceal ligation and vasoconstrictor agents without acid suppression. PMID:28118373

  18. Evaporation suppression from reservoirs using floating covers: Lab scale wind-tunnel observations and mechanistic model predictions

    NASA Astrophysics Data System (ADS)

    Or, Dani; Lehmann, Peter; Aminzadeh, Milad; Sommer, Martina; Wey, Hannah; Krentscher, Christiane; Wunderli, Hans; Breitenstein, Daniel

    2017-04-01

    The competition over dwindling fresh water resources is expected to intensify with projected increase in human population in arid regions, expansion of irrigated land and changes in climate and drought patterns. The volume of water stored in reservoirs would also increase to mitigate seasonal shortages due to rainfall variability and to meet irrigation water needs. By some estimates up to half of the stored water is lost to evaporation, thereby exacerbating the water scarcity problem. Recently, there is an upsurge in the use of self-assembling floating covers to suppress evaporation, yet the design and implementation remain largely empirical. We report a systematic experimental evaluation of different cover types and external drivers (radiation, wind, wind plus radiation) on evaporation suppression and energy balance of a 1.4 m2 basin placed in a wind-tunnel. Surprisingly, evaporation suppression by black and white floating covers (balls and plates) were similar despite significantly different energy balance regimes over the cover surfaces. Moreover, the evaporation suppression efficiency was a simple function of the uncovered area (square root of the uncovered fraction) with linear relations with the covered area in some cases. The thermally decoupled floating covers offer an efficient solution to the evaporation suppression with limited influence of the surface energy balance (water temperature for black and white covers was similar and remained nearly constant). The results will be linked with a predictive evaporation-energy balance model and issues of spatial scales and long exposure times will be studied.

  19. Suppression of hepatic fatty acid oxidation and food intake in men.

    PubMed

    Kahler, A; Zimmermann, M; Langhans, W

    1999-01-01

    We investigated the effects of the fatty acid oxidation inhibitor etomoxir (ETO) on food intake and on fat and carbohydrate metabolism in two double-blind crossover studies in male, normal-weight subjects. In study 1, ETO (75 mg [+]-racemate) or placebo was given orally 30 min after completion of a standardized, fat-enriched (total energy: 2698 kJ, 40% from fat) lunch. The subjects (n = 15) were isolated from external time cues and free to choose when to eat dinner from an oversized serving (total energy: 6656 kJ, 60% from fat). In study 2, subjects (n = 13) were selected for habitually high fat intake (mean: 44% of energy intake). ETO (150 mg) or placebo was given after an overnight fast, 2.5 h before offering an oversized high fat breakfast (6960 kJ, 72% from fat). In both studies, blood samples were taken and the respiratory quotient (RQ) was measured several times during each test period. In study 1, ETO (75 mg) did not affect the timing and size of the dinner or subjective feelings of hunger and satiety. Although ETO (75 mg) did not affect the RQ, it decreased plasma beta-hydroxybutyrate (BHB) and increased plasma lactate compared with placebo. Plasma triacylglycerols (TG), free fatty acids (FFA), glucose, and insulin were not affected by ETO. In study 2, ETO (150 mg) enhanced hunger feelings and increased the size of the breakfast by 22.7%. ETO did not affect the RQ, but baseline RQ was lower in study 2 than in study 1 (0.83 versus 0.89, P < 0.01). Compared with placebo, ETO (150 mg) decreased plasma BHB and increased plasma FFA and plasma lactate. Baseline plasma concentrations of BHB, FFA, and lactate were higher in study 2 than in study 1 (BHB: 242 versus 81 mumol/L, P < 0.001; FFA: 0.674 versus 0.406 mmol/L, P < 0.01; lactate: 1.08 versus 0.74 mmol/L, P < 0.05). Plasma concentrations of TG, glucose, and insulin were not affected by ETO. The results suggest that inhibition of hepatic fatty acid oxidation stimulates eating in men when baseline fatty acid

  20. Rosmarinic acid and arbutin suppress osteoclast differentiation by inhibiting superoxide and NFATc1 downregulation in RAW 264.7 cells.

    PubMed

    Omori, Akina; Yoshimura, Yoshitaka; Deyama, Yoshiaki; Suzuki, Kuniaki

    2015-07-01

    The present study investigated the effect of the natural polyphenols, rosmarinic acid and arbutin, on osteoclast differentiation in RAW 264.7 cells. Rosmarinic acid and arbutin suppressed osteoclast differentiation and had no cytotoxic effect on osteoclast precursor cells. Rosmarinic acid and arbutin inhibited superoxide production in a dose-dependent manner. mRNA expression of the master regulator of osteoclastogenesis, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and the osteoclast marker genes, matrix metalloproteinase-9, tartrate-resistant acid phosphatase and cathepsin-K, decreased following treatments with rosmarinic acid and arbutin. Furthermore, resorption activity decreased with the number of osteoclasts. These results suggest that rosmarinic acid and arbutin may be useful for the prevention and treatment of bone diseases, such as osteoporosis, through mechanisms involving inhibition of superoxide and downregulation of NFATc1.

  1. Rosmarinic acid and arbutin suppress osteoclast differentiation by inhibiting superoxide and NFATc1 downregulation in RAW 264.7 cells

    PubMed Central

    OMORI, AKINA; YOSHIMURA, YOSHITAKA; DEYAMA, YOSHIAKI; SUZUKI, KUNIAKI

    2015-01-01

    The present study investigated the effect of the natural polyphenols, rosmarinic acid and arbutin, on osteoclast differentiation in RAW 264.7 cells. Rosmarinic acid and arbutin suppressed osteoclast differentiation and had no cytotoxic effect on osteoclast precursor cells. Rosmarinic acid and arbutin inhibited superoxide production in a dose-dependent manner. mRNA expression of the master regulator of osteoclastogenesis, nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and the osteoclast marker genes, matrix metalloproteinase-9, tartrate-resistant acid phosphatase and cathepsin-K, decreased following treatments with rosmarinic acid and arbutin. Furthermore, resorption activity decreased with the number of osteoclasts. These results suggest that rosmarinic acid and arbutin may be useful for the prevention and treatment of bone diseases, such as osteoporosis, through mechanisms involving inhibition of superoxide and downregulation of NFATc1. PMID:26171153

  2. Effects of Fatty Acid Quality and Quantity in the Japanese Diet on the Suppression of Lipid Accumulation.

    PubMed

    Sakamoto, Yu; Yamamoto, Kazushi; Hatakeyama, Yu; Tsuduki, Tsuyoshi

    2016-01-01

    Japan has been known as a healthy country since its life expectancy became among the highest in the world in the 1980s. The influence of the Japanese diet is one of the factors explaining Japan's high life expectancy. Our recent study that fed representative freeze-dried and powdered Japanese diets from 1960, 1975, 1990, and 2005 based on National Health and Nutrition Research to mice showed the 1975 Japanese diet exhibited the strongest visceral fat accumulation suppression and overall health benefits. However, it is unclear why. We investigated the effects of the fatty acid composition in Japanese diets on visceral fat accumulation in mice. ICR mice were fed diets replicating the fatty acid composition and macronutrient ratios of Japanese diets from 1960, 1975, 1990, and 2005 for four weeks. The 1975 diet suppressed visceral fat accumulation and adipocyte hypertrophy. DNA microarray analysis showed the 1975 diet suppressed Acyl-CoA synthetase and prostaglandin D2 synthase mRNA expressions in white adipose tissue. As the effects of the 1975 diet are likely due to differences in fatty acid intake and/or composition, we investigated test diets that replicated only the fatty acid composition of Japanese diets. There were no significant differences in visceral fat mass. Therefore, both the quality and quantity of fatty acids are involved in the anti-obesity effects of the 1975 Japanese diet.

  3. Chicoric acid suppresses BAFF expression in B lymphocytes by inhibiting NF-κB activity.

    PubMed

    Chen, Lingxi; Huang, Gang; Gao, Min; Shen, Xiaodong; Gong, Wei; Xu, Zhizhen; Zeng, Yijun; He, Fengtian

    2017-03-01

    B cell activating factor belonging to the TNF family (BAFF) plays a critical role in the pathogenesis of autoimmune diseases. The inhibition of BAFF expression is an emerging therapeutic approach for these disorders. Chicoric acid (CA), a bioactive phytochemical found in several widely used traditional medicinal plants, has significant anti-inflammatory activity and anti-arthritic effects. However, the role of CA in modulation of BAFF expression remains unknown. In this study, we demonstrated that CA reduced BAFF expression in human B lymphocyte cell lines and decreased the DNA-binding activity of nuclear factor-κB (NF-κB) in the BAFF promoter region. Furthermore, CA inhibited both the nuclear translocation of p65 (the subunit of NF-κB) and the phosphorylation of IκBα (inhibitor of NF-κB). These results suggest that CA suppresses BAFF expression by inhibiting NF-κB activity, and CA may serve as a novel therapeutic agent to down-regulate excessive BAFF expression in autoimmune diseases.

  4. Quality of healing of gastric ulcers: Natural products beyond acid suppression

    PubMed Central

    Kangwan, Napapan; Park, Jong-Min; Kim, Eun-Hee; Hahm, Ki Baik

    2014-01-01

    Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors (PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suffered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing (QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products. PMID:24891974

  5. Effectiveness and costs of implementation strategies to reduce acid suppressive drug prescriptions: a systematic review

    PubMed Central

    Smeets, Hugo M; Hoes, Arno W; de Wit, Niek J

    2007-01-01

    Background Evaluation of evidence for the effectiveness of implementation strategies aimed at reducing prescriptions for the use of acid suppressive drugs (ASD). Methods A systematic review of intervention studies with a design according to research quality criteria and outcomes related to the effect of reduction of ASD medication retrieved from Medline, Embase and the Cochrane Library. Outcome measures were the strategy of intervention, quality of methodology and results of treatment to differences of ASD prescriptions and costs. Results The intervention varied from a single passive method to multiple active interactions with GPs. Reports of study quality had shortcomings on subjects of data-analysis. Not all outcomes were calculated but if so rction of prescriptions varied from 8% up to 40% and the cost effectiveness was in some cases negative and in others positive. Few studies demonstrated good effects from the interventions to reduce ASD. Conclusion Poor quality of some studies is limiting the evidence for effective interventions. Also it is difficult to compare cost-effectiveness between studies. However, RCT studies demonstrate that active interventions are required to reduce ASD volume. Larger multi-intervention studies are necessary to evaluate the most successful intervention instruments. PMID:17983477

  6. Identifying Risk Factors Associated with Inappropriate Use of Acid Suppressive Therapy at a Community Hospital

    PubMed Central

    Bodukam, Vijay; Saigal, Kirit; Bahl, Jaya; Wang, Yvette; Hanlon, Alexandra; Lu, Yinghui; Davis, Michael

    2016-01-01

    Purpose. By examining the prescribing patterns and inappropriate use of acid suppressive therapy (AST) during hospitalization and at discharge we sought to identify the risk factors associated with such practices. Methods. In this retrospective observational study, inpatient records were reviewed from January 2011 to December 2013. Treatment with AST was considered appropriate if the patient had a known specific indication or met criteria for stress ulcer prophylaxis. Results. In 2011, out of 58 patients who were on AST on admission, 32 were newly started on it and 23 (72%) were inappropriate cases. In 2012, out of 97 patients on AST, 61 were newly started on it and 51 (84%) were inappropriate cases. In 2013, 99 patients were on AST, of which 48 were newly started on it and 36 (75%) were inappropriate cases. 19% of the patients inappropriately started on AST were discharged on it in three years. Younger age, female sex, and 1 or more handoffs between services were significantly associated with increased risk of inappropriate AST. Conclusion. Our findings reflect inappropriate prescription of AST which leads to increase in costs of care and unnecessarily puts the patient at risk for potential adverse events. The results of this study emphasize the importance of examining the patient's need for AST at each level of care especially when the identified risk factors are present. PMID:27818680

  7. Genetic ablation of the fatty acid binding protein FABP5 suppresses HER2-induced mammary tumorigenesis

    PubMed Central

    Levi, Liraz; Lobo, Glenn; Doud, Mary Kathryn; von Lintig, Johannes; Seachrist, Darcie; Tochtrop, Gregory P.; Noy, Noa

    2014-01-01

    The fatty acid binding protein FABP5 shuttles ligands from the cytosol to the nuclear receptor PPARβ/δ (encoded for by Pparδ), thereby enhancing the transcriptional activity of the receptor. This FABP5/PPARδ pathway is critical for induction of proliferation of breast carcinoma cells by activated EGFR. In this study, we show that FABP5 is highly upregulated in human breast cancers and we provide genetic evidence of the pathophysiological significance of FABP5 in mammary tumorigenesis. Ectopic expression of FABP5 was found to be oncogenic in 3T3 fibroblasts where it augmented the ability of PPARδ to enhance cell proliferation, migration and invasion. To determine whether FABP5 was essential for EGFR-induced mammary tumor growth, we interbred FABP5-null mice with MMTV-ErbB2/HER2 oncomice which spontaneously develop mammary tumors. FABP5 ablation relieved activation of EGFR downstream effector signals, decreased expression of PPARδ target genes that drive cell proliferation, and suppressed mammary tumor development. Our findings establish that FABP5 is critical for mammary tumor development, rationalizing the development of FABP5 inhibitors as novel anticarcinogenic drugs. PMID:23722546

  8. Suppression of Adult Neurogenesis Increases the Acute Effects of Kainic Acid

    PubMed Central

    Iyengar, Sloka S.; LaFrancois, John J.; Friedman, Daniel; Drew, Liam J.; Denny, Christine A.; Burghardt, Nesha S.; Wu, Melody V.; Hsieh, Jenny; Hen, René; Scharfman, Helen E.

    2016-01-01

    Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA. PMID:25476494

  9. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins.

    PubMed

    Göbel, Andy; Browne, Andrew J; Thiele, Stefanie; Rauner, Martina; Hofbauer, Lorenz C; Rachner, Tilman D

    2015-12-01

    The Wnt-inhibitor dickkopf-1 (DKK-1) promotes cancer-induced osteolytic bone lesions by direct inhibition of osteoblast differentiation and indirect activation of osteoclasts. DKK-1 is highly expressed in human breast cancer cells and can be suppressed by inhibitors of the mevalonate pathway such as statins and amino-bisphosphonates. However, supraphysiological concentrations are required to suppress DKK-1. We show that a sequential mevalonate pathway blockade using statins and amino-bisphosphonates suppresses DKK-1 more significantly than the individual agents alone. Thus, the reduction of the DKK-1 expression and secretion in the human osteotropic tumor cell lines MDA-MB-231, MDA-MET, and MDA-BONE by zoledronic acid was potentiated by the combination with low concentrations of statins (atorvastatin, simvastatin, and rosuvastatin) by up to 75% (p < 0.05). The specific rescue of prenylation using farnesyl pyrophosphate or geranylgeranyl pyrophosphate revealed that these effects were mediated by suppressed geranylgeranylation rather than by suppressed farnesylation. Moreover, combining low concentrations of statins (1 µM atorvastatin or 0.25 µM simvastatin) and zoledronic acid at low concentrations resulted in an at least 50% reversal of breast cancer-derived DKK-1-mediated inhibition of osteogenic markers in C2C12 cells (p < 0.05). Finally, the intratumoral injection of atorvastatin and zoledronic acid in as subcutaneous MDA-MB-231 mouse model reduced the serum level of human DKK-1 by 25% compared to untreated mice. Hence our study reveals that a sequential mevalonate pathway blockade allows for the combined use of low concentration of statins and amino-bisphosphonates. This combination still significantly suppresses breast cancer-derived DKK-1 to levels where it can no longer inhibit Wnt-mediated osteoblast differentiation.

  10. The quantitative prediction of bitterness-suppressing effect of sweeteners on the bitterness of famotidine by sweetness-responsive sensor.

    PubMed

    Hashimoto, Yoshimi; Matsunaga, Chiharu; Tokuyama, Emi; Tsuji, Eriko; Uchida, Takahiro; Okada, Hiroaki

    2007-05-01

    The purpose of the present study was the quantitative prediction of the bitterness-suppressing effect of sweeteners (sucrose or sugar alcohols) on the bitterness of famotidine (or quinine sulfate as control) solutions using an artificial taste sensor. Firstly, we examined the response characteristics of the sensor response to sweetness. The sensor membrane is charged negatively in the presence of sweeteners, which tend to receive protons from one of the components of the sensor membrane. The magnitude of the sensor response was shown to increase in direct proportion to the concentration of the sweetener. Secondly, we used direct or indirect methods to evaluate and predict the bitterness-suppressing effect of sweeteners on 1 mg/ml famotidine and 81.4 microM quinine sulfate solutions. In direct method, a regression between the sensor output of the sweetness-responsive sensor and the bitterness intensity obtained in human gustatory tests of famotidine solutions containing sweeteners at various concentrations, was performed. As a result, we were able to predict directly the bitterness intensity of the mixed solution. Finally, we also evaluated the bitterness intensity of the dissolution media of commercially available, orally disintegrating tablets containing famotidine by the combined usage of bitterness- and sweetness-responsive sensor. We found that the sugar alcohols in the tablet seem to be effective in the bitterness-suppression of famotidine from these tablets, especially in the initial phase (within 30 s) of the disintegration process.

  11. Antifungal and sprout regulatory bioactivities of phenylacetic acid, indole-3-acetic acid, and tyrosol isolated from the potato dry rot suppressive bacterium Enterobacter cloacae S11:T:07.

    PubMed

    Slininger, P J; Burkhead, K D; Schisler, D A

    2004-12-01

    Enterobacter cloacae S11: T:07 (NRRL B-21050) is a promising biological control agent that has significantly reduced both fungal dry rot disease and sprouting in laboratory and pilot potato storages. The metabolites phenylacetic acid (PAA), indole-3-acetic acid (IAA), and tyrosol (TSL) were isolated from S11:T:07 liquid cultures provided with three different growth media. The bioactivities of these metabolites were investigated via thin-layer chromatography bioautography of antifungal activity, wounded potato assays of dry rot suppressiveness, and cored potato eye assays of sprout inhibition. Relative accumulations of PAA, IAA, and TSL in cultures were nutrient dependent. For the first time, IAA, TSL, and PAA were shown to have antifungal activity against the dry rot causative pathogen Gibberella pulicaris, and to suppress dry rot infection of wounded potatoes. Disease suppression was optimal when all three metabolites were applied in combination. Dosages of IAA that resulted in disease suppression also resulted in sprout inhibition. These results suggest the potential for designing culture production and formulation conditions to achieve a dual purpose biological control agent able to suppress both dry rot and sprouting of stored potatoes.

  12. Medium-chain fatty acid nanoliposomes suppress body fat accumulation in mice.

    PubMed

    Liu, Wei-Lin; Liu, Wei; Liu, Cheng-Mei; Yang, Shui-Bing; Liu, Jian-Hua; Zheng, Hui-Juan; Su, Kun-Ming

    2011-11-01

    Medium-chain fatty acids (MCFA) are widely used in diets for patients with obesity. To develop a delivery system for suppressing dietary fat accumulation into adipose tissue, MCFA were encapsulated in nanoliposomes (NL), which can overcome the drawbacks of MCFA and keep their properties unchanged. In the present study, crude liposomes were first produced by the thin-layer dispersion method, and then dynamic high-pressure microfluidisation (DHPM) and DHPM combined with freeze-thawing methods were used to prepare MCFA NL (NL-1 and NL-2, respectively). NL-1 exhibited smaller average size (77.6 (SD 4.3) nm), higher zeta potential (- 40.8 (SD 1.7) mV) and entrapment efficiency (73.3 (SD 16.1) %) and better stability, while NL-2 showed narrower distribution (polydispersion index 0.193 (SD 0.016)). The body fat reduction property of NL-1 and NL-2 were evaluated by short-term (2 weeks) and long-term (6 weeks) experiments of mice. In contrast to the MCFA group, the NL groups had overcome the poor palatability of MCFA because the normal diet of mice was maintained. The body fat and total cholesterol (TCH) of NL-1 (1.54 (SD 0.30) g, P = 0.039 and 2.33 (SD 0.44) mmol/l, P = 0.021, respectively) and NL-2 (1.58 (SD 0.69) g, P = 0.041 and 2.29 (SD 0.38) mmol/l, P = 0.015, respectively) significantly decreased when compared with the control group (2.11 (SD 0.82) g and 2.99 (SD 0.48) mmol/l, respectively). The TAG concentration of the NL-1 group (0.55 (SD 0.14) mmol/l) was remarkably lower (P = 0.045) than the control group (0.94 (SD 0.37) mmol/l). No significant difference in weight and fat gain, TCH and TAG was detected between the MCFA NL and MCFA groups. Therefore, MCFA NL could be potential nutritional candidates for obesity to suppress body fat accumulation.

  13. Predicting the Multisensory Consequences of One’s Own Action: BOLD Suppression in Auditory and Visual Cortices

    PubMed Central

    van Kemenade, Bianca M.; Arikan, B. Ezgi; Fiehler, Katja; Leube, Dirk T.; Harris, Laurence R.; Kircher, Tilo

    2017-01-01

    Predictive mechanisms are essential to successfully interact with the environment and to compensate for delays in the transmission of neural signals. However, whether and how we predict multisensory action outcomes remains largely unknown. Here we investigated the existence of multisensory predictive mechanisms in a context where actions have outcomes in different modalities. During fMRI data acquisition auditory, visual and auditory-visual stimuli were presented in active and passive conditions. In the active condition, a self-initiated button press elicited the stimuli with variable short delays (0-417ms) between action and outcome, and participants had to detect the presence of a delay for auditory or visual outcome (task modality). In the passive condition, stimuli appeared automatically, and participants had to detect the number of stimulus modalities (unimodal/bimodal). For action consequences compared to identical but unpredictable control stimuli we observed suppression of the blood oxygen level depended (BOLD) response in a broad network including bilateral auditory and visual cortices. This effect was independent of task modality or stimulus modality and strongest for trials where no delay was detected (undetectedpredictive mechanisms lead to BOLD suppression in multiple sensory brain regions. These findings support the hypothesis of multisensory predictive mechanisms, which are probably conducted in the left cerebellum. PMID:28060861

  14. Inability to suppress salient distractors predicts low visual working memory capacity

    PubMed Central

    Gaspar, John M.; Christie, Gregory J.; Prime, David J.; Jolicœur, Pierre; McDonald, John J.

    2016-01-01

    According to contemporary accounts of visual working memory (vWM), the ability to efficiently filter relevant from irrelevant information contributes to an individual’s overall vWM capacity. Although there is mounting evidence for this hypothesis, very little is known about the precise filtering mechanism responsible for controlling access to vWM and for differentiating low- and high-capacity individuals. Theoretically, the inefficient filtering observed in low-capacity individuals might be specifically linked to problems enhancing relevant items, suppressing irrelevant items, or both. To find out, we recorded neurophysiological activity associated with attentional selection and active suppression during a competitive visual search task. We show that high-capacity individuals actively suppress salient distractors, whereas low-capacity individuals are unable to suppress salient distractors in time to prevent those items from capturing attention. These results demonstrate that individual differences in vWM capacity are associated with the timing of a specific attentional control operation that suppresses processing of salient but irrelevant visual objects and restricts their access to higher stages of visual processing. PMID:26903654

  15. Inability to suppress salient distractors predicts low visual working memory capacity.

    PubMed

    Gaspar, John M; Christie, Gregory J; Prime, David J; Jolicœur, Pierre; McDonald, John J

    2016-03-29

    According to contemporary accounts of visual working memory (vWM), the ability to efficiently filter relevant from irrelevant information contributes to an individual's overall vWM capacity. Although there is mounting evidence for this hypothesis, very little is known about the precise filtering mechanism responsible for controlling access to vWM and for differentiating low- and high-capacity individuals. Theoretically, the inefficient filtering observed in low-capacity individuals might be specifically linked to problems enhancing relevant items, suppressing irrelevant items, or both. To find out, we recorded neurophysiological activity associated with attentional selection and active suppression during a competitive visual search task. We show that high-capacity individuals actively suppress salient distractors, whereas low-capacity individuals are unable to suppress salient distractors in time to prevent those items from capturing attention. These results demonstrate that individual differences in vWM capacity are associated with the timing of a specific attentional control operation that suppresses processing of salient but irrelevant visual objects and restricts their access to higher stages of visual processing.

  16. Predicting protein amidation sites by orchestrating amino acid sequence features

    NASA Astrophysics Data System (ADS)

    Zhao, Shuqiu; Yu, Hua; Gong, Xiujun

    2017-08-01

    Amidation is the fourth major category of post-translational modifications, which plays an important role in physiological and pathological processes. Identifying amidation sites can help us understanding the amidation and recognizing the original reason of many kinds of diseases. But the traditional experimental methods for predicting amidation sites are often time-consuming and expensive. In this study, we propose a computational method for predicting amidation sites by orchestrating amino acid sequence features. Three kinds of feature extraction methods are used to build a feature vector enabling to capture not only the physicochemical properties but also position related information of the amino acids. An extremely randomized trees algorithm is applied to choose the optimal features to remove redundancy and dependence among components of the feature vector by a supervised fashion. Finally the support vector machine classifier is used to label the amidation sites. When tested on an independent data set, it shows that the proposed method performs better than all the previous ones with the prediction accuracy of 0.962 at the Matthew's correlation coefficient of 0.89 and area under curve of 0.964.

  17. Prediction of protein disorder on amino acid substitutions.

    PubMed

    Anoosha, P; Sakthivel, R; Gromiha, M Michael

    2015-12-15

    Intrinsically disordered regions of proteins are known to have many functional roles in cell signaling and regulatory pathways. The altered expression of these proteins due to mutations is associated with various diseases. Currently, most of the available methods focus on predicting the disordered proteins or the disordered regions in a protein. On the other hand, methods developed for predicting protein disorder on mutation showed a poor performance with a maximum accuracy of 70%. Hence, in this work, we have developed a novel method to classify the disorder-related amino acid substitutions using amino acid properties, substitution matrices, and the effect of neighboring residues that showed an accuracy of 90.0% with a sensitivity and specificity of 94.9 and 80.6%, respectively, in 10-fold cross-validation. The method was evaluated with a test set of 20% data using 10 iterations, which showed an average accuracy of 88.9%. Furthermore, we systematically analyzed the features responsible for the better performance of our method and observed that neighboring residues play an important role in defining the disorder of a given residue in a protein sequence. We have developed a prediction server to identify disorder-related mutations, and it is available at http://www.iitm.ac.in/bioinfo/DIM_Pred/. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Genomic prediction for beef fatty acid profile in Nellore cattle.

    PubMed

    Chiaia, Hermenegildo Lucas Justino; Peripoli, Elisa; Silva, Rafael Medeiros de Oliveira; Aboujaoude, Carolyn; Feitosa, Fabiele Loise Braga; Lemos, Marcos Vinicius Antunes de; Berton, Mariana Piatto; Olivieri, Bianca Ferreira; Espigolan, Rafael; Tonussi, Rafael Lara; Gordo, Daniel Gustavo Mansan; Bresolin, Tiago; Magalhães, Ana Fabrícia Braga; Júnior, Gerardo Alves Fernandes; Albuquerque, Lúcia Galvão de; Oliveira, Henrique Nunes de; Furlan, Joyce de Jesus Mangini; Ferrinho, Adrielle Mathias; Mueller, Lenise Freitas; Tonhati, Humberto; Pereira, Angélica Simone Cravo; Baldi, Fernando

    2017-06-01

    The objective of this study was to compare SNP-BLUP, BayesCπ, BayesC and Bayesian Lasso methodologies to predict the direct genomic value for saturated, monounsaturated, and polyunsaturated fatty acid profile, omega 3 and 6 in the Longissimus thoracis muscle of Nellore cattle finished in feedlot. A total of 963 Nellore bulls with phenotype for fatty acid profiles, were genotyped using the Illumina BovineHD BeadChip (Illumina, San Diego, CA) with 777,962 SNP. The predictive ability was evaluated using cross validation. To compare the methodologies, the correlation between DGV and pseudo-phenotypes was calculated. The accuracy varied from -0.40 to 0.62. Our results indicate that none of the methods excelled in terms of accuracy, however, the SNP-BLUP method allows obtaining less biased genomic evaluations, thereby; this method is more feasible when taking into account the analyses' operating cost. Despite the lowest bias observed for EBV, the adjusted phenotype is the preferred pseudophenotype considering the genomic prediction accuracies regarding the context of the present study.

  19. Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

    PubMed

    Inoue, Takayuki; Tanaka, Masashi; Masuda, Shinya; Ohue-Kitano, Ryuji; Yamakage, Hajime; Muranaka, Kazuya; Wada, Hiromichi; Kusakabe, Toru; Shimatsu, Akira; Hasegawa, Koji; Satoh-Asahara, Noriko

    2017-02-22

    Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD(+) level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

  20. Mechanism of fatty acids induced suppression of cardiovascular reflexes in rats.

    PubMed

    Shaltout, Hossam A; Abdel-Rahman, Abdel A

    2005-09-01

    A blunted baroreflex sensitivity (BRS), impaired heart rate variability (HRV), and high plasma nonesterified fatty acids (NEFA) are predictors of adverse cardiovascular outcomes. We tested the hypothesis that elevation of NEFA negatively impacts the cardiac baroreflex response and undertook spectral analyses and molecular studies to delineate the mechanism of action. We used two interventions to elevate serum NEFA: 1) overnight fasting (n = 7) and 2) i.v. infusion of 1.2 ml/kg intralipid 20% + heparin (I/H) over 10 min (n = 9) in conscious unrestrained male rats. Elevated NEFA caused by fasting complemented by I/H infusion were associated with a concentration-dependent reduction in spontaneous BRS measured by spectral analysis [low-frequency alpha and high-frequency alpha (HFalpha) indices] and sequence method and HRV measured by frequency domain as power of RR interval (RRI) spectra (low-frequency RRI and high-frequency RRI) and by time domain as standard deviation of beat-to-beat interval and root mean square of successive differences along with increase in blood pressure variability measured as standard deviation of mean arterial pressure and power of systolic arterial pressure spectra (low-frequency systolic arterial pressure). Because elevated NEFA suppressed the vagal component of the baroreflex response (HFalpha), we tested the hypothesis that NEFA-evoked sequestration of myocardial muscarinic receptor (M2-mAChR) contributes to the reduced BRS. High NEFA level was accompanied by increased caveolar sequestration of cardiac M2-mAChRs without changing M2-mAChR protein expression. We report the first detailed analyses of NEFA's effect on the cardiac baroreflex and show that increased caveolar sequestration of cardiac M2-mAChRs constitutes a cellular mechanism for elevated NEFA-related deleterious cardiovascular outcomes.

  1. NFX1-LIKE2 (NFXL2) Suppresses Abscisic Acid Accumulation and Stomatal Closure in Arabidopsis thaliana

    PubMed Central

    Lisso, Janina; Schröder, Florian; Fisahn, Joachim; Müssig, Carsten

    2011-01-01

    The NFX1-LIKE1 (NFXL1) and NFXL2 genes were identified as regulators of salt stress responses. The NFXL1 protein is a nuclear factor that positively affects adaptation to salt stress. The nfxl1-1 loss-of-function mutant displayed reduced survival rates under salt and high light stress. In contrast, the nfxl2-1 mutant, defective in the NFXL2 gene, and NFXL2-antisense plants exhibited enhanced survival under these conditions. We show here that the loss of NFXL2 function results in abscisic acid (ABA) overaccumulation, reduced stomatal conductance, and enhanced survival under drought stress. The nfxl2-1 mutant displayed reduced stomatal aperture under all conditions tested. Fusicoccin treatment, exposition to increasing light intensities, and supply of decreasing CO2 concentrations demonstrated full opening capacity of nfxl2-1 stomata. Reduced stomatal opening presumably is a consequence of elevated ABA levels. Furthermore, seedling growth, root growth, and stomatal closure were hypersensitive to exogenous ABA. The enhanced ABA responses may contribute to the improved drought stress resistance of the mutant. Three NFXL2 splice variants were cloned and named NFXL2-78, NFXL2-97, and NFXL2-100 according to the molecular weight of the putative proteins. Translational fusions to the green fluorescent protein suggest nuclear localisation of the NFXL2 proteins. Stable expression of the NFXL2-78 splice variant in nfxl2-1 plants largely complemented the mutant phenotype. Our data show that NFXL2 controls ABA levels and suppresses ABA responses. NFXL2 may prevent unnecessary and costly stress adaptation under favourable conditions. PMID:22073231

  2. IRF8 Regulates Acid Ceramidase Expression to Mediate Apoptosis and Suppresses Myelogeneous Leukemia

    PubMed Central

    Hu, Xiaolin; Yang, Dafeng; Zimmerman, Mary; Liu, Feiyan; Yang, Jine; Kannan, Swati; Burchert, Andreas; Szulc, Zdzislaw; Bielawska, Alicja; Ozato, Keiko; Bhalla, Kapil; Liu, Kebin

    2011-01-01

    IFN regulatory factor 8 (IRF8) is a key transcription factor for myeloid cell differentiation and its expression is frequently lost in hematopoietic cells of human myeloid leukemia patients. IRF8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML). Therefore, IRF8 is a myeloid leukemia suppressor. While the understanding of IRF8 function in CML has recently improved, the molecular mechanisms underlying IRF8 function in CML is still largely unknown. In this study, we identified acid ceramidase (A-CDase) as a general transcription target of IRF8. We demonstrated that IRF8 expression is regulated by IRF8 promoter DNA methylation in myeloid leukemia cells. Restoration of IRF8 expression repressed A-CDase expression, resulting in C16 ceramide accumulation and increased sensitivity of CML cells to FasL-induced apoptosis. In myeloid cells derived from IRF8-deficient mice, A-CDase protein level was dramatically increased. Furthermore, we demonstrated that IRF8 directly bind to the A-CDase promoter. At the functional level, inhibition of A-CDase activity, silencing A-CDase expression or application of exogenous C16 ceramide sensitized CML cells to FasL-induced apoptosis, whereas, overexpression of A-CDase decreased CML cells sensitivity to FasL-induced apoptosis. Consequently, restoration of IRF8 expression suppressed CML development in vivo at least partially through a Fas-dependent mechanism. In summary, our findings determine the mechanism of IRF8 downregulation in CML cells and they determine a primary pathway of resistance to Fas-mediated apoptosis and disease progression. PMID:21487040

  3. Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis

    PubMed Central

    Parajuli, Keshab R; Zhang, Qiuyang; Liu, Sen; Patel, Neil K; Lu, Hua; Zeng, Shelya X; Wang, Guangdi; Zhang, Changde; You, Zongbing

    2014-01-01

    Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA’s effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer. PMID:25606576

  4. Structured triacylglycerol containing behenic and oleic acids suppresses triacylglycerol absorption and prevents obesity in rats

    PubMed Central

    2010-01-01

    Background Dietary 1(3)-behenoyl-2,3(1)-dioleoyl-rac-glycerol (BOO) has been reported to inhibit pancreatic lipase activity in vitro and suppress postprandial hypertriacylglycerolemia in humans. In the present study, the anti-obesity activities of BOO and its inhibitory effects on lymphatic triacylglycerol (TAG) absorption were investigated in rats. Methods In Experiment 1, rats were fed either BOO or soybean oil (SO) diet for 6 weeks. In the BOO diet, 20% of SO was replaced with an experimental oil rich in BOO. In Experiments 2 and 3, rats cannulated in the thoracic duct were administered an emulsions containing trioleoylglycerol (OOO) or an oil mixture (OOO:BOO, 9:1). Tri[1-14C]oleoylglycerol (14C-OOO) was added to the emulsions administered in Experiment 3. Results No observable differences were detected in food intake or body weight gain between the BOO and SO groups in Experiment 1. Plasma and liver TAG concentrations and visceral fat weights were significantly lower in the BOO group than in the SO group. The apparent absorption rate of fat was significantly lower in the BOO group than in the SO group. In Experiment 2, the lymphatic recovery of oleic and behenic acids was significantly lower at 5 and 6 h after BOO administration than after OOO administration. In Experiment 3, the lymphatic recovery of 14C-OOO was significantly lower at 5 and 6 h after BOO administration than after OOO administration. Conclusions These results suggest that BOO prevents deposition of visceral fat and hepatic TAG by lowering and delaying intestinal absorption of TAG. PMID:20653972

  5. Acid Suppressive Therapy for Stress Ulcer Prophylaxis in Noncritically Ill Patients.

    PubMed

    Hong, Minh T; Monye, Leslie C; Seifert, Charles F

    2015-09-01

    The current literature discourages the use of acid suppressive therapy (AST) for stress ulcer prophylaxis (SUP) in noncritically ill patients. However, several sources indicate that the majority of noncritically ill patients are given AST for SUP while there may only be a small proportion of high-risk patients who need SUP therapy. There is a new scoring system to aid practitioners in stratifying the risk of stress ulcer-related gastrointestinal bleeding in noncritically ill patients developed by Herzig et al and appropriately prescribe AST for SUP in this population. Our primary objective was to determine the current usage of AST in noncritically ill patients at a tertiary teaching hospital and use the new scoring system to identify non-intensive care unit patients who were inappropriately given AST. We retrospectively determined the percentage of noncritically ill patients who were given AST on medical floors between January 2010 and December 2012. After identifying these patients, we randomly selected a sample and retrospectively collected data from their medical record to determine the gastrointestinal bleeding risk score to determine if the patient was appropriately given AST. Of the 42 600 admissions, 22 949 (53.7%) noncritically ill patients were given AST. A total of 442 patients were randomly selected for data collection and 156 patients were excluded. Gastrointestinal bleeding risk score was calculated in 286 patients. This new risk stratification tool identified 253 (88.5%) patients to have a low (≤7) and low-medium risk score (8-9). A large percentage of noncritically ill patients were given AST during their hospital stay; 88.5% of these medications were given inappropriately to patients who were at extremely low risk of gastrointestinal bleeding. Using the above information and the AST prescribing patterns at our institution, we estimate a potential inpatient medication cost savings of $114 622 for the study period. © The Author(s) 2015.

  6. PPARα Association With Sirt1 Suppresses Cardiac Fatty Acid Metabolism in the Failing Heart

    PubMed Central

    Oka, Shin-ichi; Zhai, Peiyong; Yamamoto, Takanobu; Ikeda, Yoshiyuki; Byun, Jaemin; Hsu, Chiao-Po; Sadoshima, Junichi

    2015-01-01

    Background Heart failure (HF) is accompanied by changes in cardiac metabolism characterized by reduced fatty acid (FA) utilization. However, the underlying mechanism and its causative involvement in the progression of HF are poorly understood. The peroxisome proliferator activated receptor-α (PPARα)/retinoid X receptor (RXR) heterodimer promotes transcription of genes involved in FA metabolism through binding to the PPAR response element, called direct repeat 1 (DR1). Silent information regulator 1 (Sirt1) is a histone deacetylase which interacts with PPARα. Methods and Results To investigate the role of PPARα in the impaired FA utilization observed during HF, genetically altered mice were subjected to pressure overload (PO). The DNA binding of PPARα, RXRα and Sirt1 to DR1 was evaluated with oligonucleotide pull-down and chromatin immunoprecipitation assays. Although the binding of PPARα to DR1 was enhanced in response to PO, that of RXRα was attenuated. Sirt1 competes with RXRα to dimerize with PPARα, thereby suppressing FA utilization in the failing heart. DR1 sequence analysis indicated that the typical DR1 sequence favors PPARα/RXRα heterodimerization, whereas the switch from RXRα to Sirt1 takes place on degenerate DR1s. Sirt1 bound to PPARα through a region homologous to the PPARα binding domain in RXRα. A short peptide corresponding to the RXRα domain not only inhibited the interaction between PPARα and Sirt1 but also improved FA metabolism and ameliorated cardiac dysfunction. Conclusions A change in the heterodimeric partner of PPARα from RXRα to Sirt1 is responsible for the impaired FA metabolism and cardiac dysfunction in the failing heart. PMID:26443578

  7. Repetition Suppression in the Left Inferior Frontal Gyrus Predicts Tone Learning Performance.

    PubMed

    Asaridou, Salomi S; Takashima, Atsuko; Dediu, Dan; Hagoort, Peter; McQueen, James M

    2016-06-01

    Do individuals differ in how efficiently they process non-native sounds? To what extent do these differences relate to individual variability in sound-learning aptitude? We addressed these questions by assessing the sound-learning abilities of Dutch native speakers as they were trained on non-native tone contrasts. We used fMRI repetition suppression to the non-native tones to measure participants' neuronal processing efficiency before and after training. Although all participants improved in tone identification with training, there was large individual variability in learning performance. A repetition suppression effect to tone was found in the bilateral inferior frontal gyri (IFGs) before training. No whole-brain effect was found after training; a region-of-interest analysis, however, showed that, after training, repetition suppression to tone in the left IFG correlated positively with learning. That is, individuals who were better in learning the non-native tones showed larger repetition suppression in this area. Crucially, this was true even before training. These findings add to existing evidence that the left IFG plays an important role in sound learning and indicate that individual differences in learning aptitude stem from differences in the neuronal efficiency with which non-native sounds are processed.

  8. Suppressed Alpha Oscillations Predict Intelligibility of Speech and its Acoustic Details

    PubMed Central

    Weisz, Nathan

    2012-01-01

    Modulations of human alpha oscillations (8–13 Hz) accompany many cognitive processes, but their functional role in auditory perception has proven elusive: Do oscillatory dynamics of alpha reflect acoustic details of the speech signal and are they indicative of comprehension success? Acoustically presented words were degraded in acoustic envelope and spectrum in an orthogonal design, and electroencephalogram responses in the frequency domain were analyzed in 24 participants, who rated word comprehensibility after each trial. First, the alpha power suppression during and after a degraded word depended monotonically on spectral and, to a lesser extent, envelope detail. The magnitude of this alpha suppression exhibited an additional and independent influence on later comprehension ratings. Second, source localization of alpha suppression yielded superior parietal, prefrontal, as well as anterior temporal brain areas. Third, multivariate classification of the time–frequency pattern across participants showed that patterns of late posterior alpha power allowed best for above-chance classification of word intelligibility. Results suggest that both magnitude and topography of late alpha suppression in response to single words can indicate a listener's sensitivity to acoustic features and the ability to comprehend speech under adverse listening conditions. PMID:22100354

  9. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    SciTech Connect

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  10. Mms Sensitivity of All Amino Acid-Requiring Mutants in Aspergillus and Its Suppression by Mutations in a Single Gene

    PubMed Central

    Käfer, Etta

    1987-01-01

    All available amino acid-requiring mutants of Aspergillus nidulans were found to be hypersensitive to MMS (methyl methanesulfonate) to various degrees. On MMS media, secondary mutations could be selected which suppress this MMS sensitivity but do not affect the requirement. Many such mutations were analyzed and found to be alleles of one gene, smsA (= suppressor of MMS sensitivity), which mapped distal on the right arm of chromosome V. This gene is more likely to be involved in general regulation of amino acid biosynthesis than MMS uptake, since a variety of pathway interactions were clearly modified by smsA suppressors in the absence of MMS. PMID:3556318

  11. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    SciTech Connect

    Zhai, Yingying; Chen, Xi; Yu, Dehai; Li, Tao; Cui, Jiuwei; Wang, Guanjun; Hu, Ji-Fan; Li, Wei

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

  12. Prediction of protein antigenic determinants from amino acid sequences

    SciTech Connect

    Hopp, T.P.; Woods, K.R.

    1981-06-01

    A method is presented for locating protein antigenic determinants by analyzing amino acid sequences in order to find the point of greatest local hydrophilicity. This is accomplished by assigning each amino acid a numerical value (hydrophilicity value) and then repetitively averaging these values along the peptide chain. The point of highest local average hydrophilicity is invariably located in, or immediately adjacent to, an antigenic determinant. It was found that the prediction success rate depended on averaging group length, with hexapeptide averages yielding optimal results. The method was developed using 12 proteins for which extensive immunochemical analysis has been carried out and subsequently was used to predict antigenic determinants for the following proteins: hepatitis B surface antigen, influenza hemagglutinis, fowl plague virus hemagglutinin, human histocompatibility antigen HLA-B7, human interferons, Escherichia coli and cholera enterotoxins, ragweed allergens Ra3 and Ra5, and streptococcal M protein. The hepatitis B surface antigen sequence was synthesized by chemical means and was shown to have antigenic activity by radioimmunoassay.

  13. Airborne Precursors Predict Maternal Serum Perfluoroalkyl Acid Concentrations.

    PubMed

    Makey, Colleen M; Webster, Thomas F; Martin, Jonathan W; Shoeib, Mahiba; Harner, Tom; Dix-Cooper, Linda; Webster, Glenys M

    2017-07-05

    Human exposure to persistent perfluoroalkyl acids (PFAAs), including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctanesulfonate (PFOS), can occur directly from contaminated food, water, air, and dust. However, precursors to PFAAs (PreFAAs), such as dipolyfluoroalkyl phosphates (diPAPs), fluorotelomer alcohols (FTOHs), perfluorooctyl sulfonamides (FOSAs), and sulfonamidoethanols (FOSEs), which can be biotransformed to PFAAs, may also be a source of exposure. PFAAs were analyzed in 50 maternal sera samples collected in 2007-2008 from participants in Vancouver, Canada, while PFAAs and PreFAAs were measured in matching samples of residential bedroom air collected by passive sampler and in sieved vacuum dust (<150 μm). Concentrations of PreFAAs were higher than for PFAAs in air and dust. Positive associations were discovered between airborne 10:2 FTOH and serum PFOA and PFNA and between airborne MeFOSE and serum PFOS. On average, serum PFOS concentrations were 2.3 ng/mL (95%CI: 0.40, 4.3) higher in participants with airborne MeFOSE concentrations in the highest tertile relative to the lowest tertile. Among all PFAAs, only PFNA in air and vacuum dust predicted serum PFNA. Results suggest that airborne PFAA precursors were a source of PFOA, PFNA, and PFOS exposure in this population.

  14. Inhibition of Hyaluronic Acid Synthesis Suppresses Angiogenesis in Developing Endometriotic Lesions

    PubMed Central

    Olivares, Carla N.; Alaniz, Laura D.; Menger, Michael D.; Barañao, Rosa I.; Laschke, Matthias W.; Meresman, Gabriela F.

    2016-01-01

    Background The development and long-term survival of endometriotic lesions is crucially dependent on an adequate vascularization. Hyaluronic acid (HA) through its receptor CD44 has been described to be involved in the process of angiogenesis. Objective To study the effect of HA synthesis inhibition using non-toxic doses of 4-methylumbelliferone (4-MU) on endometriosis-related angiogenesis. Materials and Methods The cytotoxicity of different in vitro doses of 4-MU on endothelial cells was firstly tested by means of a lactate dehydrogenase assay. The anti-angiogenic action of non-cytotoxic doses of 4-MU was then assessed by a rat aortic ring assay. In addition, endometriotic lesions were induced in dorsal skinfold chambers of female BALB/c mice, which were daily treated with an intraperitoneal injection of 0.9% NaCl (vehicle group; n = 6), 20mg/kg 4-MU (n = 8) or 80mg/kg 4-MU (n = 7) throughout an observation period of 14 days. The effect of 4-MU on their vascularization, survival and growth were studied by intravital fluorescence microscopy, histology and immunohistochemistry. Main Results Non-cytotoxic doses of 4-MU effectively inhibited vascular sprout formation in the rat aortic ring assay. Endometriotic lesions in dorsal skinfold chambers of 4-MU-treated mice dose-dependently exhibited a significantly smaller vascularized area and lower functional microvessel density when compared to vehicle-treated controls. Histological analyses revealed a downregulation of HA expression in 4-MU-treated lesions. This was associated with a reduced density of CD31-positive microvessels within the lesions. In contrast, numbers of PCNA-positive proliferating and cleaved caspase-3-positive apoptotic cells did not differ between 4-MU-treated and control lesions. Conclusions The present study demonstrates for the first time that targeting the synthesis of HA suppresses angiogenesis in developing endometriotic lesions. Further studies have to clarify now whether in the future this

  15. Quantification of Head Movement Predictability and Implications for Suppression of Vestibular Input during Locomotion

    PubMed Central

    MacNeilage, Paul R.; Glasauer, Stefan

    2017-01-01

    Achieved motor movement can be estimated using both sensory and motor signals. The value of motor signals for estimating movement should depend critically on the stereotypy or predictability of the resulting actions. As predictability increases, motor signals become more reliable indicators of achieved movement, so weight attributed to sensory signals should decrease accordingly. Here we describe a method to quantify this predictability for head movement during human locomotion by measuring head motion with an inertial measurement unit (IMU), and calculating the variance explained by the mean movement over one stride, i.e., a metric similar to the coefficient of determination. Predictability exhibits differences across activities, being most predictable during running, and changes over the course of a stride, being least predictable around the time of heel-strike and toe-off. In addition to quantifying predictability, we relate this metric to sensory-motor weighting via a statistically optimal model based on two key assumptions: (1) average head movement provides a conservative estimate of the efference copy prediction, and (2) noise on sensory signals scales with signal magnitude. The model suggests that differences in predictability should lead to changes in the weight attributed to vestibular sensory signals for estimating head movement. In agreement with the model, prior research reports that vestibular perturbations have greatest impact at the time points and during activities where high vestibular weight is predicted. Thus, we propose a unified explanation for time-and activity-dependent modulation of vestibular effects that was lacking previously. Furthermore, the proposed predictability metric constitutes a convenient general method for quantifying any kind of kinematic variability. The probabilistic model is also general; it applies to any situation in which achieved movement is estimated from both motor signals and zero-mean sensory signals with signal

  16. Concomitant Administration of a Histamine2 Receptor Antagonist and Proton Pump Inhibitor Enhances Gastric Acid Suppression.

    PubMed

    Abdul-Hussein, Mustafa; Freeman, Janice; Castell, Donald

    2015-12-01

    ranitidine alone (27.94%, p=0.0002). When a PPI and H2 RA were administered concomitantly 30 minutes before breakfast, the H2 RA did not decrease the acid suppressive ability of the PPI; rather, it improved gastric acid control. Thus these results failed to support the initial hypothesis of this study. Further prospective studies are needed to test these findings in patients with gastroesophageal reflux disease as well as those with erosive esophagitis. © 2015 Pharmacotherapy Publications, Inc.

  17. Suppression Effects of Betaine-Enriched Spinach on Hyperhomocysteinemia Induced by Guanidinoacetic Acid and Choline Deficiency in Rats

    PubMed Central

    Liu, Yi-Qun; Jia, Zheng; Han, Feng; Inakuma, Takahiro; Miyashita, Tatsuya; Sugiyama, Kimio; Sun, Li-Cui; Xiang, Xue-Song; Huang, Zhen-Wu

    2014-01-01

    Betaine is an important natural component of rich food sources, especially spinach. Rats were fed diets with betaine or spinach powder at the same level of betaine for 10 days to investigate the dose-dependent effects of spinach powder supplementation on hyperhomocysteinemia induced by guanidinoacetic acid (GAA) addition and choline deprivation. The GAA-induced hyperhomocysteinemia in rats fed 25% casein diet (25C) was significantly suppressed by supplementation with betaine or spinach, and it was completely suppressed by taking 11.0% spinach supplementation. The choline deprivation-induced enhancement of plasma homocysteine concentration in rats fed 25% soybean protein diet (25S) was markedly suppressed by 3.82% spinach. Supplementation with betaine or spinach partially prevented the effects of GAA on hepatic concentrations of methionine metabolites. The decrease in activity of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine β-synthase (CBS) in GAA-induced hyperhomocysteinemia was recovered by supplementation with betaine or spinach. Supplementation with betaine or spinach did not affect BHMT activity, whereas it partially restored CBS activity in choline-deprived 25S. The results indicated that betaine or spinach could completely suppress the hyperhomocysteinemia induced by choline deficiency resulting from stimulating the homocysteine removal by both remethylation and cystathionine formation. PMID:25250392

  18. Young Age Predicts Poor Antiretroviral Adherence and Viral Load Suppression Among Injection Drug Users

    PubMed Central

    Hadland, Scott E.; Milloy, M.-J.; Kerr, Thomas; Zhang, Ruth; Guillemi, Silvia; Hogg, Robert S.; Montaner, Julio S.

    2012-01-01

    Abstract Previous studies of adherence to antiretroviral therapy (ART) for HIV among young injection drug users (IDU) have been limited because financial barriers to care disproportionately affect youth, thus confounding results. This study examines adherence among IDU in a unique setting where all medical care is provided free-of-charge. From May 1996 to April 2008, we followed a prospective cohort of 545 HIV-positive IDU of 18 years of age or older in Vancouver, Canada. Using generalized estimating equations (GEE), we studied the association between age and adherence (obtaining ART≥95% of the prescribed time), controlling for potential confounders. Using Cox proportional hazards regression, we also studied the effect of age on time to viral load suppression (<500 copies per milliliter), and examined adherence as a mediating variable. Five hundred forty-five participants were followed for a median of 23.8 months (interquartile range [IQR]=8.5–91.6 months). Odds of adherence were significantly lower among younger IDU (adjusted odds ratio [AOR]=0.76 per 10 years younger; 95% confidence interval [CI], 0.65–0.89). Younger IDU were also less likely to achieve viral load suppression (adjusted hazard ratio [AHR]=0.75 per 10 years younger; 95% CI, 0.64–0.88). Adding adherence to the model eliminated this association with age, supporting the role of adherence as a mediating variable. Despite absence of financial barriers, younger IDU remain less likely to adhere to ART, resulting in inferior viral load suppression. Interventions should carefully address the unique needs of young HIV-positive IDU. PMID:22429003

  19. Predictive Factors of Plasma HIV Suppression during Pregnancy: A Prospective Cohort Study in Benin

    PubMed Central

    Ogouyemi-Hounto, Aurore; Azon-Kouanou, Angèle; d'Almeida, Marcelline; Azondékon, Alain; Alao, Marouf J.; Dossou-Gbété, Véronique; Afangnihoun, Aldric; Girard, Pierre-Marie; Cot, Michel; Zannou, Djimon-Marcel

    2013-01-01

    Objective To investigate the factors associated with HIV1 RNA plasma viral load (pVL) below 40 copies/mL at the third trimester of pregnancy, as part of prevention of mother-to-child transmission (PMTCT) in Benin. Design Sub study of the PACOME clinical trial of malaria prophylaxis in HIV-infected pregnant women, conducted before and after the implementation of the WHO 2009 revised guidelines for PMTCT. Methods HIV-infected women were enrolled in the second trimester of pregnancy. Socio-economic characteristics, HIV history, clinical and biological characteristics were recorded. Malaria prevention and PMTCT involving antiretroviral therapy (ART) for mothers and infants were provided. Logistic regression helped identifying factors associated with virologic suppression at the end of pregnancy. Results Overall 217 third trimester pVLs were available, and 71% showed undetectability. Virologic suppression was more frequent in women enrolled after the change in PMTCT recommendations, advising to start ART at 14 weeks instead of 28 weeks of pregnancy. In multivariate analysis, Fon ethnic group (the predominant ethnic group in the study area), regular job, first and second pregnancy, higher baseline pVL and impaired adherence to ART were negative factors whereas higher weight, higher antenatal care attendance and longer ART duration were favorable factors to achieve virologic suppression. Conclusions This study provides more evidence that ART has to be initiated before the last trimester of pregnancy to achieve an undetectable pVL before delivery. In Benin, new recommendations supporting early initiation were well implemented and, together with a high antenatal care attendance, led to high rate of virologic control. PMID:23555035

  20. Fructose suppresses uric acid excretion to the intestinal lumen as a result of the induction of oxidative stress by NADPH oxidase activation.

    PubMed

    Kaneko, Chihiro; Ogura, Jiro; Sasaki, Shunichi; Okamoto, Keisuke; Kobayashi, Masaki; Kuwayama, Kaori; Narumi, Katsuya; Iseki, Ken

    2017-03-01

    A high intake of fructose increases the risk for hyperuricemia. It has been reported that long-term fructose consumption suppressed renal uric acid excretion and increased serum uric acid level. However, the effect of single administration of fructose on excretion of uric acid has not been clarified. We used male Wistar rats, which were orally administered fructose (5g/kg). Those rats were used in each experiment at 12h after administration. Single administration of fructose suppressed the function of ileal uric acid excretion and had no effect on the function of renal uric acid excretion. Breast cancer resistance protein (BCRP) predominantly contributes to intestinal excretion of uric acid as an active homodimer. Single administration of fructose decreased BCRP homodimer level in the ileum. Moreover, diphenyleneiodonium (DPI), an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), recovered the suppression of the function of ileal uric acid excretion and the Bcrp homodimer level in the ileum of rats that received single administration of fructose. Single administration of fructose decreases in BCRP homodimer level, resulting in the suppression the function of ileal uric acid excretion. The suppression of the function of ileal uric acid excretion by single administration of fructose is caused by the activation of Nox. The results of our study provide a new insight into the mechanism of fructose-induced hyperuricemia. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. The suppression of the N-nitrosating reaction by chlorogenic acid.

    PubMed Central

    Kono, Y; Shibata, H; Kodama, Y; Sawa, Y

    1995-01-01

    N-Nitrosation of a model aromatic amine (2,3-diamino-naphthalene) by the N-nitrosating agent produced by nitrite in acidic solution was inhibited by a polyphenol, chlorogenic acid, which is an ester of caffeic acid quinic acid. Caffeic acid also inhibited the N-nitrosation, but quinic acid did not. 1,2-Benzenediols and 3,4-dihydroxybenzoic acid had inhibitory activities. Chlorogenic acid, caffeic acid, 1,2-benzenediols and 3,4-dihydroxybenzoic acid were able to scavenge the stable free radical, 1,1-diphenyl-2-picrylhydrazyl. Chlorogenic acid was found to be nitrated by acidic nitrite. The kinetic studies and the nitration observed only by bubbling of nitric oxide plus nitrogen dioxide gases indicated that the nitrating agent was nitrogen sesquioxide. The observations showed that the mechanism by which chlorogenic acid inhibited N-nitrosation of 2,3-diamino-naphthalene is due to its ability to scavenge the nitrosating agent, nitrogen sesquioxide. Chlorogenic acid may be effective not only in protecting against oxidative damage but also in inhibiting potentially mutagenic and carcinogenic reactions in vivo. PMID:8554543

  2. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting

    EPA Science Inventory

    T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and...

  3. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting

    EPA Science Inventory

    T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and...

  4. Computer Aided Prediction of Biological Activity Spectra: Study of Correlation between Predicted and Observed Activities for Coumarin-4-Acetic Acids

    PubMed Central

    Basanagouda, M.; Jadhav, V. B.; Kulkarni, M. V.; Rao, R. Nagendra

    2011-01-01

    Coumarin-4-acetic acids have been synthesized from various phenols and citric acid under Pechmann cyclisation conditions. All the compounds have been evaluated for antiinflammatory and analgesic activity in acute models. Compounds have also been evaluated for their ulcerogenic potential. Using the computer program, prediction of activity spectra for substances, prediction results and their Pharma Expert software, we have found a correlation between the observed and predicted antiinflammatory activity. PMID:22131629

  5. A Clostridium Group IV Species Dominates and Suppresses a Mixed Culture Fermentation by Tolerance to Medium Chain Fatty Acids Products.

    PubMed

    Andersen, Stephen J; De Groof, Vicky; Khor, Way Cern; Roume, Hugo; Props, Ruben; Coma, Marta; Rabaey, Korneel

    2017-01-01

    A microbial community is engaged in a complex economy of cooperation and competition for carbon and energy. In engineered systems such as anaerobic digestion and fermentation, these relationships are exploited for conversion of a broad range of substrates into products, such as biogas, ethanol, and carboxylic acids. Medium chain fatty acids (MCFAs), for example, hexanoic acid, are valuable, energy dense microbial fermentation products, however, MCFA tend to exhibit microbial toxicity to a broad range of microorganisms at low concentrations. Here, we operated continuous mixed population MCFA fermentations on biorefinery thin stillage to investigate the community response associated with the production and toxicity of MCFA. In this study, an uncultured species from the Clostridium group IV (related to Clostridium sp. BS-1) became enriched in two independent reactors that produced hexanoic acid (up to 8.1 g L(-1)), octanoic acid (up to 3.2 g L(-1)), and trace concentrations of decanoic acid. Decanoic acid is reported here for the first time as a possible product of a Clostridium group IV species. Other significant species in the community, Lactobacillus spp. and Acetobacterium sp., generate intermediates in MCFA production, and their collapse in relative abundance resulted in an overall production decrease. A strong correlation was present between the community composition and both the hexanoic acid concentration (p = 0.026) and total volatile fatty acid concentration (p = 0.003). MCFA suppressed species related to Clostridium sp. CPB-6 and Lactobacillus spp. to a greater extent than others. The proportion of the species related to Clostridium sp. BS-1 over Clostridium sp. CPB-6 had a strong correlation with the concentration of octanoic acid (p = 0.003). The dominance of this species and the increase in MCFA resulted in an overall toxic effect on the mixed community, most significantly on the Lactobacillus spp., which resulted in a decrease in total

  6. A Clostridium Group IV Species Dominates and Suppresses a Mixed Culture Fermentation by Tolerance to Medium Chain Fatty Acids Products

    PubMed Central

    Andersen, Stephen J.; De Groof, Vicky; Khor, Way Cern; Roume, Hugo; Props, Ruben; Coma, Marta; Rabaey, Korneel

    2017-01-01

    A microbial community is engaged in a complex economy of cooperation and competition for carbon and energy. In engineered systems such as anaerobic digestion and fermentation, these relationships are exploited for conversion of a broad range of substrates into products, such as biogas, ethanol, and carboxylic acids. Medium chain fatty acids (MCFAs), for example, hexanoic acid, are valuable, energy dense microbial fermentation products, however, MCFA tend to exhibit microbial toxicity to a broad range of microorganisms at low concentrations. Here, we operated continuous mixed population MCFA fermentations on biorefinery thin stillage to investigate the community response associated with the production and toxicity of MCFA. In this study, an uncultured species from the Clostridium group IV (related to Clostridium sp. BS-1) became enriched in two independent reactors that produced hexanoic acid (up to 8.1 g L−1), octanoic acid (up to 3.2 g L−1), and trace concentrations of decanoic acid. Decanoic acid is reported here for the first time as a possible product of a Clostridium group IV species. Other significant species in the community, Lactobacillus spp. and Acetobacterium sp., generate intermediates in MCFA production, and their collapse in relative abundance resulted in an overall production decrease. A strong correlation was present between the community composition and both the hexanoic acid concentration (p = 0.026) and total volatile fatty acid concentration (p = 0.003). MCFA suppressed species related to Clostridium sp. CPB-6 and Lactobacillus spp. to a greater extent than others. The proportion of the species related to Clostridium sp. BS-1 over Clostridium sp. CPB-6 had a strong correlation with the concentration of octanoic acid (p = 0.003). The dominance of this species and the increase in MCFA resulted in an overall toxic effect on the mixed community, most significantly on the Lactobacillus spp., which resulted in a decrease in total

  7. Dynamic vortex interactions with flexible fibers and edges for prediction of owl noise suppression

    NASA Astrophysics Data System (ADS)

    Korykora, Sarah; Jaworski, Justin

    2015-11-01

    The compliant trailing-edge fringe of owls and the soft downy material on their upper wing surfaces are thought to enable their silent flight by weakening the interaction of boundary layer turbulence with these flexible structures. Previous analysis of turbulence noise generation by wave-bearing elastic edges have shown that the far-field acoustic power scaling can be weakened by up to the square of the Mach number relative to a rigid edge. However, it is unclear whether or not the wave-bearing feature or simply the flexible nature of the edge scatterer produces this noise suppression. To assess this distinction, a dynamic vortex interaction model is developed whereby the motion of a line vortex round a rigid but elastically-restrained wall-mounted fiber or trailing edge is determined numerically. Special attention is paid to the dynamic interaction between the flexible structure and vortex, which is accomplished via a conformal mapping relationship determined in closed form. Results from this analysis seek to develop a vortex sound model to discern the effect of flexible versus wave-bearing scatterers on turbulence noise suppression and help explain the mechanisms of silent owl flight.

  8. Negotiators' profit predicted by cognitive reappraisal, suppression of emotions, misrepresentation of information, and tolerance of ambiguity.

    PubMed

    Yurtsever, Gülçimen

    2008-04-01

    This study examined the relationship between negative emotions and variables that affect negotiators' profit. Based on a simulated negotiation, this study induced emotions by providing negative feedback on how negotiating partners perceived and evaluated each other's behavior. Then relationships were examined between negative emotions and emotional regulation strategies, misrepresentation of information, tolerance of ambiguity, and negotiators' profit. A total of 228 undergraduate students enrolled in an economics course in the Faculty of Law and the Faculty of Management at a university in Ankara participated. There were 130 students in the experimental group and 98 students in the control group; 102 were men and 126 were women, ages 17 to 35 years (M =22.6 yr., SD = 2.3). A simulated negotiation process was used. Regression coefficients suggested positive relation between Emotional Reaction and the use of a Suppression strategy and Misrepresentation of Information. Negative coefficients were obtained from scores between Emotional Reaction and Cognitive Reappraisal and Tolerance of Ambiguity. The regression also suggested there were negative regression coefficients linking Misrepresentation of Information and Suppression strategies to Negotiators' Profit. Positive regression coefficients linked Tolerance of Ambiguity to Negotiators' Profit. Mediating variables explained 55% of variance in Negotiators' Profit; the majority (43%) was explained by Cognitive Reappraisal.

  9. Predicting the Viscosity of Low VOC Vinyl Ester and Fatty Acid-Based Resins

    DTIC Science & Technology

    2005-12-01

    The sample was titrated with the perchloric acid / peracetic acid solution (Aldrich) until the indicator, 0.1% crystal violet in acetic acid (Aldrich...Predicting the Viscosity of Low VOC Vinyl Ester and Fatty Acid -Based Resins by John J. La Scala, Amutha Jeyarajasingam, Cherise Winston...Aberdeen Proving Ground, MD 21005-5069 ARL-TR-3681 December 2005 Predicting the Viscosity of Low VOC Vinyl Ester and Fatty Acid -Based

  10. Plasma long-chain free fatty acids predict mammalian longevity.

    PubMed

    Jové, Mariona; Naudí, Alba; Aledo, Juan Carlos; Cabré, Rosanna; Ayala, Victoria; Portero-Otin, Manuel; Barja, Gustavo; Pamplona, Reinald

    2013-11-28

    Membrane lipid composition is an important correlate of the rate of aging of animals and, therefore, the determination of their longevity. In the present work, the use of high-throughput technologies allowed us to determine the plasma lipidomic profile of 11 mammalian species ranging in maximum longevity from 3.5 to 120 years. The non-targeted approach revealed a specie-specific lipidomic profile that accurately predicts the animal longevity. The regression analysis between lipid species and longevity demonstrated that the longer the longevity of a species, the lower is its plasma long-chain free fatty acid (LC-FFA) concentrations, peroxidizability index, and lipid peroxidation-derived products content. The inverse association between longevity and LC-FFA persisted after correction for body mass and phylogenetic interdependence. These results indicate that the lipidomic signature is an optimized feature associated with animal longevity, emerging LC-FFA as a potential biomarker of longevity.

  11. Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors

    PubMed Central

    Kang, Jaeseung; Kim, Eunjoon

    2015-01-01

    Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits. PMID:26074764

  12. HIV-Protease Inhibitors Suppress Skeletal Muscle Fatty Acid Oxidation by Reducing CD36 and CPT-I Fatty Acid Transporters

    PubMed Central

    Richmond, Scott R.; Carper, Michael J.; Lei, Xiaoyong; Zhang, Sheng; Yarasheski, Kevin E.; Ramanadham, Sasanka

    2010-01-01

    Infection with human immunodeficiency virus (HIV) and treatment with HIV-protease inhibitor (PI)-based highly active antiretroviral therapies (HAART) is associated with dysregulated fatty acid and lipid metabolism. Enhanced lipolysis, increased circulating fatty acid levels, and hepatic and intramuscular lipid accumulation appear to contribute to insulin resistance in HIV-infected people treated with PI-based HAART. However, it is unclear whether currently prescribed HIV-PIs directly alter skeletal muscle fatty acid transport, oxidation, and storage. We find that ritonavir (r, 5 μmol/l) plus 20 μmol/l of atazanavir (ATV), lopinavir (LPV), or darunavir (DRV) reduce palmitate oxidation(16-21%) in differentiated C2C12 myotubes. Palmitate oxidation was increased following exposure to high fatty acid media but this effect was blunted when myotubes were pre-exposed to the HIV-PIs. However, LPV/r and DRV/r, but not ATV/r suppressed palmitate uptake into myotubes. We found no effect of the HIV-PIs on FATP1, FATP4, or FABPpm but both CD36/FAT and carnitine palmitoyltransferase I (CPTI) were reduced by all three regimens though ATV/r caused only a small decrease in CPT1, relative to LPV/r or DRV/r. In contrast, sterol regulatory element binding protein-1 was increased by all 3 HIV-PIs. These findings suggest that HIV-PIs suppress fatty acid oxidation in murine skeletal muscle cells and that this may be related to decreases in cytosolic- and mitochondrial-associated fatty acid transporters. HIV-PIs may also directly impair fatty acid handling and partitioning in skeletal muscle, and this may contribute to the cluster of metabolic complications that occur in people living with HIV. PMID:20117238

  13. Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis.

    PubMed

    Ali, Asem H; Mundi, Manpreet; Koutsari, Christina; Bernlohr, David A; Jensen, Michael D

    2015-08-01

    Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-(13)C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L(-1) (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min(-1) (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min(-1), respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid(-1) ⋅ min(-1), respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway.

  14. Adipose Tissue Free Fatty Acid Storage In Vivo: Effects of Insulin Versus Niacin as a Control for Suppression of Lipolysis

    PubMed Central

    Ali, Asem H.; Mundi, Manpreet; Koutsari, Christina; Bernlohr, David A.

    2015-01-01

    Insulin stimulates the translocation fatty acid transport protein 1 (FATP1) to plasma membrane, and thus greater free fatty acid (FFA) uptake, in adipocyte cell models. Whether insulin stimulates greater FFA clearance into adipose tissue in vivo is unknown. We tested this hypothesis by comparing direct FFA storage in subcutaneous adipose tissue during insulin versus niacin-medicated suppression of lipolysis. We measured direct FFA storage in abdominal and femoral subcutaneous fat in 10 and 11 adults, respectively, during euglycemic hyperinsulinemia or after oral niacin to suppress FFA compared with 11 saline control experiments. Direct palmitate storage was assessed using a [U-13C]palmitate infusion to measure palmitate kinetics and an intravenous palmitate radiotracer bolus/timed biopsy. Plasma palmitate concentrations and flux were suppressed to 23 ± 3 and 26 ± 5 µmol ⋅ L−1 (P = 0.91) and 44 ± 4 and 39 ± 5 µmol ⋅ min−1 (P = 0.41) in the insulin and niacin groups, respectively, much less (P < 0.001) than the saline control group (102 ± 8 and 104 ± 12 µmol ⋅ min−1, respectively). In the insulin, niacin, and saline groups, abdominal palmitate storage rates were 0.25 ± 0.05 vs. 0.25 ± 0.07 vs. 0.32 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS), and femoral adipose storage rates were 0.19 ± 0.06 vs. 0.20 ± 0.05 vs. 0.31 ± 0.05 µmol ⋅ kg adipose lipid−1 ⋅ min−1, respectively (P = NS). In conclusion, insulin does not increase FFA storage in adipose tissue compared with niacin, which suppresses lipolysis via a different pathway. PMID:25883112

  15. Hyaluronic Acid Suppresses the Expression of Metalloproteinases in Osteoarthritic Cartilage Stimulated Simultaneously by Interleukin 1β and Mechanical Load

    PubMed Central

    Pohlig, Florian; Guell, Florian; Lenze, Ulrich; Lenze, Florian W.; Mühlhofer, Heinrich M. L.; Schauwecker, Johannes; Toepfer, Andreas; Mayer-Kuckuk, Philipp; von Eisenhart-Rothe, Rüdiger; Burgkart, Rainer; Salzmann, Gian M.

    2016-01-01

    Purpose In patients with osteoarthritis (OA), intraarticular injection of hyaluronic acid (HA) frequently results in reduced pain and improved function for prolonged periods of time, i.e. more than 6 months. However, the mechanisms underlying these effects are not fully understood. Our underlying hypothesis is that HA modifies the enzymatic breakdown of joint tissues. Methods To test this hypothesis, we examined osteochondral cylinders from 12 OA patients. In a bioreactor, these samples were stimulated by interleukin 1β (Il1ß) (2 ng/ml) plus mechanical load (2.0 Mpa at 0.5 Hz horizontal and 0.1 Hz vertical rotation), thus the experimental setup recapitulated both catabolic and anabolic clues of the OA joint. Results Upon addition of HA at either 1 or 3 mg/ml, we observed a significant suppression of expression of metalloproteinase (MMP)-13. A more detailed analysis based on the Kellgren and Lawrence (K&L) OA grade, showed a much greater degree of suppression of MMP-13 expression in grade IV as compared to grade II OA. In contrast to the observed MMP-13 suppression, treatment with HA resulted in a suppression of MMP-1 expression only at 1 mg/ml HA, while MMP-2 expression was not significantly affected by either HA concentration. Conclusion Together, these data suggest that under concurrent catabolic and anabolic stimulation, HA exhibits a pronounced suppressive effect on MMP-13. In the long-run these findings may benefit the development of treatment strategies aimed at blocking tissue degradation in OA patients. PMID:26934732

  16. Nine-amino-acid transactivation domain: establishment and prediction utilities.

    PubMed

    Piskacek, Simona; Gregor, Martin; Nemethova, Maria; Grabner, Martin; Kovarik, Pavel; Piskacek, Martin

    2007-06-01

    Here we describe the establishment and prediction utilities for a novel nine-amino-acid transactivation domain, 9aa TAD, that is common to the transactivation domains of a large number of yeast and animal transcription factors. We show that the 9aa TAD motif is required for the function of the transactivation domain of Gal4 and the related transcription factors Oaf1 and Pip2. The 9aa TAD possesses an autonomous transactivation activity in yeast and mammalian cells. Using sequence alignment and experimental data we derived a pattern that can be used for 9aa TAD prediction. The pattern allows the identification of 9aa TAD in other Gal4 family members or unrelated yeast, animal, and viral transcription factors. Thus, the 9aa TAD represents the smallest known denominator for a broad range of transcription factors. The wide occurrence of the 9aa TAD suggests that this domain mediates conserved interactions with general transcriptional cofactors. A computational search for the 9aa TAD is available online from National EMBnet-Node Austria at http://www.at.embnet.org/toolbox/9aatad/.

  17. Improved nucleic acid descriptors for siRNA efficacy prediction

    PubMed Central

    Sciabola, Simone; Cao, Qing; Orozco, Modesto; Faustino, Ignacio; Stanton, Robert V.

    2013-01-01

    Although considerable progress has been made recently in understanding how gene silencing is mediated by the RNAi pathway, the rational design of effective sequences is still a challenging task. In this article, we demonstrate that including three-dimensional descriptors improved the discrimination between active and inactive small interfering RNAs (siRNAs) in a statistical model. Five descriptor types were used: (i) nucleotide position along the siRNA sequence, (ii) nucleotide composition in terms of presence/absence of specific combinations of di- and trinucleotides, (iii) nucleotide interactions by means of a modified auto- and cross-covariance function, (iv) nucleotide thermodynamic stability derived by the nearest neighbor model representation and (v) nucleic acid structure flexibility. The duplex flexibility descriptors are derived from extended molecular dynamics simulations, which are able to describe the sequence-dependent elastic properties of RNA duplexes, even for non-standard oligonucleotides. The matrix of descriptors was analysed using three statistical packages in R (partial least squares, random forest, and support vector machine), and the most predictive model was implemented in a modeling tool we have made publicly available through SourceForge. Our implementation of new RNA descriptors coupled with appropriate statistical algorithms resulted in improved model performance for the selection of siRNA candidates when compared with publicly available siRNA prediction tools and previously published test sets. Additional validation studies based on in-house RNA interference projects confirmed the robustness of the scoring procedure in prospective studies. PMID:23241392

  18. Gambogic acid suppresses inflammation in rheumatoid arthritis rats via PI3K/Akt/mTOR signaling pathway.

    PubMed

    Wu, Xiaodan; Long, Li; Liu, Jian; Zhang, Jin; Wu, Tong; Chen, Xixi; Zhou, Bing; Lv, Ting-Zhuo

    2017-09-11

    Gamboge is the dried resin secreted by the Garcinia maingayi gambogic tree and is a substance that may be used to treat a variety of diseases, exhibits anti‑tumor and detoxification effects and prevents bleeding. The primary active constituent is gambogic acid. The present study aimed to investigate the anti‑inflammatory effects of gambogic acid in rheumatoid arthritis (RA) rats and to elucidate the mechanisms by which these effects occur. The swelling degree, the clinical arthritic scoring and pain threshold measurements were used to evaluate the effects of gambogic acid on RA. ELISA kits and western blot analysis were used to investigate inflammatory processes and the expression of RA‑associated proteins, respectively. The present results demonstrated that gambogic acid significantly inhibited the degree of right foot swelling, increased pain thresholds and reduced clinical arthritic scores of RA rats. Treatment with gambogic acid suppressed the activities of interleukin (IL)‑1β and IL‑6, promoted the protein expression of phosphorylated (p)‑Akt serine/threonine kinase (Akt), p‑mammalian target protein of rapamycin (mTOR) and inhibited hypoxia‑inducible factor‑1α and vascular endothelial growth factor expression in RA rats. The results of the present study therefore suggest that the anti‑inflammatory effects of gambogic acid in RA rats occur via regulation of the phosphoinositide 3‑kinase/Akt/mTOR signaling pathway.

  19. Relief of delayed oxidative stress by ascorbic acid can suppress radiation-induced cellular senescence in mammalian fibroblast cells.

    PubMed

    Kobashigawa, Shinko; Kashino, Genro; Mori, Hiromu; Watanabe, Masami

    2015-03-01

    Ionizing radiation-induced cellular senescence is thought to be caused by nuclear DNA damage that cannot be repaired. However, here we found that radiation induces delayed increase of intracellular oxidative stress after irradiation. We investigated whether the relief of delayed oxidative stress by ascorbic acid would suppress the radiation-induced cellular senescence in Syrian golden hamster embryo (SHE) cells. We observed that the level of oxidative stress was drastically increased soon after irradiation, then declined to the level in non-irradiated cells, and increased again with a peak on day 3 after irradiation. We found that the inductions of cellular senescence after X-irradiation were reduced along with suppression of the delayed induction of oxidative stress by treatment with ascorbic acid, but not when oxidative stress occurred immediately after irradiation. Moreover, treatment of ascorbic acid inhibited p53 accumulation at 3 days after irradiation. Our data suggested a delayed increase of intracellular oxidative stress levels plays an important role in the process of radiation-induced cellular senescence by p53 accumulation.

  20. Suppression of muscle wasting by the plant‐derived compound ursolic acid in a model of chronic kidney disease

    PubMed Central

    Yu, Rizhen; Chen, Ji‐an; Xu, Jing; Cao, Jin; Wang, Yanlin; Thomas, Sandhya S.

    2016-01-01

    Abstract Background Muscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF‐1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation. Methods Using in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone. Results Using cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD‐induced or dexamethasone‐induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF‐β, IL‐6 and TNFα), which are initiators of muscle‐specific ubiquitin‐E3 ligases (e.g. Atrogin‐1, MuRF‐1 and MUSA1). Conclusions Ursolic acid improves CKD‐induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis. PMID:27897418

  1. Innovations in host and microbial sialic acid biosynthesis revealed by phylogenomic prediction of nonulosonic acid structure

    PubMed Central

    Lewis, Amanda L.; Desa, Nolan; Hansen, Elizabeth E.; Knirel, Yuriy A.; Gordon, Jeffrey I.; Gagneux, Pascal; Nizet, Victor; Varki, Ajit

    2009-01-01

    Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of ≈1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the “unique” Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars. PMID:19666579

  2. Assessing the Role of ETHYLENE RESPONSE FACTOR Transcriptional Repressors in Salicylic Acid-Mediated Suppression of Jasmonic Acid-Responsive Genes.

    PubMed

    Caarls, Lotte; Van der Does, Dieuwertje; Hickman, Richard; Jansen, Wouter; Verk, Marcel C Van; Proietti, Silvia; Lorenzo, Oscar; Solano, Roberto; Pieterse, Corné M J; Van Wees, Saskia C M

    2017-02-01

    Salicylic acid (SA) and jasmonic acid (JA) cross-communicate in the plant immune signaling network to finely regulate induced defenses. In Arabidopsis, SA antagonizes many JA-responsive genes, partly by targeting the ETHYLENE RESPONSE FACTOR (ERF)-type transcriptional activator ORA59. Members of the ERF transcription factor family typically bind to GCC-box motifs in the promoters of JA- and ethylene-responsive genes, thereby positively or negatively regulating their expression. The GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Here, we investigated whether SA-induced ERF-type transcriptional repressors, which may compete with JA-induced ERF-type activators for binding at the GCC-box, play a role in SA/JA antagonism. We selected ERFs that are transcriptionally induced by SA and/or possess an EAR transcriptional repressor motif. Several of the 16 ERFs tested suppressed JA-dependent gene expression, as revealed by enhanced JA-induced PDF1.2 or VSP2 expression levels in the corresponding erf mutants, while others were involved in activation of these genes. However, SA could antagonize JA-induced PDF1.2 or VSP2 in all erf mutants, suggesting that the tested ERF transcriptional repressors are not required for SA/JA cross-talk. Moreover, a mutant in the co-repressor TOPLESS, that showed reduction in repression of JA signaling, still displayed SA-mediated antagonism of PDF1.2 and VSP2. Collectively, these results suggest that SA-regulated ERF transcriptional repressors are not essential for antagonism of JA-responsive gene expression by SA. We further show that de novo SA-induced protein synthesis is required for suppression of JA-induced PDF1.2, pointing to SA-stimulated production of an as yet unknown protein that suppresses JA-induced transcription.

  3. Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer.

    PubMed

    Babu, Ellappan; Bhutia, Yangzom D; Ramachandran, Sabarish; Gnanaprakasam, Jaya P; Prasad, Puttur D; Thangaraju, Muthusamy; Ganapathy, Vadivel

    2015-07-01

    SLC6A14 mediates Na(+)/Cl(-)-coupled concentrative uptake of a broad-spectrum of amino acids. It is expressed at low levels in many tissues but up-regulated in certain cancers. Pharmacological blockade of SLC6A14 causes amino acid starvation in estrogen receptor positive (ER+) breast cancer cells and suppresses their proliferation in vitro and in vivo. In the present study, we interrogated the role of this transporter in breast cancer by deleting Slc6a14 in mice and monitoring the consequences of this deletion in models of spontaneous breast cancer (Polyoma middle T oncogene-transgenic mouse and mouse mammary tumour virus promoter-Neu-transgenic mouse). Slc6a14-knockout mice are viable, fertile and phenotypically normal. The plasma amino acids were similar in wild-type and knockout mice and there were no major compensatory changes in the expression of other amino acid transporter mRNAs. There was also no change in mammary gland development in the knockout mouse. However, when crossed with PyMT-Tg mice or MMTV/Neu (mouse mammary tumour virus promoter-Neu)-Tg mice, the development and progression of breast cancer were markedly decreased on Slc6a14(-/-) background. Analysis of transcriptomes in tumour tissues from wild-type mice and Slc6a14-null mice indicated no compensatory changes in the expression of any other amino acid transporter mRNA. However, the tumours from the null mice showed evidence of amino acid starvation, decreased mTOR signalling and decreased cell proliferation. These studies demonstrate that SLC6A14 is critical for the maintenance of amino acid nutrition and optimal mammalian target of rapamycin (mTOR) signalling in ER+ breast cancer and that the transporter is a potential target for development of a novel class of anti-cancer drugs targeting amino acid nutrition in tumour cells.

  4. Jasmonic acid-mediated defense suppresses brassinosteroid-mediated susceptibility to Rice black streaked dwarf virus infection in rice.

    PubMed

    He, Yuqing; Zhang, Hehong; Sun, Zongtao; Li, Junmin; Hong, Gaojie; Zhu, Qisong; Zhou, Xuebiao; MacFarlane, Stuart; Yan, Fei; Chen, Jianping

    2017-04-01

    Plant hormones play a vital role in plant immune responses. However, in contrast to the relative wealth of information on hormone-mediated immunity in dicot plants, little information is available on monocot-virus defense systems. We used a high-throughput-sequencing approach to compare the global gene expression of Rice black-streaked dwarf virus (RBSDV)-infected rice plants with that of healthy plants. Exogenous hormone applications and transgenic rice were used to test RBSDV infectivity and pathogenicity. Our results revealed that the jasmonic acid (JA) pathway was induced while the brassinosteroid (BR) pathway was suppressed in infected plants. Foliar application of methyl jasmonate (MeJA) or brassinazole (BRZ) resulted in a significant reduction in RBSDV incidence, while epibrassinolide (BL) treatment increased RBSDV infection. Infection studies using coi1-13 and Go mutants demonstrated JA-mediated resistance and BR-mediated susceptibility to RBSDV infection. A mixture of MeJA and BL treatment resulted in a significant reduction in RBSDV infection compared with a single BL treatment. MeJA application efficiently suppressed the expression of BR pathway genes, and this inhibition depended on the JA coreceptor OsCOI1. Collectively, our results reveal that JA-mediated defense can suppress the BR-mediated susceptibility to RBSDV infection. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  5. Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

    PubMed Central

    Wang, Wenwen; Yan, Min; Ji, Qiuhong; Lu, Jinbiao; Ji, Yuhua

    2015-01-01

    Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I and α-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis. PMID:26557438

  6. Interactions between "what" and "when" in the auditory system: temporal predictability enhances repetition suppression.

    PubMed

    Costa-Faidella, Jordi; Baldeweg, Torsten; Grimm, Sabine; Escera, Carles

    2011-12-14

    Neural activity in the auditory system decreases with repeated stimulation, matching stimulus probability in multiple timescales. This phenomenon, known as stimulus-specific adaptation, is interpreted as a neural mechanism of regularity encoding aiding auditory object formation. However, despite the overwhelming literature covering recordings from single-cell to scalp auditory-evoked potential (AEP), stimulation timing has received little interest. Here we investigated whether timing predictability enhances the experience-dependent modulation of neural activity associated with stimulus probability encoding. We used human electrophysiological recordings in healthy participants who were exposed to passive listening of sound sequences. Pure tones of different frequencies were delivered in successive trains of a variable number of repetitions, enabling the study of sequential repetition effects in the AEP. In the predictable timing condition, tones were delivered with isochronous interstimulus intervals; in the unpredictable timing condition, interstimulus intervals varied randomly. Our results show that unpredictable stimulus timing abolishes the early part of the repetition positivity, an AEP indexing auditory sensory memory trace formation, while leaving the later part (≈ >200 ms) unaffected. This suggests that timing predictability aids the propagation of repetition effects upstream the auditory pathway, most likely from association auditory cortex (including the planum temporale) toward primary auditory cortex (Heschl's gyrus) and beyond, as judged by the timing of AEP latencies. This outcome calls for attention to stimulation timing in future experiments regarding sensory memory trace formation in AEP measures and stimulus probability encoding in animal models.

  7. Effect of gastric acid suppression with pantoprazole on the efficacy of calcium carbonate as a phosphate binder in haemodialysis patients.

    PubMed

    Cervelli, Matthew J; Shaman, Ahmed; Meade, Anthony; Carroll, Robert; McDonald, Stephen P

    2012-07-01

      Metallic phosphate binders require acidity to dissociate to the free metallic ion and bind phosphorus. Altered gastric acidity may, therefore, influence phosphate-binding efficacy. We evaluated the clinical effect of pantoprazole on the efficacy of calcium carbonate phosphate binders in haemodialysis patients.   The study had two parts: a cross-sectional study (n = 67), and an interventional, crossover, double-blind, randomized, placebo-controlled trial in 26 patients given pantoprazole 40 mg daily or placebo for two consecutive 6-week periods.   The cross-sectional study showed no difference between those on and off acid suppressants in phosphate (1.43 ± 0.45 vs 1.46 ± 0.31 mmol/L, P = 0.782) or other parameters except age (72.2 ± 9.8 vs 63.8 ± 14.8 years, P = 0.01). In the interventional study, phosphate was higher during pantoprazole than placebo (1.59 ± 0.3 vs 1.42 ± 0.3 mmol/L, P = 0.005). Serum calcium (2.37 ± 0.2 vs 2.46 ± 0.2 mmol/L, P = 0.012) and ionized calcium (1.17 ± 0.1 vs 1.22 ± 0.1 mmol/L, P = 0.013) were lower during pantoprazole treatment. CaxPO(4) (3.76 ± 0.7 vs 3.48 ± 0.7 mmol(2) /L(2) , P = 0.032) and intact parathyroid hormone (31.9 ± 21.4 vs 23.6 ± 17.7 pmol/L, P = 0.004) were higher on pantoprazole.   These results demonstrate clinical evidence for an adverse effect of gastric acid suppression on the effectiveness of calcium carbonate phosphate binders. Given their frequent co-prescription, this interaction may be a minor but common reason why some patients fail to control hyperphosphataemia. Clinicians should regularly assess the need for acid suppressants. Further studies are needed to investigate interactions with other phosphate binders. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.

  8. Controls on suppression of methane flux from a peat bog subjected to simulated acid rain sulfate deposition

    NASA Astrophysics Data System (ADS)

    Gauci, Vincent; Dise, Nancy; Fowler, David

    2002-01-01

    The effect of acid rain SO42- deposition on peatland CH4 emissions was examined by manipulating SO42- inputs to a pristine raised peat bog in northern Scotland. Weekly pulses of dissolved Na2SO4 were applied to the bog over two years in doses of 25, 50, and 100 kg S ha-1 yr-1, reflecting the range of pollutant S deposition loads experienced in acid rain-impacted regions of the world. CH4 fluxes were measured at regular intervals using a static chamber/gas chromatographic flame ionization detector method. Total emissions of CH4 were reduced by between 21 and 42% relative to controls, although no significant differences were observed between treatments. Estimated total annual fluxes during the second year of the experiment were 16.6 g m-2 from the controls and (in order of increasing SO42- dose size) 10.7, 13.2, and 9.8 g m-2 from the three SO42- treatments, respectively. The relative extent of CH4 flux suppression varied with changes in both peat temperature and peat water table with the largest suppression during cool periods and episodes of falling water table. Our findings suggest that low doses of SO42- at deposition rates commonly experienced in areas impacted by acid rain, may significantly affect CH4 emissions from wetlands in affected areas. We propose that SO42- from acid rain can stimulate sulfate-reducing bacteria into a population capable of outcompeting methanogens for substrates. We further propose that this microbially mediated interaction may have a significant current and future effect on the contribution of northern peatlands to the global methane budget.

  9. Meta-analysis: Helicobacter pylori'test and treat' compared with empirical acid suppression for managing dyspepsia.

    PubMed

    Ford, A C; Moayyedi, P; Jarbol, D E; Logan, R F A; Delaney, B C

    2008-09-01

    Which of Helicobacter pylori'test and treat' or empirical acid suppression should be preferred for the initial management of uncomplicated dyspepsia is controversial. Aim To conduct an individual patient data meta-analysis of randomized controlled trials (RCTs) of 'test and treat' vs. empirical acid suppression in adults with uncomplicated dyspepsia in primary care. Investigators provided original data sets for analysis. Effect of management strategy on symptom status and dyspepsia-related resource use at 12-month follow-up was examined by pooling symptom and cost data to obtain relative risk (RR) of remaining symptomatic at 12 months and weighted mean difference (WMD) in costs between the two strategies with 95% confidence intervals (CI). We identified three eligible RCTs containing 1547 patients, 791 (51%) of whom were assigned to 'test and treat'. There was no difference detected in symptom-cure at 12 months (RR = 0.99; 95% CI: 0.95-1.03). There was a nonsignificant trend towards cost-savings with 'test and treat' (WMD in costs = - 28.91 pound; 95% CI: - 68.48 pound to 10.65 pound). There was little difference in symptom-resolution or costs between the two strategies. A combination of patient and physician preference should determine the initial approach to the management of uncomplicated dyspepsia.

  10. Biocontrol agents-mediated suppression of oxalic acid induced cell death during Sclerotinia sclerotiorum-pea interaction.

    PubMed

    Jain, Akansha; Singh, Akanksha; Singh, Surendra; Sarma, Birinchi Kumar; Singh, Harikesh Bahadur

    2015-05-01

    Oxalic acid (OA) is an important pathogenic factor during early Sclerotinia sclerotiorum-host interaction and might work by reducing hydrogen peroxide production (H2 O2 ). In the present investigation, oxalic acid-induced cell death in pea was studied. Pea plants treated with biocontrol agents (BCAs) viz., Pseudomonas aeruginosa PJHU15, Bacillus subtilis BHHU100, and Trichoderma harzianum TNHU27 either singly and/or in consortium acted on S. sclerotiorum indirectly by enabling plants to inhibit the OA-mediated suppression of oxidative burst via induction of H2 O2 . Our results showed that BCA treated plants upon treatment with culture filtrate of the pathogen, conferred the resistance via. significantly decreasing relative cell death of pea against S. sclerotiorum compared to control plants without BCA treatment but treated with the culture filtrate of the pathogen. The results obtained from the present study indicate that the microbes especially in consortia play significant role in protection against S. sclerotiorum by modulating oxidative burst and partially enhancing tolerance by increasing the H2 O2 generation, which is otherwise suppressed by OA produced by the pathogen. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study

    PubMed Central

    Sermet-Gaudelus, Isabelle; Renouil, Michel; Fajac, Anne; Bidou, Laure; Parbaille, Bastien; Pierrot, Sébastien; Davy, Nolwen; Bismuth, Elise; Reinert, Philippe; Lenoir, Gérard; Lesure, Jean François; Rousset, Jean Pierre; Edelman, Aleksander

    2007-01-01

    protein expression, in patients with the other stop mutations investigated in vitro and those without stop mutations. Conclusion Suppression of stop mutations in the CFTR gene with parenteral gentamicin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated Cl- transport in nasal and sweat gland epithelium. PMID:17394637

  12. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    PubMed

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae

    PubMed Central

    Tiirola, Terttu M.; Strøm, Morten B.; Vuorela, Pia M.

    2016-01-01

    We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen. PMID:27280777

  14. Amphipathic β2,2-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae.

    PubMed

    Hanski, Leena; Ausbacher, Dominik; Tiirola, Terttu M; Strøm, Morten B; Vuorela, Pia M

    2016-01-01

    We demonstrate in the current work that small cationic antimicrobial β2,2-amino acid derivatives (Mw < 500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (< 5 μM, i.e. < 3.4 μg/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the β2,2-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these β2,2-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic β2,2-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-to-treat intracellular pathogen.

  15. Dietary, but not topical, alpha-linolenic acid suppresses UVB-induced skin injury in hairless mice when compared with linoleic acids.

    PubMed

    Takemura, Naoya; Takahashi, Kazuhiko; Tanaka, Hiroshi; Ihara, Yuka; Ikemoto, Atsushi; Fujii, Yoichi; Okuyama, Harumi

    2002-12-01

    Peroxidizability of fatty acids in the air is roughly proportional to the number of double bonds, but in vivo peroxidation proceeds in a more complex manner. Here, we compared the effects of dietary and topically applied oils enriched with linoleic acid (LA, 18:2n-6) or alpha-linolenic acid (ALA, 18:3n-3) on UV-induced skin injury in a strain of hairless mice. The UVB-induced erythema score was significantly lower in mice with topically applied creams containing LA and ALA than in mice with the basal cream; no significant increase in the score was detected in the ALA group compared with the LA group. However, dietary ALA inhibited the increase in erythema score after UVB irradiation compared with LA. The peroxidizability index of the skin total lipids was significantly higher, but UVB-induced prostaglandin E2 (PGE2) production was significantly lower in the group fed an ALA-rich diet compared with the group fed an LA-rich diet. The levels of thiobarbituric acid-reactive substances, estimated in the presence of butylated hydroxytoluene in the assay mixture, were not affected by UVB treatment or by the dietary fatty acids, but the severity of the skin lesion was associated with PGE2 levels. These results indicate that the type of fatty acids, n-6 or n-3, is critical for the suppression of UVB-induced skin lesion when the skin fatty acids are modified by dietary manipulation. Anti-inflammatory activity of dietary flaxseed oil with relatively high ALA and low LA contents was demonstrated in UVB-irradiated hairless mice.

  16. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    PubMed Central

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  17. Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression.

    PubMed

    Kim, Yoon Jae; Lee, Jeong Sang; Hong, Kyung Sook; Chung, Jun Won; Kim, Ju Hyun; Hahm, Ki Baik

    2010-08-01

    Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammation-dysplasia-carcinoma" sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid-reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of beta-catenin-accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitis-induced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression.

  18. Dexamethasone suppression test predicts later development of an impaired adrenal function after a 14-day course of prednisone in healthy volunteers.

    PubMed

    Neidert, Stefanie; Schuetz, Philipp; Mueller, Beat; Christ-Crain, Mirjam

    2010-05-01

    Suppression of the adrenal function after glucocorticoid treatment is common, potentially dangerous, and unpredictable. Identification of patients at risk is of clinical importance. We hypothesized that the dexamethasone suppression test predicts the development of corticosteroid-induced impaired adrenal function. We included 39 healthy male volunteers. After a 1-microg ACTH test, all participants underwent an overnight 0.5-mg dexamethasone suppression test. Participants then took prednisone, 0.5 mg/kg body weight, for 14-day. After the withdrawal of prednisone, a 1-microg ACTH test was performed and a clinical score was assessed on days 1, 3, 7, and 21. On days 1, 3, 7, and 21, 100, 50, 26.5 and 32.4% of the participants had a suppressed adrenal function. The risk of developing suppressed adrenal function decreased from 44 to 0% in patients with cortisol levels after the administration of dexamethasone in the lowest and highest quartiles respectively. Receiver operating curve (ROC) analysis performed to predict a suppressed adrenal function on day 7 after the withdrawal of prednisone showed an area under the curve (AUC) of 0.76 (95% confidence interval (CI) 0.58-0.89) for cortisol after the administration of dexamethasone, which was in the range of the AUC of 0.78 (95% CI 0.6-0.9) for pre-intervention cortisol after the administration of ACTH. Basal cortisol before intake of prednisone (AUC 0.62 (95% CI 0.44-0.78)) and the clinical score (AUC 0.64 (95% CI 0.45-0.79)) had significantly lower AUCs. Circulating cortisol levels after a dexamethasone suppression test and a pre-intervention-stimulated cortisol level are predictive of later development of a suppressed adrenal function after a 14-day course of prednisone, and are superior to a clinical score or basal cortisol levels. This may allow a more targeted concept for the need of stress prophylaxis after cessation of steroid therapy.

  19. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Goldberg, A. L.

    1992-01-01

    To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals.

  20. Maslinic Acid Inhibits Proliferation of Renal Cell Carcinoma Cell Lines and Suppresses Angiogenesis of Endothelial Cells

    PubMed Central

    Thakor, Parth; Song, Wenzhe; Subramanian, Ramalingam B.; Thakkar, Vasudev R.; Vesey, David A.

    2017-01-01

    Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC) remains a treatment-resistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1), endothelial cells (human umbilical vein endothelial cell line [HUVEC]), and primary cultures of kidney proximal tubular epithelial cells (PTEC) were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy. PMID:28405545

  1. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency

    NASA Technical Reports Server (NTRS)

    Tawa, N. E. Jr; Goldberg, A. L.

    1992-01-01

    To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals.

  2. Identification of the amino acid residues and domains in the cysteine-rich protein of Chinese wheat mosaic virus that are important for RNA silencing suppression and subcellular localization.

    PubMed

    Sun, Liying; Andika, Ida Bagus; Kondo, Hideki; Chen, Jianping

    2013-04-01

    Cysteine-rich proteins (CRPs) encoded by some plant viruses in diverse genera function as RNA silencing suppressors. Within the N-terminal portion of CRPs encoded by furoviruses, there are six conserved cysteine residues and a Cys-Gly-X-X-His motif (Cys, cysteine; Gly, glycine; His, histidine; X, any amino acid residue) with unknown function. The central domains contain coiled-coil heptad amino acid repeats that usually mediate protein dimerization. Here, we present evidence that the conserved cysteine residues and Cys-Gly-X-X-His motif in the CRP of Chinese wheat mosaic virus (CWMV) are critical for protein stability and silencing suppression activity. Mutation of a leucine residue in the third coiled-coil heptad impaired CWMV CRP activity for suppression of local silencing, but not for the promotion of cell-to-cell movement of Potato virus X (PVX). In planta and in vitro analysis of wild-type and mutant proteins indicated that the ability of the CRP to self-interact was correlated with its suppression activity. Deletion of up to 40 amino acids at the C-terminus did not abolish suppression activity, but disrupted the association of CRP with endoplasmic reticulum (ER), and reduced its activity in the enhancement of PVX symptom severity. Interestingly, a short region in the C-terminal domain, predicted to form an amphipathic α-helical structure, was responsible for the association of CWMV CRP with ER. Overall, our results demonstrate that the N-terminal and central regions are the functional domains for suppression activity, whereas the C-terminal region primarily functions to target CWMV CRP to the ER. © 2012 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2012 BSPP AND BLACKWELL PUBLISHING LTD.

  3. Suppression of tricarboxylic acid cycle in Escherichia coli exposed to sub-MICs of aminoglycosides.

    PubMed Central

    Cavallero, A; Eftimiadi, C; Radin, L; Schito, G C

    1990-01-01

    The metabolic activity of Escherichia coli ATCC 25922 challenged with sub-MICs of aminoglycosides was analyzed with a batch calorimeter. High-performance and gas-liquid chromatographic techniques were utilized to evaluate the concentrations of metabolic reactants, intermediates, and end products. The data reported indicate that aminoglycosides inhibit or delay bacterial catabolism of carboxylic acids, with the following relative degrees of activity: amikacin greater than gentamicin greater than sisomicin greater than netilmicin greater than kanamycin. The decrease in total biomass production was proportional to the degree of tricarboxylic acid cycle inhibition. PMID:2183717

  4. The value of an acute octreotide suppression test in predicting short-term efficacy of somatostatin analogues in acromegaly.

    PubMed

    Wang, Meng; Shen, Ming; He, Wenqiang; Yang, Yeping; Liu, Wenjuan; Lu, Yun; Ma, Zengyi; Ye, Zhao; Zhang, Yichao; Zhao, Xiaolong; Lu, Bin; Hu, Ji; Huang, Yun; Shou, Xuefei; Wang, Yongfei; Ye, Hongying; Li, Yiming; Li, Shiqi; Zhao, Yao; Zhang, Zhaoyun

    2016-09-30

    Predicting the efficacy of long-acting somatostatin analogues (SSA) remains a challenge. We aim to quantitatively evaluate the predictive value of the octreotide suppression test (OST) in short-term efficacy of SSA in active acromegaly. Sixty-seven newly diagnosed acromegaly patients were assessed with OST. Subsequently, all patients were treated with long-acting SSA for 3 months, followed by reassessment. Nine parameters were tested, including GHn (the nadir GH during OST), ΔGH1 (= [GH0h-GHn]/GH0h, GH0h was the baseline GH during OST), ΔGH2 (= [GHm-GHn]/GHm, GHm was the mean GH on day curve), AUC(0-6h) (the GH area under the curve during OST) , ΔAUC1 (= [GH0h-AUC(0-6h)]/GH0h), ΔAUC2 (=[GHm-AUC(0-6h)]/GHm), AUC(m-6h) (the GH AUC during OST where GHm was used instead of GH0h), ΔAUC1' (=[GH0h-AUC(m-6h)]/GH0h) and ΔAUC2' (=[GHm-AUC(m-6h)]/GHm). The Youden indices were calculated to determine the optimal cutoffs to predict the short-term efficacy of SSA. ΔGH2 more than 86.83%, ΔAUC2 more than -57.48% and ΔAUC2' more than -57.98% provided the best predictors of a good GH response (sensitivity 93.8%, specificity 85.7%). ΔGH2 more than 90.51% provided the best predictor of a good tumor size response (sensitivity 84.8%, specificity 87.5%). The percentage fall of GHn (ΔGH) was a better predictive parameter than GHn. OST showed higher efficiency in predicting the efficacy of octreotide LAR than lanreotide SR. In conclusion, OST is a valid tool to predict both GH and tumor size response to short-term efficacy of SSA in acromegaly, especially for octreotide LAR. GHm is better to be used as basal GH than GH0 during OST.

  5. Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs.

    USDA-ARS?s Scientific Manuscript database

    We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pi...

  6. Tipping the balance: Sclerotinia sclerotiorum secreted oxalic acid suppresses host defenses by manipulating the host redox environment.

    PubMed

    Williams, Brett; Kabbage, Mehdi; Kim, Hyo-Jin; Britt, Robert; Dickman, Martin B

    2011-06-01

    Sclerotinia sclerotiorum is a necrotrophic ascomycete fungus with an extremely broad host range. This pathogen produces the non-specific phytotoxin and key pathogenicity factor, oxalic acid (OA). Our recent work indicated that this fungus and more specifically OA, can induce apoptotic-like programmed cell death (PCD) in plant hosts, this induction of PCD and disease requires generation of reactive oxygen species (ROS) in the host, a process triggered by fungal secreted OA. Conversely, during the initial stages of infection, OA also dampens the plant oxidative burst, an early host response generally associated with plant defense. This scenario presents a challenge regarding the mechanistic details of OA function; as OA both suppresses and induces host ROS during the compatible interaction. In the present study we generated transgenic plants expressing a redox-regulated GFP reporter. Results show that initially, Sclerotinia (via OA) generates a reducing environment in host cells that suppress host defense responses including the oxidative burst and callose deposition, akin to compatible biotrophic pathogens. Once infection is established however, this necrotroph induces the generation of plant ROS leading to PCD of host tissue, the result of which is of direct benefit to the pathogen. In contrast, a non-pathogenic OA-deficient mutant failed to alter host redox status. The mutant produced hypersensitive response-like features following host inoculation, including ROS induction, callose formation, restricted growth and cell death. These results indicate active recognition of the mutant and further point to suppression of defenses by the wild type necrotrophic fungus. Chemical reduction of host cells with dithiothreitol (DTT) or potassium oxalate (KOA) restored the ability of this mutant to cause disease. Thus, Sclerotinia uses a novel strategy involving regulation of host redox status to establish infection. These results address a long-standing issue involving the

  7. Tipping the Balance: Sclerotinia sclerotiorum Secreted Oxalic Acid Suppresses Host Defenses by Manipulating the Host Redox Environment

    PubMed Central

    Williams, Brett; Kabbage, Mehdi; Kim, Hyo-Jin; Britt, Robert; Dickman, Martin B.

    2011-01-01

    Sclerotinia sclerotiorum is a necrotrophic ascomycete fungus with an extremely broad host range. This pathogen produces the non-specific phytotoxin and key pathogenicity factor, oxalic acid (OA). Our recent work indicated that this fungus and more specifically OA, can induce apoptotic-like programmed cell death (PCD) in plant hosts, this induction of PCD and disease requires generation of reactive oxygen species (ROS) in the host, a process triggered by fungal secreted OA. Conversely, during the initial stages of infection, OA also dampens the plant oxidative burst, an early host response generally associated with plant defense. This scenario presents a challenge regarding the mechanistic details of OA function; as OA both suppresses and induces host ROS during the compatible interaction. In the present study we generated transgenic plants expressing a redox-regulated GFP reporter. Results show that initially, Sclerotinia (via OA) generates a reducing environment in host cells that suppress host defense responses including the oxidative burst and callose deposition, akin to compatible biotrophic pathogens. Once infection is established however, this necrotroph induces the generation of plant ROS leading to PCD of host tissue, the result of which is of direct benefit to the pathogen. In contrast, a non-pathogenic OA-deficient mutant failed to alter host redox status. The mutant produced hypersensitive response-like features following host inoculation, including ROS induction, callose formation, restricted growth and cell death. These results indicate active recognition of the mutant and further point to suppression of defenses by the wild type necrotrophic fungus. Chemical reduction of host cells with dithiothreitol (DTT) or potassium oxalate (KOA) restored the ability of this mutant to cause disease. Thus, Sclerotinia uses a novel strategy involving regulation of host redox status to establish infection. These results address a long-standing issue involving the

  8. Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids.

    PubMed

    Svahn, Sara L; Väremo, Leif; Gabrielsson, Britt G; Peris, Eduard; Nookaew, Intawat; Grahnemo, Louise; Sandberg, Ann-Sofie; Wernstedt Asterholm, Ingrid; Jansson, John-Olov; Nielsen, Jens; Johansson, Maria E

    2016-01-01

    Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ.

  9. Six Tissue Transcriptomics Reveals Specific Immune Suppression in Spleen by Dietary Polyunsaturated Fatty Acids

    PubMed Central

    Gabrielsson, Britt G.; Peris, Eduard; Nookaew, Intawat; Grahnemo, Louise; Sandberg, Ann-Sofie; Wernstedt Asterholm, Ingrid; Jansson, John-Olov; Nielsen, Jens

    2016-01-01

    Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ. PMID:27166587

  10. The application of medium-chain fatty acids: edible oil with a suppressing effect on body fat accumulation.

    PubMed

    Takeuchi, Hiroyuki; Sekine, Seiji; Kojima, Keiichi; Aoyama, Toshiaki

    2008-01-01

    The bulk of fatty acids found in our diets consists of long-chain fatty acids (LCFA), which are molecules containing 12 or more carbon atoms. In contrast, medium-chain fatty acids (MCFA) are composed of 8-10 carbon atoms, and are found in palm kernel oil, among other types of foods. MCFA have attracted attention as being part of a healthy diet, because they are absorbed directly into the portal vein, transported rapidly to the liver for beta-oxidation, and thus increase diet-induced thermogenesis. In contrast, long-chain triacylglycerols are absorbed via the intestinal lymphatic ducts and transported by chylomicrons through the thoracic duct into the systemic circulation. Because medium-chain triacylglycerols (MCT) containing solely MCFA have a few disadvantages when used for deep frying, we have developed a new kind of triacylglycerol product: medium- and long-chain triacylglycerol (MLCT). MLCT is produced by lipase-catalyzed enzymatic transesterification. Long-term clinical trials have demonstrated that MLCT and MCT result in less body fat accumulation in humans. MLCT oil has been approved as FOSHU (Food for Specified Health Use) for use as cooking oil with a suppressing effect on body fat accumulation.

  11. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43.

    PubMed

    Kimura, Ikuo; Ozawa, Kentaro; Inoue, Daisuke; Imamura, Takeshi; Kimura, Kumi; Maeda, Takeshi; Terasawa, Kazuya; Kashihara, Daiji; Hirano, Kanako; Tani, Taeko; Takahashi, Tomoyuki; Miyauchi, Satoshi; Shioi, Go; Inoue, Hiroshi; Tsujimoto, Gozoh

    2013-01-01

    The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis.

  12. Development of a sampling plan in winter wheat that estimates cereal aphid parasitism levels and predicts population suppression.

    PubMed

    Giles, Kristopher L; Jones, Douglas B; Royer, Tom A; Elliott, Norman C; Kindler, S Dean

    2003-06-01

    From 1998 to 2001, the relationship between the proportion of tillers with >0 mummified aphids (Ptm) and the proportion of cereal aphids parasitized (Pp) was estimated on 57 occasions in fields of hard red winter wheat located in central and western Oklahoma. Both original (57 fields) and validation data (34 fields; 2001-2002) revealed weak relationships between Ptm and Pp, however, when Ptm > 0.1, Pp always exceeded the recommended parasitism natural enemy threshold of 0.2. Based on the relationship between Ptm and Pp, upper (Ptm1) and lower (Ptm0) decision threshold proportions were set at 0.1 and 0.02, respectively. We monitored cereal aphid populations in 16-25 winter wheat fields over time, and based on the upper and lower decision threshold proportions (Ptm1 = 0.1, Ptm0 = 0.02), predicted whether aphid intensities (# per tiller) would increase above or be maintained below selected economic thresholds (3, 9, and 15 aphids per tiller). Results of this validation study revealed that aphid intensity exceeded an economic threshold in only one field when predicted to remain below Ptm > 0.1, but aphid intensity reached a maximum of only four aphids per tiller. The sampling plan developed during this study allowed us to quickly classify Ptm, and independent of initial cereal aphid intensities, very accurately predict suppression of populations by parasitoids. Sequential sampling stop lines based on sequential probability ratio tests for classifying proportions were calculated for Ptm1 = 0.1 and Ptm0 = 0.02. A minimum of 26 tiller samples are required to classify Ptm as above 0.1 or below 0.02. Based on the results of this study, we believe that simultaneous use of aphid and parasitoid sampling plans will be efficient and useful tools for consultants and producers in the southern plains and decrease the number of unnecessary insecticide applications.

  13. PrDOS: prediction of disordered protein regions from amino acid sequence.

    PubMed

    Ishida, Takashi; Kinoshita, Kengo

    2007-07-01

    PrDOS is a server that predicts the disordered regions of a protein from its amino acid sequence (http://prdos.hgc.jp). The server accepts a single protein amino acid sequence, in either plain text or FASTA format. The prediction system is composed of two predictors: a predictor based on local amino acid sequence information and one based on template proteins. The server combines the results of the two predictors and returns a two-state prediction (order/disorder) and a disorder probability for each residue. The prediction results are sent by e-mail, and the server also provides a web-interface to check the results.

  14. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide

    PubMed Central

    2011-01-01

    produced no detectable inactivation of either BV-associated bacteria or vaginal lactobacilli. Moreover, at very high concentrations, H2O2 was more toxic to vaginal lactobacilli than to BV-associated bacteria. On the basis of these in vitro observations, we conclude that lactic acid, not H2O2, is likely to suppress BV-associated bacteria in vivo. PMID:21771337

  15. Hypoxia suppresses Kv 2.1 channel expression through endogenous 15-hydroxyeicosatetraenoic acid in rat pulmonary artery.

    PubMed

    Guo, Lei; Qiu, Zhaoping; Zhang, Lei; Chen, Shuo; Zhu, Daling

    2010-09-01

    We have previously reported that hypoxia activates lung 15-lipoxygenase (15-LOX), which catalyzes arachidonic acid to produce 15-HETE, leading to constriction of neonatal rabbit pulmonary arteries. Hypoxia suppresses Kv2.1 channel expression. Although the Kv channel inhibition by hypoxia is likely to be mediated through 15-HETE, direct evidence is still lacking. To explore whether 15-LOX/15-HETE pathway contributes to the hypoxia-induced down-regulation of Kv2.1 channel, we performed studies using 15-LOX blockers, semi-quantitative PCR and western blot analysis. We found that Kv2.1 channel expression at the mRNA and protein levels was greatly up-regulated in pulmonary arterial smooth muscle cells (PASMCs) and pulmonary artery (PA) after blockade of endogenous 15-HETE under hypoxic condition. 15-HETE further decreased Kv2.1 channel expression in comparison with 12-HETE and 5-HETE in cultured PASMCs and PA under normoxic conditions. These data indicate that hypoxia suppresses Kv2.1 channel expression through endogenous 15-HETE in PA.

  16. Ascorbic acid deficiency leads to increased grain chalkiness in transgenic rice for suppressed of L-GalLDH.

    PubMed

    Yu, Le; Liu, Yonghai; Lu, Lina; Zhang, Qilei; Chen, Yezheng; Zhou, Liping; Chen, Hua; Peng, Changlian

    2017-04-01

    The grain chalkiness of rice (Oryza sativa L.), which determines the rice quality and price, is a major concern in rice breeding. Reactive oxygen species (ROS) plays a critical role in regulating rice endosperm chalkiness. Ascorbic acid (Asc) is a major plant antioxidant, which strictly regulates the levels of ROS. l-galactono-1, 4-lactone dehydrogenase (L-GalLDH, EC 1.3.2.3) is an enzyme that catalyzes the last step of Asc biosynthesis in higher plants. Here we show that the L-GalLDH-suppressed transgenic rice, GI-1 and GI-2, which have constitutively low (between 30% and 50%) leaf and grain Asc content compared with the wild-type (WT), exhibit significantly increased grain chalkiness. Further examination showed that the deficiency of Asc resulted in a higher lipid peroxidation and H2O2 content, accompanied by a lower hydroxyl radical scavenging rate, total antioxidant capacity and photosynthetic ability. In addition, changes of the enzyme activities and gene transcript abundances related to starch synthesis were also observed in GI-1 and GI-2 grains. The results we presented here suggest a close correlation between Asc deficiency and grain chalkiness in the L-GalLDH-suppressed transgenics. Asc deficiency leads to the accumulation of H2O2, affecting antioxidant capacity and photosynthetic function, changing enzyme activities and gene transcript abundances related to starch synthesis, finally leading to the increased grain chalkiness. Copyright © 2017 Elsevier GmbH. All rights reserved.

  17. Machine learning and hurdle models for improving regional predictions of stream water acid neutralizing capacity

    Treesearch

    Nicholas A. Povak; Paul F. Hessburg; Keith M. Reynolds; Timothy J. Sullivan; Todd C. McDonnell; R. Brion Salter

    2013-01-01

    In many industrialized regions of the world, atmospherically deposited sulfur derived from industrial, nonpoint air pollution sources reduces stream water quality and results in acidic conditions that threaten aquatic resources. Accurate maps of predicted stream water acidity are an essential aid to managers who must identify acid-sensitive streams, potentially...

  18. Acetyl Eburicoic Acid from Laetiporus sulphureus var. miniatus Suppresses Inflammation in Murine Macrophage RAW 264.7 Cells

    PubMed Central

    Saba, Evelyn; Son, Youngmin; Jeon, Bo Ra; Kim, Seong-Eun; Lee, In-Kyoung

    2015-01-01

    The basidiomycete Laetiporus sulphureus var. miniatus belongs to the Aphyllophorales, Polyporaceae, and grows on the needleleaf tree. The fruiting bodies of Laetiporus species are known to produce N-methylated tyramine derivatives, polysaccharides, and various lanostane triterpenoids. As part of our ongoing effort to discover biologically active compounds from wood-rotting fungi, an anti-inflammatory triterpene, LSM-H7, has been isolated from the fruiting body of L. sulphureus var. miniatus and identified as acetyl eburicoic acid. LSM-H7 dose-dependently inhibited the NO production in RAW 264.7 cells without any cytotoxicity at the tested concentrations. Furthermore it suppressed the production of proinflammatory cytokines, mainly inducible nitric oxide synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6 and tumor necrosis factor α, when compared with glyceraldehyde 3-phosphate dehydrogenase. These data suggest that LSM-H7 is a crucial component for the anti-inflammatory activity of L. sulphureus var. miniatus. PMID:26190920

  19. Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor.

    PubMed

    Tsuji, Masako; Murota, Se-itsu; Morita, Ikuo

    2003-05-01

    It is generally accepted that n-3 polyunsaturated fatty acids have beneficial effects on vascular homeostasis. Among the several functions of endothelial cells, angiogenesis contributes to tumor growth, inflammation, and microangiopathy. We have already demonstrated that eicosapentaenoic acid (EPA, 20:5, n-3) suppressed angiogenesis. In this paper, we examined the effect of docosapentaenoic acid (DPA, 22:5, n-3), an elongated metabolite of EPA, on tube-forming activity in bovine aortic endothelial cells (BAE cells) incubated between type I collagen gels. The pretreatment of BAE cells with DPA suppressed tube-forming activity induced by vascular endothelial growth factor (VEGF). The effect of DPA was stronger than those of EPA and docosahexaenoic acid (22:6, n-3). The migrating activity of endothelial cells stimulated with VEGF was also suppressed by DPA pretreatment. The treatment of BAE cells with DPA caused the suppression of VEGF receptor-2 (VEGFR-2, the kinase insert domain-containing receptor, KDR) expression in both plastic dish and collagen gel cultures. These data indicate that DPA has a potent inhibitory effect on angiogenesis through the suppression of VEGFR-2 expression.

  20. TGA Transcription Factors Activate the Salicylic Acid-Suppressible Branch of the Ethylene-Induced Defense Program by Regulating ORA59 Expression1[C][W

    PubMed Central

    Zander, Mark; Thurow, Corinna; Gatz, Christiane

    2014-01-01

    Salicylic acid (SA), a hormone essential for defense against biotrophic pathogens, triggers increased susceptibility of plants against necrotrophic attackers by suppressing the jasmonic acid-ethylene (ET) defense response. Here, we show that this disease-promoting SA effect is abolished in plants lacking the three related TGACG sequence-specific binding proteins TGA2, TGA5, and TGA6 (class II TGAs). After treatment of plants with the ET precursor 1-aminocyclopropane-1-carboxylic acid (ACC), activation of all those genes that are suppressed by SA depended on class II TGAs. Rather than TGA binding sites, GCC-box motifs were significantly enriched in the corresponding promoters. GCC-box motifs are recognized by members of the superfamily of APETALA2/ETHYLENE RESPONSE FACTORs (ERFs). Of 11 activating ACC-induced APETALA2/ERFs, only ORA59 (for OCTADECANOID-RESPONSIVE ARABIDOPSIS APETALA2/ETHYLENE RESPONSE FACTOR domain protein59) and ERF96 were strongly suppressed by SA. ORA59 is the master regulator of the jasmonic acid-ET-induced defense program. ORA59 transcript levels do not reach maximal levels in the tga2 tga5 tga6 triple mutant, and this residual activity cannot be suppressed by SA. The ORA59 promoter contains an essential TGA binding site and is a direct target of class II TGAs as revealed by chromatin immunoprecipitation experiments. We suggest that class II TGAs at the ORA59 promoter constitute an important regulatory hub for the activation and SA suppression of ACC-induced genes. PMID:24989234

  1. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells

    PubMed Central

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy. PMID:27073325

  2. AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.

    PubMed

    Jing, Yue; Wang, Gang; Ge, Ying; Xu, Minjie; Tang, Shuainan; Gong, Zhunan

    2016-01-01

    Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.

  3. Oropharyngeal flora in patients admitted to the medical intensive care unit: clinical factors and acid suppressive therapy.

    PubMed

    Frandah, Wesam; Colmer-Hamood, Jane; Mojazi Amiri, Hoda; Raj, Rishi; Nugent, Kenneth

    2013-05-01

    Acid suppression therapy in critically ill patients significantly reduces the incidence of stress ulceration and gastrointestinal (GI) bleeding; however, recent studies suggest that proton pump inhibitors (PPIs) increase the risk of pneumonia. We wanted to test the hypothesis that acid suppressive therapy promotes alteration in the bacterial flora in the GI tract and leads to colonization of the upper airway tract with pathogenic species, potentially forming the biological basis for the observed increased incidence of pneumonia in these patients. This was a prospective observational study on patients (adults 18 years or older) admitted to the medical intensive care unit (MICU) at a tertiary care centre. Exclusion criteria included all patients with a diagnosis of pneumonia at admission, with infection in the upper airway, or with a history of significant dysphagia. Oropharyngeal cultures were obtained on day 1 and days 3 or 4 of admission. We collected data on demographics, clinical information, and severity of the underlying disease using APACHE II scores. There were 110 patients enrolled in the study. The mean age was 49±16 years, 50 were women, and the mean APACHE II score was 9.8 ± 6.5. Twenty per cent of the patients had used a PPI in the month preceding admission. The first oropharyngeal specimen was available in 110 cases; a second specimen at 72-96 h was available in 68 cases. Seventy-five per cent of the patients admitted to the MICU had abnormal flora. In multivariate logistic regression, diabetes mellitus and PPI use were associated with abnormal oral flora on admission. Chronic renal failure and a higher body mass index reduced the frequency of abnormal oral flora on admission. Most critically ill patients admitted to our MICU have abnormal oral flora. Patients with diabetes and a history of recent PPI use are more likely to have abnormal oral flora on admission.

  4. Suppressed Helicobacter pylori-associated gastric tumorigenesis in Fat-1 transgenic mice producing endogenous ω-3 polyunsaturated fatty acids

    PubMed Central

    Jeong, Migyeung; Park, Jong-Min; Go, Eun-Jin; Kang, Jing X; Hong, Sung Pyo; Hahm, Ki Baik

    2016-01-01

    Dietary approaches to preventing Helicobacter pylori (H. pylori)-associated gastric carcinogenesis are widely accepted because surrounding break-up mechanisms are mandatory for cancer prevention, however, eradication alone has been proven to be insufficient. Among these dietary interventions, omega-3-polyunsaturated-fatty acids (ω-3 PUFAs) are often the first candidate selected. However, there was no trial of fatty acids in preventing H. pylori-associated carcinogenesis and inconclusive results have been reported, likely based on inconsistent dietary administration. In this study, we developed an H. pylori initiated-, high salt diet promoted-gastric tumorigenesis model and conducted a comparison between wild-type (WT) and Fat-1-transgenic (TG)-mice. Gross and pathological lesions in mouse stomachs were evaluated at 16, 24, 32, and 45 weeks after H. pylori infection, and the underlying molecular changes to explain the cancer preventive effects were investigated. Significant changes in: i) ameliorated gastric inflammations at 16 weeks of H. pylori infection, ii) decreased angiogenic growth factors at 24 weeks, iii) attenuated atrophic gastritis and tumorigenesis at 32 weeks, and iv) decreased gastric cancer at 45 weeks were all noted in Fat-1-TG-mice compared to WT-mice. While an increase in the expression of Cyclooxygenase (COX)-2, and reduced expression of the tumor suppressive 15-PGDH were observed in WT-mice throughout the experimental periods, the expression of Hydroxyprostaglandin dehydrogenase (15-PGDH) was preserved in Fat-1-TG-mice. Using a comparative protein array, attenuated expressions of proteins implicated in proliferation and inflammation were observed in Fat-1-TG-mice compared to WT-mice. Conclusively, long-term administration of ω-3 PUFAs can suppress H. pylori-induced gastric tumorigenesis through a dampening of inflammation and reduced proliferation in accordance with afforded rejuvenation. PMID:27528223

  5. Ferulic Acid Suppresses Amyloid β Production in the Human Lens Epithelial Cell Stimulated with Hydrogen Peroxide

    PubMed Central

    Nagai, Noriaki; Kotani, Sachiyo; Mano, Yu; Ueno, Akina; Ito, Yoshimasa; Kitaba, Toshio; Takata, Takumi

    2017-01-01

    It is well known that oxidative stresses induce the production of amyloid β (Aβ) in the brain, lens, and retina, leading to age-related diseases. In the present study, we investigated the effects of ferulic acid on the Aβ levels in H2O2-stimulated human lens epithelial (HLE) SRA 01/04 cells. Three types of Aβ peptides (Aβ1-40, Aβ1-42, and Aβ1-43) were measured by ELISA, and the levels of mRNA for the expressed proteins related to Aβ production (APP, BACE1, and PS proteins) and degradation (ADAM10, NEP, and ECE1 proteins) were determined by quantitative real-time RT-PCR. H2O2 stimulation augmented gene expression of the proteins related to Aβ production, resulting in the production of three types of Aβ peptides. Treatment with 0.1 μM ferulic acid attenuated the augmentations of gene expression and production of the proteins related to the secretion of three types of Aβ peptides in the H2O2-stimulated HLE cells. These results provided evidence of antioxidative functions of ferulic acid for lens epithelial cells. PMID:28409157

  6. Lower serum uric acid level predicts mortality in dialysis patients

    PubMed Central

    Bae, Eunjin; Cho, Hyun-Jeong; Shin, Nara; Kim, Sun Moon; Yang, Seung Hee; Kim, Dong Ki; Kim, Yong-Lim; Kang, Shin-Wook; Yang, Chul Woo; Kim, Nam Ho; Kim, Yon Su; Lee, Hajeong

    2016-01-01

    Abstract We evaluated the impact of serum uric acid (SUA) on mortality in patients with chronic dialysis. A total of 4132 adult patients on dialysis were enrolled prospectively between August 2008 and September 2014. Among them, we included 1738 patients who maintained dialysis for at least 3 months and had available SUA in the database. We categorized the time averaged-SUA (TA-SUA) into 5 groups: <5.5, 5.5–6.4, 6.5–7.4, 7.5–8.4, and ≥8.5 mg/dL. Cox regression analysis was used to calculate the hazard ratio (HR) of all-cause mortality according to SUA group. The mean TA-SUA level was slightly higher in men than in women. Patients with lower TA-SUA level tended to have lower body mass index (BMI), phosphorus, serum albumin level, higher proportion of diabetes mellitus (DM), and higher proportion of malnourishment on the subjective global assessment (SGA). During a median follow-up of 43.9 months, 206 patients died. Patients with the highest SUA had a similar risk to the middle 3 TA-SUA groups, but the lowest TA-SUA group had a significantly elevated HR for mortality. The lowest TA-SUA group was significantly associated with increased all-cause mortality (adjusted HR, 1.720; 95% confidence interval, 1.007–2.937; P = 0.047) even after adjusting for demographic, comorbid, nutritional covariables, and medication use that could affect SUA levels. This association was prominent in patients with well nourishment on the SGA, a preserved serum albumin level, a higher BMI, and concomitant DM although these parameters had no significant interaction in the TA-SUA-mortality relationship except DM. In conclusion, a lower TA-SUA level <5.5 mg/dL predicted all-cause mortality in patients with chronic dialysis. PMID:27310949

  7. Copper suppresses abscisic acid catabolism and catalase activity, and inhibits seed germination of rice.

    PubMed

    Ye, Nenghui; Li, Haoxuan; Zhu, Guohui; Liu, Yinggao; Liu, Rui; Xu, Weifeng; Jing, Yu; Peng, Xinxiang; Zhang, Jianhua

    2014-11-01

    Although copper (Cu) is an essential micronutrient for plants, a slight excess of Cu in soil can be harmful to plants. Unfortunately, Cu contamination is a growing problem all over the world due to human activities, and poses a soil stress to plant development. As one of the most important biological processes, seed germination is sensitive to Cu stress. However, little is known about the mechanism of Cu-induced inhibition of seed germination. In the present study, we investigated the relationship between Cu and ABA which is the predominant regulator of seed germination. Cu at a concentration of 30 µM effectively inhibited germination of rice caryopsis. ABA content in germinating seeds under copper stress was also higher than that under control conditions. Quantitative real-time PCR (qRT-PCR) revealed that Cu treatment reduced the expression of OsABA8ox2, a key gene of ABA catabolism in rice seeds. In addition, both malondialdehyde (MDA) and H2O2 contents were increased by Cu stress in the germinating seeds. Antioxidant enzyme assays revealed that only catalase activity was reduced by excess Cu, which was consistent with the mRNA profile of OsCATa during seed germination under Cu stress. Together, our results demonstrate that suppression of ABA catabolism and catalase (CAT) activity by excess Cu leads to the inhibition of seed germination of rice.

  8. Suppression of adipocyte differentiation and lipid accumulation by stearidonic acid (SDA) in 3T3-L1 cells.

    PubMed

    Li, Yueru; Rong, Yinghui; Bao, Lisui; Nie, Ben; Ren, Guang; Zheng, Chen; Amin, Rajesh; Arnold, Robert D; Jeganathan, Ramesh B; Huggins, Kevin W

    2017-09-25

    Increased consumption of omega-3 (ω-3) fatty acids found in cold-water fish and fish oil has been reported to protect against obesity. A potential mechanism may be through reduction in adipocyte differentiation. Stearidonic acid (SDA), a plant-based ω-3 fatty acid, has been targeted as a potential surrogate for fish-based fatty acids; however, its role in adipocyte differentiation is unknown. This study was designed to evaluate the effects of SDA on adipocyte differentiation in 3T3-L1 cells. 3T3-L1 preadipocytes were differentiated in the presence of SDA or vehicle-control. Cell viability assay was conducted to determine potential toxicity of SDA. Lipid accumulation was measured by Oil Red O staining and triglyceride (TG) quantification in differentiated 3T3-L1 adipocytes. Adipocyte differentiation was evaluated by adipogenic transcription factors and lipid accumulation gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Fatty acid analysis was conducted by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). 3T3-L1 cells treated with SDA were viable at concentrations used for all studies. SDA treatment reduced lipid accumulation in 3T3-L1 adipocytes. This anti-adipogenic effect by SDA was a result of down-regulation of mRNA levels of the adipogenic transcription factors CCAAT/enhancer-binding proteins alpha and beta (C/EBPα, C/EBPβ), peroxisome proliferator-activated receptor gamma (PPARγ), and sterol-regulatory element binding protein-1c (SREBP-1c). SDA treatment resulted in decreased expression of the lipid accumulation genes adipocyte fatty-acid binding protein (AP2), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD-1), lipoprotein lipase (LPL), glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK). The transcriptional activity of PPARγ was found to be decreased with SDA treatment. SDA treatment led to significant EPA enrichment in 3T3-L1 adipocytes compared to vehicle-control. These

  9. Induction of CYP1A and cyp2-mediated arachidonic acid epoxygenation and suppression of 20-hydroxyeicosatetraenoic acid by imidazole derivatives including the aromatase inhibitor vorozole.

    PubMed

    Diani-Moore, Silvia; Papachristou, Fotini; Labitzke, Erin; Rifkind, Arleen B

    2006-08-01

    Cytochrome P450 (P450) enzymes metabolize the membrane lipid arachidonic acid to stable biologically active epoxides [eicosatrienoic acids (EETs)] and 20-hydroxyeicosatetraenoic acid (20-HETE). These products have cardiovascular activity, primarily acting as vasodilators and vasoconstrictors, respectively. EET formation can be increased by the prototype CYP1A or CYP2 inducers, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or phenobarbital (PB), respectively. We report here that imidazole derivative drugs: the anthelminthics, albendazole and thiabendazole; the proton pump inhibitor, omeprazole; the thromboxane synthase inhibitor, benzylimidazole; and the aromatase (CYP19) inhibitor vorozole (R76713, racemate; and R83842, (+) enantiomer) increased hepatic microsomal EET formation in a chick embryo model. Albendazole increased EETs by transcriptional induction of CYP1A5 and the others by combined induction of CYP1A5 and CYP2H, the avian orthologs of mammalian CYP1A2 and CYP2B, respectively. All inducers increased formation of the four EET regioisomers, but TCDD and albendazole had preference for 5,6-EET and PB and omeprazole for 14,15-EET. Vorozole, benzylimidazole, and TCDD also suppressed 20-HETE formation. Vorozole was a remarkably effective and potent inducer of multiple hepatic P450s at a dose range which overlapped its inhibition of ovarian aromatase. Increased CYP1A activity in mouse Hepa 1-6 and human HepG2 cells by vorozole and other imidazole derivatives demonstrated applicability of the findings to mammalian cells. The findings suggest that changes in P450-dependent arachidonic acid metabolism may be a new source of side effects for drugs that induce CYP1A or CYP2. They demonstrate further that in vivo induction of multiple hepatic P450s produces additive increases in arachidonic acid epoxygenase activity and can occur concurrently with inhibition of ovarian aromatase activity.

  10. Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells.

    PubMed

    George, Kerri L; Saltman, Laura H; Stein, Gary S; Lian, Jane B; Zurier, Robert B

    2008-03-01

    Oral administration of ajulemic acid (AjA), a cannabinoid acid devoid of psychoactivity, prevents joint tissue injury in rats with adjuvant induced arthritis. Because activation of osteoclasts is central to the pathogenesis of bone erosion in patients with rheumatoid arthritis (RA), we investigated the influence of AjA on osteoclast differentiation and survival. Osteoclast cultures were established by stimulation of RAW264.7 cells and primary mouse bone marrow cultures with receptor activator of NF-kappaB ligand (RANKL). Simultaneous addition of AjA (15 and 30 microM) and RANKL to both culture systems significantly suppressed development of multinucleated osteoclasts (osteoclastogenesis) in a dose dependent manner, as determined by quantification of multinuclear, tartrate-resistant acid phosphatase (TRAP)-positive cells. AjA impaired growth of RAW264.7 monocytes and prevented further osteoclast formation in cultures in which osteoclastogenesis had already begun. Reduction by AjA of both monocyte growth and osteoclast formation was associated with apoptosis, assayed by annexin V and propidium iodide staining, and caspase activity. The anti-osteoclastogenic effects of AjA did not require the continuous presence of AjA in the cell cultures. Based on these findings, we propose that AjA or other nonpsychoactive synthetic analogs of Cannabis constituents may be useful therapy for diseases such as RA and osteoporosis in which bone resorption is a central feature.

  11. ω-3 Fatty Acids Ethyl Esters Suppress Cerebral Vasospasm and Improve Clinical Outcome Following Aneurysmal Subarachnoid Hemorrhage.

    PubMed

    Nakagawa, Ichiro; Yokoyama, Shohei; Omoto, Koji; Takeshima, Yasuhiro; Matsuda, Ryosuke; Nishimura, Fumihiko; Yamada, Shuichi; Yokota, Hiroshi; Motoyama, Yasushi; Park, Young-Su; Nakase, Hiroyuki

    2017-03-01

    Occurrence of cerebral vasospasm after onset of aneurysmal subarachnoid hemorrhage (SAH) is a critical factor determining clinical prognosis. Eicosapentaenoic acid and docosahexaenoic acid, both ω-3 fatty acids (ω-3FA), can suppress cerebral vasospasm, and docosahexaenoic acid can relax vessel vasoconstriction and have neuroprotective effects. We investigated whether administration of ω-3FA prevented cerebral vasospasm occurrence and improved clinical outcomes after aneurysmal SAH. From 2012 to 2015, 100 consecutive patients with aneurysmal SAH were divided into 2 periods. Between 2012 and 2013 (control period), 45 patients received standard management. Between 2014 and 2015 (ω-3FA period), 55 patients were prospectively treated with additional ω-3FA. Occurrence of cerebral vasospasm, occurrence of cerebral infarction caused by vasospasm, and modified Rankin Scale scores at 30 days and 90 days after onset of SAH for each period were evaluated and compared. The frequency of angiographic cerebral vasospasm in the ω-3FA period was significantly lower than in the control period (12 patients vs. 23 patients, P = 0.004). The frequency of new infarction caused by vasospasm in the ω-3FA period was also significantly lower than in the control period (5 patients vs. 14 patients, P = 0.011). There was a significant difference in modified Rankin Scale scores at 90 days after onset of SAH between the groups (P = 0.031). No adverse events were associated with ω-3FA administration. Administration of ω-3FA after aneurysmal SAH may reduce the frequency of cerebral vasospasm and may improve clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Cut-off net acid generation pH in predicting acid-forming potential in mine spoils.

    PubMed

    Liao, B; Huang, L N; Ye, Z H; Lan, C Y; Shu, W S

    2007-01-01

    Acidification of mine wastes can lead to a series of environmental problems, such as acid drainage, heavy metal mobilization, and ecosystem degradation. Prediction of acid-forming potential is one of the key steps in management of sulfide-bearing mine wastes. In this paper, the acid-forming potential of 180 mine waste samples collected from 17 mine sites in China were studied using a net acid generation (NAG) method. The samples contained different contents of total sulfur (ranging from 0.6 to 200 g kg(-1)), pyritic sulfur (ranging from 0 to 100 g kg(-1)), and acid neutralization capacity (ANC, ranging from -41 to 274 kg H2SO4 t(-1)). Samples with high acid-forming potential are generally due to their high sulfur content or low acid neutralization capacity. After the samples were oxidized by H2O2, the amounts of acid generation and the final NAG pH were measured. Results indicated that the final NAG pH gave a well-defined demarcation between acid-forming and non-acid-forming materials. Samples with final NAG pH >or= 5 could be classified as non-acid-forming materials, while those with NAG pH acid-forming materials. Materials with NAG pH > 2.5, but < 5, had low risk of being acid-forming. The confirmation of cut-off NAG pH will be used as a rapid and cost-effective operational monitoring tool for the in-pit prediction of acid-forming potential of mine wastes and classification of waste types.

  13. PGC-1β suppresses saturated fatty acid-induced macrophage inflammation by inhibiting TAK1 activation.

    PubMed

    Chen, Hongen; Liu, Yan; Li, Di; Song, Jiayi; Xia, Min

    2016-02-01

    Inflammation of infiltrated macrophages in adipose tissue is a key contributor to the initiation of adipose insulin resistance. These macrophages are exposed to high local concentrations of free fatty acids (FFAs) and can be proinflammatory activated by saturated fatty acids (SFAs). However, the regulatory mechanisms on SFA-induced macrophage inflammation are still elusive. Peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) is a member of the PGC-1 family of transcriptional coactivators and has been reported to play a key role in SFAs metabolism and in the regulation of inflammatory signaling. However, it remains unclear whether PGC-1β is involved in SFA-induced macrophage inflammation. In this study, we found that PGC-1β expression was significantly decreased in response to palmitic acid (PA) in macrophages in a dose dependent manner. PGC-1β inhibited PA induced TNFα, MCP-1, and IL-1β mRNA and protein expressions. Furthermore, PGC-1β significantly antagonized PA induced macrophage nuclear factor-κB (NF-κB) p65 and JUN N-terminal kinase activation. Mechanistically, we revealed that TGF-β-activated kinase 1 (TAK1) and its adaptor protein TAK1 binding protein 1 (TAB1) played a dominant role in the regulatory effects of PGC-1β. We confirmed that PGC-1β inhibited downstream inflammatory signals via binding with TAB1 and thus preventing TAB1/TAK1 binding and TAK1 activation. Finally, we showed that PGC-1β overexpression in PA treated macrophages improved adipocytes PI3K-Akt insulin signaling in a paracrine fashion. Collectively, our results uncovered a novel mechanism on how macrophage inflammation induced by SFAs was regulated and suggest a potential target in the treatment of obesity induced insulin resistance.

  14. VPA response in SMA is suppressed by the fatty acid translocase CD36.

    PubMed

    Garbes, Lutz; Heesen, Ludwig; Hölker, Irmgard; Bauer, Tim; Schreml, Julia; Zimmermann, Katharina; Thoenes, Michaela; Walter, Michael; Dimos, John; Peitz, Michael; Brüstle, Oliver; Heller, Raoul; Wirth, Brunhilde

    2013-01-15

    Functional loss of SMN1 causes proximal spinal muscular atrophy (SMA), the most common genetic condition accounting for infant lethality. Hence, the hypomorphic copy gene SMN2 is the only resource of functional SMN protein in SMA patients and influences SMA severity in a dose-dependent manner. Consequently, current therapeutic approaches focus on SMN2. Histone deacetylase inhibitors (HDACi), such as the short chain fatty acid VPA (valproic acid), ameliorate the SMA phenotype by activating the SMN2 expression. By analyzing blood SMN2 expression in 16 VPA-treated SMA patients, about one-third of individuals were identified as positive responders presenting increased SMN2 transcript levels. In 66% of enrolled patients, a concordant response was detected in the respective fibroblasts. Most importantly, by taking the detour of reprograming SMA patients' fibroblasts, we showed that the VPA response was maintained even in GABAergic neurons derived from induced pluripotent stem cells (iPS) cells. Differential expression microarray analysis revealed a complete lack of response to VPA in non-responders, which was associated with an increased expression of the fatty acid translocase CD36. The pivotal role of CD36 as the cause of non-responsiveness was proven in various in vitro approaches. Most importantly, knockdown of CD36 in SMA fibroblasts converted non- into pos-responders. In summary, the concordant response from blood to the central nervous system (CNS) to VPA may allow selection of pos-responders prior to therapy. Increased CD36 expression accounts for VPA non-responsiveness. These findings may be essential not only for SMA but also for other diseases such as epilepsy or migraine frequently treated with VPA.

  15. Prediction of jet mean flow structure in support of HSCT noise suppression concepts. [High Speed Civilian Transport

    NASA Technical Reports Server (NTRS)

    Sinha, N.; Dash, S. M.; York, B. J.; Lee, R. A.

    1991-01-01

    The paper describes the application of techniques based on computational fluid dynamics to the simulation of jet flowfields. A solution code for the Reynolds-averaged Navier-Stokes equations is supplemented by conventional two-equation turbulence models based on the Boussinesq approximation. The axisymmetric SCIPVIS code is enhanced with the PARCH and CRAFT codes to examine plug-jet flowfields and imperfectly expanded axisymmetric free round jets. The sensitivity of shock/boundary layer interactions is observed in simulations of the plug case, and the adaptive gridding in the disk region and turbulence levels generated at the triple point are identified as areas in the Mach case that require improvement. Jet-wave structure in the region beyond the first several shock cells can be predicted, and turbulence modeling can be undertaken with respect to improving compressibility, length scale, vorticity, and energy budget. The mean flow structure of imperfectly expanded jets can be studied to develop related noise suppression concepts for the High-Speed Civilian Transport (HSCT).

  16. YMO1 suppresses invasion and metastasis by inhibiting RhoC signaling and predicts favorable prognosis in hepatocellular carcinoma

    PubMed Central

    Chang, Rui-Min; Pei, Lei; Fang, Feng; Xu, Jiang-Feng; Yang, Hao; Zuo, Chao-Hui; Zhou, Jian-Hua; Luo, Geng-Qiu; Yang, Lian-Yue

    2016-01-01

    Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity. PMID:27487132

  17. Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.

    PubMed

    McKallip, Robert J; Ban, Hao; Uchakina, Olga N

    2015-01-01

    Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.

  18. Suppression of Jasmonic Acid-Dependent Defense in Cotton Plant by the Mealybug Phenacoccus solenopsis

    PubMed Central

    Zhang, Pengjun; Zhu, Xiaoyun; Huang, Fang; Liu, Yong; Zhang, Jinming; Lu, Yaobin; Ruan, Yongming

    2011-01-01

    The solenopsis mealybug, Phenacoccus solenopsis, has been recently recognized as an aggressively invasive pest in China, and is now becoming a serious threat to the cotton industry in the country. Thus, it is necessary to investigate the molecular mechanisms employed by cotton for defending against P. solenopsis before the pest populations reach epidemic levels. Here, we examined the effects of exogenous jasmonic acid (JA), salicylic acid (SA), and herbivory treatments on feeding behavior and on development of female P. solenopsis. Further, we compared the volatile emissions of cotton plants upon JA, SA, and herbivory treatments, as well as the time-related changes in gossypol production and defense-related genes. Female adult P. solenopsis were repelled by leaves from JA-treated plant, but were not repelled by leaves from SA-treated plants. In contrast, females were attracted by leaves from plants pre-infested by P. solenopsis. The diverse feeding responses by P. solenopsis were due to the difference in volatile emission of plants from different treatments. Furthermore, we show that JA-treated plants slowed P. solenopsis development, but plants pre-infested by P. solenopsis accelerated its development. We also show that P. solenopsis feeding inhibited the JA-regulated gossypol production, and prevented the induction of JA-related genes. We conclude that P. solenopsis is able to prevent the activation of JA-dependent defenses associated with basal resistance to mealybugs. PMID:21818315

  19. Suppression of jasmonic acid-dependent defense in cotton plant by the mealybug Phenacoccus solenopsis.

    PubMed

    Zhang, Pengjun; Zhu, Xiaoyun; Huang, Fang; Liu, Yong; Zhang, Jinming; Lu, Yaobin; Ruan, Yongming

    2011-01-01

    The solenopsis mealybug, Phenacoccus solenopsis, has been recently recognized as an aggressively invasive pest in China, and is now becoming a serious threat to the cotton industry in the country. Thus, it is necessary to investigate the molecular mechanisms employed by cotton for defending against P. solenopsis before the pest populations reach epidemic levels. Here, we examined the effects of exogenous jasmonic acid (JA), salicylic acid (SA), and herbivory treatments on feeding behavior and on development of female P. solenopsis. Further, we compared the volatile emissions of cotton plants upon JA, SA, and herbivory treatments, as well as the time-related changes in gossypol production and defense-related genes. Female adult P. solenopsis were repelled by leaves from JA-treated plant, but were not repelled by leaves from SA-treated plants. In contrast, females were attracted by leaves from plants pre-infested by P. solenopsis. The diverse feeding responses by P. solenopsis were due to the difference in volatile emission of plants from different treatments. Furthermore, we show that JA-treated plants slowed P. solenopsis development, but plants pre-infested by P. solenopsis accelerated its development. We also show that P. solenopsis feeding inhibited the JA-regulated gossypol production, and prevented the induction of JA-related genes. We conclude that P. solenopsis is able to prevent the activation of JA-dependent defenses associated with basal resistance to mealybugs.

  20. Treatment with the hyaluronic acid synthesis inhibitor 4-methylumbelliferone suppresses SEB-induced lung inflammation.

    PubMed

    McKallip, Robert J; Hagele, Harriet F; Uchakina, Olga N

    2013-10-17

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  1. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    PubMed Central

    McKallip, Robert J.; Hagele, Harriet F.; Uchakina, Olga N.

    2013-01-01

    Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB. PMID:24141285

  2. Abscisic Acid Promotes Susceptibility to the Rice Leaf Blight Pathogen Xanthomonas oryzae pv oryzae by Suppressing Salicylic Acid-Mediated Defenses

    PubMed Central

    Xu, Jing; Audenaert, Kris

    2013-01-01

    The plant hormone abscisic acid (ABA) is involved in a wide variety of plant processes, including the initiation of stress-adaptive responses to various environmental cues. Recently, ABA also emerged as a central factor in the regulation and integration of plant immune responses, although little is known about the underlying mechanisms. Aiming to advance our understanding of ABA-modulated disease resistance, we have analyzed the impact, dynamics and interrelationship of ABA and the classic defense hormone salicylic acid (SA) during progression of rice infection by the leaf blight pathogen Xanthomonas oryzae pv. oryzae (Xoo). Consistent with ABA negatively regulating resistance to Xoo, we found that exogenously administered ABA renders rice hypersusceptible to infection, whereas chemical and genetic disruption of ABA biosynthesis and signaling, respectively, led to enhanced Xoo resistance. In addition, we found successful Xoo infection to be associated with extensive reprogramming of ABA biosynthesis and response genes, suggesting that ABA functions as a virulence factor for Xoo. Interestingly, several lines of evidence indicate that this immune-suppressive effect of ABA is due at least in part to suppression of SA-mediated defenses that normally serve to limit pathogen growth. Resistance induced by the ABA biosynthesis inhibitor fluridone, however, appears to operate in a SA-independent manner and is likely due to induction of non-specific physiological stress. Collectively, our findings favor a scenario whereby virulent Xoo hijacks the rice ABA machinery to cause disease and highlight the importance of ABA and its crosstalk with SA in shaping the outcome of rice-Xoo interactions. PMID:23826294

  3. Antigen-specific T cell-mediated suppression. V. H-2-linked genetic control of distinct antigen-specific defects in the production and activity of L-glutamic acid50-L-tyrosine50 suppressor factor

    PubMed Central

    1980-01-01

    The occurrence of distinct genetic defects affecting the generation of T cell-derived suppressor factor (TsF) or the suppressive activity of such TsF was investigated. For the synthetic polypeptide L-glutamic acid50-L-tyrosine50 (GT), it could be shown that the nonsuppressor strain A/J fails to produce suppressor T cells (Ts1) capable of GT-TsF generation upon challenge with GT. Conversely, B6, another nonsuppressor strain, produces GT-TsF active on other allogeneic strains such as A/J, but itself fails to be suppressed by this material. (B6A)F1 mice both make GT-TsF, and are suppressed by it. Further experiments revealed that the production of GT-TsF and the ability to be suppressed by GT-TsF are under the control of H-2-linked genes. Finally, the defect in GT-TsF activity in B6 mice was shown to be exquisitely antigen specific, in that this strain can be suppressed by a closely related TsF specific for L-glutamic acid60-L-alanine30-L- tyrosine10. It is suggested that H-2 (I) control of suppressor T cell (Ts) activity may reflect the involvement of I-A and I-C gene products in antigen presentation to Ts in analog with other T cell subsets, and that TsF function might also involve such presentation, in this case of the idiotypic structures of the TsF-combining site. Predictions deriving from this hypothesis are discussed, including the possibility that H-2 linked immune response genes regulate auto-anti-idiotypic responses in immune networks. PMID:6445400

  4. Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation

    SciTech Connect

    Hugenberg, S.T.; Myers, S.L.; Brandt, K.D.

    1989-04-01

    We recently found that injection of 2 mCi of yttrium 90 (90Y; approximately 23,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty-four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S-GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that in control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis.

  5. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression.

    PubMed

    Lauring, Brett; Taggart, Andrew K P; Tata, James R; Dunbar, Richard; Caro, Luzelena; Cheng, Kang; Chin, Jayne; Colletti, Steven L; Cote, Josee; Khalilieh, Sauzanne; Liu, Jiajun; Luo, Wen-Lin; Maclean, Alexandra A; Peterson, Laurence B; Polis, Adam B; Sirah, Waheeda; Wu, Tsuei-Ju; Liu, Xuan; Jin, Lan; Wu, Kenneth; Boatman, P Douglas; Semple, Graeme; Behan, Dominic P; Connolly, Daniel T; Lai, Eseng; Wagner, John A; Wright, Samuel D; Cuffie, Cynthia; Mitchel, Yale B; Rader, Daniel J; Paolini, John F; Waters, M Gerard; Plump, Andrew

    2012-08-22

    Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.

  6. Predictable conformational diversity in foldamers of sugar amino acids.

    PubMed

    Menyhard, Dora K; Hudaky, Ilona; Jákli, Imre; Juhász, György; Perczel, András

    2017-03-27

    Systematic conformational search was carried out for monomers and homohexamers of furanoid β-amino acids: cis-(S,R) and trans-(S,S) stereoisomers of aminocyclopentane carboxylic acid (ACPC), two different aminofuranuronic-acids (AFU(α) and AFU(β)), their isopropylidene derivatives (AFU(ip)) as well as the key intermediate β-aminotetrahydrofurancarboxylic acid (ATFC). Stereochemistry of the building blocks was chosen to match with that of natural sugar amino acid (xylose and ribose) precursors. Results show that hexamers of cis furanoid β-amino acids show great variability: while hydrophobic cyclopentane (cis(ACPC)6), and hydrophilic (cisXylAFU(α/β))6 foldamers favor two different zigzagged conformation as hexamers, the backbone fold turns into a helix in case of (cisATFC)6 (10-helix) and (cisAFU(ip))6 (14-helix). Trans stereochemistry resulted in hexamers exclusively of right-handed helix conformation, (H12(P))6, regardless of their polarity. We found that the preferred oligomeric structure of cis/(S,R)AFU(α/β) is conformationally compatible with β-pleated sheets, while that of the trans/(S,S) units match with α-helices of α-proteins.

  7. Low Na intake suppresses expression of CYP2C23 and arachidonic acid-induced inhibition of ENaC.

    PubMed

    Sun, Peng; Lin, Dao-Hong; Wang, Tong; Babilonia, Elisa; Wang, Zhijian; Jin, Yan; Kemp, Rowena; Nasjletti, Alberto; Wang, Wen-Hui

    2006-12-01

    We previously demonstrated that arachidonic acid (AA) inhibits epithelial Na channels (ENaC) through the cytochrome P-450 (CYP) epoxygenase-dependent pathway (34). In the present study, we tested the hypothesis that low Na intake suppresses the expression of CYP2C23, which is mainly responsible for converting AA to epoxyeicosatrienoic acid (EET) in the kidney (11) and attenuates the AA-induced inhibition of ENaC. Immunostaining showed that CYP2C23 is expressed in the Tamm-Horsfall protein (THP)-positive and aquaporin 2 (AQP2)-positive tubules. This suggests that CYP2C23 is expressed in the thick ascending limb (TAL) and collecting duct (CD). Na restriction significantly suppressed the expression of CYP2C23 in the TAL and CD. Western blot also demonstrated that the expression of CYP2C23 in renal cortex and outer medulla diminished in rats on Na-deficient diet (Na-D) but increased in those on high-Na diet (4%). Moreover, the content of 11,12-epoxyeicosatrienoic acid (EET) decreased in the isolated cortical CD from rats on Na-D compared with those on a normal-Na diet (0.5%). Patch-clamp study showed that application of 15 microM AA inhibited the activity of ENaC by 77% in the CCD of rats on a Na-D for 3 days. However, the inhibitory effect of AA on ENaC was significantly attenuated in rats on Na-D for 14 days. Furthermore, inhibition of CYP epoxygenase with MS-PPOH increased the ENaC activity in the CCD of rats on a control Na diet. We also used microperfusion technique to examine the effect of MS-PPOH on Na transport in the distal nephron. Application of MS-PPOH significantly increased Na absorption in the distal nephron of control rats but had no significant effect on Na absorption in rats on Na-D for 14 days. We conclude that low Na intake downregulates the activity and expression of CYP2C23 and attenuates the inhibitory effect of AA on Na transport.

  8. Accurate ab initio prediction of NMR chemical shifts of nucleic acids and nucleic acids/protein complexes

    PubMed Central

    Victora, Andrea; Möller, Heiko M.; Exner, Thomas E.

    2014-01-01

    NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3–0.6 ppm and correlation coefficients (r2) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization. PMID:25404135

  9. Enhancing Cation Diffusion and Suppressing Anion Diffusion via Lewis-Acidic Polymer Electrolytes.

    PubMed

    Savoie, Brett M; Webb, Michael A; Miller, Thomas F

    2017-02-02

    Solid polymer electrolytes (SPEs) have the potential to increase both the energy density and stability of lithium-based batteries, but low Li(+) conductivity remains a barrier to technological viability. SPEs are designed to maximize Li(+) diffusivity relative to the anion while maintaining sufficient salt solubility. It is thus remarkable that poly(ethylene oxide) (PEO), the most widely used SPE, exhibits Li(+) diffusivity that is an order of magnitude smaller than that of typical counterions at moderate salt concentrations. We show that Lewis-basic polymers like PEO favor slow cation and rapid anion diffusion, while this relationship can be reversed in Lewis-acidic polymers. Using molecular dynamics, polyboranes are identified that achieve up to 10-fold increases in Li(+) diffusivities and significant decreases in anion diffusivities, relative to PEO in the dilute-ion regime. These results illustrate a general principle for increasing Li(+) diffusivity and transference number with chemistries that exhibit weaker cation and stronger anion coordination.

  10. Prediction of nucleic acid binding probability in proteins: a neighboring residue network based score.

    PubMed

    Miao, Zhichao; Westhof, Eric

    2015-06-23

    We describe a general binding score for predicting the nucleic acid binding probability in proteins. The score is directly derived from physicochemical and evolutionary features and integrates a residue neighboring network approach. Our process achieves stable and high accuracies on both DNA- and RNA-binding proteins and illustrates how the main driving forces for nucleic acid binding are common. Because of the effective integration of the synergetic effects of the network of neighboring residues and the fact that the prediction yields a hierarchical scoring on the protein surface, energy funnels for nucleic acid binding appear on protein surfaces, pointing to the dynamic process occurring in the binding of nucleic acids to proteins.

  11. Suppressive effects of Calendula micrantha essential oil and gibberelic acid (PGR) on repro ductive potential of the Mediterranean fruit fly Ceratitis capitata Wied. (Diptera: Tephritidae).

    PubMed

    Hussein, Karam T

    2005-08-01

    The volatile oil of Calendula micrtantha plant was extracted and the components were identified by Gc/Ms. Adulticidal efficiency of the volatile oil and gibberelic acid "plant growth promoting hormone" as well as their mixture was assessed against the Mediterranean fruit fly Ceratitis capitata. The result showed that the two compounds capable have characteristic resembling to insect juvenile hormones and have suppressive effect on reproductive potential. They induced the significant disturbances in the ovarian protein fraction and the amino acids patterns.

  12. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status

    PubMed Central

    Blum, A; Arnold, R; Stolte, M; Fischer, M; Koelz, H; the, F

    2000-01-01

    BACKGROUND AND AIMS—Treatment of functional dyspepsia with acid inhibitors is controversial and it is not known if the presence of Helicobacter pylori infection influences the response.
METHODS—After a complete diagnostic workup, 792 patients with functional dyspepsia unresponsive to one week of low dose antacid treatment were randomised to two weeks of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, or omeprazole 20 mg daily. Individual dyspeptic and other abdominal symptoms were evaluated before and after treatment according to H pylori status.
RESULTS—The proportions of patients considered to be in remission (intention to treat) at the end of treatment with placebo, ranitidine 150 mg, omeprazole 10 mg, and omeprazole 20 mg were, respectively, 42%, 50%, 48%, and 59% in the H pylori positive group and 66%, 73%, 64%, and 71% in the H pylori negative group. In H pylori positive patients, the therapeutic gain over placebo was significant for omeprazole 20 mg (17.6%, 95% confidence intervals (CI) 4.2-31.0; p<0.014 using the Bonferroni-adjusted p level of 0.017) but not for omeprazole 10 mg (6.8%, 95% CI −6.7-20.4) or ranitidine 150 mg (8.9%, 95% CI −4.2-21.9). There was no significant therapeutic gain from active treatment over placebo in H pylori negative patients. Complete disappearance of symptoms and improvement in quality of life also occurred most frequently with omeprazole 20 mg and was significant in both H pylori positive and H pylori negative groups. The six month relapse rate of symptoms requiring treatment was low (<20%) in all groups.
CONCLUSIONS—Omeprazole 20 mg per day had a small but significant favourable effect on outcome in H pylori positive patients. The differential response in these patients may be explained by an enhanced antisecretory response in the presence of H pylori. The effect of weaker acid inhibition was unsatisfactory.


Keywords: functional dyspepsia; omeprazole; ranitidine

  13. 18β-Glycyrrhetinic Acid Suppresses Cell Proliferation through Inhibiting Thromboxane Synthase in Non-Small Cell Lung Cancer

    PubMed Central

    Huang, Qing-Chun; Chen, Xiu-Min; Jiang, Ze-Bo; Zhang, Xian; Zeng, Xing

    2014-01-01

    18β-glycyrrhetinic acid (18β-GA) is a bioactive component of licorice. The anti-cancer activity of 18β-GA has been studied in many cancer types, whereas its effects in lung cancer remain largely unknown. We first showed that 18β-GA effectively suppressed cell proliferation and inhibited expression as well as activity of thromboxane synthase (TxAS) in non-small cell lung cancer (NSCLC) cells A549 and NCI-H460. In addition, the administration of 18β-GA did not have any additional inhibitory effect on the decrease of cell proliferation induced by transfection with TxAS small interference RNA (siRNA). Moreover, 18β-GA failed to inhibit cell proliferation in the immortalized human bronchial epithelial cells 16HBE-T and another NSCLC cell line NCI-H23, both of which expressed minimal level of TxAS as compared to A549 and NCI-H460. However, 18β-GA abolished the enhancement of cell proliferation induced by transfection of NCI-H23 with pCMV6-TxAS plasmid. Further study found that the activation of both extracellular signal-regulated kinase (ERK)1/2 and cyclic adenosine monophosphate response element binding protein (CREB) induced by TxAS cDNA transfection could be totally blocked by 18β-GA. Altogether, we have delineated that, through inhibiting TxAS and its initiated ERK/CREB signaling, 18β-GA suppresses NSCLC cell proliferation. Our study has highlighted the significance of 18β-GA with respect to prevention and treatment of NSCLC. PMID:24695790

  14. Suppression of free fatty acid-induced insulin resistance by phytopolyphenols in C2C12 mouse skeletal muscle cells.

    PubMed

    Deng, Yea-Tzy; Chang, Tsai-Wen; Lee, Ming-Shyue; Lin, Jen-Kun

    2012-02-01

    It was reported that increased plasma levels of free fatty acids (FFAs) are associated with profound insulin resistance in skeletal muscle and may also play a critical role in the insulin resistance of obesity and type 2 diabetes mellitus. Skeletal muscle is the major site for insulin-stimulated glucose uptake and is involved in energy regulation and homeostasis. In this study, we used 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C (PKC) activator, and palmitate to induce insulin resistance in C2C12 mouse skeletal muscle cells. Our data show that epigallocatechin gallate (EGCG) and curcumin treatment reduce insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation, and curcumin is more potent to increase Akt phosphorylation in TPA induction. Moreover, we found that after 5 h of palmitate incubation, epicatechin gallate (ECG) can suppress IRS-1 Ser307 phosphorylation and significantly promote Akt, ERK1/2, p38 MAPK, and AMP-activated protein kinase activation. With a longer incubation with palmitate, IRS-1 exhibited a dramatic depletion, and treatment with EGCG, ECG, and curcumin could reverse IRS-1 expression, Akt phosphorylation, and MAPK signaling cascade activation and improve glucose uptake in C2C12 skeletal muscle cells, especially ECG and curcumin. In addition, treatment with these polyphenols can suppress acetyl-CoA carboxylase activation, but only EGCG could inhibit lipid accumulation in the intracellular site. These findings may suggest that curcumin shows the best capacity to improve FFA-induced insulin resistance than the other two, and ECG was more effective than EGCG in attenuating insulin resistance.

  15. The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling

    PubMed Central

    Sun, Guangchun; Mackey, Lily V.; Coy, David H.; Yu, Cui-Yun; Sun, Lichun

    2015-01-01

    Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents. PMID:26366213

  16. Photodynamic therapy mediated by 5-aminolevulinic acid suppresses gliomas growth by decreasing the microvessels.

    PubMed

    Yi, Wei; Xu, Hai-tao; Tian, Dao-feng; Wu, Li-quan; Zhang, Shen-qi; Wang, Long; Ji, Bao-wei; Zhu, Xiao-nan; Okechi, Humphrey; Liu, Gang; Chen, Qian-xue

    2015-04-01

    Although 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) has been demonstrated to be a novel and effective therapeutic modality for some human malignancies, its effect and mechanism on glioma are still controversial. Previous studies have reported that 5-ALA-PDT induced necrosis of C6 rat glioma cells in vitro. The aim of this study was to further investigate the effect and mechanism of 5-ALA-PDT on C6 gliomas implanted in rats in vivo. Twenty-four rats bearing similar size of subcutaneously implanted C6 rat glioma were randomly divided into 3 groups: receiving 5-ALA-PDT (group A), laser irradiation (group B), and mock procedures but without any treatment (group C), respectively. The growth, histology, microvessel density (MVD), and apoptosis of the grafts in each group were determined after the treatments. As compared with groups B and C, the volume of tumor grafts was significantly reduced (P<0.05), MVD was significantly decreased (P<0.001), and the cellular necrosis was obviously increased in group A. There was no significant difference in apoptosis among the three groups. The in vivo studies confirmed that 5-ALA-PDT may be an effective treatment for gliomas by inhibiting the tumor growth. The mechanism underlying may involve increasing the cellular necrosis but not inducing the cellular apoptosis, which may result from the destruction of the tumor microvessels.

  17. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

    PubMed Central

    Guntermann, Christine; Piaia, Alessandro; Hamel, Marie-Laure; Theil, Diethilde; Rubic-Schneider, Tina; del Rio-Espinola, Alberto; Dong, Linda; Billich, Andreas; Kaupmann, Klemens; Dawson, Janet; Hoegenauer, Klemens; Orain, David; Hintermann, Samuel; Stringer, Rowan; Patel, Dhavalkumar D.; Doelemeyer, Arno; Deurinck, Mark

    2017-01-01

    Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with neoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk. PMID:28289717

  18. Lipoic acid suppresses compound 48/80-induced anaphylaxis-like reaction

    PubMed Central

    Choi, Yun Ho; Chai, Ok Hee; Han, Eui-Hyeog; Choi, Su-Young; Kim, Hyoung Tae

    2010-01-01

    Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor in metabolic reactions involved in energy utilization. LA improves glycemic control, reduces diabetic polyneuropathies, atherosclerosis, and allergic inflammation. The effects of LA on mast cell-mediated anaphylactic reactions, however, are unknown. LA dose-dependently inhibited systemic and passive cutaneous anaphylaxis-like reactions in mice induced by compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine and formaldehyde. Pretreatment with LA, prior to induction of the systemic anaphylaxis-like reaction with compound 48/80, reduced plasma histamine levels in a dose-dependent manner. In our in vitro study, LA decreased histamine release from rat peritoneal mast cells (RPMCs) triggered by compound 48/80. Moreover, an increase in calcium uptake activated by compound 48/80 was inhibited by LA. LA also significantly elevated intracellular cyclic adenosine-3',5' monophosphate (cAMP) levels in RPMCs. This inhibition of mediator release from RPMCs may be due to inhibition of calcium uptake and augmentation of intracellular cAMP levels. Based on these results, we suggest that LA may be a potential remedy for allergy-related diseases. PMID:21267406

  19. Salvianolic acid B ameliorates CNS autoimmunity by suppressing Th1 responses.

    PubMed

    Dong, Zhihui; Ma, Dihui; Gong, Ye; Yu, Tingmin; Yao, Gang

    2016-04-21

    Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a Th1 and Th17 cell-mediated CNS autoimmune disease. Therefore, immune regulation is a key target for therapy. Salvianolic acid B (Sal B) is a major water-soluble bioactive component of the famous traditional Chinese medicine Salvia miltiorrhiza, which is notable for its anti-oxidative and anti-inflammatory effects. Thus Sal B, by impairing Th1 or Th17 responses in EAE/MS, might ameliorate the crippling symptoms. Here we show that the intraperitoneal administration of 30mg/kg Sal B daily for 14 days after the onset of MOG-induced EAE in mice effectively reduced its severity. Additionally, Sal B treatment downgraded the infiltration of inflammatory cells, limited astrogliosis and blocked Th1 responses other than that of Th17. These results indicated that Sal B may serve as an effective therapeutic agent for MS/EAE by inhibiting Th1 cell responses.

  20. MODERATING INFLUENCE OF THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID ON A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LUTEINIZING HORMONE SURGE IN FEMALE RATS.

    EPA Science Inventory

    The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigat...

  1. DISRUPTION IN RAT ESTROUS CYCLICITY BY THE DRINKING WATER DISINFECTANT BY-PRODUCT DIBROMOACETIC ACID: RELATIONSHIP TO A SUPPRESSION ON ESTRADIOL METABOLISM?

    EPA Science Inventory

    Disruption in Rat Estrous Cyclicity by the Drinking Water Disinfectant By-Product Dibromoacetic Acid: Relationship to A Suppression on Estradiol Metabolism?

    Ashley S. Murr and Jerome M. Goldman, Endocrinology Branch, Reproductive Toxicology Division National Health and En...

  2. DISRUPTION IN RAT ESTROUS CYCLICITY BY THE DRINKING WATER DISINFECTANT BY-PRODUCT DIBROMOACETIC ACID: RELATIONSHIP TO A SUPPRESSION ON ESTRADIOL METABOLISM?

    EPA Science Inventory

    Disruption in Rat Estrous Cyclicity by the Drinking Water Disinfectant By-Product Dibromoacetic Acid: Relationship to A Suppression on Estradiol Metabolism?

    Ashley S. Murr and Jerome M. Goldman, Endocrinology Branch, Reproductive Toxicology Division National Health and En...

  3. MODERATING INFLUENCE OF THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID ON A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LUTEINIZING HORMONE SURGE IN FEMALE RATS.

    EPA Science Inventory

    The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigat...

  4. Bacterial lipopolysaccharide suppresses the production of catalytically active lysosomal acid hydrolases in human macrophages

    PubMed Central

    1986-01-01

    Sub-microgram quantities of bacterial lipopolysaccharide (LPS) have been found to substantially reduce the intracellular catalytic activities of three representative lysosomal enzymes (namely, acid phosphatase, hexosaminidase, and beta-glucuronidase) in human monocyte- derived macrophages. This response was not associated with a concurrent increase in enzyme catalytic activity in the culture supernatant, and hence, could not be explained by mobilization of preformed material. By conducting experiments in the presence and absence of indomethacin, a cyclooxygenase inhibitor, the reduction in lysosomal enzyme catalytic activities was shown not to be dependent on the ability of LPS to induce prostaglandin E2 production. The response was not found to be the result of a more generalized LPS-dependent reduction in the ability of the cells to synthesize protein, since the presence of LPS in macrophage cultures did not appreciably affect the amount of [35S]methionine incorporated into total cellular proteins. A kinetic analysis of the effect of LPS on the down-regulation of enzyme catalytic activities indicated that this was an early response of the cells to LPS exposure. An investigation of the effects of blockade of enzyme catabolism (using the lysosomotropic weak-base, methylamine) indicated that the reduction of catalytic enzyme activities in response to LPS was probably due to a decreased rate of production of active product, rather than an enhanced rate of enzyme catabolism. This suggestion was confirmed by experiments in which the synthesis of pro- hexosaminidase (measured by biosynthetic labeling with [35S]methionine and specific immunoprecipitation of labeled pro-hexosaminidase) was found to be reduced by 42% after a 24-h exposure to LPS (although the synthesis of complement component C3 was stimulated by a factor of 4.5). It is suggested that the ability of LPS to regulate the functional expression of protein products contributes to changes in the overall

  5. Glycyrrhizic acid suppresses Cox-2-mediated anti-inflammatory responses during Leishmania donovani infection.

    PubMed

    Bhattacharjee, Surajit; Bhattacharjee, Amrita; Majumder, Saikat; Majumdar, Suchandra Bhattacharya; Majumdar, Subrata

    2012-08-01

    The aim of the present study was to characterize glycyrrhizic acid (GA) and assess its immunomodulatory potential in a model of experimental visceral leishmaniasis. The antileishmanial activity of GA was tested in an amastigote-macrophage model and its non-cytotoxic dose was measured by a cell viability assay. To understand the effector mechanism of GA-treated macrophages against leishmanial parasites, real-time PCR analysis of inducible nitric oxide synthase 2 (iNOS2) was carried out followed by measurement of nitric oxide generation by Griess reagent. The effect of GA on the production of cytokines, such as interleukin (IL)-12, tumour necrosis factor (TNF)-α, IL-10 and transforming growth factor (TGF)-β, was measured by ELISA (protein) and real-time PCR. The expression of iNOS2 and cyclooxygenase-2 (Cox-2) was studied by western blotting. The parasite burden of the liver and spleen following GA treatment was determined by the stamp-smear method, and T cell proliferation was assessed via [³H]thymidine uptake, measured by a liquid scintillation counter. Results showed that GA treatment caused an enhanced expression of iNOS2 along with inhibition of Cox-2 in Leishmania donovani-infected macrophages. GA treatment in infected macrophages enhanced the expression of IL-12 and TNF-α, concomitant with a down-regulation of IL-10 and TGF-β. GA increased macrophage effector responses via inhibition of Cox-2-mediated prostaglandin E2 release in L. donovani-infected macrophages. GA also decreased hepatic and splenic parasite burden and increased T cell proliferation in Leishmania-infected BALB/c mice. These results provide a mechanistic understanding of GA-mediated protection against leishmanial parasites within the host.

  6. Does acid suppression by antacids and H2 receptor antagonists increase the incidence of atrophic gastritis in patients with or without H. pylori gastritis?

    PubMed

    Carter, M; Katz, D L; Haque, S; DeLuca, V A

    1999-09-01

    Currently there is controversial evidence that suggests that the accepted incidence of atrophic gastritis of 1.2 to 3.3% in patients with Helicobacter pylori gastritis may be increased by the long-term suppression of acid by a proton pump inhibitor (omeprazole). The purpose of this study is to show whether lesser forms of acid suppression by antacids or H2 receptor antagonists may have an influence on the development of atrophic gastritis. The authors recently reported a study in which a cohort of 36 patients with symptoms of dyspepsia were followed clinically for a period of 7 to 19 years. In that report all subjects underwent upper endoscopy with two biopsy specimens each from the antrum and fundus, on at least two occasions, 7 to 19 years apart. A diagnosis of atrophic gastritis was based on the interpretation of these biopsies by two gastrointestinal pathologists. The presence of H. pylori colonization was determined by tissue sampling and by a campylobacter-like organisms test of the antrum. Of the 36 patients in the authors' previous report, 33 had adequate baseline and follow-up data on medications consumed throughout the period of the study. In their current report they now present the findings of a retrospective review in which they correlate the presence of atrophic gastritis with the sole use of antacids and H2 receptor antagonists throughout the period of the study. In the cohort of 33 patients evaluated from the previous report, the authors found that atrophic gastritis had developed in all 28 patients positive for H. pylori, and in none of the 5 patients negative for H. pylori (p < 0.0001). A retrospective analysis of this previously studied cohort of 33 patients revealed that the use of antacids and H2 receptor antagonists did not predict the development of atrophic gastritis in either H. pylori-negative or -positive subjects. In a retrospective analysis of a cohort of 33 patients followed for an average of 11.7 years, atrophic gastritis developed in

  7. Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action

    PubMed Central

    Tsujita-Kyutoku, Miki; Yuri, Takashi; Danbara, Naoyuki; Senzaki, Hideto; Kiyozuka, Yasuhiko; Uehara, Norihisa; Takada, Hideho; Hada, Takahiko; Miyazawa, Teruo; Ogawa, Yutaka; Tsubura, Airo

    2004-01-01

    Introduction The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). Methods KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. Results CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 μmol/l and 270 μmol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. Conclusion CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system. PMID:15217495

  8. Predicting Secondary Structural Folding Kinetics for Nucleic Acids

    PubMed Central

    Zhao, Peinan; Zhang, Wen-Bing; Chen, Shi-Jie

    2010-01-01

    Abstract We report a new computational approach to the prediction of RNA secondary structure folding kinetics. In this approach, each elementary kinetic step is represented as the transformation between two secondary structures that differ by a helix. Based on the free energy landscape analysis, we identify three types of dominant pathways and the rate constants for the kinetic steps: 1), formation; 2), disruption of a helix stem; and 3), helix formation with concomitant partial melting of a competing (incompatible) helix. The third pathway, termed the tunneling pathway, is the low-barrier dominant pathway for the conversion between two incompatible helices. Comparisons with experimental data indicate that this new method is quite reliable in predicting the kinetics for RNA secondary structural folding and structural rearrangements. The approach presented here may provide a robust first step for further systematic development of a predictive theory for the folding kinetics for large RNAs. PMID:20409482

  9. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX).

    PubMed

    Ohia, Sunny E; Opere, Catherine A; LeDay, Angela M; Bagchi, Manashi; Bagchi, Debasis; Stohs, Sidney J

    2002-09-01

    A growing body of evidence demonstrates the efficacy of Garcinia cambogia-derived natural (-)-hydroxycitric acid (HCA) in weight management by curbing appetite and inhibiting body fat biosynthesis. However, the exact mechanism of action of this novel phytopharmaceutical has yet to be fully understood. In a previous study, we showed that in the rat brain cortex a novel HCA extract (HCA-SX, Super CitriMax) increases the release/availability of radiolabeled 5-hydroxytryptamine or serotonin ([3H]-5-HT), a neurotransmitter implicated in the regulation of eating behavior and appetite control. The aim of the present study was 2-fold: (a) to determine the effect of HCA-SX on 5-HT uptake in rat brain cortex in vitro; and (b) to evaluate the safety of HCA-SX in vivo. Isolated rat brain cortex slices were incubated in oxygenated Krebs solution for 20 min and transferred to buffer solutions containing [3H]-5-HT for different time intervals. In some experiments, tissues were exposed to HCA-SX (10 microM - 1 mM) and the serotonin receptor reuptake inhibitors (SRRI) fluoxetine (100 microM) plus clomipramine (10 microM). Uptake of [3H]-5-HT was expressed as d.p.m./mg wet weight. A time-dependent uptake of [3H]-5-HT occurred in cortical slices reaching a maximum at 60 min. HCA-SX, and fluoxetine plus clomipramine inhibited the time-dependent uptake of [3H]-5-HT. At 90 min, HCA-SX (300 microM) caused a 20% decrease, whereas fluoxetine plus clomipramine inhibited [3H]-5-HT uptake by 30%. In safety studies, acute oral toxicity, acute dermal toxicity, primary dermal irritation and primary eye irritation, were conducted in animals using various doses of HCA-SX. Results indicate that the LD50 of HCA-SX is greater than 5,000 mg/kg when administered once orally via gastric intubation to fasted male and female Albino rats. No gross toxicological findings were observed under the experimental conditions. Taken together, these in vivo toxicological studies demonstrate that HCA-SX is a safe

  10. Insulin Resistance, Defective Insulin-Mediated Fatty Acid Suppression, and Coronary Artery Calcification in Subjects With and Without Type 1 Diabetes

    PubMed Central

    Schauer, Irene E.; Snell-Bergeon, Janet K.; Bergman, Bryan C.; Maahs, David M.; Kretowski, Adam; Eckel, Robert H.; Rewers, Marian

    2011-01-01

    OBJECTIVE To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls. RESEARCH DESIGN AND METHODS Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female). RESULTS Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters. CONCLUSIONS Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes. PMID:20978091

  11. Prediction of phase equilibrium and hydration free energy of carboxylic acids by Monte Carlo simulations.

    PubMed

    Ferrando, Nicolas; Gedik, Ibrahim; Lachet, Véronique; Pigeon, Laurent; Lugo, Rafael

    2013-06-13

    In this work, a new transferable united-atom force field has been developed to predict phase equilibrium and hydration free energy of carboxylic acids. To take advantage of the transferability of the AUA4 force field, all Lennard-Jones parameters of groups involved in the carboxylic acid chemical function are reused from previous parametrizations of this force field. Only a unique set of partial electrostatic charges is proposed to reproduce the experimental gas phase dipole moment, saturated liquid densities and vapor pressures. Phase equilibrium properties of various pure carboxylic acids (acetic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid) and one diacid (1,5-pentanedioic) are studied through Monte Carlo simulations in the Gibbs ensemble. A good accuracy is obtained for pure compound saturated liquid densities and vapor pressures (average deviation of 2% and 6%, respectively), as well as for critical points. The vaporization enthalpy is, however, poorly predicted for short acids, probably due to a limitation of the force field to correctly describe the significant dimerization in the vapor phase. Pressure-composition diagrams for two binary mixtures (acetic acid + n-butane and propanoic acid + pentanoic acid) are also computed with a good accuracy, showing the transferability of the proposed force field to mixtures. Hydration free energies are calculated for three carboxylic acids using thermodynamic integration. A systematic overestimation of around 10 kJ/mol is observed compared to experimental data. This new force field parametrized only on saturated equilibrium properties appears insufficient to reach an acceptable precision for this property, and only relative hydration free energies between two carboxylic acids can be correctly predicted. This highlights the limitation of the transferability feature of force fields to properties not included in the parametrization database.

  12. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice

    PubMed Central

    Su, Jin; Sherman, Alexandra; Doerfler, Phillip A.; Byrne, Barry J.; Herzog, Roland W.; Daniell, Henry

    2015-01-01

    Summary Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. PMID:26053072

  13. Pseudolaric acid B exerts antitumor activity via suppression of the Akt signaling pathway in HeLa cervical cancer cells.

    PubMed

    Li, Mingqun; Hong, Li

    2015-08-01

    Pseudolaric acid B (PAB) is a diterpene acid isolated from the bark of the root and trunk of Pseudolarix kaempferi Gordon (Pinaceae), which has demonstrated cytotoxic effects against various types of cancer. However, the mechanisms underlying the anticancer effects of PAB have remained to be elucidated. In the present study, the effects of PAB on the viability and apoptosis of HeLa cells were investigated by MTT assay, flow cytometric analysis of Annexin V-fluorescein isothiocyanate/propidium iodide staining, Rhodamine 123 staining and western blot analysis. The results demonstrated that PAB had antiproliferative and apoptosis-inducing effects on HeLa cells. PAB markedly inhibited HeLa cell viability in a time- and concentration-dependent manner. Flow cytometric analysis indicated that PAB induced apoptosis in HeLa cells in a dose-dependent manner. Treatment with PAB suppressed the expression of anti-apoptotic factor B cell lymphoma-2, and promoted the expression of pro-apoptotic factor Bcl-2-associated X protein. In addition, PAB induced an increase in Caspase-3 activity and loss of mitochondrial membrane potential, suggesting that this apoptosis may be mediated by mitochondrial pathways. Furthermore, the results of western blot analysis indicated that PAB was able to reduce Akt phosphorylation, thereby inhibiting the Akt pathway. These results suggested that PAB inhibited cell proliferation and induced apoptosis in HeLa cells, and that the anti-tumor effects of PAB were associated with inhibition of the Akt pathway. In conclusion, the results of the present study suggested that PAB may represent a novel therapeutic strategy for the treatment of human cervical cancer. However, additional studies are required to investigate the underlying apoptotic mechanisms.

  14. NDRG2 overexpression suppresses hepatoma cells survival during metabolic stress through disturbing the activation of fatty acid oxidation.

    PubMed

    Pan, Tao; Zhang, Mei; Zhang, Fang; Yan, Guang; Ru, Yi; Wang, Qinhao; Zhang, Yao; Wei, Xuehui; Xu, Xinyuan; Shen, Lan; Zhang, Jian; Wu, Kaichun; Yao, Libo; Li, Xia

    2017-02-05

    Because of the high nutrient consumption and inadequate vascularization, solid tumor constantly undergoes metabolic stress during tumor development. Oncogenes and tumor suppressor genes participated in cancer cells' metabolic reprogramming. N-Myc downstream regulated gene 2 (NDRG2) is a recently identified tumor suppressor gene, but its function in cancer metabolism, particularly during metabolic stress, remains unclear. In this study, we found that NDRG2 overexpression significantly reduced hepatoma cell proliferation and enhanced cell apoptosis under glucose limitation. Moreover, NDRG2 overexpression aggravated energy imbalance and oxidative stress by decreasing the intracellular ATP and NADPH generation and increasing ROS levels. Strikingly, NDRG2 inhibited the activation of fatty acid oxidation (FAO), which preserves ATP and NADPH purveyance in the absence of glucose. Finally, mechanistic investigation showed that NDRG2 overexpression suppressed the glucose-deprivation induced AMPK/ACC pathway activation in hepatoma cells, whereas the expression of a constitutively active form of AMPK abrogated glucose-deprivation induced AMPK activation and cell apoptosis. Thus, as a negative regulator of AMPK, NDRG2 disturbs the induction of FAO genes by glucose limitation, leading to dysregulation of ATP and NADPH, and thus reduces the tolerance of hepatoma cells to glucose limitation.

  15. Antibiotics suppress Cyp3a in the mouse liver by reducing lithocholic acid-producing intestinal flora.

    PubMed

    Toda, Takahiro; Ohi, Kanna; Kudo, Toshiyuki; Yoshida, Tomoyuki; Ikarashi, Nobutomo; Ito, Kiyomi; Sugiyama, Kiyoshi

    2009-05-01

    We previously demonstrated that ciprofloxacin (CPX), a new quinolone antibiotic, suppresses Cyp3a in the mouse liver by reducing the hepatic level of lithocholic acid (LCA) produced by intestinal flora. The present study investigated the possibility that other antibiotics with antibacterial activity against LCA-producing bacteria also cause a decrease in the LCA level in the liver, leading to reduced expression of Cyp3a11. While the mRNA expression of Cyp3a11 in the liver was significantly reduced when SPF mice were administered antibiotics such as ampicillin, CPX, levofloxacin, or a combination of vancomycin and imipenem, no significant changes were observed after antibiotic treatment of GF mice lacking intestinal flora. LCA-producing bacteria in the feces as well as the hepatic level of the taurine conjugate of LCA were significantly reduced in the antibiotic-treated SPF mice, suggesting that the decrease in Cyp3a11 expression can be attributed to the reduction in LCA-producing intestinal flora following antibiotic administration. These results suggest that the administration of antibiotics with activity against LCA-producing bacteria can also cause a decrease in the LCA level in humans, which may lower CYP3A4 expression. The intestinal flora are reported to be altered not only by drugs, such as antibiotics, but also by stress, disease, and age. The findings of the present study suggest that these changes in intestinal flora could modify CYP expression and contribute to the individual differences in pharmacokinetics.

  16. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Shen, Haitao; Jin, Shuai; Zhang, Shun

    2016-06-15

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. The aim of our study was to investigate the molecular mechanism involved in the protective effects of GA in lipopolysaccharide (LPS) stimulated rat mesangial cells (HBZY-1) and septic rats. Sepsis model was established by injection of 5mg/kg LPS in rats or incubation with 1μg/ml LPS for 24h in HBZY-1 cells. A variety of molecular biological experiments were carried out to assess the effects of GA on inflammation, apoptosis, and oxidative stress. First we found that GA alleviated sepsis-induced kidney injury in vivo. Furthermore, GA suppressed inflammatory response in vivo and in vitro. Additionally, GA inhibited cell apoptosis and the changes in expressions of apoptosis related proteins induced by LPS. Moreover, GA markedly inhibited oxidative stress induced by LPS via activation of ERK signaling pathway. Finally GA could inhibit the activation of NF-κ B induced by LPS. Our present study indicates that GA has a protective effect against sepsis-induced inflammatory response, apoptosis, and oxidative stress damage, which provides a molecular basis for a new medical treatment of septic acute kidney injury.

  17. Ursolic Acid Inhibits Leucine-Stimulated mTORC1 Signaling by Suppressing mTOR Localization to Lysosome

    PubMed Central

    Ou, Xiang; Liu, Meilian; Luo, Hairong; Dong, Lily Q.; Liu, Feng

    2014-01-01

    Ursolic acid (UA), a pentacyclic triterpenoid widely found in medicinal herbs and fruits, has been reported to possess a wide range of beneficial properties including anti-hyperglycemia, anti-obesity, and anti-cancer. However, the molecular mechanisms underlying the action of UA remain largely unknown. Here we show that UA inhibits leucine-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway in C2C12 myotubes. The UA-mediated inhibition of mTORC1 is independent of Akt, tuberous sclerosis complex 1/2 (TSC1/2), and Ras homolog enriched in brain (Rheb), suggesting that UA negatively regulates mTORC1 signaling by targeting at a site downstream of these mTOR regulators. UA treatment had no effect on the interaction between mTOR and its activator Raptor or inhibitor Deptor, but suppressed the binding of RagB to Raptor and inhibited leucine-induced mTOR lysosomal localization. Taken together, our study identifies UA as a direct negative regulator of the mTORC1 signaling pathway and suggests a novel mechanism by which UA exerts its beneficial function. PMID:24740400

  18. Apoptotic effect of gambogic acid in esophageal squamous cell carcinoma cells via suppression of the NF-κB pathway

    PubMed Central

    LIU, WEN-YUE; WU, XU; LIAO, CHENG-QUAN; SHEN, JIE; LI, JUN

    2016-01-01

    Despite extensive investigations of therapeutic improvements for surgical techniques, chemotherapy and chemoradiotherapy, esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive forms of cancer, and the prognosis for patients with advanced ESCC remains poor. Therefore, effective therapies are urgently required in order to improve the prognosis of patients with ESCC. TE-1 cells were treated with gambogic acid (GA), and then subjected to western blot analysis, TUNEL assay and caspase activity analysis. GA significantly induced apoptosis in ESCC TE-1 cells. In addition, the antitumor activity of GA was accompanied by the decreased expression of phosphorylated-protein kinase B (p-AKT) and nuclear factor of κ light polypeptide gene enhancer in B-cells 1 (NF-κB). The inhibition of protein kinase B (AKT) and NF-κB activation by chemical inhibitors augmented the apoptotic effect responses to GA in the TE-1 cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) decreased GA-induced apoptosis. Furthermore, zVAD attenuated GA-induced growth inhibition in TE-1 cells. GA induced apoptosis in ESCC TE-1 via suppression of NF-κB pathway. The findings of the present study may provide a novel insight into ESCC treatment. PMID:27284372

  19. High serum uric acid concentration predicts poor survival in patients with breast cancer.

    PubMed

    Yue, Cai-Feng; Feng, Pin-Ning; Yao, Zhen-Rong; Yu, Xue-Gao; Lin, Wen-Bin; Qian, Yuan-Min; Guo, Yun-Miao; Li, Lai-Sheng; Liu, Min

    2017-08-26

    Uric acid is a product of purine metabolism. Recently, uric acid has gained much attraction in cancer. In this study, we aim to investigate the clinicopathological and prognostic significance of serum uric acid concentration in breast cancer patients. A total of 443 female patients with histopathologically diagnosed breast cancer were included. After a mean follow-up time of 56months, survival was analysed using the Kaplan-Meier method. To further evaluate the prognostic significance of uric acid concentrations, univariate and multivariate Cox regression analyses were applied. Of the clinicopathological parameters, uric acid concentration was associated with age, body mass index, ER status and PR status. Univariate analysis identified that patients with increased uric acid concentration had a significantly inferior overall survival (HR 2.13, 95% CI 1.15-3.94, p=0.016). In multivariate analysis, we found that high uric acid concentration is an independent prognostic factor predicting death, but insufficient to predict local relapse or distant metastasis. Kaplan-Meier analysis indicated that high uric acid concentration is related to the poor overall survival (p=0.013). High uric acid concentration predicts poor survival in patients with breast cancer, and might serve as a potential marker for appropriate management of breast cancer patients. Copyright © 2017. Published by Elsevier B.V.

  20. Oral administration of whole dihomo-γ-linolenic acid-producing Saccharomyces cerevisiae suppresses cutaneous inflammatory responses induced by croton oil application in mice.

    PubMed

    Watanabe, Naoko; Masubuchi, Daiki; Itoh, Maki; Teradu, Soichiro; Yazawa, Hisashi; Uemura, Hiroshi

    2014-10-01

    Polyunsaturated fatty acids have been attracting considerable interest because of their many biological activities and important roles in human health and nutrition. Dihomo-γ-linolenic acid (DGLA; C20: 3n-6) is known to have an anti-inflammatory activity, but its range of effects was not well studied because of its limited natural sources. Taking advantage of genetic tractability and increasing wealth of accessible data of Saccharomyces cerevisiae, we have previously constructed a DGLA-producing yeast strain by introducing two types of desaturase and one elongase genes to convert endogenous oleic acid (C18:1n-9) to DGLA. In this study, we investigated the efficacy of oral intake of heat-killed whole DGLA-producing yeast cells in the absence of lipid purification on cutaneous inflammation. Topical application of croton oil to mouse ears induces ear swelling in parallel with the increased production of chemokines and accumulation of infiltrating cells into the skin sites. These inflammatory reactions were significantly suppressed in a dose-dependent manner by oral intake of the DGLA-producing yeast cells for only 7 days. This suppression was not observed by the intake of the γ-linolenic acid-producing (C18:3n-6, an immediate precursor of DGLA) yeast, indicating DGLA itself suppressed the inflammation. Further analysis demonstrated that DGLA exerted an anti-inflammatory effect via prostaglandin E1 formation because naproxen, a cyclooxygenase inhibitor, attenuated the suppression. Since 25-fold of purified DGLA compared with that provided as a form of yeast was not effective, oral administration of the whole DGLA-producing yeast is considered to be a simple but efficient method to suppress inflammatory responses.

  1. TGA Transcription Factors Activate the Salicylic Acid-Suppressible Branch of the Ethylene-Induced Defense Program by Regulating ORA59 Expression.

    PubMed

    Zander, Mark; Thurow, Corinna; Gatz, Christiane

    2014-08-01

    Salicylic acid (SA), a hormone essential for defense against biotrophic pathogens, triggers increased susceptibility of plants against necrotrophic attackers by suppressing the jasmonic acid-ethylene (ET) defense response. Here, we show that this disease-promoting SA effect is abolished in plants lacking the three related TGACG sequence-specific binding proteins TGA2, TGA5, and TGA6 (class II TGAs). After treatment of plants with the ET precursor 1-aminocyclopropane-1-carboxylic acid (ACC), activation of all those genes that are suppressed by SA depended on class II TGAs. Rather than TGA binding sites, GCC-box motifs were significantly enriched in the corresponding promoters. GCC-box motifs are recognized by members of the superfamily of APETALA2/ETHYLENE RESPONSE FACTORs (ERFs). Of 11 activating ACC-induced APETALA2/ERFs, only ORA59 (for OCTADECANOID-RESPONSIVE ARABIDOPSIS APETALA2/ETHYLENE RESPONSE FACTOR domain protein59) and ERF96 were strongly suppressed by SA. ORA59 is the master regulator of the jasmonic acid-ET-induced defense program. ORA59 transcript levels do not reach maximal levels in the tga2 tga5 tga6 triple mutant, and this residual activity cannot be suppressed by SA. The ORA59 promoter contains an essential TGA binding site and is a direct target of class II TGAs as revealed by chromatin immunoprecipitation experiments. We suggest that class II TGAs at the ORA59 promoter constitute an important regulatory hub for the activation and SA suppression of ACC-induced genes. © 2014 American Society of Plant Biologists. All Rights Reserved.

  2. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.

    PubMed

    Hak, Eelko; Mulder, Bianca; Schuiling-Veninga, Catharina C M; de Vries, Tjalling W; Jick, Susan S

    2013-11-01

    Recent studies have reported an association between maternal use of gastric acid-suppressive drugs during pregnancy and asthma in the offspring, but the association could have been confounded by unmeasured risk factors. We assessed the association between the use of acid-suppressive drugs during pregnancy and the risk of developing childhood asthma using a bidirectional crossover design. Mother-infant matched sets in the UK General Practitioners Research Database were used to identify children with a drug-treated asthma diagnosis during the years 2006-2010 who were matched to a sibling without asthma as controls. Primary exposure was use of any anti-suppressive drug during pregnancy, and subgroup analyses were conducted according to drug class (e.g. proton pump inhibitors or histamine 2 receptor antagonists) and trimester. Conditional logistic regression was used to estimate odds ratios (OR) with their corresponding 95 % confidence intervals (CIs). A total of 1,874 children with asthma and 1,874 control siblings were included in the analysis. The exposure rate among case and control pregnancies was 22 and 20 %, respectively. After adjustments for gender, birth order, mother's age and general practice visits, the exposure to any gastric-acid suppressive drug during pregnancy slightly increased the risk for developing asthma (OR 1.23, 95 % CI 1.01-1.51; p = 0.042). A trend towards increased risks was observed for those who used proton pump inhibitors and/or histamine 2 receptor antagonists (adjusted OR 1.72, 95 % CI 1.00-2.98; p = 0.048). These findings lend support to the emerging evidence that exposure to acid-suppressive drugs during pregnancy is associated with childhood asthma. More basic research is now warranted to investigate the mechanisms.

  3. Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen.

    PubMed

    Ogura, Jiro; Kuwayama, Kaori; Sasaki, Shunichi; Kaneko, Chihiro; Koizumi, Takahiro; Yabe, Keisuke; Tsujimoto, Takashi; Takeno, Reiko; Takaya, Atsushi; Kobayashi, Masaki; Yamaguchi, Hiroaki; Iseki, Ken

    2015-09-01

    The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging.

  4. Randomised clinical trial: mucosal protection combined with acid suppression in the treatment of non-erosive reflux disease - efficacy of Esoxx, a hyaluronic acid-chondroitin sulphate based bioadhesive formulation.

    PubMed

    Savarino, V; Pace, F; Scarpignato, C

    2017-03-01

    Several studies have shown that patients with non-erosive reflux disease (NERD) are less responsive to proton pump inhibitors (PPIs) than those with erosive disease as they belong to different subgroups, in whom factors other than acid can trigger symptoms. To evaluate whether combined therapy (mucosal protection plus acid suppression) would improve symptom relief compared to PPI treatment alone. In a multicenter, randomised, double-blind trial, 154 patients with NERD were randomised to receive Esoxx (Alfa Wassermann, Bologna, Italy), a hyaluronic acid-chondroitin sulphate based bioadhesive formulation, or placebo, in addition to acid suppression with standard dose PPIs for 2 weeks. Symptoms (heartburn, acid regurgitation, retrosternal pain and acid taste in the mouth) and health-related quality of life (HRQL) were evaluated before and after treatment. The primary endpoint was the proportion of patients with at least a 3-point reduction in the total symptom score. At the end of treatment, the primary endpoint was reached by 52.6% of patients taking Esoxx compared to 32.1% of those given placebo (P < 0.01). The same was true also for HRQL, evaluated by means of the Short Form-36 questionnaire, which improved with both treatments, but some items were significantly better after Esoxx plus PPI therapy. The synergistic effect of Essox with PPI treatment suggests that mucosal protection added to acid suppression could improve symptoms and HRQL in NERD patients. © 2017 The Authors. Alimentary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.

  5. Helicteric Acid, Oleanic Acid, and Betulinic Acid, Three Triterpenes from Helicteres angustifolia L., Inhibit Proliferation and Induce Apoptosis in HT-29 Colorectal Cancer Cells via Suppressing NF-κB and STAT3 Signaling

    PubMed Central

    2017-01-01

    Colorectal cancer (CRC) is one of the most common malignancies and most frequent cause of cancer death worldwide. The activation of both NF-κB and STAT3 signaling and the crosstalk between them play an important role in colorectal tumor. Helicteres angustifolia L. is a type of commonly used Chinese medicinal herb and possesses a wide variety of biological activities. In the present study, we investigate the effects of three triterpenes from H. angustifolia (HT) such as helicteric acid (HA), oleanic acid (OA), and betulinic acid (BA), on inhibiting CRC progression. Our results showed that HT extracts could decrease proliferation and induce apoptosis in HT-29 colorectal cancer cells. Moreover, HT extracts could suppress LPS-triggered phosphorylation of IKK, IκB, and NF-κB, attenuate IL-6-induced phosphorylation of JAK2 and STAT3, and suppress the expression of c-Myc, cyclin-D1, and BCL-xL, the downstream gene targets of NF-κB and STAT3. Therefore, HT extracts showed potent therapeutic and antitumor effects on CRC via inhibiting NF-κB and STAT3 signaling. PMID:28331523

  6. A medium-chain fatty acid, capric acid, inhibits RANKL-induced osteoclast differentiation via the suppression of NF-κB signaling and blocks cytoskeletal organization and survival in mature osteoclasts.

    PubMed

    Kim, Hyun-Ju; Yoon, Hye-Jin; Kim, Shin-Yoon; Yoon, Young-Ran

    2014-08-01

    Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (MCSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced IκBα phosphorylation, p65 nuclear translocation, and NF-κB transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKL-mediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.

  7. Multipolar Electrostatic Energy Prediction for all 20 Natural Amino Acids Using Kriging Machine Learning.

    PubMed

    Fletcher, Timothy L; Popelier, Paul L A

    2016-06-14

    A machine learning method called kriging is applied to the set of all 20 naturally occurring amino acids. Kriging models are built that predict electrostatic multipole moments for all topological atoms in any amino acid based on molecular geometry only. These models then predict molecular electrostatic interaction energies. On the basis of 200 unseen test geometries for each amino acid, no amino acid shows a mean prediction error above 5.3 kJ mol(-1), while the lowest error observed is 2.8 kJ mol(-1). The mean error across the entire set is only 4.2 kJ mol(-1) (or 1 kcal mol(-1)). Charged systems are created by protonating or deprotonating selected amino acids, and these show no significant deviation in prediction error over their neutral counterparts. Similarly, the proposed methodology can also handle amino acids with aromatic side chains, without the need for modification. Thus, we present a generic method capable of accurately capturing multipolar polarizable electrostatics in amino acids.

  8. Pharmacometabolomics in Endogenous Drugs: A New Approach for Predicting the Individualized Pharmacokinetics of Cholic Acid.

    PubMed

    Zhang, Zhixin; Gu, Hao; Zhao, Huizhen; Liu, Yuehong; Fu, Shuang; Wang, Meiling; Zhou, Wenjuan; Xie, Ziye; Yu, Honghong; Huang, Zhenghai; Gao, Xiaoyan

    2017-09-01

    The evaluation of individual variability in endogenous drugs' metabolism and disposition is a very challenging task. We developed and validated a metabotype to pharmacokinetics (PK) matching approach by taking cholic acid as an example to predict the individualized PK of endogenous drugs. The stable isotope-labeled cholic acid was selected as the substitute analyte of cholic acid to ensure the accurate measurement of blood concentration. First, large-scale metabolite profiling studies were performed on the predose urine samples of 28 rats. Then, to examine the individualized PK of deuterium 4-cholic acid (d4-cholic acid) in these rats, we determined its plasma concentrations and calculated the differential AUC values. Subsequently, we conducted a two-stage partial least-squares analysis in which 31 baseline metabolites were screened initially for predicting the individualized AUC values of d4-cholic acid using the data of predose urine metabolites. Finally, network biology analysis was applied to give the biological interpretation of the individual variances in cholic acid metabolism and disposition, and the result further narrowed the selection of baseline metabolites from 31 to 2 (sarcosine and S-adenosyl-l-homocysteine) for such prediction. Collectively, this pharmacometabolomics research provided a new strategy for predicting individualized PK of endogenous drugs.

  9. Using Hounsfield unit measurement and urine parameters to predict uric acid stones.

    PubMed

    Spettel, Sara; Shah, Paras; Sekhar, Kiran; Herr, Allen; White, Mark D

    2013-07-01

    To determine the in vivo ability to predict uric acid stone composition by Hounsfield units (HU) with the addition of urine parameters. We reviewed all consecutive stones sent for analysis during a 4-year period from our institution for patients with an in-house computed tomography (CT) scan within the prior 6 months and urinalysis within the prior week. CT scans were independently reviewed by a radiologist blinded to stone composition. Of the 507 patients with stones sent for analysis, 235 met the criteria for inclusion. Analysis showed 212 stones were predominantly calcium-based, and 22 were predominantly uric acid in composition. There was a significant difference between calcium stones and uric acid stones in mean HU (890 ± 20 vs 484 ± 44; P <.01) and urine pH (6.4 ± 0.8 vs 5.1 ± 0.2; P <.01). Receiver operating characteristic curve evaluation gave optimal predictive values of HU ≤494 (rounded to 500) and pH of ≤5.5 to predict uric acid stones. The combination of HU and pH criteria resulted in a sensitivity of 86% and a specificity of 98%, with a positive predictive value of 80%, which increased to 90% if we limited to stones >4 mm. Uric acid stones show a significant difference in HU and urine pH from calcium stones, and the use of both criteria is superior to either separately. For a stone >4 mm, a HU ≤500 and pH ≤5.5 has a positive predictive value of 90% for uric acid composition. Our prediction model gives a straightforward tool that can be easily measured to predict a uric acid stone. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Removing perfluorooctane sulfonate and perfluorooctanoic acid from solid matrices, paper, fabrics, and sand by mineral acid suppression and supercritical carbon dioxide extraction.

    PubMed

    Chen, Hsiang-Yu; Liao, Weisheng; Wu, Ben-Zen; Nian, Hungchi; Chiu, KongHwa; Yak, Hwa-Kwang

    2012-09-01

    The removal of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from solid matrices has received considerable attention because of the environmental persistence, bioaccumulation, and potential toxicity of these compounds. This study presents a simple method using concentrated HNO(3) as a suppression agent, and methanol-modified supercritical carbon dioxide (Sc-CO(2)) extraction for removing PFOS and PFOA from solid matrices. The optimal conditions were 16 M HNO(3) and 20% (v/v) methanol containing Sc-CO(2), under a pressure of 20.3 MPa and a temperature of 50 °C. Extraction time was set at 70 min (40 min for static and 30 min for dynamic extraction). PFOA and PFOS were identified and quantitated by liquid chromatography/mass spectrometry. The extraction efficiencies (with double extractions) were close to 100% for PFOA and 80% for PFOS for both paper and fabric matrices. The extraction efficiencies for sand were approximately 77% for PFOA and 59% for PFOS. The results show that this method is accurate, and effective, and that it provides a promising and convenient approach to remediate the environment of hazardous PFOA and PFOS contamination. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. High Dietary Acid Load Predicts ESRD among Adults with CKD

    PubMed Central

    Crews, Deidra C.; Wesson, Donald E.; Tilea, Anca M.; Saran, Rajiv; Ríos-Burrows, Nilka; Williams, Desmond E.; Powe, Neil R.

    2015-01-01

    Small clinical trials have shown that a reduction in dietary acid load (DAL) improves kidney injury and slows kidney function decline; however, the relationship between DAL and risk of ESRD in a population-based cohort with CKD remains unexamined. We examined the association between DAL, quantified by net acid excretion (NAEes), and progression to ESRD in a nationally representative sample of adults in the United States. Among 1486 adults with CKD age≥20 years enrolled in the National Health and Nutrition Examination Survey III, DAL was determined by 24-h dietary recall questionnaire. The development of ESRD was ascertained over a median 14.2 years of follow-up through linkage with the Medicare ESRD Registry. We used the Fine–Gray competing risks method to estimate the association of high, medium, and low DAL with ESRD after adjusting for demographics, nutritional factors, clinical factors, and kidney function/damage markers and accounting for intervening mortality events. In total, 311 (20.9%) participants developed ESRD. Higher levels of DAL were associated with increased risk of ESRD; relative hazards (95% confidence interval) were 3.04 (1.58 to 5.86) for the highest tertile and 1.81 (0.89 to 3.68) for the middle tertile compared with the lowest tertile in the fully adjusted model. The risk of ESRD associated with DAL tertiles increased as eGFR decreased (P trend=0.001). Among participants with albuminuria, high DAL was strongly associated with ESRD risk (P trend=0.03). In conclusion, high DAL in persons with CKD is independently associated with increased risk of ESRD in a nationally representative population. PMID:25677388

  12. High Dietary Acid Load Predicts ESRD among Adults with CKD.

    PubMed

    Banerjee, Tanushree; Crews, Deidra C; Wesson, Donald E; Tilea, Anca M; Saran, Rajiv; Ríos-Burrows, Nilka; Williams, Desmond E; Powe, Neil R

    2015-07-01

    Small clinical trials have shown that a reduction in dietary acid load (DAL) improves kidney injury and slows kidney function decline; however, the relationship between DAL and risk of ESRD in a population-based cohort with CKD remains unexamined. We examined the association between DAL, quantified by net acid excretion (NAEes), and progression to ESRD in a nationally representative sample of adults in the United States. Among 1486 adults with CKD age≥20 years enrolled in the National Health and Nutrition Examination Survey III, DAL was determined by 24-h dietary recall questionnaire. The development of ESRD was ascertained over a median 14.2 years of follow-up through linkage with the Medicare ESRD Registry. We used the Fine-Gray competing risks method to estimate the association of high, medium, and low DAL with ESRD after adjusting for demographics, nutritional factors, clinical factors, and kidney function/damage markers and accounting for intervening mortality events. In total, 311 (20.9%) participants developed ESRD. Higher levels of DAL were associated with increased risk of ESRD; relative hazards (95% confidence interval) were 3.04 (1.58 to 5.86) for the highest tertile and 1.81 (0.89 to 3.68) for the middle tertile compared with the lowest tertile in the fully adjusted model. The risk of ESRD associated with DAL tertiles increased as eGFR decreased (P trend=0.001). Among participants with albuminuria, high DAL was strongly associated with ESRD risk (P trend=0.03). In conclusion, high DAL in persons with CKD is independently associated with increased risk of ESRD in a nationally representative population.

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

    PubMed

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

    2013-09-01

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

  14. Suppression of gastric acid increases the risk of developing Immunoglobulin E-mediated drug hypersensitivity: human diclofenac sensitization and a murine sensitization model

    PubMed Central

    Riemer, A. B.; Gruber, S.; Pali-Schöll, I.; Kinaciyan, T.; Untersmayr, E.; Jensen-Jarolim, E.

    2010-01-01

    Summary Background Hypersensitivity reactions towards non-steroidal anti-inflammatory drugs (NSAID) are common, although true allergies are detectable only in a subgroup of patients. The current study was prompted by a case observation, where a patient experienced generalized urticaria following his second course of diclofenac and proton pump inhibitor medication, and was found to have diclofenac-specific IgE. During recent years, our group has been investigating the importance of gastric digestion in the development of food allergies, demonstrating anti-acid medication as a risk factor for sensitization against food proteins. Objective Here, we aimed to investigate whether the mechanism of food allergy induction described can also be causative in NSAID allergy, using diclofenac as a paradigm. Methods We subjected BALB/c mice to several oral immunization regimens modelled after the patient’s medication intake. Diclofenac was applied with or without gastric acid suppression, in various doses, alone or covalently coupled to albumin, a protein abundant in gastric juices. Immune responses were assessed on the antibody level, and functionally examined by in vitro and in vivo crosslinking assays. Results Only mice receiving albumin-coupled diclofenac under gastric acid suppression developed anti-diclofenac IgG1 and IgE, whereas no immune responses were induced by the drug alone or without gastric acid suppression. Antibody induction was dose dependent with the group receiving the higher dose of the drug showing sustained anti-diclofenac titres. The antibodies induced triggered basophil degranulation in vitro and positive skin tests in vivo. Conclusion Gastric acid suppression was found to be a causative mechanism in the induction of IgE-mediated diclofenac allergy. PMID:19817752

  15. X-29 flight - Acid test for design predictions

    NASA Technical Reports Server (NTRS)

    Putnam, T. W.; Petersen, K. L.; Ishmael, S. D.; Sefic, W. J.

    1986-01-01

    The X-29 flight test data are being disseminated to interested industrial and military users as fast as it becomes available. The aircraft is extensively instrumented with accelerometers and pressure sensors and optical sensors for measuring wing deflection. The thoroughness of preflight preparations permitted a rapid advance through initial test checkpoints, which have both confirmed many predictions and revealed several discrepancies. The flight envelope had been expanded to Mach 1.1 and an altitude of 40,000 ft by December 1985. Notably, the X-29 has provided in-flight data which could not be faithfully depicted in a simulator, e.g., flare procedures during landing, and has shown that the stability adjustments, although adequate for controlling the aircraft, are not rapid enough to offer a satisfactory margin of harmony. The tests are now being performed in the transonic regime, where supercritical airfoil and forward swept wing drag reduction become significant factors.

  16. Prediction and suppression of HIFU-induced vessel rupture using passive cavitation detection in an ex vivo model

    PubMed Central

    2014-01-01

    emission amplitude. Time to rupture was compared between these feedback-controlled trials and paired controller-inactive trials using a paired Wilcoxon signed-rank test. Results Subharmonic emissions were found to be the most predictive of vessel rupture (areas under the receiver operating characteristic curve (AUROC) = 0.757, p < 10-16) compared to low-frequency (AUROC = 0.657, p < 10-11) and broadband (AUROC = 0.729, p < 10-16) emissions. An independent-sample t test comparing pre-rupture to intact-vessel emissions revealed a statistically significant difference between the two groups for broadband and subharmonic emissions (p < 10-3), but not for low-frequency emissions (p = 0.058). In a one-sided paired Wilcoxon signed-rank test, activation of the control module was shown to increase the time to vessel rupture (T- = 8, p = 0.0244, N = 10). In one-sided paired t tests, activation of the control module was shown to cause no significant difference in time-averaged focal intensity (t = 0.362, p = 0.363, N = 10), but was shown to cause delivery of significantly greater total acoustic energy (t = 2.037, p = 0.0361, N = 10). Conclusions These results suggest that acoustic cavitation plays an important role in HIFU-induced vessel rupture. In HIFU treatments for vessel occlusion, passive monitoring of acoustic emissions may be useful in avoiding hemorrhage due to vessel rupture, as shown in the rupture suppression experiments. PMID:25232483

  17. Cdc2-like kinase 2 suppresses hepatic fatty acid oxidation and ketogenesis through disruption of the PGC-1α and MED1 complex.

    PubMed

    Tabata, Mitsuhisa; Rodgers, Joseph T; Hall, Jessica A; Lee, Yoonjin; Jedrychowski, Mark P; Gygi, Steven P; Puigserver, Pere

    2014-05-01

    Hepatic ketogenesis plays an important role in catabolism of fatty acids during fasting along with dietary lipid overload, but the mechanisms regulating this process remain poorly understood. Here, we show that Cdc2-like kinase 2 (Clk2) suppresses fatty acid oxidation and ketone body production during diet-induced obesity. In lean mice, hepatic Clk2 protein is very low during fasting and strongly increased during feeding; however, in diet-induced obese mice, Clk2 protein remains elevated through both fed and fasted states. Liver-specific Clk2 knockout mice fed a high-fat diet exhibit increased fasting levels of blood ketone bodies, reduced respiratory exchange ratio, and increased gene expression of fatty acid oxidation and ketogenic pathways. This effect of Clk2 is cell-autonomous, because manipulation of Clk2 in hepatocytes controls genes and rates of fatty acid utilization. Clk2 phosphorylation of peroxisome proliferator-activated receptor γ coactivator (PGC-1α) disrupts its interaction with Mediator subunit 1, which leads to a suppression of PGC-1α activation of peroxisome proliferator-activated receptor α target genes in fatty acid oxidation and ketogenesis. These data demonstrate the importance of Clk2 in the regulation of fatty acid metabolism in vivo and suggest that inhibition of hepatic Clk2 could provide new therapies in the treatment of fatty liver disease.

  18. Molecular concentration of deoxyHb in human prefrontal cortex predicts the emergence and suppression of consciousness.

    PubMed

    Leon-Dominguez, Umberto; Izzetoglu, Meltem; Leon-Carrion, Jose; Solís-Marcos, Ignacio; Garcia-Torrado, Francisco Jose; Forastero-Rodríguez, Ana; Mellado-Miras, Patricia; Villegas-Duque, Diego; Lopez-Romero, Juan Luis; Onaral, Banu; Izzetoglu, Kurtulus

    2014-01-15

    This is the first study to use fNIRS to explore anaesthetic depth and awakening during surgery with general anaesthesia. A 16 channel continuous wave (CW) functional near-infrared system (fNIRS) was used to monitor PFC activity. These outcomes were compared to BIS measures. The results indicate that deoxyHb concentration in the PFC varies during the suppression and emergence of consciousness. During suppression, deoxyHb levels increase, signalling the deactivation of the PFC, while during emergence, deoxyHb concentration drops, initiating PFC activation and the recovery of consciousness. Furthermore, BIS and deoxyHb concentrations in the PFC display a high negative correlation throughout the different anaesthetic phases. These findings suggest that deoxyHb could be a reliable marker for monitoring anaesthetic depth, and that the PFC intervenes in the suppression and emergence of consciousness.

  19. Identification of differentially expressed genes in SHSY5Y cells exposed to okadaic acid by suppression subtractive hybridization

    PubMed Central

    2012-01-01

    Background Okadaic acid (OA), a toxin produced by several dinoflagellate species is responsible for frequent food poisonings associated to shellfish consumption. Although several studies have documented the OA effects on different processes such as cell transformation, apoptosis, DNA repair or embryogenesis, the molecular mechanistic basis for these and other effects is not completely understood and the number of controversial data on OA is increasing in the literature. Results In this study, we used suppression subtractive hybridization in SHSY5Y cells to identify genes that are differentially expressed after OA exposure for different times (3, 24 and 48 h). A total of 247 subtracted clones which shared high homology with known genes were isolated. Among these, 5 specific genes associated with cytoskeleton and neurotransmission processes (NEFM, TUBB, SEPT7, SYT4 and NPY) were selected to confirm their expression levels by real-time PCR. Significant down-regulation of these genes was obtained at the short term (3 and 24 h OA exposure), excepting for NEFM, but their expression was similar to the controls at 48 h. Conclusions From all the obtained genes, 114 genes were up-regulated and 133 were down-regulated. Based on the NCBI GenBank and Gene Ontology databases, most of these genes are involved in relevant cell functions such as metabolism, transport, translation, signal transduction and cell cycle. After quantitative PCR analysis, the observed underexpression of the selected genes could underlie the previously reported OA-induced cytoskeleton disruption, neurotransmission alterations and in vivo neurotoxic effects. The basal expression levels obtained at 48 h suggested that surviving cells were able to recover from OA-caused gene expression alterations. PMID:22284234

  20. Enterococcus faecalis lipoteichoic acid suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced IL-8 expression in human periodontal ligament cells.

    PubMed

    Im, Jintaek; Baik, Jung Eun; Kim, Kyoung Whun; Kang, Seok-Seong; Jeon, Jun Ho; Park, Ok-Jin; Kim, Hyun Young; Kum, Kee-Yeon; Yun, Cheol-Heui; Han, Seung Hyun

    2015-08-01

    Periodontitis is caused by multi-bacterial infection and Aggregatibacter actinomycetemcomitans and Enterococcus faecalis are closely associated with inflammatory periodontal diseases. Although lipopolysaccharide (LPS) of A. actinomycetemcomitans (Aa.LPS) and lipoteichoic acid of E. faecalis (Ef.LTA) are considered to be major virulence factors evoking inflammatory responses, their combinatorial effect on the induction of chemokines has not been investigated. In this study, we investigated the interaction between Aa.LPS and Ef.LTA on IL-8 expression in human periodontal ligament (PDL) cells. Aa.LPS, but not Ef.LTA, substantially induced IL-8 expression at the protein and mRNA levels. Interestingly, Ef.LTA suppressed Aa.LPS-induced IL-8 expression without affecting the binding of Aa.LPS to Toll-like receptor (TLR) 4. Ef.LTA reduced Aa.LPS-induced phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38 kinase. Furthermore, Ef.LTA inhibited the Aa.LPS-induced transcriptional activities of the activating protein 1, CCAAT/enhancer-binding protein and nuclear factor-kappa B transcription factors, all of which are known to regulate IL-8 gene expression. Ef.LTA augmented the expression of IL-1 receptor-associated kinase-M (IRAK-M), a negative regulator of TLR intracellular signaling pathways, in the presence of Aa.LPS at both the mRNA and protein levels. Small interfering RNA silencing IRAK-M reversed the attenuation of Aa.LPS-induced IL-8 expression by Ef.LTA. Collectively, these results suggest that Ef.LTA down-regulates Aa.LPS-induced IL-8 expression in human PDL cells through up-regulation of the negative regulator IRAK-M.

  1. Fatty acid amide hydrolase (FAAH) blockade ameliorates experimental colitis by altering microRNA expression and suppressing inflammation.

    PubMed

    Shamran, Haidar; Singh, Narendra P; Zumbrun, Elizabeth E; Murphy, Angela; Taub, Dennis D; Mishra, Manoj K; Price, Robert L; Chatterjee, Saurabh; Nagarkatti, Mitzi; Nagarkatti, Prakash S; Singh, Udai P

    2017-01-01

    Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which is thought to result from immune-mediated inflammatory disorders, leads to high morbidity and health care cost. Fatty acid amide hydrolase (FAAH) is an enzyme crucially involved in the modulation of intestinal physiology through anandamide (AEA) and other endocannabinoids. Here we examined the effects of an FAAH inhibitor (FAAH-II), on dextran sodium sulphate (DSS)-induced experimental colitis in mice. Treatments with FAAH-II improved overall clinical scores by reversing weight loss and colitis-associated pathogenesis. The frequencies of activated CD4(+) T cells in spleens, mesenteric lymph nodes (MLNs), Peyer's patches (PPs), and colon lamina propiria (LP) were reduced by FAAH inhibition. Similarly, the frequencies of macrophages, neutrophils, natural killer (NK), and NKT cells in the PPs and LP of mice with colitis declined after FAAH blockade, as did concentrations of systemic and colon inflammatory cytokines. Microarray analysis showed that 26 miRNAs from MLNs and 217 from PPs had a 1.5-fold greater difference in expression after FAAH inhibition. Among them, 8 miRNAs were determined by reverse-transcription polymerase chain reaction (RT-PCR) analysis to have anti-inflammatory properties. Pathway analysis demonstrated that differentially regulated miRNAs target mRNA associated with inflammation. Thus, FAAH-II ameliorates experimental colitis by reducing not only the number of activated T cells but also the frequency of macrophages, neutrophils, and NK/NKT cell, as well as inflammatory miRNAs and cytokine at effector sites in the colon. These studies demonstrate for the first time that FAAH-II inhibitor may suppress colitis through regulation of pro-inflammatory miRNAs expression.

  2. 4,5-Di-O-Caffeoylquinic Acid from Ligularia fischeri Suppresses Inflammatory Responses Through TRPV1 Activation.

    PubMed

    Kim, Yiseul; Kim, Jung Tae; Park, Joonwoo; Son, Hee Jin; Kim, Eun-Young; Lee, Young Joo; Rhyu, Mee-Ra

    2017-10-01

    Ligularia fischeri (Ledeb.) Turcz., a perennial plant native to northeastern Asia, has long been used as folk remedies for the alleviation of inflammatory symptoms. We investigated whether the extract of L. fischeri (LFEx) and caffeoylquinic acid (CQA) derivatives, the pharmacologically active ingredients identified from L. fischeri, regulate inflammation via a transient receptor potential vanilloid 1 (TRPV1)-mediated pathway. Changes in intracellular Ca(2+) levels to the LFEx and trans-5-O-CQA, 3,4-di-O-CQA, 3,5-di-O-CQA, and 4,5-di-O-CQA were monitored in TRPV1-expressing human embryonic kidney cell HEK 293T. LFEx and 4,5-di-O-CQA (EC50  = 69.34 ± 1.12 μM) activated TRPV1, and these activations were significantly inhibited by ruthenium red, a general blocker of TRP channels, and capsazepine, a specific antagonist of TRPV1. 4,5-Di-O-CQA has been determined having antiinflammatory effect under hypoxic conditions by detecting the expression of cyclooxygenase-2 (COX-2), a representative inflammatory marker, and cellular migration in human pulmonary epithelial A549 cells. 4,5-Di-O-CQA suppressed COX-2 expression and cell migration, and this inhibition was countered by co-treatment with capsazepine. This study provides evidence that L. fischeri is selective to inflammatory responses via a TRPV1-mediated pathway, and 4,5-di-O-CQA might play a key role to create these effects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  3. Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis.

    PubMed

    Ren, Younan; Tao, Shanjun; Zheng, Shuguo; Zhao, Mengqiu; Zhu, Yuanmei; Yang, Jieren; Wu, Yuanjie

    2016-11-15

    Vascular endothelial cell injury is an initial event in atherosclerosis. Salvianolic acid B (Sal B), a main bioactive component in the root of Salvia miltiorrhiza, has vascular protective effect in diabetes, but the underlying mechanisms remain unclear. The present study investigated the effect of Sal B on vascular endothelial function in diabetic rats with blood glucose fluctuations and the possible mechanisms implicated. The results showed that diabetic rats developed marked endothelial dysfunction as exhibited by impaired acetylcholine induced vasodilation. Supplementation with Sal B resulted in an evident improvement of endothelial function. Phosphorylation (Ser 1177) of endothelial nitric oxide synthase (eNOS) was significantly restored in Sal B treated diabetic rats, accompanied by an evident recovery of NO metabolites. Sal B effectively reduced vascular endothelial cell apoptosis, with Bcl-2 protein up-regulated and Bax protein down-regulated markedly. Treatment with Sal B led to an evident amelioration of oxidative stress in diabetic rats as manifested by enhanced antioxidant capacity and decreased contents of malondialdehyde in aortas. Protein levels of NOX2 and NOX4, two main isoforms of NADPH oxidase known as the major source of reactive oxygen species in the vasculature, were markedly decreased in Sal B treated groups. In addition, treatment with Sal B led to an evident decrease of serum lipids. Taken together, this study indicates that Sal B is capable of improving endothelial function in diabetic rats with blood glucose fluctuations, of which the underlying mechanisms might be related to suppression of endothelial cell apoptosis and stimulation of eNOS phosphorylation (Ser 1177).

  4. Identification of differentially expressed genes in SHSY5Y cells exposed to okadaic acid by suppression subtractive hybridization.

    PubMed

    Valdiglesias, Vanessa; Fernández-Tajes, Juan; Pásaro, Eduardo; Méndez, Josefina; Laffon, Blanca

    2012-01-27

    Okadaic acid (OA), a toxin produced by several dinoflagellate species is responsible for frequent food poisonings associated to shellfish consumption. Although several studies have documented the OA effects on different processes such as cell transformation, apoptosis, DNA repair or embryogenesis, the molecular mechanistic basis for these and other effects is not completely understood and the number of controversial data on OA is increasing in the literature. In this study, we used suppression subtractive hybridization in SHSY5Y cells to identify genes that are differentially expressed after OA exposure for different times (3, 24 and 48 h). A total of 247 subtracted clones which shared high homology with known genes were isolated. Among these, 5 specific genes associated with cytoskeleton and neurotransmission processes (NEFM, TUBB, SEPT7, SYT4 and NPY) were selected to confirm their expression levels by real-time PCR. Significant down-regulation of these genes was obtained at the short term (3 and 24 h OA exposure), excepting for NEFM, but their expression was similar to the controls at 48 h. From all the obtained genes, 114 genes were up-regulated and 133 were down-regulated. Based on the NCBI GenBank and Gene Ontology databases, most of these genes are involved in relevant cell functions such as metabolism, transport, translation, signal transduction and cell cycle. After quantitative PCR analysis, the observed underexpression of the selected genes could underlie the previously reported OA-induced cytoskeleton disruption, neurotransmission alterations and in vivo neurotoxic effects. The basal expression levels obtained at 48 h suggested that surviving cells were able to recover from OA-caused gene expression alterations.

  5. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  6. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.

    PubMed

    Cheng, Kang; Wu, Tsuei-Ju; Wu, Kenneth K; Sturino, Claudio; Metters, Kathleen; Gottesdiener, Keith; Wright, Samuel D; Wang, Zhaoyin; O'Neill, Gary; Lai, Eseng; Waters, M Gerard

    2006-04-25

    Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.

  7. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans

    PubMed Central

    Cheng, Kang; Wu, Tsuei-Ju; Wu, Kenneth K.; Sturino, Claudio; Metters, Kathleen; Gottesdiener, Keith; Wright, Samuel D.; Wang, Zhaoyin; O’Neill, Gary; Lai, Eseng; Waters, M. Gerard

    2006-01-01

    Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2−/− mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/−, and DP1−/− mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP−/− mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans. PMID:16617107

  8. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells

    PubMed Central

    Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

    2017-01-01

    Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H2O2)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H2O2-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H2O2-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells. PMID:28230729

  9. Identification of amino acids inserted during suppression of UAA and UGA termination codons at the gag-pol junction of Moloney murine leukemia virus.

    PubMed Central

    Feng, Y X; Copeland, T D; Oroszlan, S; Rein, A; Levin, J G

    1990-01-01

    Expression of the murine leukemia virus pol gene occurs by translational readthrough of an in-frame UAG codon between the gag and pol coding regions. In a previous study, we mutated the UAG codon to UAA or UGA and demonstrated that both of these termination codons could be suppressed in reticulocyte lysates and in infected cells with the same efficiency as UAG. We now report the identity of the amino acids inserted in vitro in response to UAA and UGA in fusion products containing the gag-pol junction region. The results show that UAA, like UAG, directs the incorporation of glutamine, whereas UGA directs the incorporation of three amino acids, arginine, cysteine, and tryptophan. To our knowledge, this is the first report indicating misreading of UAA as glutamine and UGA as arginine and cysteine in higher eukaryotes. Interestingly, although our protein synthesis system presumably contains other known UAG and UGA suppressors, these tRNAs did not suppress the termination codons in our experiments. Thus, it seems possible that the sequence surrounding the gag-pol junction not only promotes suppression but also helps determine which tRNAs function in suppression. Images PMID:2247457

  10. Catechol Groups Enable Reactive Oxygen Species Scavenging-Mediated Suppression of PKD-NFkappaB-IL-8 Signaling Pathway by Chlorogenic and Caffeic Acids in Human Intestinal Cells.

    PubMed

    Shin, Hee Soon; Satsu, Hideo; Bae, Min-Jung; Totsuka, Mamoru; Shimizu, Makoto

    2017-02-20

    Chlorogenic acid (CHA) and caffeic acid (CA) are phenolic compounds found in coffee, which inhibit oxidative stress-induced interleukin (IL)-8 production in intestinal epithelial cells, thereby suppressing serious cellular injury and inflammatory intestinal diseases. Therefore, we investigated the anti-inflammatory mechanism of CHA and CA, both of which inhibited hydrogen peroxide (H₂O₂)-induced IL-8 transcriptional activity. They also significantly suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional activity, nuclear translocation of the p65 subunit, and phosphorylation of IκB kinase (IKK). Additionally, upstream of IKK, protein kinase D (PKD) was also suppressed. Finally, we found that they scavenged H₂O₂-induced reactive oxygen species (ROS) and the functional moiety responsible for the anti-inflammatory effects of CHA and CA was the catechol group. Therefore, we conclude that the presence of catechol groups in CHA and CA allows scavenging of intracellular ROS, thereby inhibiting H₂O₂-induced IL-8 production via suppression of PKD-NF-κB signaling in human intestinal epithelial cells.

  11. Frequencies of amino acid strings in globular protein sequences indicate suppression of blocks of consecutive hydrophobic residues

    PubMed Central

    Schwartz, Russell; Istrail, Sorin; King, Jonathan

    2001-01-01

    Patterns of hydrophobic and hydrophilic residues play a major role in protein folding and function. Long, predominantly hydrophobic strings of 20–22 amino acids each are associated with transmembrane helices and have been used to identify such sequences. Much less attention has been paid to hydrophobic sequences within globular proteins. In prior work on computer simulations of the competition between on-pathway folding and off-pathway aggregate formation, we found that long sequences of consecutive hydrophobic residues promoted aggregation within the model, even controlling for overall hydrophobic content. We report here on an analysis of the frequencies of different lengths of contiguous blocks of hydrophobic residues in a database of amino acid sequences of proteins of known structure. Sequences of three or more consecutive hydrophobic residues are found to be significantly less common in actual globular proteins than would be predicted if residues were selected independently. The result may reflect selection against long blocks of hydrophobic residues within globular proteins relative to what would be expected if residue hydrophobicities were independent of those of nearby residues in the sequence. PMID:11316883

  12. Identification of the domains of cauliflower mosaic virus protein P6 responsible for suppression of RNA silencing and salicylic acid signalling

    PubMed Central

    Laird, Janet; McInally, Carol; Carr, Craig; Doddiah, Sowjanya; Yates, Gary; Chrysanthou, Elina; Khattab, Ahmed; Love, Andrew J.; Geri, Chiara; Sadanandom, Ari; Smith, Brian O.; Kobayashi, Kappei

    2013-01-01

    Cauliflower mosaic virus (CaMV) encodes a 520 aa polypeptide, P6, which participates in several essential activities in the virus life cycle including suppressing RNA silencing and salicylic acid-responsive defence signalling. We infected Arabidopsis with CaMV mutants containing short in-frame deletions within the P6 ORF. A deletion in the distal end of domain D-I (the N-terminal 112 aa) of P6 did not affect virus replication but compromised symptom development and curtailed the ability to restore GFP fluorescence in a GFP-silenced transgenic Arabidopsis line. A deletion in the minimum transactivator domain was defective in virus replication but retained the capacity to suppress RNA silencing locally. Symptom expression in CaMV-infected plants is apparently linked to the ability to suppress RNA silencing. When transiently co-expressed with tomato bushy stunt virus P19, an elicitor of programmed cell death in Nicotiana tabacum, WT P6 suppressed the hypersensitive response, but three mutants, two with deletions within the distal end of domain D-I and one involving the N-terminal nuclear export signal (NES), were unable to do so. Deleting the N-terminal 20 aa also abolished the suppression of pathogen-associated molecular pattern-dependent PR1a expression following agroinfiltration. However, the two other deletions in domain D-I retained this activity, evidence that the mechanisms underlying these functions are not identical. The D-I domain of P6 when expressed alone failed to suppress either cell death or PR1a expression and is therefore necessary but not sufficient for all three defence suppression activities. Consequently, concerns about the biosafety of genetically modified crops carrying truncated ORFVI sequences appear unfounded. PMID:24088344

  13. Tannic acid, a higher galloylated pentagalloylglucose, suppresses antigen-specific IgE production by inhibiting ɛ germline transcription induced by STAT6 activation.

    PubMed

    Kim, Yoon Hee; Yoshimoto, Miki; Nakayama, Kazuko; Tanino, Sousuke; Fujimura, Yoshinori; Yamada, Koji; Tachibana, Hirofumi

    2013-01-01

    Interleukin (IL)-4 is a critical stimulator that induces ɛ germline transcripts (ɛGT) for switch recombination to initiate immunoglobulin (Ig) E and is important in allergic disease pathogenesis. We found pentagalloylglucose (PGG) inhibited IL-4-induced ɛGT expression. PGG exerted its inhibitory function by suppressing IL-4-induced activation of IL-4Rα, JAK3 and STAT6. Furthermore, tannic acid, a higher galloylated PGG, attenuated ovalbumin-induced IgE production in vivo by inhibiting IL-4-induced ɛGT expression and the IL-4 signaling pathway. In conclusion, our results suggest that tannic acid may attenuate allergic diseases by suppressing IgE production by inhibiting IL-4-induced signaling.

  14. Mutations in Plastidial 5-Aminolevulinic Acid Biosynthesis Genes Suppress a Pleiotropic Defect in Shoot Development of a Mitochondrial GABA Shunt Mutant in Arabidopsis.

    PubMed

    Toyokura, Koichi; Yamaguchi, Katsushi; Shigenobu, Shuji; Fukaki, Hidehiro; Tatematsu, Kiyoshi; Okada, Kiyotaka

    2015-06-01

    Plant developmental processes are co-ordinated with the status of cell metabolism, not only in mitochondria but also in plastids. In Arabidopsis thaliana, succinic semialdehyde (SSA), a GABA shunt metabolite, links the specific mitochondrial metabolic pathway to shoot development. To understand the mechanism of SSA-mediated development, we isolated a succinic semialdehyde dehydrogenase (ssadh) suppressor mutant, affected in its ability to catalyze SSA to succinic acid. We found that pleiotropic developmental phenotypes of ssadh are suppressed by a mutation in GLUTAMATE-1-SEMIALDEHYDE 2, 1-AMINOMUTASE 2 (GSA2), which encodes a plastidial enzyme converting glutatamate-1-semialdehyde to 5-aminolevulinic acid (5-ALA). In addition, a mutation in either HEMA1 or GSA1, two other enzymes for 5-ALA synthesis, also suppressed ssadh fully and partially, respectively. Furthermore, exogenous application of 5-ALA and SSA disturbed leaf development. These results suggest that metabolism in both mitochondria and plastids affect shoot development.

  15. Salicylic acid alleviates aluminum toxicity in rice seedlings better than magnesium and calcium by reducing aluminum uptake, suppressing oxidative damage and increasing antioxidative defense.

    PubMed

    Pandey, Poonam; Srivastava, Rajneesh Kumar; Dubey, R S

    2013-05-01

    Aluminum toxicity is a major constraint to crop production in acid soils. The present study was undertaken to examine the comparative ameliorating effects of salicylic acid, Ca and Mg on Al toxicity in rice (Oryza sativa L.) seedlings grown in hydroponics. Al treatment (0.5 mM AlCl3) caused decrease in plant vigour, loss of root plasma membrane integrity, increased contents of O 2 (∙-) , H2O2, lipid peroxidation, protein carbonyls and decline in the level of protein thiol. Al treatment caused significant changes in activity of antioxidative enzymes in rice seedlings. Exogenously added salicylic acid (60 μM), Ca (1 mM) and Mg (0.25 mM) significantly alleviated Al toxicity effects in the seedlings marked by restoration of growth, suppression of Al uptake, restoration of root plasma membrane integrity and decline in O 2 (∙-) , H2O2, lipid peroxidation and protein carbonyl contents. Salicylic acid, Ca and Mg suppressed Al-induced increase in SOD, GPX and APX activities while it elevated Al-induced decline in CAT activity. By histochemical staining of O 2 (∙-) using NBT and H2O2 using DAB, it was further confirmed that added salicylic acid, Ca or Mg decreased Al-induced accumulation of O 2 (∙-) and H2O2 in the leaf tissues. Results indicate that exogenously added salicylic acid, Ca or Mg alleviates Al toxicity in rice seedlings by suppressing Al uptake, restoring root membrane integrity, reducing ROS level and ROS induced oxidative damage and regulating the level of antioxidative enzyme activities. Further salicylic appears to be superior to Mg and Ca in alleviating Al toxicity effects in rice plants.

  16. Impact of persistent, frequent regurgitation on quality of life in heartburn responders treated with acid suppression: a multinational primary care study.

    PubMed

    Kahrilas, P J; Howden, C W; Wernersson, B; Denison, H; Nuevo, J; Gisbert, J P

    2013-05-01

    In gastro-oesophageal reflux disease (GERD), heartburn responds well to acid suppression, but regurgitation is a common cause of incomplete treatment response. To assess the prevalence and burden of persistent, frequent regurgitation in primary care patients with GERD treated with acid suppression. We analysed observational data from 134 sites across six European countries in patients diagnosed with GERD. Within 3 months of the index visit, symptoms were assessed using the Reflux Disease Questionnaire, and their impact on sleep and work productivity with the Quality of Life in Reflux and Dyspepsia questionnaire and the Work Productivity and Activity Impairment Questionnaire, respectively. Patients provided information on concomitant over-the-counter (OTC) GERD medication use. Persistent, frequent (3-7 days/week) regurgitation was reported by 13.2% (153/1156) of GERD patients with no heartburn on acid suppression; the prevalence was very similar for patients with up to 2 days/week of ongoing mild heartburn. Among patients without heartburn, sleep disturbance of any type was reported by 50.7-60.1% with persistent, frequent regurgitation, compared with 38.1-51.1% and 14.4-19.2% of those with less frequent or no regurgitation respectively. Persistent, frequent regurgitation was associated with increased use of OTC medication and more hours of work missed, whether mild, infrequent heartburn was present or not. Frequent regurgitation, which persisted in 12-13% of patients with no or infrequent, mild heartburn on acid suppression, negatively affected sleep and work productivity, and increased use of OTC medication. Persistent, frequent regurgitation is problematic for primary care patients with GERD. © 2013 Blackwell Publishing Ltd.

  17. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARa and T- and B-cell targeting

    EPA Pesticide Factsheets

    Dosing information, body weights during exposure and immune system endpoints. This dataset is associated with the following publication:DeWitt, J., W. Williams , J. Creech, and R. Luebke. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting. JOURNAL OF IMMUNOTOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, USA, 13(1): 38-45, (2016).

  18. Suppressive effect of viscous dietary fiber on elevations of uric acid in serum and urine induced by dietary RNA in rats is associated with strength of viscosity.

    PubMed

    Koguchi, Takashi; Nakajima, Hisao; Koguchi, Hiromi; Wada, Masahiro; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokoro, Tadahiro

    2003-10-01

    This study was performed to clarify how dietary fiber (DF) with different viscosities would be associated with dietary RNA metabolism. Male Wistar strain rats, four weeks old, were fed diets containing a 3% (w/w) yeast RNA and a 5% (w/w) viscous DF for five days. Viscosity of DF samples used, in order of strength, were xanthan gum (XG) > guar gum (GG) > locust bean gum (LBG) > karaya gum (KG) > pectin (PE) = arabic gum (AG) > CM-cellulose (CMC) = inulin (IN). The serum uric acid concentration in the viscous DF groups significantly decreased as compared with that in the cellulose (CL) group. The urinary excretions of uric acid and allantoin in the respective groups given AG, GG, IN, KG, PE, and XG were significantly suppressed as compared with those in the CL group. The fecal RNA excretion was markedly increased in the IN, KG, PE, and XG groups in comparison to the CL group. The DF with high viscosity significantly suppressed RNA digestion by RNase A and decreased uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in rat jejunum. The results reveal that the suppressive effect of DF on elevation of serum uric acid concentration induced by dietary RNA in rats is associated with the strength of DF viscosity. The mechanism by which this is accomplished is suggested to be attributed to the inhibitions of digestion for dietary RNA and/or absorption of the hydrolyzed compounds.

  19. Prediction of liquid-liquid equilibrium for systems of vegetable oils, fatty acids, and ethanol

    SciTech Connect

    Batista, E.; Monnerat, S.; Stragevitch, L.; Pina, C.G.; Goncalves, C.B.; Meirelles, A.J.A.

    1999-12-01

    Group interaction parameters for the UNIFAC and ASOG models were specially adjusted for predicting liquid-liquid equilibrium (LLE) for systems of vegetable oils, fatty acids, and ethanol at temperatures ranging from 20 to 45 C. Experimental liquid-liquid equilibrium data for systems of triolein, oleic acid, and ethanol and of triolein, stearic acid, and ethanol were measured and utilized in the adjustment. The average percent deviation between experimental and calculated compositions was 0.79% and 0.52% for the UNIFAC and ASOG models, respectively. The prediction of liquid-liquid equilibrium for systems of vegetable oils, fatty acids, and ethanol was quite successful, with an average deviation of 1.31% and 1.32% for the UNIFAC and ASOG models, respectively.

  20. Characterizing and predicting carboxylic acid reductase activity for diversifying bioaldehyde production.

    PubMed

    Moura, Matthew; Pertusi, Dante; Lenzini, Stephen; Bhan, Namita; Broadbelt, Linda J; Tyo, Keith E J

    2016-05-01

    Chemicals with aldehyde moieties are useful in the synthesis of polymerization reagents, pharmaceuticals, pesticides, flavors, and fragrances because of their high reactivity. However, chemical synthesis of aldehydes from carboxylic acids has unfavorable thermodynamics and limited specificity. Enzymatically catalyzed reductive bioaldehyde synthesis is an attractive route that overcomes unfavorable thermodynamics by ATP hydrolysis in ambient, aqueous conditions. Carboxylic acid reductases (Cars) are particularly attractive, as only one enzyme is required. We sought to increase the knowledge base of permitted substrates for four Cars. Additionally, the Lys2 enzyme family was found to be mechanistically the same as Cars and two isozymes were also tested. Our results show that Cars prefer molecules where the carboxylic acid is the only polar/charged group. Using this data and other published data, we develop a support vector classifier (SVC) for predicting Car reactivity and make predictions on all carboxylic acid metabolites in iAF1260 and Model SEED.

  1. Machine learning and hurdle models for improving regional predictions of stream water acid neutralizing capacity

    NASA Astrophysics Data System (ADS)

    Povak, Nicholas A.; Hessburg, Paul F.; Reynolds, Keith M.; Sullivan, Timothy J.; McDonnell, Todd C.; Salter, R. Brion

    2013-06-01

    In many industrialized regions of the world, atmospherically deposited sulfur derived from industrial, nonpoint air pollution sources reduces stream water quality and results in acidic conditions that threaten aquatic resources. Accurate maps of predicted stream water acidity are an essential aid to managers who must identify acid-sensitive streams, potentially affected biota, and create resource protection strategies. In this study, we developed correlative models to predict the acid neutralizing capacity (ANC) of streams across the southern Appalachian Mountain region, USA. Models were developed using stream water chemistry data from 933 sampled locations and continuous maps of pertinent environmental and climatic predictors. Environmental predictors were averaged across the upslope contributing area for each sampled stream location and submitted to both statistical and machine-learning regression models. Predictor variables represented key aspects of the contributing geology, soils, climate, topography, and acidic deposition. To reduce model error rates, we employed hurdle modeling to screen out well-buffered sites and predict continuous ANC for the remainder of the stream network. Models predicted acid-sensitive streams in forested watersheds with small contributing areas, siliceous lithologies, cool and moist environments, low clay content soils, and moderate or higher dry sulfur deposition. Our results confirmed findings from other studies and further identified several influential climatic variables and variable interactions. Model predictions indicated that one quarter of the total stream network was sensitive to additional sulfur inputs (i.e., ANC < 100 µeq L-1), while <10% displayed much lower ANC (<50 µeq L-1). These methods may be readily adapted in other regions to assess stream water quality and potential biotic sensitivity to acidic inputs.

  2. A computational method to predict genetically encoded rare amino acids in proteins

    PubMed Central

    Chaudhuri, Barnali N; Yeates, Todd O

    2005-01-01

    In several natural settings, the standard genetic code is expanded to incorporate two additional amino acids with distinct functionality, selenocysteine and pyrrolysine. These rare amino acids can be overlooked inadvertently, however, as they arise by recoding at certain stop codons. We report a method for such recoding prediction from genomic data, using read-through similarity evaluation. A survey across a set of microbial genomes identifies almost all the known cases as well as a number of novel candidate proteins. PMID:16168086

  3. Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression.

    PubMed

    Scarpignato, Carmelo; Gatta, Luigi; Zullo, Angelo; Blandizzi, Corrado

    2016-11-09

    The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions. Herein, we aim to review the current literature on PPI use and develop a position paper addressing the benefits and potential harms of acid suppression with the purpose of providing evidence-based guidelines on the appropriate use of these medications. The topics, identified by a Scientific Committee, were assigned to experts selected by three Italian Scientific Societies, who independently performed a systematic search of the relevant literature using Medline/PubMed, Embase, and the Cochrane databases. Search outputs were distilled, paying more attention to systematic reviews and meta-analyses (where available) representing the best evidence. The draft prepared on each topic was circulated amongst all the members of the Scientific Committee. Each expert then provided her/his input to the writing, suggesting changes and the inclusion of new material and/or additional relevant references. The global recommendations were then thoroughly discussed in a specific meeting, refined with regard to both content and wording, and approved to obtain a summary of current evidence. Twenty-five years after their introduction into clinical practice, PPIs remain the mainstay of the treatment of acid-related diseases, where their use in gastroesophageal reflux disease, eosinophilic esophagitis, Helicobacter pylori infection, peptic ulcer disease and bleeding as well as, and Zollinger-Ellison syndrome is

  4. Inhibitory effect of α-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats.

    PubMed

    Fujii, Yuta; Segawa, Risa; Kimura, Masayuki; Wang, Liyun; Ishii, Yuji; Yamamoto, Ryuichi; Morita, Reiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2013-09-25

    To investigate the protective effect of α-lipoic acid (a-LA) on the hepatocarcinogenic process promoted by thioacetamide (TAA), we used a two-stage liver carcinogenesis model in N-diethylnitrosamine (DEN)-initiated and TAA-promoted rats. We examined the modifying effect of co-administered a-LA on the liver tissue environment surrounding preneoplastic hepatocellular lesions, with particular focus on hepatic macrophages and the mechanism behind the decrease in apoptosis of cells surrounding preneoplastic hepatocellular lesions during the early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in the liver. Co-administration with a-LA suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) hepatic macrophages as well as the number of CD3(+) lymphocytes. These effects were also suppressed by a-LA. Transcript levels of some inflammation-related genes were upregulated by TAA and downregulated by a-LA in real-time RT-PCR analysis. Outside the GST-P(+) foci, a-LA reduced the numbers of apoptotic cells, active caspase-8(+) cells and death receptor (DR)-5(+) cells. These results suggest that hepatic macrophages producing proinflammatory factors may be activated in TAA-induced tumor promotion. a-LA may suppress tumor-promoting activity by suppressing the activation of these macrophages and the subsequent inflammatory responses. Furthermore, a-LA may suppress tumor-promoting activity by suppressing the DR5-mediated extrinsic pathway of apoptosis and the subsequent regeneration of liver cells outside GST-P(+) foci.

  5. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I

    PubMed Central

    Park, Seung Bum; Seronello, Scott; Mayer, Wasima; Ojcius, David M.

    2016-01-01

    Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain) were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity. PMID:27404108

  6. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment

    PubMed Central

    Prasad, Sahdeo; Yadav, Vivek R.; Sung, Bokyung; Gupta, Subash C.; Tyagi, Amit K.; Aggarwal, Bharat B.

    2016-01-01

    The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis. PMID:26909608

  7. Prediction of Coal ash leaching behavior in acid mine water, comparison of laboratory and field studies

    SciTech Connect

    ANNA, KNOX

    2005-01-10

    Strongly alkaline fluidized bed combustion ash is commonly used to control acid mine drainage in West Virginia coal mines. Objectives include acid neutralization and immobilization of the primary AMD pollutants: iron, aluminum and manganese. The process has been successful in controlling AMD though doubts remain regarding mobilization of other toxic elements present in the ash. In addition, AMD contains many toxic elements in low concentrations. And, each mine produces AMD of widely varying quality. So, predicting the effect of a particular ash on a given coal mine's drainage quality is of particular interest. In this chapter we compare the results of a site-specific ash leaching procedure with two large-scale field applications of FBC ash. The results suggested a high degree of predictability for roughly half of the 25 chemical parameters and poor predictability for the remainder. Of these, seven parameters were successfully predicted on both sites: acidity, Al, B, Ba, Fe, Ni and Zn while electrical conductivity, Ca, Cd, SO4, Pb and Sb were not successfully predicted on either site. Trends for the remaining elements: As, Ag, Be, Cu, Cr, Hg, Mg, Mn, pH, Se Tl and V were successfully predicted on one but not both mine sites.

  8. Stearic acid suppresses mammary gland development by inhibiting PI3K/Akt signaling pathway through GPR120 in pubertal mice.

    PubMed

    Meng, Yingying; Yuan, Cong; Zhang, Jing; Zhang, Fenglin; Fu, Qin; Zhu, Xiaotong; Shu, Gang; Wang, Lina; Gao, Ping; Xi, Qianyun; Sun, Jiajie; Zhang, Yongliang; Jiang, Qingyan; Wang, Songbo

    2017-09-09

    It has been demonstrated that dietary high fat diet negatively affects the pubertal mammary gland development. The aim of the present study was to investigate the effects of stearic acid (SA), an 18-carbon chain saturated fatty acid, on mammary gland development in pubertal mice and to explore the underlying mechanism. Our results demonstrated that dietary supplementation of 2% SA suppressed mammary duct development, with significant reduction of terminal end bud (TEB) number and ductal branch. In accord, the expression of proliferative marker Cyclin D1 was markedly decreased by dietary SA. Furthermore, dietary SA led to increase of G protein-coupled receptor 120 (GPR120) expression and inhibition of PI3K/Akt signaling pathway in mammary gland of pubertal mice. In good agreement with the in vivo findings, the in vitro results showed that 40 μM SA significantly suppressed proliferation of mouse mammary epithelial cell HC11 by regulating mRNA and/or protein expression of proliferative markers such as Cyclin D1/3, p21, and PCNA. Meanwhile, SA activated GPR120 and inhibited PI3K/Akt signaling pathway in a GPR120-dependent manner. In addition, SA-induced inhibition of PI3K/Akt signaling pathway, suppression of HC11 proliferation, and alteration of proliferative markers expression were abolished by knockdown of GPR120 with siRNA. Collectively, these findings showed that SA suppressed mammary gland development of pubertal mice, which was coincident with the SA-inhibited HC11 proliferation, and was associated with inhibition of PI3K/Akt signaling pathway through activation of GPR120. These data provided new insights into the regulation of mammary gland development by dietary fatty acids. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Evaluating and predicting the oxidative stability of vegetable oils with different fatty acid compositions.

    PubMed

    Li, Hongyan; Fan, Ya-wei; Li, Jing; Tang, Liang; Hu, Jiang-ning; Deng, Ze-yuan

    2013-04-01

    The aim of this research was to evaluate the oxidative stabilities and qualities of different vegetable oils (almond, blend 1-8, camellia, corn, palm, peanut, rapeseed, sesame, soybean, sunflower, and zanthoxylum oil) based on peroxide value (PV), vitamin E content, free fatty acid, and fatty acid composition. The vegetable oils with different initial fatty acid compositions were studied under accelerated oxidation condition. It showed that PV and n-3 polyunsaturated fatty acid (PUFA) changed significantly during 21 d accelerated oxidation storage. Based on the changes of PV and fatty acid composition during the oxidation process, mathematical models were hypothesized and the models were simulated by Matlab to generate the proposed equations. These equations were established on the basis of the different PUFA contents as 10% to 28%, 28% to 46%, and 46% to 64%, respectively. The simulated models were proven to be validated and valuable for assessing the degree of oxidation and predicting the shelf life of vegetable oils.

  10. Prediction algorithm for amino acid types with their secondary structure in proteins (PLATON) using chemical shifts.

    PubMed

    Labudde, D; Leitner, D; Krüger, M; Oschkinat, H

    2003-01-01

    The algorithm PLATON is able to assign sets of chemical shifts derived from a single residue to amino acid types with its secondary structure (amino acid species). A subsequent ranking procedure using optionally two different penalty functions yields predictions for possible amino acid species for the given set of chemical shifts. This was demonstrated in the case of the alpha-spectrin SH3 domain and applied to 9 further protein data sets taken from the BioMagRes database. A database consisting of reference chemical shift patterns (reference CSPs) was generated from assigned chemical shifts of proteins with known 3D-structure. This reference CSP database is used in our approach for extracting distributions of amino acid types with their most likely secondary structure elements (namely alpha-helix, beta-sheet, and coil) for single amino acids by comparison with query CSPs. Results obtained for the 10 investigated proteins indicates that the percentage of correct amino acid species in the first three positions in the ranking list, ranges from 71.4% to 93.2% for the more favorable penalty function. Where only the top result of the ranking list for these 10 proteins is considered, 36.5% to 83.1% of the amino acid species are correctly predicted. The main advantage of our approach, over other methods that rely on average chemical shift values is the ability to increase database content by incorporating newly derived CSPs, and therefore to improve PLATON's performance over time.

  11. Effect of suppressor current intensity on the determination of glyphosate and aminomethylphosphonic acid by suppressed conductivity ion chromatography.

    PubMed

    Dimitrakopoulos, Ioannis K; Thomaidis, Nikolaos S; Megoulas, Nikolaos C; Koupparis, Michael A

    2010-05-28

    This paper presents the application of ion chromatography with electrolytic eluent generation and mobile phase suppression for the direct conductimetric detection of glyphosate and its degradation product aminomethylphosphonic acid (AMPA). The compounds were separated on a Dionex AS18 anion exchange column with a 12-40 mM KOH step gradient from 9 to 9.5 min. The effect of the suppressor current intensity on the electrostatic interaction of these amphoteric compounds with the suppressor cation exchange membranes was evaluated. A suppressor current gradient technique was proposed for the limitation of peak broadening and baseline noise, in order to improve method sensitivity and detectability. It was observed that residual sample carbonates co-eluted with AMPA when a large injection loop was installed for the low level determination of both compounds in natural waters. For this reason, glyphosate was isocratically eluted using 33 mM KOH in order to decrease analysis time within 10 min and a column clean up step using 100 mM KOH was used to ensure retention time reproducibility. The developed method was applied to the analysis of drinking and natural water and it was further successfully applied to orange samples with slight modifications. Instrumental LOD for glyphosate was 0.24 microg/L, while method LOD was 0.54 microg/L for spring waters and 0.01 mg/kg for oranges using a 1000 microL direct loop injection of the sample. Intra-day and inter-day precision (as %RSD) for water samples was 4.6% and 12% at a spiking level of 2 microg/L, and the recovery ranged from 64% to 88% depending on sample conductivity. For orange samples, the inter-day precision was 1.4% at a spiking level of 4.4 mg/kg, while overall recovery was 103%. The developed method is direct, fast, sensitive and relatively inexpensive, and could be used as an ideal fast screening tool for the monitoring of glyphosate residues in water and fruit samples. Copyright 2010 Elsevier B.V. All rights reserved.

  12. Two phenotypically distinct T cells are involved in ultraviolet-irradiated urocanic acid-induced suppression of the efferent delayed-type hypersensitivity response to herpes simplex virus, type 1 in vivo

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.

    1987-09-01

    When UVB-irradiated urocanic acid, the putative photoreceptor/mediator for UVB suppression, is administered to mice it induces a dose-dependent suppression of the delayed-type hypersensitivity response to herpes simplex virus, type 1 (HSV-1), of similar magnitude to that induced by UV irradiation of mice. In this study, the efferent suppression of delayed-type hypersensitivity by UV-irradiated urocanic acid is demonstrated to be due to 2 phenotypically distinct T cells, (Thy1+, L3T4-, Ly2+) and (Thy1+, L3T4+, Ly2-). The suppression is specific for HSV-1. This situation parallels the generation of 2 distinct T-suppressor cells for HSV-1 by UV irradiation of mice and provides further evidence for the involvement of urocanic acid in the generation of UVB suppression.

  13. Does folic acid supplementation prevent or promote colorectal cancer? Results from model-based predictions.

    PubMed

    Luebeck, E Georg; Moolgavkar, Suresh H; Liu, Amy Y; Boynton, Alanna; Ulrich, Cornelia M

    2008-06-01

    Folate is essential for nucleotide synthesis, DNA replication, and methyl group supply. Low-folate status has been associated with increased risks of several cancer types, suggesting a chemopreventive role of folate. However, recent findings on giving folic acid to patients with a history of colorectal polyps raise concerns about the efficacy and safety of folate supplementation and the long-term health effects of folate fortification. Results suggest that undetected precursor lesions may progress under folic acid supplementation, consistent with the role of folate role in nucleotide synthesis and cell proliferation. To better understand the possible trade-offs between the protective effects due to decreased mutation rates and possibly concomitant detrimental effects due to increased cell proliferation of folic acid, we used a biologically based mathematical model of colorectal carcinogenesis. We predict changes in cancer risk based on timing of treatment start and the potential effect of folic acid on cell proliferation and mutation rates. Changes in colorectal cancer risk in response to folic acid supplementation are likely a complex function of treatment start, duration, and effect on cell proliferation and mutations rates. Predicted colorectal cancer incidence rates under supplementation are mostly higher than rates without folic acid supplementation unless supplementation is initiated early in life (before age 20 years). To the extent to which this model predicts reality, it indicates that the effect on cancer risk when starting folic acid supplementation late in life is small, yet mostly detrimental. Experimental studies are needed to provide direct evidence for this dual role of folate in colorectal cancer and to validate and improve the model predictions.

  14. Uric Acid Excretion Predicts Increased Blood Pressure Among American Adolescents of African Descent.

    PubMed

    Mrug, Sylvie; Mrug, Michal; Morris, Anjana Madan; Reynolds, Nina; Patel, Anita; Hill, Danielle C; Feig, Daniel I

    2017-04-01

    Hyperuricemia predicts the incidence of hypertension in adults and its treatment has blood pressure (BP)-lowering effects in adolescents. To date, no studies have examined the predictive usage of hyperuricemia or urinary uric acid excretion on BP changes in adolescents. Mechanistic models suggest that uric acid impairs both endothelial function and vascular compliance, which would potentially exacerbate a myriad of hypertensive mechanisms, yet little is known about interaction of uric acid and other hypertension risk factors. The primary study was aimed at the effects of stress on BP in adolescents. A community sample of 84 low-income, urban adolescents (50% male, 95% African American, mean age = 13.36 ± 1 years) was recruited from public schools. Youth completed a 12-hour (overnight) urine collection at home and their BP was measured during rest and in response to acute psychosocial stress. Seventy-six of the adolescents participated in a follow-up visit at 1.5 years when their resting BP was reassessed. In this substudy, we assessed the relationship of renal urate excretion and BP reactivity. After adjusting for resting BP levels at baseline and other covariates, higher levels of uric acid excretion predicted greater BP reactivity to acute psychosocial stress and higher resting BP at 18 months. Urinary excretion of uric acid can serve as an alternative, noninvasive measure of serum uric acid levels that are predictive of BP changes. As hyperuricemia-associated hypertension is treatable, urban adolescents may benefit from routine screening for hyperuricemia or high uric acid excretion. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  15. Genetic analysis of groups of mid-infrared predicted fatty acids in milk.

    PubMed

    Narayana, S G; Schenkel, F S; Fleming, A; Koeck, A; Malchiodi, F; Jamrozik, J; Johnston, J; Sargolzaei, M; Miglior, F

    2017-06-01

    The objective of this study was to investigate genetic variability of mid-infrared predicted fatty acid groups in Canadian Holstein cattle. Genetic parameters were estimated for 5 groups of fatty acids: short-chain (4 to 10 carbons), medium-chain (11 to 16 carbons), long-chain (17 to 22 carbons), saturated, and unsaturated fatty acids. The data set included 49,127 test-day records from 10,029 first-lactation Holstein cows in 810 herds. The random regression animal test-day model included days in milk, herd-test date, and age-season of calving (polynomial regression) as fixed effects, herd-year of calving, animal additive genetic effect, and permanent environment effects as random polynomial regressions, and random residual effect. Legendre polynomials of the third degree were selected for the fixed regression for age-season of calving effect and Legendre polynomials of the fourth degree were selected for the random regression for animal additive genetic, permanent environment, and herd-year effect. The average daily heritability over the lactation for the medium-chain fatty acid group (0.32) was higher than for the short-chain (0.24) and long-chain (0.23) fatty acid groups. The average daily heritability for the saturated fatty acid group (0.33) was greater than for the unsaturated fatty acid group (0.21). Estimated average daily genetic correlations were positive among all fatty acid groups and ranged from moderate to high (0.63-0.96). The genetic correlations illustrated similarities and differences in their origin and the makeup of the groupings based on chain length and saturation. These results provide evidence for the existence of genetic variation in mid-infrared predicted fatty acid groups, and the possibility of improving milk fatty acid profile through genetic selection in Canadian dairy cattle. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  16. Dietary fiber suppresses elevation of uric acid and urea nitrogen concentrations in serum of rats with renal dysfunction induced by dietary adenine.

    PubMed

    Koguchi, Takashi; Koguchi, Hiromi; Nakajima, Hisao; Takano, Saburo; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokoro, Tadahiro

    2004-07-01

    This study was conducted to examine the effects of several kinds of dietary fiber (DF) with different physical properties on the elevation of uric acid and urea nitrogen concentrations in serum of rats induced by dietary adenine. DF decreased an uptake of 14C-labeled adenine in the rat jejunum in vitro, but the reduction varied with the physical property of DF. Male Wistar rats (3 weeks old) were fed a diet with or without a 0.4% adenine and a 5% DF (cellulose, chitin, chitosan, or xanthan gum) for 20 days. Feeding of adenine in the fiber-free group elevated the concentrations of uric acid, creatinine, and urea nitrogen in serum, but decreased the excretions of these compounds into urine and increased the amounts of 2,8-dihydroxyadenine (2,8-DHA) in kidney and urine. The test DF was found to suppress the elevation of uric acid, creatinine, and urea nitrogen concentrations in serum induced by dietary adenine, and to mitigate the decreased excretions of these compounds into urine and the increased retention of 2,8-DHA in kidney and urine. This phenomenon was remarkable in the xanthan gum group. These results suggest that DF suppresses the elevation of uric acid and urea nitrogen concentrations in serum by attenuating the absorption of dietary adenine.

  17. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    SciTech Connect

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  18. Caffeic acid phenethyl ester suppresses monocyte adhesion to the endothelium by inhibiting NF-κB/NOX2-derived ROS signaling

    PubMed Central

    Nakahara, Risa; Makino, Junya; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), one of the major polyphenols, exhibits anti-oxidative, anti-bacterial, and anti-cancer properties. Atherosclerosis is a chronic inflammatory disease, the progression of which is closely related to the accumulated adhesion of inflammatory monocytes/macrophages to the endothelium. We herein determined whether CAPE and its derivatives suppressed THP-1 cell adhesion to human umbilical vein endothelial cells (HUVEC). Of the four polyphenols tested, CAPE significantly suppressed the 12-O-tetradecanoylphorbol 13-acetate (TPA)-elicited expression of cluster for differentiation (CD) 11b, 14, and 36, and this was accompanied by the inhibition of THP-1 cell adhesion to HUVEC. CAPE also suppressed the activation of TPA-elicited nuclear factor-κB (NF-κB) and accumulation of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS), but did not affect extracellular signal-regulated kinase (ERK) phosphorylation. Taken together, these results demonstrated that CAPE suppressed THP-1 cell adhesion to HUVEC through, at least in part, the NF-κB, NOX2, and ROS-derived signaling axis. PMID:27257341

  19. Using electromagnetic induction technology to predict volatile fatty acid, source area differences

    USDA-ARS?s Scientific Manuscript database

    Subsurface sampling techniques have been adapted to measure manure accumulation on feedlot surface. Objectives of this study were to determine if sensor data could be used to predict differences in volatile fatty acids (VFA) and other volatiles produced on the feedlot surface three days following a...

  20. Amino acid composition analysis of human secondary transport proteins and implications for reliable membrane topology prediction.

    PubMed

    Saidijam, Massoud; Azizpour, Sonia; Patching, Simon G

    2017-04-01

    Secondary transporters in humans are a large group of proteins that transport a wide range of ions, metals, organic and inorganic solutes involved in energy transduction, control of membrane potential and osmotic balance, metabolic processes and in the absorption or efflux of drugs and xenobiotics. They are also emerging as important targets for development of new drugs and as target sites for drug delivery to specific organs or tissues. We have performed amino acid composition (AAC) and phylogenetic analyses and membrane topology predictions for 336 human secondary transport proteins and used the results to confirm protein classification and to look for trends and correlations with structural domains and specific substrates and/or function. Some proteins showed statistically high contents of individual amino acids or of groups of amino acids with similar physicochemical properties. One recurring trend was a correlation between high contents of charged and/or polar residues with misleading results in predictions of membrane topology, which was especially prevalent in Mitochondrial Carrier family proteins. We demonstrate how charged or polar residues located in the middle of transmembrane helices can interfere with their identification by membrane topology tools resulting in missed helices in the prediction. Comparison of AAC in the human proteins with that in 235 secondary transport proteins from Escherichia coli revealed similar overall trends along with differences in average contents for some individual amino acids and groups of similar amino acids that are presumed to result from a greater number of functions and complexity in the higher organism.

  1. A Drug-Repositioning Screening Identifies Pentetic Acid as a Potential Therapeutic Agent for Suppressing the Elastase-Mediated Virulence of Pseudomonas aeruginosa

    PubMed Central

    Gi, Mia; Jeong, Junhui; Lee, Keehoon; Lee, Kang-Mu; Toyofuku, Masanori; Yong, Dong Eun

    2014-01-01

    Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn2+ or Mn2+ ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection. PMID:25246397

  2. A drug-repositioning screening identifies pentetic acid as a potential therapeutic agent for suppressing the elastase-mediated virulence of Pseudomonas aeruginosa.

    PubMed

    Gi, Mia; Jeong, Junhui; Lee, Keehoon; Lee, Kang-Mu; Toyofuku, Masanori; Yong, Dong Eun; Yoon, Sang Sun; Choi, Jae Young

    2014-12-01

    Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn(2+) or Mn(2+) ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  3. Analysis of a simplified normalized covariance measure based on binary weighting functions for predicting the intelligibility of noise-suppressed speech.

    PubMed

    Chen, Fei; Loizou, Philipos C

    2010-12-01

    The normalized covariance measure (NCM) has been shown previously to predict reliably the intelligibility of noise-suppressed speech containing non-linear distortions. This study analyzes a simplified NCM measure that requires only a small number of bands (not necessarily contiguous) and uses simple binary (1 or 0) weighting functions. The rationale behind the use of a small number of bands is to account for the fact that the spectral information contained in contiguous or nearby bands is correlated and redundant. The modified NCM measure was evaluated with speech intelligibility scores obtained by normal-hearing listeners in 72 noisy conditions involving noise-suppressed speech corrupted by four different types of maskers (car, babble, train, and street interferences). High correlation (r = 0.8) was obtained with the modified NCM measure even when only one band was used. Further analysis revealed a masker-specific pattern of correlations when only one band was used, and bands with low correlation signified the corresponding envelopes that have been severely distorted by the noise-suppression algorithm and/or the masker. Correlation improved to r = 0.84 when only two disjoint bands (centered at 325 and 1874 Hz) were used. Even further improvements in correlation (r = 0.85) were obtained when three or four lower-frequency (<700 Hz) bands were selected.

  4. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation.

    PubMed

    Chiang, Chun-Te; Way, Tzong-Der; Tsai, Shang-Jie; Lin, Jen-Kun

    2007-12-22

    Fatty acid synthase (FAS) expression is markedly elevated in HER2-overexpressing breast cancer cells. In this study, diosgenin, a plant-derived steroid, was found to be effective in suppressing FAS expression in HER2-overexpressing breast cancer cells. Diosgenin preferentially inhibited proliferation and induced apoptosis in HER2-overexpressing cancer cells. Furthermore, diosgenin inhibited the phosphorylation of Akt and mTOR, and enhanced phosphorylation of JNK. The use of pharmacological inhibitors revealed that the modulation of Akt, mTOR and JNK phosphorylation was required for diosgenin-induced FAS suppression. Finally, we showed that diosgenin could enhance paclitaxel-induced cytotoxicity in HER2-overexpressing cancer cells. These results suggested that diosgenin has the potential to advance as chemopreventive or chemotherapeutic agent for cancers that overexpress HER2.

  5. Induction of suppression of delayed type hypersensitivity to herpes simplex virus by epidermal cells exposed to UV-irradiated urocanic acid in vivo

    SciTech Connect

    Ross, J.A.; Howie, S.E.; Norval, M.; Maingay, J.P. )

    1987-01-01

    Urocanic acid (UCA), the putative photoreceptor for ultraviolet radiation (UV)-induced suppression, undergoes a UV-dependent trans to cis isomerisation. Epidermal cells from mice painted with UCA, containing a known proportion of the cis-isomer, generate suppression of the delayed type hypersensitivity response to herpes simplex virus type 1 (HSV-1) when transferred to naive syngeneic recipients at the same time and site as infection with HSV-1. One T suppressor cell subset, of phenotype (Thy1+, L3T4+, Ly2-), is induced by the cis-UCA modified epidermal cell transfer. Flow cytometric analysis of the epidermal cells from skin treated with UV or cis-UCA indicates an overall reduction from normal in the number of cells expressing MHC Class II antigens, but no alteration in the number expressing I-J antigens.

  6. First-trimester fetal sex prediction by deoxyribonucleic acid analysis of maternal peripheral blood.

    PubMed

    Falcinelli, C; Battafarano, S; Neri, C; Mazza, V; Ranzi, A; Volpe, A; Forabosco, A

    1999-09-01

    We investigated whether the number of weeks of gestation influences the accuracy of first-trimester fetal sex prediction by analysis of deoxyribonucleic acid extracted from whole maternal blood. A comparison was also made to determine whether a difference exists between this approach and the deoxyribonucleic acid analysis of transcervical cells performed on the same group of subjects. Deoxyribonucleic acid was isolated from 50 maternal blood samples taken between gestational weeks 7 and 11. The sex of the fetus was assessed by nested polymerase chain reaction specific for the amelogenin gene. A receiver-operating characteristic curve analysis was used to correlate the accuracy of fetal gender prediction with the gestational age and also to compare the goodness of the 2 methods under investigation. Analysis of the receiver-operating characteristic curve provided a cutoff value of 9 weeks 4 days of gestation for both tests, indicating that a higher degree of accuracy in the sex assignment was obtained in those samples taken before or at this time. However, this difference was statistically significant only for analysis of deoxyribonucleic acid from maternal blood. The comparison between tests of deoxyribonucleic acid from maternal blood and from transcervical cells showed that the first approach is better, although a statistically significant difference was not found. Analysis of maternal blood deoxyribonucleic acid is a better approach than analysis of trans-cervical cell deoxyribonucleic acid in fetal sex prediction. The highest degree of accuracy is obtained when blood is drawn before 10 weeks of gestation. This can be important when sampling of chorionic villi should be avoided because of the risk of an X-linked disease when the fetal sex is female.

  7. Hemoglobin levels do not predict biochemical outcome for localized prostate cancer treated with neoadjuvant androgen-suppression therapy and external-beam radiotherapy

    SciTech Connect

    Pai, Howard Huaihan . E-mail: hpai@bccancer.bc.ca; Ludgate, Charles; Pickles, Tom; Paltiel, Chuck M.Sc.; Agranovich, Alex; Berthelet, Eric; Duncan, Graeme; Kim-Sing, Charmaine; Kwan, Winkle; Lim, Jan; Liu, Mitchell; Tyldesley, Scott

    2006-07-15

    Purpose: To investigate whether hemoglobin (Hb) levels affect outcome in men with localized prostate adenocarcinoma (LPA) treated with neoadjuvant androgen-suppression therapy (NAST) and external-beam radiotherapy (EBRT). Methods and Materials: A total of 563 men with LPA treated with NAST (median: 5.3 months) and EBRT who had Hb levels during treatment were retrospectively reviewed. Patient, tumor, and treatment variables, including the following Hb variables, were subjected to univariate and multivariable analyses to identify factors that predict biochemical control (bNED) and overall survival (OS): pre-EBRT Hb, Hb nadir during EBRT, and change in Hb from pre-EBRT to nadir during EBRT. Results: Median PSA follow-up was 4.25 years. Forty-nine percent of men were anemic during EBRT, with a median Hb of 13.4 g/dL, and 68% experienced a decline in Hb from pre-EBRT to during EBRT of median 0.6 g/dL. Five-year Nadir + 2 bNED and OS rates were similar for anemic and nonanemic patients during EBRT. High percent-positive biopsies, PSA and Gleason score, and use of AA monotherapy predicted worse bNED. High stage and age predicted worse OS. Hb variables were not predictive of bNED or OS. Conclusions: Anemia is a common side effect of NAST and is usually mild. Hb levels, however, do not predict biochemical control or survival.

  8. 3,4-Dihydroxy-Benzohydroxamic Acid (Didox) Suppresses Pro-inflammatory Profiles and Oxidative Stress in TLR4-Activated RAW264.7 Murine Macrophages

    PubMed Central

    Matsebatlela, Thabe M.; Anderson, Amy L.; Gallicchio, Vincent S.; Elford, Howard; Rice, Charles D.

    2015-01-01

    Didox (3,4-dihydroxy-benzohydroxamic acid), is a synthetic ribonucleotide reductase (RR) inhibitor derived from polyhydroxy-substituted benzohydroxamic acid, and originally developed as an anti-cancer agent. Some studies indicate that didox may have anti-oxidative stress-like properties, while other studies hint that didox may have anti-inflammatory properties. Using nitric oxide production in response to LPS treatment as a sensitive screening assay for anti-inflammatory compounds, we show that didox is very potent at levels as low as 6.25 μM, with maximal inhibition at 100 μM. A qRT-PCR array was then employed to screen didox for other potential anti-inflammatory and anti-oxidative stress-related properties. Didox was very potent in suppressing the expression of these arrayed mRNA in response to LPS, and in some cases didox alone suppressed expression. Using qRT-PCR as a follow up to the array, we demonstrated that didox suppresses LPS-induced mRNA levels of iNOS, IL-6, IL-1, TNF-α, NF-κβ (p65), and p38-α, after 24 h of treatment. Treatment with didox also suppresses the secretion of nitric oxide, IL-6, and IL-10. Furthermore, oxidative stress, as quantified by intracellular ROS levels in response to macrophage activators LPS and phorbol ester (PMA), and the glutathione depleting agent BSO, is reduced by treatment with didox. Moreover, we demonstrate that nuclear translocation of NF-κβ (p65) in response to LPS is inhibited by didox. These findings were supported by qRT-PCR for oxidative stress genes SOD1 and catalase. Overall, this study supports the conclusion that didox may have a future role in managing acute and chronic inflammatory diseases and oxidative stress due to high production of ROS. PMID:25843059

  9. [Nondestructive test on predicting sugar content and valid acidity of mango by spectroscopy technology].

    PubMed

    Yu, Jia-jia; He, Yong; Bao, Yi-dan

    2008-12-01

    Mango is a kind of popular tropic fruit in the word, and its quality will affect the health of consumers. Unsaturated acid is an important component in mango. So it is very important and necessary to detect the sugar content and valid acidity in mango fast and non-destructively. Visible and short-wave near-infrared reflectance spectroscopy (VIS/SWNIRS) was applied in the present study to predict sugar content and valid acidity of mango. Because of the non-linear information in spectral data characteristics of the pattern were analyzed by neural network optimized by genetic algorithm (GA-BP). Spectral data were compressed by the partial least squares (PLS). The best number of principal components (PCs) was selected according the accumulative reliabilities (AR). PCs could be used to replace the complex spectral data. After some preprocessing and through full cross validation, 17 principal components presenting important information of spectra were confirmed as the best number of principal components for valid acidity, and 18 PCs as best number of principal components for sugar content. Then, these best principal components were taken as the input of GA-BP neural network. One hundred thirty five samples were randomly collected as modeling, and the remaining 45 as samples to check the forecast results by the model. For the sake of testing the GA-BP model, at the same time we took the BP neural network on the same PCs. The quality of the calibration model was evaluated by the correlation coefficients (R) and standard error of calibration (SECV), and the prediction results were assessed by correlation coefficients (R) and standard error of prediction (SEP). Comparing PLS-BP model with PLS-GA-BP model, the coefficients of determination (R) of 0.788/0.83699 and standard errors of prediction (SEP) of 0.133312/0.109447 were calculated in valid acidity. The sugar content result was calculated by the coefficients of determination (R) = 0.75705/0.85409 and standard errors of

  10. Computational scheme for the prediction of metal ion binding by a soil fulvic acid

    USGS Publications Warehouse

    Marinsky, J.A.; Reddy, M.M.; Ephraim, J.H.; Mathuthu, A.S.

    1995-01-01

    The dissociation and metal ion binding properties of a soil fulvic acid have been characterized. Information thus gained was used to compensate for salt and site heterogeneity effects in metal ion complexation by the fulvic acid. An earlier computational scheme has been modified by incorporating an additional step which improves the accuracy of metal ion speciation estimates. An algorithm is employed for the prediction of metal ion binding by organic acid constituents of natural waters (once the organic acid is characterized in terms of functional group identity and abundance). The approach discussed here, currently used with a spreadsheet program on a personal computer, is conceptually envisaged to be compatible with computer programs available for ion binding by inorganic ligands in natural waters.

  11. Feature selection from short amino acid sequences in phosphorylation prediction problem

    NASA Astrophysics Data System (ADS)

    Wecławski, Jakub; Jankowski, Stanisław; Szymański, Zbigniew

    The paper describes solution of feature selection from amino acid sequences in phosphorylation prediction problem. We show that even for short sequences the variable selection leads to better classification performance. Moreover, the final simplicity of models allows for better data understanding and can be used by an expert for further analysis. The feature selection process is divided into two parts: i) the classification tree is used for finding the most relevant positions in amino acid sequences, ii) then the contrast pattern kernel is applied for pattern selection. This work summarizes the research made on classification of short amino acid sequences. The results of the research allowed us to propose a general scheme of amino acid sequence analysis.

  12. PreSSAPro: a software for the prediction of secondary structure by amino acid properties.

    PubMed

    Costantini, Susan; Colonna, Giovanni; Facchiano, Angelo M

    2007-10-01

    PreSSAPro is a software, available to the scientific community as a free web service designed to provide predictions of secondary structures starting from the amino acid sequence of a given protein. Predictions are based on our recently published work on the amino acid propensities for secondary structures in either large but not homogeneous protein data sets, as well as in smaller but homogeneous data sets corresponding to protein structural classes, i.e. all-alpha, all-beta, or alpha-beta proteins. Predictions result improved by the use of propensities evaluated for the right protein class. PreSSAPro predicts the secondary structure according to the right protein class, if known, or gives a multiple prediction with reference to the different structural classes. The comparison of these predictions represents a novel tool to evaluate what sequence regions can assume different secondary structures depending on the structural class assignment, in the perspective of identifying proteins able to fold in different conformations. The service is available at the URL http://bioinformatica.isa.cnr.it/PRESSAPRO/.

  13. Uric acid measurement improves prediction of cardiovascular mortality in later life.

    PubMed

    Dutta, Ambarish; Henley, William; Pilling, Luke C; Wallace, Robert B; Melzer, David

    2013-03-01

    To estimate the association between uric acid and cardiovascular mortality in older adults, independent of traditional risk factors, and to estimate the risk prediction gain by adding uric acid measurements to the Framingham Cardiovascular Risk Score (FCRS). Longitudinal observational study of two population-based cohorts. The Established Populations for Epidemiologic Studies of the Elderly, Iowa (Iowa-EPESE) and the Third National Health and Nutritional Examination Survey (NHANES III). One thousand twenty-eight Iowa-EPESE participants and 1,316 NHANES III participants. Selected participants were aged 70 and older without overt cardiovascular disease, renal dysfunction, or diuretic use who lived for 3 years or longer after baseline. Outcome was age at cardiovascular death during follow-up (12–20 years). Uric acid and cardiovascular risk factors such as smoking, systolic blood pressure, diabetes mellitus, obesity, serum cholesterol, and high-density lipoprotein cholesterol were measured at baseline. High serum uric acid (>7.0 mg/dL) was associated with male sex, obesity, lipid levels, and estimated glomerular filtration rate at baseline. Fully adjusted hazard ratios (HRs) for cardiovascular death with high uric acid versus normal were 1.36 (95% confidence interval (CI) = 1.10–1.69) in Iowa-EPESE and 1.43 (95% CI = 1.04–1.99) in NHANES III; pooled HR was 1.38 (95% CI = 1.16–1.61). The net reclassification improvement achieved by adding uric acid measurement to the FCRS was 9% to 20%. In individuals aged 70 and older without overt CVD, renal dysfunction, or diuretic use, serum uric acid greater than 7.0 mg/dL was associated with greater CVD mortality independent of classic CVD risk factors. Adding uric acid measurement to the FCRS would improve prediction in older adults.

  14. Prediction of Bacillus weihenstephanensis acid resistance: the use of gene expression patterns to select potential biomarkers.

    PubMed

    Desriac, N; Postollec, F; Coroller, L; Sohier, D; Abee, T; den Besten, H M W

    2013-10-01

    Exposure to mild stress conditions can activate stress adaptation mechanisms and provide cross-resistance towards otherwise lethal stresses. In this study, an approach was followed to select molecular biomarkers (quantitative gene expressions) to predict induced acid resistance after exposure to various mild stresses, i.e. exposure to sublethal concentrations of salt, acid and hydrogen peroxide during 5 min to 60 min. Gene expression patterns of unstressed and mildly stressed cells of Bacillus weihenstephanensis were correlated to their acid resistance (3D value) which was estimated after exposure to lethal acid conditions. Among the twenty-nine candidate biomarkers, 12 genes showed expression patterns that were correlated either linearly or non-linearly to acid resistance, while for the 17 other genes the correlation remains to be determined. The selected genes represented two types of biomarkers, (i) four direct biomarker genes (lexA, spxA, narL, bkdR) for which expression patterns upon mild stress treatment were linearly correlated to induced acid resistance; and (ii) nine long-acting biomarker genes (spxA, BcerKBAB4_0325, katA, trxB, codY, lacI, BcerKBAB4_1716, BcerKBAB4_2108, relA) which were transiently up-regulated during mild stress exposure and correlated to increased acid resistance over time. Our results highlight that mild stress induced transcripts can be linearly or non-linearly correlated to induced acid resistance and both approaches can be used to find relevant biomarkers. This quantitative and systematic approach opens avenues to select cellular biomarkers that could be incremented in mathematical models to predict microbial behaviour.

  15. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models

    PubMed Central

    Svensson, Robert U.; Parker, Seth J.; Eichner, Lillian J.; Kolar, Matthew J.; Wallace, Martina; Brun, Sonja N.; Lombardo, Portia S.; Van Nostrand, Jeanine L.; Hutchins, Amanda; Vera, Lilliana; Gerken, Laurie; Greenwood, Jeremy; Bhat, Sathesh; Harriman, Geraldine; Westlin, William F.; Harwood, H. James; Saghatelian, Alan; Kapeller, Rosana; Metallo, Christian M.; Shaw, Reuben J.

    2016-01-01

    Continuous de novo fatty acid synthesis is a common feature of cancer required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here, we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain de novo fatty acid synthesis needed for growth and viability of non-small cell lung cancer (NSCLC). We describe the ability of ND-646—an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization—to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53−/− (also known as KRAS p53) and Kras;Stk11−/− (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology. PMID:27643638

  16. Colonic delivery of docosahexaenoic acid improves impaired glucose tolerance via GLP-1 secretion and suppresses pancreatic islet hyperplasia in diabetic KK-A(y) mice.

    PubMed

    Shida, Takayuki; Kamei, Noriyasu; Takeda-Morishita, Mariko; Isowa, Koichi; Takayama, Kozo

    2013-06-25

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates the insulin secretion depending on blood glucose level. Recent studies show that the unsaturated fatty acids can promote GLP-1 secretion from intestinal L-cells. We have shown previously that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) administered into a mouse closed intestinal loop, especially into the colonic segment, stimulate GLP-1 and insulin secretion and have a hypoglycemic effect, suggesting that DHA and EPA have potential as antidiabetic agents. The present study examined the antidiabetic effect of DHA following long-term in vivo delivery to the colon using normal ddY and diabetic KK-A(y) mice. The plasma GLP-1 concentration of KK-A(y) mice increased after long-term DHA administration, and this had a significant hypoglycemic effect. In contrast, although GLP-1 secretion in ddY mice tended to increase after DHA administration, blood glucose concentration did not differ between vehicle- and DHA-treated ddY mice. Immunostaining of the pancreas after long-term DHA administration showed that continuous DHA treatment stimulated β-cell apoptosis and accordingly suppressed islet cell growth in KK-A(y) mice. Colon targeting of DHA may provide a new strategy for improving impaired glucose tolerance in type 2 diabetes mellitus by stimulating GLP-1 secretion, which may subsequently suppress the compensatory hyperplasia of pancreatic islets. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Surfactants, Aromatic and Isoprenoid Compounds, and Fatty Acid Biosynthesis Inhibitors Suppress Staphylococcus aureus Production of Toxic Shock Syndrome Toxin 1▿

    PubMed Central

    McNamara, Peter J.; Syverson, Rae Ellen; Milligan-Myhre, Kathy; Frolova, Olga; Schroeder, Sarah; Kidder, Joshua; Hoang, Thanh; Proctor, Richard A.

    2009-01-01

    Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1. PMID:19223628

  18. Tiller number is altered in the ascorbic acid-deficient rice suppressed for L-galactono-1,4-lactone dehydrogenase.

    PubMed

    Liu, Yonghai; Yu, Le; Tong, Jianhua; Ding, Junhui; Wang, Ruozhong; Lu, Yusheng; Xiao, Langtao

    2013-03-01

    The tiller of rice (Oryza sativa L.), which determines the panicle number per plant, is an important agronomic trait for grain production. Ascorbic acid (Asc) is a major plant antioxidant that serves many functions in plants. L-Galactono-1,4-lactone dehydrogenase (GLDH, EC 1.3.2.3) is an enzyme that catalyzes the last step of Asc biosynthesis in plants. Here we show that the GLDH-suppressed transgenic rices, GI-1 and GI-2, which have constitutively low (between 30% and 50%) leaf Asc content compared with the wild-type plants, exhibit a significantly reduced tiller number. Moreover, lower growth rate and plant height were observed in the Asc-deficient plants relative to the trait values of the wild-type plants at different tillering stages. Further examination showed that the deficiency of Asc resulted in a higher lipid peroxidation, a loss of chlorophyll, a loss of carotenoids, and a lower rate of CO(2) assimilation. In addition, the level of abscisic acid was higher in GI-1 plants, while the level of jasmonic acid was higher in GI-1 and GI-2 plants at different tillering stages. The results we presented here indicated that Asc deficiency was likely responsible for the promotion of premature senescence, which was accompanied by a marked decrease in photosynthesis. These observations support the conclusion that the deficiency of Asc alters the tiller number in the GLDH-suppressed transgenics through promoting premature senescence and changing phytohormones related to senescence.

  19. Dietary fiber suppresses elevations of uric acid and allantoin in serum and urine induced by dietary RNA and increases its excretion to feces in rats.

    PubMed

    Koguchi, Takashi; Nakajima, Hisao; Wada, Masahiro; Yamamoto, Yuji; Innami, Satoshi; Maekawa, Akio; Tadokor, Tadahiro

    2002-06-01

    This study was performed to examine the effects of several kinds of dietary fibers (DF) with different physical properties on dietary RNA metabolism. Male Wistar strain rats, 4 wk old, were fed diets with or without a 3% yeast RNA and a 5% DF (cellulose, chitin, chitosan, inulin, and xanthan gum) for 20 d (Experiment 1) or 5 d (Experiment 2). Feeding DF tested lowered the serum uric acid and allantoin concentrations and the urinary excretions of their compounds and increased the amount of RNA excreted into the feces compared with fiber-free. The water-holding capacity and nucleotide adsorption of chitin and chitosan in acidic solutions were higher than those of cellulose. The digestion rate of RNA by RNase A in vitro was found to be lower in the DF tested than in fiber-free. The decrease was remarkable in chitosan and xanthan gum. The uptakes of 14C-labeled adenosine and adenosine 5'-monophosphate (5'-AMP) in the rat jejunum were markedly decreased in regard to chitosan and xanthan gum in comparison with the fiber-free. These phenomena suggest that DF with high viscosity is more strongly associated with the suppression of RNA digestion by RNase A and the depression of the uptake of purine compounds to jejunum. The present results reveal that the elevation of serum uric acid concentration induced by dietary RNA can be suppressed by DF in rats.

  20. A novel web server predicts amino acid residue protection against hydrogen-deuterium exchange.

    PubMed

    Lobanov, Mikhail Yu; Suvorina, Masha Yu; Dovidchenko, Nikita V; Sokolovskiy, Igor V; Surin, Alexey K; Galzitskaya, Oxana V

    2013-06-01

    To clarify the relationship between structural elements and polypeptide chain mobility, a set of statistical analyses of structures is necessary. Because at present proteins with determined spatial structures are much less numerous than those with amino acid sequence known, it is important to be able to predict the extent of proton protection from hydrogen-deuterium (HD) exchange basing solely on the protein primary structure. Here we present a novel web server aimed to predict the degree of amino acid residue protection against HD exchange solely from the primary structure of the protein chain under study. On the basis of the amino acid sequence, the presented server offers the following three possibilities (predictors) for user's choice. First, prediction of the number of contacts occurring in this protein, which is shown to be helpful in estimating the number of protons protected against HD exchange (sensitivity 0.71). Second, probability of H-bonding in this protein, which is useful for finding the number of unprotected protons (specificity 0.71). The last is the use of an artificial predictor. Also, we report on mass spectrometry analysis of HD exchange that has been first applied to free amino acids. Its results showed a good agreement with theoretical data (number of protons) for 10 globular proteins (correlation coefficient 0.73). We pioneered in compiling two datasets of experimental HD exchange data for 35 proteins. The H-Protection server is available for users at http://bioinfo.protres.ru/ogp/ Supplementary data are available at Bioinformatics online.

  1. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARα and T- and B-cell targeting.

    PubMed

    DeWitt, Jamie C; Williams, Wanda C; Creech, N Jonathan; Luebke, Robert W

    2016-01-01

    T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARα)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARα constitutive knockout (PPARα KO; B6.129S4-Ppar(tm1Gonz)N12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30 mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific IgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5 mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected for analyses of antigen-specific IgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5 mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to ≥1.88 mg PFOA/kg suppressed the TIAR; exposure to 30 mg PFOA/kg suppressed the TDAR in both PPARα KO and WT mice. The percentage of splenic B-cells was unchanged. Results obtained in the PPARα KO mice indicated that PPARα suppression of TDAR was independent of PPARα involvement. Suppression of the TIAR and the TDAR with minimal lymphocyte sub-population effects suggested that effects on humoral immunity are likely mediated by disruption of B-cell/plasma cell function.

  2. Near-infrared reflectance spectroscopy for predicting amino acids content in intact processed animal proteins.

    PubMed

    De la Haba, Maria José; Garrido-Varo, Ana; Guerrero-Ginel, José Emilio; Pérez-Marín, Dolores C

    2006-10-04

    Near-infrared calibrations were developed for the instantaneous prediction of amino acids composition of processed animal proteins (PAPs). Two sample presentation modes were compared (ground vs intact) for demonstrating the viability of the analysis in the intact form, avoiding the need for milling. Modified partial least-squares (MPLS) equations for the prediction of amino acids in PAPs were developed using the same set of samples (N = 92 PAPs) analyzed in ground and intact form and in three cups differing in the optical window size. The standard error for cross validation (SECV) and the coefficient of determination (1-VR) values yielded with the calibrations developed using the samples analyzed in the intact form showed similar or even better accuracy than those obtained with finely ground samples. The excellent predictive ability (1-VR > 0.90; CV < 3.0%) obtained for the prediction of amino acids in intact processed animal proteins opens an enormous expectative for the on-line implementation of NIRS technology in the processing and marketing of these important protein feed ingredients, alleviating the costs and time associated with the routine quality controls.

  3. Whole-genome prediction of fatty acid composition in meat of Japanese Black cattle.

    PubMed

    Onogi, A; Ogino, A; Komatsu, T; Shoji, N; Shimizu, K; Kurogi, K; Yasumori, T; Togashi, K; Iwata, H

    2015-10-01

    Because fatty acid composition influences the flavor and texture of meat, controlling it is particularly important for cattle breeds such as the Japanese Black, characterized by high meat quality. We evaluated the predictive ability of single-step genomic best linear unbiased prediction (ssGBLUP) in fatty acid composition of Japanese Black cattle by assessing the composition of seven fatty acids in 3088 cattle, of which 952 had genome-wide marker genotypes. All sires of the genotyped animals were genotyped, but their dams were not. Cross-validation was conducted for the 952 animals. The prediction accuracy was higher with ssGBLUP than with best linear unbiased prediction (BLUP) for all traits, and in an empirical investigation, the gain in accuracy of using ssGBLUP over BLUP increased as the deviations in phenotypic values of the animals increased. In addition, the superior accuracy of ssGBLUP tended to be more evident in animals whose maternal grandsire was genotyped than in other animals, although the effect was small.

  4. Prediction of retention times of proteins in hydrophobic interaction chromatography using only their amino acid composition.

    PubMed

    Salgado, J Cristian; Rapaport, Ivan; Asenjo, Juan A

    2005-12-09

    This paper focuses on the prediction of the dimensionless retention time of proteins (DRT) in hydrophobic interaction chromatography (HIC) by means of mathematical models based, essentially, only on aminoacidic composition. The results show that such prediction is indeed possible. Our main contribution was the design of models that predict the DRT using the minimal information concerning a protein: its aminoacidic composition. The performance is similar to that observed in models that use much more sophisticated information such as the three-dimensional structure of proteins. Three models that, in addition to the amino acid composition, use different assumptions about the amino acids tendency to be exposed to the solvent, were evaluated in 12 proteins with known experimental DRT. In all the cases analyzed, the model that obtained the best results was the one based on a linear estimation of the aminoacidic surface composition. The models were adjusted using a collection of 74 vectors of aminoacidic properties plus a set of 6388 vectors derived from these using two mathematical tools: k-means and self-organizing maps (SOM) algorithms. The best vector was generated by the SOM algorithm and was interpreted as a hydrophobicity scale based partly on the tendency of the amino acids to be hidden in proteins. The prediction error (MSE(JK)) obtained by this model was almost 35% smaller than that obtained by the model that supposes that all the amino acids are completely exposed and 40% smaller than that obtained by the model that uses a simple correction factor considering the general tendency of each amino acid to be exposed to the solvent. In fact, the performance of the best model based on the aminoacidic composition was 5% better than that observed in the model based on the three-dimensional structure of proteins.

  5. Suppression of p53-inducible gene 3 is significant for glioblastoma progression and predicts poor patient prognosis.

    PubMed

    Quan, Jishu; Li, Yong; Jin, Meihua; Chen, Dunfu; Yin, Xuezhe; Jin, Ming

    2017-03-01

    Glioblastoma is the most malignant and invasive brain tumor with extremely poor prognosis. p53-inducible gene 3, a downstream molecule of the tumor suppressor p53, has been found involved in apoptosis and oxidative stress response. However, the functions of p53-inducible gene 3(PIG3) in cancer are far from clear including glioblastoma. In this study, we found that p53-inducible gene 3 expression was suppressed in glioblastoma tissues compared with normal tissues. And the expression of p53-inducible gene 3 was significantly associated with the World Health Organization grade. Patients with high p53-inducible gene 3 expression have a significantly longer median survival time (15 months) than those with low p53-inducible gene 3 expression (8 months). According to Cox regression analysis, p53-inducible gene 3 was an independent prognostic factor with multivariate hazard ratio of 0.578 (95% confidence interval, 0.352-0.947; p = 0.030) for overall survival. Additionally, gain and loss of function experiments showed that knockdown of p53-inducible gene 3 significantly increased the proliferation and invasion ability of glioblastoma cells while overexpression of p53-inducible gene 3 inhibited the proliferation and invasion ability. The results of in vivo glioblastoma models further confirmed that p53-inducible gene 3 suppression promoted glioblastoma progression. Altogether, our data suggest that high expression of p53-inducible gene 3 is significant for glioblastoma inhibition and p53-inducible gene 3 independently indicates good prognosis in patients, which might be a novel prognostic biomarker or potential therapeutic target in glioblastoma.

  6. BEDAM Binding Free Energy Predictions for the SAMPL4 Octa-Acid Host Challenge

    PubMed Central

    Gallicchio, Emilio; Chen, Haoyuan; Chen, He; Fitzgerald, Michael; Gao, Yang; He, Peng; Kalyanikar, Malathi; Kao, Chuan; Lu, Beidi; Niu, Yijie; Pethe, Manasi; Zhu, Jie; Levy, Ronald M.

    2015-01-01

    The Binding Energy Distribution Analysis Method (BEDAM) protocol has been employed as part of the SAMPL4 blind challenge to predict the binding free energies of a set of octa-acid host-guest complexes. The resulting predictions were consistently judged as some of the most accurate predictions in this category of the SAMPL4 challenge in terms of quantitative accuracy and statistical correlation relative to the experimental values, which were not known at the time the predictions were made. The work has been conducted as part of a hands-on graduate class laboratory session. Collectively the students, aided by automated setup and analysis tools, performed the bulk of the calculations and the numerical and structural analysis. The success of the experiment confirms the reliability of the BEDAM methodology and it shows that physics-based atomistic binding free energy estimation models, when properly streamlined and automated, can be successfully employed by non-specialists. PMID:25726024

  7. Suppression of asymmetric acid efflux and gravitropism in maize roots treated with auxin transport inhibitors of sodium orthovanadate

    NASA Technical Reports Server (NTRS)

    Mulkey, T. J.; Evans, M. L.

    1982-01-01

    In gravitropically stimulated roots of maize (Zea mays L., hybrid WF9 x 38MS), there is more acid efflux on the rapidly growing upper side than on the slowly growing lower side. In light of the Cholodny/Went hypothesis of gravitropism which states that gravitropic curvature results from lateral redistribution of auxin, the effects of auxin transport inhibitors on the development of acid efflux asymmetry and curvature in gravistimulated roots were examined. All the transport inhibitors tested prevented both gravitropism and the development of asymmetric acid efflux in gravistimulated roots. The results indicate that auxin redistribution may cause the asymmetry of acid efflux, a finding consistent with the Cholodny/Went hypothesis of gravitropism. As further evidence that auxin-induced acid efflux asymmetry may mediate gravitropic curvature, sodium orthovanadate, an inhibitor of auxin-induced H+ efflux was found to prevent both gravitropism and the development of asymmetric acid efflux in gravistimulated roots.

  8. SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations

    PubMed Central

    Petukh, Marharyta; Dai, Luogeng; Alexov, Emil

    2016-01-01

    Predicting the effect of amino acid substitutions on protein–protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/. PMID:27077847

  9. SAAMBE: Webserver to Predict the Charge of Binding Free Energy Caused by Amino Acids Mutations.

    PubMed

    Petukh, Marharyta; Dai, Luogeng; Alexov, Emil

    2016-04-12

    Predicting the effect of amino acid substitutions on protein-protein affinity (typically evaluated via the change of protein binding free energy) is important for both understanding the disease-causing mechanism of missense mutations and guiding protein engineering. In addition, researchers are also interested in understanding which energy components are mostly affected by the mutation and how the mutation affects the overall structure of the corresponding protein. Here we report a webserver, the Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) webserver, which addresses the demand for tools for predicting the change of protein binding free energy. SAAMBE is an easy to use webserver, which only requires that a coordinate file be inputted and the user is provided with various, but easy to navigate, options. The user specifies the mutation position, wild type residue and type of mutation to be made. The server predicts the binding free energy change, the changes of the corresponding energy components and provides the energy minimized 3D structure of the wild type and mutant proteins for download. The SAAMBE protocol performance was tested by benchmarking the predictions against over 1300 experimentally determined changes of binding free energy and a Pearson correlation coefficient of 0.62 was obtained. How the predictions can be used for discriminating disease-causing from harmless mutations is discussed. The webserver can be accessed via http://compbio.clemson.edu/saambe_webserver/.

  10. Suppression of interleukin 2-dependent human T cell growth in vitro by prostaglandin E (PGE) and their precursor fatty acids. Evidence for a PGE-independent mechanism of inhibition by the fatty acids.

    PubMed Central

    Santoli, D; Phillips, P D; Colt, T L; Zurier, R B

    1990-01-01

    PGE represent oxygenation products of polyunsaturated essential fatty acids and are important regulators of cell-mediated immune responses. Because oils enriched in such fatty acids reduce inflammation and tissue injury in vivo, we examined the effects of these PGE precursors on IL-2-driven growth of human T lymphocytes. Dihomogamma linoleic acid (DGLA), AA, and their metabolites (PGE1 and PGE2, respectively) strongly inhibited short- and long-term growth of IL-2-dependent T cell cultures; EPA was much less inhibitory and its product, PGE3, failed to suppress IL-2 responses. Short-term pretreatment of the cells with DGLA or AA and removal of the fatty acids before the proliferation assay resulted in a smaller reduction in [3H]TdR incorporation. PGE and fatty acids did not alter the number of high affinity IL-2 binding sites on the T cell cultures but reduced the percentage of cells expressing CD25 and HLA class II molecules. No PGE was detected in supernatants from the fatty acid-treated cultures. Moreover, indomethacin, a cyclooxygenase inhibitor, did not reverse the antiproliferative effects of the fatty acids. Together, these findings indicate that fatty acids can inhibit IL-2-driven T cell growth via a PGE-independent mechanism and might be relevant to inflammatory diseases associated with persistent T cell activation. Images PMID:2298918

  11. Carnosic acid nanoparticles suppress liver ischemia/reperfusion injury by inhibition of ROS, Caspases and NF-κB signaling pathway in mice.

    PubMed

    Li, Hui; Sun, Jian-Jun; Chen, Guo-Yong; Wang, Wei-Wei; Xie, Zhan-Tao; Tang, Gao-Feng; Wei, Si-Dong

    2016-08-01

    Living donor liver transplantation (LDLT) requires ischemia/reperfusion (I/R), which can lead to early graft injury. However, the detailed molecular mechanism of I/R injury remains unclear. Carnosic acid, as a phenolic diterpene with function of anti-inflammation, anti-cancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. Administration of carnosic acid nanoparticles was thought to be sufficient to lead to considerable inhibition of liver injury progression induced by ischemia/reperfusion. In our study, liver ischemia/reperfusion injury was established successfully with C57BL/6 animal model. 10 and 20mg/kg carnosic acid nanoparticles were injected to mice for five days prior to ischemia. After liver ischemia/reperfusion, the levels of serum AST, ALT and APL were increased, which was attenuated by pre-treatment with carnosic acid nanoparticles. In addition, carnosic acid nanoparticles inhibited ROS production via its related signals regulation. And carnosic acid nanoparticles also suppressed the ischemia/reperfusion-induced up-regulation in the pro-apoptotic protein and mRNA levels of Bax, Cyto-c, Apaf-1 and Caspase-9/3 while increased ischemia/reperfusion-induced decrease of anti-apoptotic factor of Bcl-2. Further, ischemia/reperfusion-induced inflammation was also inhibited for carnosic acid nanoparticles administration via inactivating NF-κB signaling pathway, leading to down-regulation of pro-inflammatory cytokines releasing. In conclusion, our study suggested that carnosic acid nanoparticles protected against liver ischemia/reperfusion injury via its role of anti-oxidative, anti-apoptotic and anti-inflammatory bioactivity.

  12. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPAR{sub β/δ} in HepG2 cells

    SciTech Connect

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua; Berggren-Söderlund, Maria; Nilsson-Ehle, Peter; Zhang, Xiaoying; Xu, Ning

    2014-02-28

    Highlights: • Palmitic acid significantly inhibited APOM gene expression in HepG2 cells. • Palmitic acid could obviously increase PPARB/D mRNA levels in HepG2 cells. • PPAR{sub β/δ} antagonist, GSK3787, had no effect on APOM expression. • GSK3787 could reverse the palmitic acid-induced down-regulation of APOM expression. • Palmitic acid induced suppression of APOM expression is mediated via the PPAR{sub β/δ} pathway. - Abstract: It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPAR{sub β/δ}) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPAR{sub β/δ} pathway.

  13. Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice.

    PubMed

    Van den Bossche, Lien; Hindryckx, Pieter; Devisscher, Lindsey; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Vilchez-Vargas, Ramiro; Vital, Marius; Pieper, Dietmar H; Vanden Bussche, Julie; Vanhaecke, Lynn; Van de Wiele, Tom; De Vos, Martine; Laukens, Debby

    2017-04-01

    The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD.IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we

  14. Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

    PubMed Central

    Van den Bossche, Lien; Hindryckx, Pieter; Devisscher, Lindsey; Devriese, Sarah; Van Welden, Sophie; Holvoet, Tom; Vilchez-Vargas, Ramiro; Vital, Marius; Pieper, Dietmar H.; Vanden Bussche, Julie; Vanhaecke, Lynn; Van de Wiele, Tom; De Vos, Martine

    2017-01-01

    ABSTRACT The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered

  15. Quantum Chemical Prediction of Equilibrium Acidities of Ureas, Deltamides, Squaramides, and Croconamides.

    PubMed

    Ho, Junming; Zwicker, Vincent E; Yuen, Karen K Y; Jolliffe, Katrina A

    2017-09-11

    Robust quantum chemical methods are employed to predict the pKa's of several families of dual hydrogen-bonding organocatalysts/anion receptors, including deltamides and croconamides as well as their thio derivatives. The average accuracy of these predictions is ∼1 pKa unit and allows for a comparison of the acidity between classes of receptors and for quantitative studies of substituent effects. These computational insights further explain the relationship between pKa and chloride anion affinity of these receptors that will be important for designing future anion receptors and organocatalysts.

  16. Fast computational methods for predicting protein structure from primary amino acid sequence

    DOEpatents

    Agarwal, Pratul Kumar

    2011-07-19

    The present invention provides a method utilizing primary amino acid sequence of a protein, energy minimization, molecular dynamics and protein vibrational modes to predict three-dimensional structure of a protein. The present invention also determines possible intermediates in the protein folding pathway. The present invention has important applications to the design of novel drugs as well as protein engineering. The present invention predicts the three-dimensional structure of a protein independent of size of the protein, overcoming a significant limitation in the prior art.

  17. The prediction of the degree of exposure to solvent of amino acid residues via genetic programming

    SciTech Connect

    Handley, S.

    1994-12-31

    In this paper I evolve programs that predict the degree of exposure to solvent (the buriedness) of amino acid residues given only the primary structure. I use genetic programming to evolve programs that take as input the primary structure and that output the buriedness of each residue. I trained these programs on a set of 82 proteins from the Brookhaven Protein Data Bank (PDB) and cross-validated them on a separate testing set of 40 proteins, also from the PDB. The best program evolved had a correlation of 0.434 between the predicted and observed buriednesses on the testing set.

  18. Membrane bile acid receptor TGR5 predicts good prognosis in ampullary adenocarcinoma patients with hyperbilirubinemia

    PubMed Central

    Chen, Min-Chan; Chen, Yi-Ling; Wang, Tzu-Wen; Hsu, Hui-Ping; Lai, Ming-Derg

    2016-01-01

    Bile acids are potential carcinogens in gastrointestinal cancer, and interact with nuclear and membrane receptors to initiate downstream signaling. The effect of TGR5 [also known as G protein-coupled bile acid receptor 1 (GPBAR1)] on cancer progression is dependent on the tissue where it is activated. In this report, the function of TGR5 expression in cancer was studied using a bioinformatic approach. TGR5 expression in ampullary adenocarcinoma and normal duodenum was compared by western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry (IHC). High GPBAR1 gene expression was found to be an indicator of worse prognosis in gastric and breast cancer patients, and an indication of better prognosis in ovarian cancer patients. The level of GPBAR1 gene expression was higher in bile-acid exposed cancer than in other types of cancer, and was increased in well-differentiated ampullary adenocarcinoma. Negative, weak or mild expression of TGR5 was correlated with younger age, higher plasma level of total/direct bilirubin, higher plasma concentration of CA-125, advanced tumor stage and advanced AJCC TNM stage. The disease-specific survival rate was highest in ampullary adenocarcinoma patients with high TGR5 expression and high total bilirubin level. In summary, TGR5 functions as a tumor-suppressor in patients with ampullary adenocarcinoma and preoperative hyperbilirubinemia. Further study of the suppressive mechanism may provide a new therapeutic option for patients with ampullary adenocarcinoma. PMID:27510297

  19. Studies on Synthesis of Electrochemically Exfoliated Functionalized Graphene and Polylactic Acid/Ferric Phytate Functionalized Graphene Nanocomposites as New Fire Hazard Suppression Materials.

    PubMed

    Feng, Xiaming; Wang, Xin; Cai, Wei; Qiu, Shuilai; Hu, Yuan; Liew, Kim Meow

    2016-09-28

    Practical application of functionalized graphene in polymeric nanocomposites is hampered by the lack of cost-effective and eco-friendly methods for its production. Here, we reported a facile and green electrochemical approach for preparing ferric phytate functionalized graphene (f-GNS) by simultaneously utilizing biobased phytic acid as electrolyte and modifier for the first time. Due to the presence of phytic acid, electrochemical exfoliation leads to low oxidized graphene sheets (a C/O ratio of 14.8) that are tens of micrometers large. Successful functionalization of graphene was confirmed by the appearance of phosphorus and iron peaks in the X-ray photoelectron spectrum. Further, high-performance polylactic acid/f-GNS nanocomposites are readily fabricated by a convenient masterbatch strategy. Notably, inclusion of well-dispersed f-GNS resulted in dramatic suppression on fire hazards of polylactic acid in terms of reduced peak heat-release rate (decreased by 40%), low CO yield, and formation of a high graphitized protective char layer. Moreover, obviously improvements in crystallization rate and thermal conductivities of polylactic acid nanocomposites were observed, highlighting its promising potential in practical application. This novel strategy toward the simultaneous exfoliation and functionalization for graphene demonstrates a simple yet very effective approach for fabricating graphene-based flame retardants.

  20. A bis-malonic acid fullerene derivative significantly suppressed IL-33-induced IL-6 expression by inhibiting NF-κB activation.

    PubMed

    Funakoshi-Tago, Megumi; Miyagawa, Yurika; Ueda, Fumihito; Mashino, Tadahiko; Moriwaki, Yasuhiro; Tago, Kenji; Kasahara, Tadashi; Tamura, Hiroomi

    2016-11-01

    IL-33 functions as a ligand for ST2L, which is mainly expressed in immune cells, including mast cells. IL-33 is a potent inducer of pro-inflammatory cytokines, such as IL-6, and has been implicated in the pathogenesis of allergic inflammatory diseases. Therefore, IL-33 has recently been attracting attention as a new target for the treatment of inflammatory diseases. In the present study, we demonstrated that a water-soluble bis-malonic acid fullerene derivative (C60-dicyclopropane-1,1,1',1'-tetracarboxylic acid) markedly diminished the IL-33-induced expression of IL-6 in bone marrow-derived mast cells (BMMC). The bis-malonic acid fullerene derivative suppressed the canonical signaling steps required for NF-κB activation such as the degradation of IκBα and nuclear translocation of NF-κB by directly inhibiting the IL-33-induced IKK activation. Although p38 and JNK also contributed to IL-33-induced expression of IL-6, the bis-malonic acid fullerene derivative did not affect their activation. Furthermore, the bis-malonic acid fullerene derivative had no effect on the NF-κB activation pathway induced by TNFα and IL-1. These results suggest that the bis-malonic fullerene derivative has potential as a specific drug for the treatment of IL-33-induced inflammatory diseases by specifically inhibiting the NF-κB activation pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Suppression by eicosapentaenoic acid of oxidized low-density lipoprotein and lysophosphatidylcholine-induced migration in cultured rat vascular smooth muscle cells.

    PubMed

    Kohno, M; Yasunari, K; Minami, M; Kano, H; Maeda, K; Yoshikawa, J

    2000-05-01

    The migration of medial smooth muscle cells into the intima is proposed to be an initial process of intimal thickening in atherosclerotic lesions. The present study was designed to determine whether pretreatment with the antiatherogenic agent eicosapentaenoic acid (EPA) inhibits the migration induced by oxidized low-density lipoprotein (LDL) and its major phospholipid component, lysophosphatidylcholine (lyso-PC), in cultured rat vascular smooth muscle cells (VSMCs) using Boyden's chamber method. The effects of EPA pretreatment on angiotensin II (Ang II)- and platelet-derived growth factor BB (PDGF BB)-induced migration were also examined in these cells. Oxidized LDL and lyso-PC induced migration in a concentration-dependent manner. EPA pretreatment clearly suppressed oxidized LDL (200 microg/mL)- and lyso-PC (10(-5) mol/L)-induced migration between 40 and 160 micromol/L. EPA pretreatment also suppressed Ang 11 (10(-7) mol/L)- and PDGF BB (5 ng/mL)-induced migration at a concentration of 80 and 160 micromol/L. However, in a trypan blue exclusion test, dead cells stained with trypan blue were not found 24 hours after treatment with EPA. These results suggest that EPA suppresses VSMC migration induced by oxidized LDL and lyso-PC, as well as Ang II and PDGF BB. These preliminary data concerning the effects of EPA may partly explain the antiatherosclerotic effects of this agent.

  2. Environment-specific amino acid substitution tables: tertiary templates and prediction of protein folds.

    PubMed Central

    Overington, J.; Donnelly, D.; Johnson, M. S.; Sali, A.; Blundell, T. L.

    1992-01-01

    The local environment of an amino acid in a folded protein determines the acceptability of mutations at that position. In order to characterize and quantify these structural constraints, we have made a comparative analysis of families of homologous proteins. Residues in each structure are classified according to amino acid type, secondary structure, accessibility of the side chain, and existence of hydrogen bonds from the side chains. Analysis of the pattern of observed substitutions as a function of local environment shows that there are distinct patterns, especially for buried polar residues. The substitution data tables are available on diskette with Protein Science. Given the fold of a protein, one is able to predict sequences compatible with the fold (profiles or templates) and potentially to discriminate between a correctly folded and misfolded protein. Conversely, analysis of residue variation across a family of aligned sequences in terms of substitution profiles can allow prediction of secondary structure or tertiary environment. PMID:1304904

  3. [Uric acid predicts type 2 diabetes mellitus in the general population].

    PubMed

    Cardona, Fernando; Rojo-Martínez, Gemma; de la Cruz Almaraz, María; Soriguer, Federico; García-Fuentes, Eduardo; Tinahones, Francisco José

    2009-02-01

    Abnormal uric acid levels are considered by some to be a risk factor for metabolic disorders, whereas others consider it to be just a marker. We therefore examined the association between plasma uric acid concentrations and the risk of type 2 diabetes mellitus. We undertook a prospective, 8-year study of 411 persons from the general population with no carbohydrate metabolism disorder at the start of the study evaluated by oral glucose overload. The following variables were measured at the beginning and end of the study: uric acid, triglycerides, cholesterol, high-density lipoprotein cholesterol, glucose and insulin in plasma, body mass index and waist-to-hip ratio. The participants were classified according to their plasma uric acid concentration, with a cut-off at the 33rd percentile (men, 291.45 and women, 208.18 micromol/l). Participants with plasma uric acid concentrations above the 33rd percentile at the start of the study had worse lipid and anthropometric profiles. These persons were at greater risk for carbohydrate disorder at the end of the 8- year follow-up study (relative risk, 1.73; 95% confidence interval, 1.04-2.8). No significant differences were found in age or in the remaining variables studied between these two groups. Increased uric acid levels in response to a possible chronic increase in oxidative stress may predict future disorders or complications such as type 2 diabetes in otherwise healthy persons.

  4. Effects of dietary supplementation of ferulic acid and gamma-oryzanol on integument color and suppression of oxidative stress in cultured red sea bream, Pagrus major.

    PubMed

    Maoka, Takashi; Tanimoto, Fumio; Sano, Mitsuhiko; Tsurukawa, Kanji; Tsuno, Takuo; Tsujiwaki, Satomi; Ishimaru, Katsuya; Takii, Kenji

    2008-01-01

    The effects of ferulic acid (FA) and gamma-oryzanol (OZ) supplementation on cultured red sea bream were examined. Commercial brown fish meal diets supplemented with FA (0.01-0.5%) or OZ (0.05-0.5%) were given to zero-year, cultured red sea bream for 98 days. After the experiment, the brightness of the integument color ("L" value) of FA- and OZ-administrated fish was higher than that of control fish. Furthermore, 2-Thiobarbituric acid reactive substances (TBARS) in the liver of FA- and OZ-administrated fish was lower than in control fish. These results indicate that FA and OZ suppressed not only dark-color pigmentation but also oxidative stress in cultured red sea bream.

  5. Ovarian Function, Not Age, Predicts the Benefit from Ovarian Suppression or Ablation for Premenopausal Women with Breast Cancer

    PubMed Central

    Cao, Ye; Wang, Shusen; Shi, Yanxia; An, Xin; Xu, Fei; Yuan, Zhongyu

    2016-01-01

    The role of adjuvant ovarian suppression or ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer remains controversial. The purpose of our study was to examine which patients might benefit from the addition of OS/OA to tamoxifen. We analyzed the data of 2065 premenopausal patients with hormone receptor-positive invasive ductal carcinomas who were treated at Sun Yat-Sen University Cancer Center from 2000 to 2008. The five-year disease-free survival rate (DFSR) and overall survival rate (OSR) were compared by menstrual status and treatment. Compared with patients older than forty years of age, patients younger than forty years old had significant lower DFSRs and OSRs. The addition of OS/OA to tamoxifen increased the DFSR and OSR of patients with normal menstrual cycles after chemotherapy, regardless of their age at diagnosis. Patients with normal menstrual cycles after chemotherapy are the main beneficiaries of an adjuvant OS/OA. PMID:26866810

  6. MicroRNA-125b predicts clinical outcome and suppressed tumor proliferation and migration in human gallbladder cancer.

    PubMed

    Yang, Liang; Huang, Sheng; Ma, Hongbin; Wu, Xiaoxiong; Feng, Feiling

    2017-03-01

    We intended to investigate the functional role and clinical relevance of microRNA-125b in human gallbladder cancer. Quantitative real-time polymerase chain reaction was used to examine microRNA-125b expression in gallbladder cancer cell lines, and 79 pairs of gallbladder cancer and normal gallbladder clinical tissues. Clinical correlations between tumorous microRNA-125b expression and gallbladder cancer patients' clinicopathological variances or overall survivals were statistically analyzed. In gallbladder cancer cell lines, TYGBK-8 and G-415 cells, microRNA-125b was upregulated to examine its regulatory effect on gallbladder cancer proliferation and migration in vitro. MicroRNA-125b was significantly downregulated in gallbladder cancer cell lines and human gallbladder cancer tumors. MicroRNA-125b in gallbladder cancer was significantly correlated with patients' clinical stage, tumor differentiation, lymph metastasis, and tumor invasion. Low tumorous microRNA-125b expression was also found to be associated with poor overall survivals among gallbladder cancer patients. In vitro studies demonstrated that microRNA-125b upregulation significantly suppressed proliferation and migration in TYGBK-8 and G-415 cells. Tumorous microRNA-125b is an independent prognostic biomarker for patients with gallbladder cancer and possibly acts as a tumor suppressor in gallbladder cancer.

  7. Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice.

    PubMed

    Hirata, Takumi; Kawai, Toshihide; Hirose, Hiroshi; Tanaka, Kumiko; Kurosawa, Hideaki; Fujii, Chikako; Fujita, Haruhisa; Seto, Yoshiko; Matsumoto, Hideo; Itoh, Hiroshi

    2016-01-01

    The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive β-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

  8. Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

    PubMed Central

    Jackson, Eleisha L.; Spielman, Stephanie J.

    2017-01-01

    Proteins evolve through two primary mechanisms: substitution, where mutations alter a protein’s amino-acid sequence, and insertions and deletions (indels), where amino acids are either added to or removed from the sequence. Protein structure has been shown to influence the rate at which substitutions accumulate across sites in proteins, but whether structure similarly constrains the occurrence of indels has not been rigorously studied. Here, we investigate the extent to which structural properties known to covary with protein evolutionary rates might also predict protein tolerance to indels. Specifically, we analyze a publicly available dataset of single—amino-acid deletion mutations in enhanced green fluorescent protein (eGFP) to assess how well the functional effect of deletions can be predicted from protein structure. We find that weighted contact number (WCN), which measures how densely packed a residue is within the protein’s three-dimensional structure, provides the best single predictor for whether eGFP will tolerate a given deletion. We additionally find that using protein design to explicitly model deletions results in improved predictions of functional status when combined with other structural predictors. Our work suggests that structure plays fundamental role in constraining deletions at sites in proteins, and further that similar biophysical constraints influence both substitutions and deletions. This study therefore provides a solid foundation for future work to examine how protein structure influences tolerance of more complex indel events, such as insertions or large deletions. PMID:28369116

  9. A Large-Scale Assessment of Nucleic Acids Binding Site Prediction Programs

    PubMed Central

    Miao, Zhichao; Westhof, Eric

    2015-01-01

    Computational prediction of nucleic acid binding sites in proteins are necessary to disentangle functional mechanisms in most biological processes and to explore the binding mechanisms. Several strategies have been proposed, but the state-of-the-art approaches display a great diversity in i) the definition of nucleic acid binding sites; ii) the training and test datasets; iii) the algorithmic methods for the prediction strategies; iv) the performance measures and v) the distribution and availability of the prediction programs. Here we report a large-scale assessment of 19 web servers and 3 stand-alone programs on 41 datasets including more than 5000 proteins derived from 3D structures of protein-nucleic acid complexes. Well-defined binary assessment criteria (specificity, sensitivity, precision, accuracy…) are applied. We found that i) the tools have been greatly improved over the years; ii) some of the approaches suffer from theoretical defects and there is still room for sorting out the essential mechanisms of binding; iii) RNA binding and DNA binding appear to follow similar driving forces and iv) dataset bias may exist in some methods. PMID:26681179

  10. Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise

    PubMed Central

    Davidson, Terry L.; Powley, Terry L.

    2012-01-01

    In a previous report (Schier et al., Am J Physiol Regul Integr Comp Physiol 301: R1557–R1568, 2011), we demonstrated with a new behavioral procedure that rats exhibit stimulus-bound suppression of intake in response to an intraduodenal (ID) bitter tastant predicting subsequent malaise. With the use of the same modified taste aversion procedure, the present experiments evaluated whether the sweet taste properties of ID stimuli are likewise detected and encoded. Thirsty rats licked at sipper spouts for hypotonic NaCl for 30 min and received brief (first 6 min) yoked ID infusions of either the same NaCl or an isomolar lithium chloride (LiCl) solution in each session. An intestinal taste cue was mixed directly into the LiCl infusate for aversion training. Results showed that rats failed to detect intestinal sweet taste alone (20 mM Sucralose) but clearly suppressed licking in response to a nutritive sweet taste stimulus (234 mM sucrose) in the intestine that had been repeatedly paired with LiCl. Rats trained with ID sucrose in LiCl subsequently generalized responding to ID Sucralose alone at test. Replicating this, rats trained with ID Sucralose in compound with 80 mM Polycose rapidly suppressed licking to the 20 mM Sucralose alone in a later test. Furthermore, ID sweet taste signaling did not support the rapid negative feedback of sucrose or Polycose on intake when their digestion and transport were blocked. Together, these results suggest that other signaling pathways and/or transporters engaged by caloric carbohydrate stimuli potentiate detection of sweet taste signals in the intestine. PMID:22422670

  11. Rapid stimulus-bound suppression of intake in response to an intraduodenal nonnutritive sweetener after training with nutritive sugars predicting malaise.

    PubMed

    Schier, Lindsey A; Davidson, Terry L; Powley, Terry L

    2012-06-01

    In a previous report (Schier et al., Am J Physiol Regul Integr Comp Physiol 301: R1557-R1568, 2011), we demonstrated with a new behavioral procedure that rats exhibit stimulus-bound suppression of intake in response to an intraduodenal (ID) bitter tastant predicting subsequent malaise. With the use of the same modified taste aversion procedure, the present experiments evaluated whether the sweet taste properties of ID stimuli are likewise detected and encoded. Thirsty rats licked at sipper spouts for hypotonic NaCl for 30 min and received brief (first 6 min) yoked ID infusions of either the same NaCl or an isomolar lithium chloride (LiCl) solution in each session. An intestinal taste cue was mixed directly into the LiCl infusate for aversion training. Results showed that rats failed to detect intestinal sweet taste alone (20 mM Sucralose) but clearly suppressed licking in response to a nutritive sweet taste stimulus (234 mM sucrose) in the intestine that had been repeatedly paired with LiCl. Rats trained with ID sucrose in LiCl subsequently generalized responding to ID Sucralose alone at test. Replicating this, rats trained with ID Sucralose in compound with 80 mM Polycose rapidly suppressed licking to the 20 mM Sucralose alone in a later test. Furthermore, ID sweet taste signaling did not support the rapid negative feedback of sucrose or Polycose on intake when their digestion and transport were blocked. Together, these results suggest that other signaling pathways and/or transporters engaged by caloric carbohydrate stimuli potentiate detection of sweet taste signals in the intestine.

  12. Prediction of Intramolecular Polarization of Aromatic Amino Acids Using Kriging Machine Learning.

    PubMed

    Fletcher, Timothy L; Davie, Stuart J; Popelier, Paul L A

    2014-09-09

    Present computing power enables novel ways of modeling polarization. Here we show that the machine learning method kriging accurately captures the way the electron density of a topological atom responds to a change in the positions of the surrounding atoms. The success of this method is demonstrated on the four aromatic amino acids histidine, phenylalanine, tryptophan, and tyrosine. A new technique of varying training set sizes to vastly reduce training times while maintaining accuracy is described and applied to each amino acid. Each amino acid has its geometry distorted via normal modes of vibration over all local energy minima in the Ramachandran map. These geometries are then used to train the kriging models. Total electrostatic energies predicted by the kriging models for previously unseen geometries are compared to the true energies, yielding mean absolute errors of 2.9, 5.1, 4.2, and 2.8 kJ mol(-1) for histidine, phenylalanine, tryptophan, and tyrosine, respectively.

  13. Multiscale Reactive Molecular Dynamics for Absolute pKa Predictions and Amino Acid Deprotonation

    PubMed Central

    2015-01-01

    Accurately calculating a weak acid’s pKa from simulations remains a challenging task. We report a multiscale theoretical approach to calculate the free energy profile for acid ionization, resulting in accurate absolute pKa values in addition to insights into the underlying mechanism. Importantly, our approach minimizes empiricism by mapping electronic structure data (QM/MM forces) into a reactive molecular dynamics model capable of extensive sampling. Consequently, the bulk property of interest (the absolute pKa) is the natural consequence of the model, not a parameter used to fit it. This approach is applied to create reactive models of aspartic and glutamic acids. We show that these models predict the correct pKa values and provide ample statistics to probe the molecular mechanism of dissociation. This analysis shows changes in the solvation structure and Zundel-dominated transitions between the protonated acid, contact ion pair, and bulk solvated excess proton. PMID:25061442

  14. Prediction of acid hydrolysis of lignocellulosic materials in batch and plug flow reactors.

    PubMed

    Jaramillo, Oscar Johnny; Gómez-García, Miguel Ángel; Fontalvo, Javier

    2013-08-01

    This study unifies contradictory conclusions reported in literature on acid hydrolysis of lignocellulosic materials, using batch and plug flow reactors, regarding the influence of the initial liquid ratio of acid aqueous solution to solid lignocellulosic material on sugar yield and concentration. The proposed model takes into account the volume change of the reaction media during the hydrolysis process. An error lower than 8% was found between predictions, using a single set of kinetic parameters for several liquid to solid ratios, and reported experimental data for batch and plug flow reactors. For low liquid-solid ratios, the poor wetting and the acid neutralization, due to the ash presented in the solid, will both reduce the sugar yield. Also, this study shows that both reactors are basically equivalent in terms of the influence of the liquid to solid ratio on xylose and glucose yield. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Combined dermal exposure to permethrin and cis-urocanic acid suppresses the contact hypersensitivity response in C57BL/6N mice in an additive manner.

    PubMed

    Prater, M R; Blaylock, B L; Holladay, S D

    2005-01-14

    Cutaneous exposure to the pyrethroid insecticide permethrin significantly suppresses contact hypersensitivity (CH) response to oxazolone in C57BL/6N mice. Additionally, cis-urocanic acid (cUCA), an endogenous cutaneous chromophore isomerized to its active form following exposure to ultraviolet radiation, modulates cell-mediated cutaneous immune responses. This study describes cutaneous immune alterations following combined topical permethrin and intradermal cUCA exposure. Female C57BL/6N mice were administered 5, 50 or 100 microg cUCA daily for 5 consecutive days. CH was then evaluated by the mouse ear swelling test (MEST) response to oxazolone. Decreased responses of 52.3%, 76.3% and 76.3%, respectively, as compared to controls were observed. Then, mice were co-exposed to 5 microg cUCA daily for 5 days and 1.5, 5, 15, or 25 microL permethrin, on either day 1, 3 or 5 of the cUCA treatment to evaluate combined immunomodulatory effects of the two chemicals, or cUCA daily for 5 days followed by permethrin on day 3, 5, or 7 after the last cUCA injection to demonstrate prolonged immunosuppressive effects. Two days after final treatment, mice were sensitized with oxazolone and MEST was performed. Mice receiving five cUCA injections and permethrin topically on cUCA injection day 1 showed up to 93.3% suppression of MEST compared to vehicle control. CH was suppressed by 87.5%, 86.6% and 74.2% in mice treated with 25 muL permethrin on days 3, 5 and 7 after cUCA, respectively, compared to vehicle control. Taken together, these data indicate co-exposure to cUCA and permethrin profoundly suppresses cell-mediated cutaneous immunity.

  16. Lactobacillus gasseri SBT2055 suppresses fatty acid release through enlargement of fat emulsion size in vitro and promotes fecal fat excretion in healthy Japanese subjects.

    PubMed

    Ogawa, Akihiro; Kobayashi, Toshiya; Sakai, Fumihiko; Kadooka, Yukio; Kawasaki, Yoshihiro

    2015-03-20

    Lactobacillus gasseri SBT2055 (LG2055) has been shown to prevent abdominal adiposity, and suppression of lipid absorption is considered a possible mechanism, detail of which, however, are poorly understood. In the present study, we evaluated the effects of LG2055 on fat hydrolysis by determining pancreatic lipase activity and fat emulsion properties in vitro. We also examined whether LG2055 influences fecal fat excretion in humans. Pancreatic lipase activity was investigated in vitro using an artificially prepared fat emulsion and 4-methylumbelliferyl oleate (4-MUO) as substrates. The concentrations of free fatty acids and 4-methylumbelliferone were quantified. Fat emulsion droplet size was measured using a particle size analyzer. The clinical study was performed as a double-blind, randomized, placebo-controlled trial. Subjects consumed 100 g of fermented milk (FM)/d, either with or without LG2055 supplementation, for seven days. Fecal samples were collected during three-day pre-observational and FM intake periods and fecal fat levels were determined. LG2055 dose-dependently suppressed lipase activity in the fat emulsion assay but not in the 4-MUO assay. LG2055 dose-dependently increased fat emulsion droplet size. The effects of LG2055 on lipase activity and fat emulsion properties were increased compared with four other tested strains (Lactobacillus gasseri SBT0317, Lactobacillus gasseri JCM1131T, Lactobacillus. delbrueckii subsp. bulgaricus JCM1002T and Streptococcus thermophilus ATCC19258T). In our clinical study, fecal fat level after FM intake was significantly increased compared with that observed before FM intake in the LG2055-containing active FM group but not the control FM group lacking LG2055. LG2055 increased fat emulsion droplet size, resulting in the suppression of lipase-mediated fat hydrolysis. The influence of LG2055 on the physicochemical properties of fat emulsion provides a mechanism for the probiotic-mediated suppression of lipid absorption and

  17. Mito-GSAAC: mitochondria prediction using genetic ensemble classifier and split amino acid composition.

    PubMed

    Afridi, Tariq Habib; Khan, Asifullah; Lee, Yeon Soo

    2012-04-01

    Mitochondria are all-important organelles of eukaryotic cells since they are involved in processes associated with cellular mortality and human diseases. Therefore, trustworthy techniques are highly required for the identification of new mitochondrial proteins. We propose Mito-GSAAC system for prediction of mitochondrial proteins. The aim of this work is to investigate an effective feature extraction strategy and to develop an ensemble approach that can better exploit the advantages of this feature extraction strategy for mitochondria classification. We investigate four kinds of protein representations for prediction of mitochondrial proteins: amino acid composition, dipeptide composition, pseudo amino acid composition, and split amino acid composition (SAAC). Individual classifiers such as support vector machine (SVM), k-nearest neighbor, multilayer perceptron, random forest, AdaBoost, and bagging are first trained. An ensemble classifier is then built using genetic programming (GP) for evolving a complex but effective decision space from the individual decision spaces of the trained classifiers. The highest prediction performance for Jackknife test is 92.62% using GP-based ensemble classifier on SAAC features, which is the highest accuracy, reported so far on the Mitochondria dataset being used. While on the Malaria Parasite Mitochondria dataset, the highest accuracy is obtained by SVM using SAAC and it is further enhanced to 93.21% using GP-based ensemble. It is observed that SAAC has better discrimination power for mitochondria prediction over the rest of the feature extraction strategies. Thus, the improved prediction performance is largely due to the better capability of SAAC for discriminating between mitochondria and non-mitochondria proteins at the N and C terminus and the effective combination capability of GP. Mito-GSAAC can be accessed at http://111.68.99.218/Mito-GSAAC . It is expected that the novel approach and the accompanied predictor will have a

  18. Three Dimensional Structure Prediction of Fatty Acid Binding Site on Human Transmembrane Receptor CD36.

    PubMed

    Tarhda, Zineb; Semlali, Oussama; Kettani, Anas; Moussa, Ahmed; Abumrad, Nada A; Ibrahimi, Azeddine

    2013-01-01

    CD36 is an