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Sample records for valproic acid depakene

  1. Valproic Acid

    Science.gov (United States)

    ... acid is in a class of medications called anticonvulsants. It works by increasing the amount of a ... older (about 1 in 500 people) who took anticonvulsants such as valproic acid to treat various conditions ...

  2. Valproic Acid and Pregnancy

    Science.gov (United States)

    ... is possible. Studies have found that women with seizure disorders and women with bipolar disorder might have menstrual ... valproic acid to leave your body. Women with epilepsy or bipolar disorder who are planning a pregnancy ...

  3. Valproic Acid Induced Hyperammonaemic Encephalopathy

    International Nuclear Information System (INIS)

    Amanat, S.; Shahbaz, N.; Hassan, Y.

    2013-01-01

    Objective: To observe clinical and laboratory features of valproic acid-induced hyperammonaemic encephalopathy in patients taking valproic acid. Methods: Observational study was conducted at the Neurology Department, Dow University of Health Sciences, Civil Hospital, Karachi, from February 26, 2010 to March 20, 2011. Ten patients on valproic acid therapy of any age group with idiopathic or secondary epilepsy, who presented with encephalopathic symptoms, were registered and followed up during the study. Serum ammonia level, serum valproic acid level, liver function test, cerebrospinal fluid examination, electroencephalogram and brain imaging of all the patients were done. Other causes of encephalopathy were excluded after clinical and appropriate laboratory investigations. Microsoft Excel 2007 was used for statistical analysis. Results: Hyperammonaemia was found in all patients with encephalopathic symptoms. Rise in serum ammonia was independent of dose and serum level of valproic acid. Liver function was also found to be normal in 80% (n=8) of the patients. Valproic acid was withdrawn in all patients. Three (30%) patients improved only after the withdrawal of valproic acid. Six (60%) patients improved after L-Carnitine replacement, one (10%) after sodium benzoate. On followup, serum ammonia had reduced to normal in five (50%) patients and to more than half of the baseline level in two (20%) patients. Three (30%) patients were lost to followup after complete clinical improvement. Conclusion: Within therapeutic dose and serum levels, valproic acid can cause symptomatic hyperammonaemia resulting in encephalopathy. All patients taking valproic acid presenting with encephalopathic symptoms must be monitored for the condition. (author)

  4. Valproic Acid-induced Agranulocytosis

    Directory of Open Access Journals (Sweden)

    Hui-Chuan Hsu

    2009-06-01

    Full Text Available Valproic acid is considered to be the most well-tolerated antiepileptic drug. However, few cases of neutropenia or leukopenia caused by valproic acid have been reported. We present a patient who took valproic acid to treat a complication of brain surgery and in whom severe agranulocytosis occurred after 2.5 months. Valproic acid was stopped immediately, and granulocyte colony-stimulating factor was administered for 2 days. The patient's white blood cell count returned to normal within 2 weeks. The result of bone marrow aspiration was compatible with drug-induced agranulocytosis. This case illustrates that patients who take valproic acid may need regular checking of complete blood cell count.

  5. Severe Valproic Acid Intoxication Responding to Hemodialysis

    Directory of Open Access Journals (Sweden)

    Ali Ertuğ Arslanköylü

    2017-08-01

    Full Text Available Valproic acid is a commonly used antiepileptic drug which causes intoxication easily due to its narrow therapeutic window. Here, we present a child with valproic acid poisoning who responded to hemodialysis. A 14-year-old male patient with epilepsy and mental motor retardation was admitted to the pediatric intensive care unit due to valproic acid intoxication. Plasma valproic acid level was 710 µg/mL. The patient’s vital signs were stable and a decrease was observed in the valproic acid and ammonia levels with supportive treatment at the beginning. On the third day of the admission, hemodynamic and mental status of the patient deteriorated, plasma ammonia and lactate levels elevated, thus, we decided to perform hemodialysis. After hemodialysis, the patient’s hemodynamic status and mental function improved in conjunction with the reduction in valproic acid, ammonia and lactate levels. Thus he was transferred to the pediatric ward. Hemodialysis may be considered an effective treatment choice for severe valproic acid intoxication. Here, it was shown that hemodialysis may also be effective in patients with deteriorated general status under supportive treatment in the late phase of valproic acid intoxication.

  6. Use of hexadeuterated valproic acid and gas chromatography-mass spectrometry to determine the pharmacokinetics of valproic acid

    International Nuclear Information System (INIS)

    Acheampong, A.A.; Abbott, F.S.; Orr, J.M.; Ferguson, S.M.; Burton, R.W.

    1984-01-01

    Di-[( 3,3,3- 2 H3]propyl)acetic acid, a hexadeuterated analogue of valproic acid, was synthesized and its pharmacokinetic properties compared with valproic acid. Concentrations of valproic acid and [ 2 H]valproic acid in serum and saliva were determined by GC-MS using selected-ion monitoring. Saliva drug levels were measured with good precision down to 0.1 microgram/mL. Kinetic equivalence of valproic acid and [ 2 H]valproic acid was demonstrated in a single-dose study in a human volunteer. An isotope effect was observed for omega-oxidation, but the difference in metabolism was not sufficient to make [ 2 H]valproic acid biologically nonequivalent. The application of [ 2 H]valproic acid to determine the kinetics of valproic acid under steady-state concentrations was evaluated in the same volunteer. The kinetic data obtained with [ 2 H]valproic acid was consistent with previously reported values for valproic acid including kinetic differences observed between single-dose and steady-state experiments. Saliva levels of valproic acid were found to give a good correlation with total serum valproic acid under multiple-dose conditions. A concentration dependence was found for the ratio of saliva valproic acid to free valproic acid in serum, low ratios being observed at high serum concentrations of valproic acid

  7. Hyperammonemia Associated with Valproic Acid Concentrations

    Directory of Open Access Journals (Sweden)

    Marta Vázquez

    2014-01-01

    Full Text Available Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β-oxidation in the mitochondria one of its main metabolic route (40%. Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

  8. Thrombotic microangiopathy associated with Valproic acid toxicity.

    Science.gov (United States)

    Hebert, Sean A; Bohan, Timothy P; Erikson, Christian L; Swinford, Rita D

    2017-08-03

    Thrombotic microangiopathy (TMA) is a serious, sometimes life-threatening disorder marked by the presence of endothelial injury and microvascular thrombi. Drug-induced thrombotic microangiopathy (DI-TMA) is one specific TMA syndrome that occurs following drug exposure via drug-dependent antibodies or direct tissue toxicity. Common examples include calcineurin inhibitors Tacrolimus and Cyclosporine and antineoplastics Gemcitabine and Mitomycin. Valproic acid has not been implicated in DI-TMA. We present the first case of a patient meeting clinical criteria for DI-TMA following admission for valproic acid toxicity. An adolescent male with difficult to control epilepsy was admitted for impaired hepatic function while on valproic acid therapy. On the third hospital day, he developed severe metabolic lactic acidosis and multiorgan failure, prompting transfer to the pediatric intensive care unit. Progressive anemia and thrombocytopenia instigated an evaluation for thrombotic microangiopathy, where confirmed by concomitant hemolysis, elevated lactate dehydrogenase (LDH), low haptoglobin, and concurrent oliguric acute kidney injury. Thrombotic thrombocytopenic purpura was less likely with adequate ADAMTS13. Discontinuing valproic acid reversed the anemia, thrombocytopenia, and normalized the LDH and haptoglobin, supporting a drug-induced cause for the TMA. To the best of our knowledge, this is the first report of drug-induced TMA from valproic acid toxicity.

  9. Valproic Acid Suppositories for Management of Seizures for Geriatric Patients.

    Science.gov (United States)

    DiScala, Sandra L; Tran, Nhi N; Silverman, Michael A

    This case describes the use of valproic acid suppositories for secondary seizure prophylaxis in a geriatric veteran with a feeding and swallowing disorder. The effectiveness of valproic acid suppositories is outlined to reinforce the need for compounding pharmacies to have this formulation available to meet the needs of geriatric patients.

  10. Valproic acid monotherapy in pregnancy and major congenital malformations

    DEFF Research Database (Denmark)

    Jentink, Janneke; Loane, Maria A; Dolk, Helen

    2010-01-01

    The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited.......The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited....

  11. Compound list: valproic acid [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available valproic acid VPA 00005 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/valpr...oic_acid.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/valpr...oic_acid.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/valpr...edbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/valproic_acid.Rat.in_vivo.Liver.Repeat.zip ftp:...//ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/valproic_acid.Rat.in_vivo.Kidne

  12. The effect of valproic acid on rat ovarium and the protective role of ...

    African Journals Online (AJOL)

    ONOS

    2010-08-23

    Aug 23, 2010 ... specific ROS that mediates valproic acid-induced toxicity. In addition, valproic acid ... from murine pluripotent embryonic stem cells through an increase in ROS (Defoort ... vitamin E and folic acid. MATERIALS AND METHODS.

  13. Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure

    Directory of Open Access Journals (Sweden)

    Danny Bega

    2012-12-01

    Full Text Available Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 µmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate. Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

  14. Case Report: Valproic Acid and Risperidone Treatment Leading to Development of Hyperammonemia and Mania

    Science.gov (United States)

    Carlson, Teri; Reynolds, Charles A.; Caplan, Rochelle

    2007-01-01

    This case report describes two children who developed hyperammonemia together with frank manic behavior during treatment with a combination of valproic acid and risperidone. One child had been maintained on valproic acid for years and risperidone was added. In the second case, valproic acid was introduced to a child who had been treated with…

  15. Removal of valproic acid by plasmapheresis in a patient treated for multiple sclerosis

    NARCIS (Netherlands)

    Bastiaans, D.E.T.; Uden, I.W.M. van; Ruiterkamp, R.A.; Jong, B.A. de

    2013-01-01

    We present a case of a patient with multiple sclerosis who was treated with plasmapheresis and valproic acid. We used therapeutic drug monitoring to determine whether plasma concentrations of valproic acid were kept within the therapeutic window and to determine the amount of valproic acid that was

  16. Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations.

    NARCIS (Netherlands)

    Jentink, J.; Loane, M.A.; Dolk, H.; Barisic, I.; Garne, E.; de Jong-van den Berg, L.T.W.; Morris, Joan K.

    2010-01-01

    Background: The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited. Methods: We first combined data from eight published cohort studies (1565 pregnancies in which the women

  17. Valproic Acid and Sleep Duration in Children with Epilepsy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2009-09-01

    Full Text Available Sleep duration and behavior were assessed in 46 children (age range 1.7-17.4 years before and after tapering valproic acid (VPA administered for more than 6 months for epilepsy, in a study at University Children's Hospital, Zurich, Switzerland.

  18. Withdrawal of valproic acid treatment during pregnancy and seizure outcome

    DEFF Research Database (Denmark)

    Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio

    2016-01-01

    Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesi...

  19. The efficiency of valproic acid in a child with trichotillomania

    Directory of Open Access Journals (Sweden)

    Sultan Kılıç

    2011-06-01

    Full Text Available Trichotillomania is a relatively rare impulse control disorder that causes patients to pull out own hair. Studies regarding the pharmacological treatment in children or adults are scarce, and there is a lack of consensus on drug treatment. The current trend is to use mood stabilizers for reducing repetitive behaviors.We present the case of 9-years-old child whose symptoms showed remarkable improvement after the administration of valproic acid. Our case is the second case in the literature that effectively treated with valproic acid. Additionally, this report indicates that this drug is potentially effective in reducing and also terminating complaints of trichotillomania. Further studies are needed to understand course of this disorder and considering the best treatment options. J Clin Exp Invest 2011;2(2:214-5

  20. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies

    DEFF Research Database (Denmark)

    Gesche, Joanna; Khanevski, Marina; Solberg, Carl

    2017-01-01

    for refractory seizures. Resistance to valproic acid had a specificity of 100% to identify patients with drug resistance and correlated strongly with bad social outcome and seizure burden. Conversely, 21.2% of all patients with refractory seizures according to the ILAE definition later became seizure free...... (mainly with valproic acid). Our data suggest that "drug resistant GGE" must not be declared unless patients were adequately treated with valproic acid, and advocate resistance to valproic acid as a new clinical biomarker for drug-resistant GGE. A PowerPoint slide summarizing this article is available...

  1. Photocarcinogenesis of topical tazarotene and isotretinoin alone and in combination with valproic acid in hairless mice

    DEFF Research Database (Denmark)

    Lerche, Catharina Margrethe; Philipsen, Peter Alshede; Sehested, Maxwell

    2008-01-01

    Retinoids and the histone deacetylase inhibitor valproic acid have shown anticancer properties, but the photocarcinogenic or photoprotective effect is unclear. Therefore, we investigated whether a topical formulation of valproic acid is photocarcinogenic or photoprotective in hairless female C3.Cg/Tif...

  2. Valproic Acid in Women and Girls of Childbearing Age.

    Science.gov (United States)

    Gotlib, Dorothy; Ramaswamy, Rachel; Kurlander, Jacob E; DeRiggi, Alana; Riba, Michelle

    2017-09-01

    The aim of this paper is to evaluate recent literature on valproic acid (VPA) in women and girls of childbearing age and to emphasize new findings. Recent research confirms VPAs teratogenicity and risk of hormone disruption. VPA exposure in utero increases the risk for a variety of major congenital malformations (MCMs), reduced IQ and behavioral problems. In girls and women, VPA increases the risk of hormone abnormalities, obesity, and polycystic ovarian syndrome (PCOS). Despite guidelines recommending caution, VPA use continues to be prescribed to reproductive-aged women and girls. Despite significant and well-documented risk, adherence to guidelines in VPA use in reproductive-aged girls and women remains low.

  3. The use of valproic acid and multiple sclerosis

    DEFF Research Database (Denmark)

    Nielsen, Nete Munk; Svanström, Henrik; Stenager, Egon

    2014-01-01

    BACKGROUND: Animal studies have suggested that drugs inhibiting the enzyme histone deacetylase might have a beneficial effect on multiple sclerosis (MS). Valproic acid (VPA), an anti-epileptic drug, is the only widely used human drug with a histone deacetylase inhibitory effect. OBJECTIVE...... current VPA users nor recent users of VPA, who had ceased VPA treatment within the last year, were at a reduced risk of MS compared with non-users of VPA (HR = 1.30 (95% confidence interval, 0.44-3.80), n = 4, and HR = 1.22 (0.28-5.32), n = 2, respectively). Similarly, in an intention-to-treat analysis...

  4. Effect of valproic acid on 65Zn distribution in the pregnant rat

    International Nuclear Information System (INIS)

    Keen, C.L.; Peters, J.M.; Hurley, L.S.

    1989-01-01

    The effect of valproic acid on the distribution of gavaged 65 Zn in maternal and embryonic tissue of Sprague-Dawley rats was examined 24 h after gavaging of the drug on d 13 of pregnancy. Valproic acid treatment resulted in a significantly higher retention of 65 Zn in maternal liver and lower amounts in uterus, placenta and embryos than in controls. Compared to controls, gel chromatography of maternal liver from valproic acid-treated dams showed higher 65 Zn counts associated with a protein peak of molecular weight of 6,500, the approximate molecular weight of the Zn-binding protein metallothionein. These results support the idea that the teratogenicity of valproic acid is in part due to an induction of embryonic Zn deficiency secondary to a drug-induced sequestering of Zn into maternal liver that results in a decrease in maternal plasma Zn and subsequent reduction in embryonic Zn uptake

  5. Valproic acid-induced hyperammonemic encephalopathy - a potentially fatal adverse drug reaction.

    Science.gov (United States)

    Sousa, Carla

    2013-12-01

    A patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid. A patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range. Valproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily. Monitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment. Idiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected. Clinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment.

  6. Study of Valproic Acid-Enhanced Hepatocyte Steatosis

    Science.gov (United States)

    Chang, Renin; Chou, Mei-Chia; Hung, Li-Ying; Wang, Mu-En; Hsu, Meng-Chieh; Chiu, Chih-Hsien

    2016-01-01

    Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA-) induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG) synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36), low-density lipoprotein receptor-related protein 1 (Lrp1), diacylglycerol acyltransferase 2 (Dgat2), and perilipin 2 (Plin2) were increased, that of carnitine palmitoyltransferase I a (Cpt1a) was not affected, and those of acetyl-Co A carboxylase α (Acca) and fatty acid synthase (Fasn) were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ) nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation. PMID:27034954

  7. Study of Valproic Acid-Enhanced Hepatocyte Steatosis

    Directory of Open Access Journals (Sweden)

    Renin Chang

    2016-01-01

    Full Text Available Valproic acid (VPA is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA- induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36, low-density lipoprotein receptor-related protein 1 (Lrp1, diacylglycerol acyltransferase 2 (Dgat2, and perilipin 2 (Plin2 were increased, that of carnitine palmitoyltransferase I a (Cpt1a was not affected, and those of acetyl-Co A carboxylase α (Acca and fatty acid synthase (Fasn were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation.

  8. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

    International Nuclear Information System (INIS)

    Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Wissing, Karl M.; Van den Branden, Christiane; Grunsven, Leo A. van

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation

  9. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Van Beneden, Katrien, E-mail: kvbenede@vub.ac.be [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Geers, Caroline [Department of Pathology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Pauwels, Marina [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Mannaerts, Inge [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Wissing, Karl M. [Department of Nephrology, Universitair Ziekenhuis Brussel, Brussels (Belgium); Van den Branden, Christiane [Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium); Grunsven, Leo A. van, E-mail: lvgrunsv@vub.ac.be [Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels (Belgium)

    2013-09-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation.

  10. Computational characteristics of valproic acid binding to histone deacetylase

    International Nuclear Information System (INIS)

    Abou-Zeid, Laila A.; El-Mowafy, Abdalla M.; Eikel, D.; Nau, H.; El-Mazar, M.

    2007-01-01

    Recently, the anticpileptic drug valproic acid (VPA) has also demonstrated efficacy in the management of cancer and bipolar disorders. These actions are largely mediated by inhibition of the HDAC enzyme/induction of certain genes. Relative to other HDAC inhibitors such as trichostatin-A (TSA), VPA offers higher selectivity on cancer cells with virtually no detrimental effects on normal cells. The molecular underpinnings of these biological profiles for VPA remain undefined. We currently propose for an attempt to identify differences in the binding of VPA and TSA to HDAC. In this paper, conformational changes and energy calculations have derived. VPA had to accomplish conformational changes in its structure for best accommodation at the HDAC binding site. Energy computations showed that VPA has a lower binding affinitythan TSA (-53.80 vs. -66.30 Kcal/mol). These findings demonstrate that VPA binding to HDAC confers catalytic, conformational and computational characteristics that are distinct from those of TSA. These findings of VPA are consistent with a moderate inhibition of HDAC, a low toxicity on normal cells, and a higher selectivity on cancer cells than TSA. Accordingly, these newly identified binding properties of VPA can state a framework strategy for the rational design of VPA-related anticancer drugs with superior cytodifferentiating-and/or safety-profiles. (author)

  11. Neonatal episodic hypoglycemia: a finding of valproic acid withdrawal.

    Science.gov (United States)

    Çoban, Dilek; Kurtoğlu, Selim; Akın, Mustafa Ali; Akçakuş, Mustafa; Güneş, Tamer

    2010-01-01

    The treatment of epilepsy during pregnancy is a worldwide problem. Drugs need to be used to control seizures in the mothers. In utero, exposure to valproic acid (VPA) and phenytoin (PH) may cause congenital malformations and also withdrawal symptoms such as irritability, jitteriness and symptoms of hypoglycemia. We present here a newborn with episodic hypoglycemia due to in utero exposure to VPA and PH. The mother was diagnosed as having complex partial epilepsy and was treated with PH (200 mg/day) and VPA (600 mg/day). The offspring developed jitteriness on the second day of life. The infant was hypoglycemic (32 mg/dl). These findings were accepted as withdrawal symptoms, since serum levels of VPA and PH were 37.8 μg/ml (50-100 μg/ml) and 6.37 μg/dl (10-20 μg/ml), respectively. Measurement of blood glucose is important and should be carefully monitored in infants exposed to antiepileptics in utero.

  12. The valproic acid-induced rodent model of autism.

    Science.gov (United States)

    Nicolini, Chiara; Fahnestock, Margaret

    2018-01-01

    Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The effect of a histone deacetylase inhibitor - valproic acid - on nucleoli in human leukaemic myeloblasts.

    Science.gov (United States)

    Smetana, K; Zápotocký, M

    2010-01-01

    The present study was undertaken to provide more information on nucleolar changes induced by a histone deacetylase inhibitor such as valproic acid in leukaemic myeloblasts at the single-cell level. For this study, RNA in nucleoli was visualized by a simple but sensitive cytochemical procedure in unfixed cytospins of short-term bone marrow cultures from patients suffering from acute myeloid leukaemia. Valproic acid in leukaemic myeloblasts markedly reduced the nucleolar size and also produced significant transformation of "active" to "resting" and "inactive" nucleoli that reflected the alteration of the nucleolar transcription in sensitive myeloblasts. On this occasion it should be added that valproic acid significantly increased the incidence of altered myeloblasts that changed to apoptotic cells or apoptotic bodies and cell ghosts. In contrast to the above-mentioned decreased nucleolar size, the nucleolar RNA concentration, expressed by computerassisted RNA image densitometry in valproic acidtreated myeloblasts, was not significantly changed. The results of the present study clearly indicated that the nucleolar size and transformation of "active" to "sleeping" or "inactive" nucleoli are convenient markers of the sensitivity and alteration of leukaemic myeloblasts produced by a histone deacetylase inhibitor, valproic acid, at the single-cell level.

  14. Epigenetic modifications in valproic acid-induced teratogenesis

    International Nuclear Information System (INIS)

    Tung, Emily W.Y.; Winn, Louise M.

    2010-01-01

    Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400 mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24 h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3 h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.

  15. Topiramate increases the risk of valproic acid-induced encephalopathy.

    Science.gov (United States)

    Noh, Young; Kim, Dong Wook; Chu, Kon; Lee, Soon-Tae; Jung, Keun-Hwa; Moon, Hye-Jin; Lee, Sang Kun

    2013-01-01

    Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  16. The effects of valproic acid on renal corpuscle of pregnant rats and ...

    African Journals Online (AJOL)

    The effects of valproic acid on renal corpuscle of pregnant rats and protective role of folic acid and vitamin E. Ayfer Aktas, Yusuf Nergız, Yusuf Nergız, Murat Akkus, Murat Akkus, Yasemin Nasır, Yasemin Nasır ...

  17. Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease.

    Science.gov (United States)

    Royce, Simon G; Dang, William; Ververis, Katherine; De Sampayo, Nishika; El-Osta, Assam; Tang, Mimi L K; Karagiannis, Tom C

    2011-12-01

    Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targeted optimally by existing anti-inflammatory drugs. Histone deacetylase inhibitors have a wide range of effects that may potentially abrogate aspects of remodeling. One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid). Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but also inhibits class II histone deacetylases. We used valproic acid as a molecular model of histone deacetylase inhibition in vivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness. Wild-type Balb/c mice with allergic airways disease were treated with valproic acid or vehicle control. Airway inflammation was assessed by bronchoalveolar lavage fluid cell counts and examination of lung tissue sections. Remodeling was assessed by morphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmography measurement of airway resistance. Valproic acid treatment did not affect inflammation parameters; however, valproic acid treatment resulted in reduced epithelial thickness as compared to vehicle treated mice (p < 0.01), reduced subepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for the two highest doses of methacholine, respectively). These findings show that treatment with valproic acid can reduce structural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use of histone deacetylase inhibitors for the treatment of asthma.

  18. Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis

    International Nuclear Information System (INIS)

    Dencker, L.; Nau, H.; D'Argy, R.

    1990-01-01

    Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium

  19. Enhanced long term microcircuit plasticity in the valproic acid animal model of autism

    NARCIS (Netherlands)

    Silva, G.; Le Bé, J.-V.; Riachi, I.; Rinaldi, T.; Markram, K.; Markram, H.

    2009-01-01

    A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and

  20. Does folic acid use decrease the risk for spina bifida after in utero exposure to valproic acid?

    NARCIS (Netherlands)

    Jentink, J.; Bakker, M.K.; Nijenhuis, C.M.; Wilffert, B.; de Jong-van den Berg, L.T.W.

    Purpose Women with child wish are advised to take folic acid supplements to reduce the risk for spina bifida. However, there is less evidence for this protective effect in women using valproic acid (VPA). We investigated the effect of folic acid in women exposed to VPA in the first trimester of

  1. The Effect of Carnitine Supplementation on Hyperammonemia and Carnitine Deficiency Treated with Valproic Acid in a Psychiatric Setting

    OpenAIRE

    Nakamura, Masaru; Nagamine, Takahiko

    2015-01-01

    Objective: The aim of this study was to investigate the effect of levocarnitine (active isoform of carnitine, L-Carnitine) supplementation on serum ammonia and carnitine levels simultaneously, and their clinical outcomes in valproic acid-treated psychiatric subjects.

  2. Stevens - Johnson Syndrome Induced by Combination of Lamotrigine and Valproic Acid in a 9-Year-Old Boy

    LENUS (Irish Health Repository)

    Maduemem, K

    2017-06-01

    We describe the case history of a 9-year-old boy who developed Stevens-Johnson syndrome (SJS) following concomitant use of valproic acid and lamotrigine. He presented with rash and fever several weeks after introduction of lamotrigine, having been on valproic acid for seizure disorder. SJS happens to be one of the rare adverse reactions of antiepilepsy drugs (AED). Management is mainly supportive with care escalation when necessary because of the significant morbidity.

  3. Toxic epidermal necrolysis due to concomitant use of lamotrigine and valproic acid

    Directory of Open Access Journals (Sweden)

    Sukhjot Kaur

    2013-01-01

    Full Text Available Anti-epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. These rashes are well documented with older antiepileptic drugs like phenytoin, phenobarbitone and carbamazapine. Lamotrigine is a newer, unrelated antiepileptic drug that causes skin rashes in 3-10% of new users. Higher starting dose or rapid escalation, concurrent treatment with valproic acid, and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes. We report two patients with toxic epidermal necrolysis, resulting from concomitant use of lamotrigine and valproic acid. It is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine.

  4. Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism

    DEFF Research Database (Denmark)

    Silva, Guilherme Testa; Le Bé, Jean-Vincent; Riachi, Imad

    2009-01-01

    A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and ...... and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (...

  5. Enhanced long term microcircuit plasticity in the valproic acid animal model of autism

    OpenAIRE

    Guilherme T Silva; Guilherme T Silva; Jean-Vincent Le Bé; Imad Riachi; Tania Rinaldi; Kamila Markram; Henry Markram

    2009-01-01

    A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a mini-column (<50μm). In the present study, we explored whether Long Term Microcircuit ...

  6. Enhanced Long-Term Microcircuit Plasticity in the Valproic Acid Animal Model of Autism

    OpenAIRE

    Silva, Guilherme Testa; Le Bé, Jean-Vincent; Riachi, Imad; Rinaldi, Tania; Markram, Kamila; Markram, Henry

    2009-01-01

    A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (

  7. Derivatives of valproic acid are active against pentetrazol-induced seizures in immature rats

    Czech Academy of Sciences Publication Activity Database

    Mareš, Pavel; Kubová, Hana; Hen, N.; Yagen, B.; Bialer, M.

    2013-01-01

    Roč. 106, 1-2 (2013), s. 64-73 ISSN 0920-1211 R&D Projects: GA ČR(CZ) GAP304/10/1274; GA ČR(CZ) GBP304/12/G069 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : experimental seizures * anticonvulsant action * derivatives of valproic acid * immature rats Subject RIV: FH - Neurology Impact factor: 2.190, year: 2013

  8. Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Surendradoss, Jayakumar; Chang, Thomas K.H.; Abbott, Frank S., E-mail: frank.abbott@ubc.ca

    2012-11-01

    Valproic acid (VPA) undergoes cytochrome P450-mediated desaturation to form 4-ene-VPA, which subsequently yields (E)-2,4-diene-VPA by β-oxidation. Another biotransformation pathway involves β-oxidation of VPA to form (E)-2-ene-VPA, which also generates (E)-2,4-diene-VPA by cytochrome P450-mediated desaturation. Although the synthetic form of (E)-2,4-diene-VPA is more hepatotoxic than VPA as shown in various experimental models, there is no conclusive evidence to implicate the in situ generated (E)-2,4-diene-VPA in VPA hepatotoxicity. The present study investigated the effects of modulating the in situ formation of (E)-2,4-diene-VPA on markers of oxidative stress (formation of 2′,7′-dichlorofluorescein; DCF), steatosis (accumulation of BODIPY 558/568 C{sub 12}), necrosis (release of lactate dehydrogenase; LDH), and on cellular total glutathione (GSH) levels in sandwich-cultured rat hepatocytes treated with VPA or (E)-2-ene-VPA. Treatment with either of these chemicals alone increased each of the toxicity endpoints. In VPA-treated hepatocytes, (E)-2,4-diene-VPA was detected only at trace levels, even after phenobarbital (PB) pretreatment and there was no effect on the toxicity of VPA. Furthermore, pretreatment with a cytochrome P450 enzyme inhibitor, 1-aminobenzotriazole (1-ABT), did not influence the extent of VPA toxicity in both PB-pretreated and vehicle-pretreated hepatocytes. However, in (E)-2-ene-VPA-treated hepatocytes, PB pretreatment greatly enhanced the levels of (E)-2,4-diene-VPA and this was accompanied by a further enhancement of the effects of (E)-2-ene-VPA on DCF formation, BODIPY accumulation, LDH release, and GSH depletion. Pretreatment with 1-ABT reduced the concentrations of (E)-2,4-diene-VPA and the extent of (E)-2-ene-VPA toxicity; however, this occurred in PB-pretreated hepatocytes, but not in control hepatocytes. In conclusion, in situ generated (E)-2,4-diene-VPA is not responsible for the hepatocyte toxicity of VPA, whereas it

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Yingying; Chen, Xi; Yu, Dehai [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Tao [Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Cui, Jiuwei; Wang, Guanjun [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Hu, Ji-Fan, E-mail: jifan@stanford.edu [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Wei, E-mail: jdyylw@163.com [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China)

    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.

  10. Frequency of different congenital anomalies in prenatally valproic acid treated chick embryos

    International Nuclear Information System (INIS)

    Akhtar, L.; Khan, M.Y.

    2016-01-01

    To determine the frequency of different congenital anomalies in surviving chick embryo on hatching after the prenatal administration of valproic acid by comparing with age-matched controls. Study Design: Experimental study. Place and Duration of Study: Anatomy Department, College of Physicians and Surgeons Pakistan (CPSP) Regional Centre, Islamabad, from February 2010 to February 2011. Material and Methods: Thirty fertilized chicken eggs were injected with valproic acid, incubated and then evaluated for different gross congenital anomalies, on hatching or day 22 of incubation whichever was earlier. Chicks of this group were labeled as experimental group-A. Similarly, another group of thirty fertilized chicken eggs labeled as control group-B, underwent sham treatment using normal saline. The weight and length of alive chicks, the total number of chicks with gross anomalies and the number of different types of gross anomalies in both groups were noted and statistically compared. Results: In control group-B, 28 chicks hatch out on 21 day of hatching with no visible gross deformities. Whereas in experimental group-A, 23 chicks were alive, out of which, 9 chicks were with delayed hatching on 22 days of hatching. The chicks with gross deformities were 8 (p=0.0008) which included: limb abnormalities (i.e. inverted feet) in 6 chicks (p=0.006), eye abnormality (i.e. closed palpebral fissure of both eyes) in 2 chick (p=0.2), 1 chick showed multiple deformities including gastroschisis, closed palpebral fissures and inverted foot (p=0.45). There were behavioral changes in 10 chicks (p=0.0001). There was statistically significant difference in their weights (p=0.03). Conclusion: Prenatal exposure of chick embryos to valproic acid increased the incidence of different gross deformities. (author)

  11. Diffuse alveolar hemorrhage due to valproic acid: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Francesco Inzirillo

    2015-01-01

    Full Text Available Valproic acid (VPA is one of the most frequently used antiepileptic drugs for the treatment of focal and generalized epilepsies, absence seizures, and Lennox-Gastaut syndrome (LGS. VPA has been demonstrated to have a negative effect on both the intrinsic and extrinsic coagulation systems and controversy exists about the clinical relevance of such hematological abnormalities. We describe a case of reversible lung hemorrage due to VPA. In English-language literature only two other similar cases (one of which fatal have been described so far.

  12. Cytoskeleton of hippocampal neurons as a target for valproic acid in an experimental model of depression.

    Science.gov (United States)

    Ferrero, Alejandro J; Cereseto, Marina; Sifonios, Laura L; Reinés, Analía; Peixoto, Estanislao; Rubio, Modesto C; Wikinski, Silvia

    2007-10-01

    Atrophy of pyramidal hippocampal neurons and of the entire hippocampus has been reported in experimental models of depression and in depressive patients respectively. We investigated the efficacy of valproic acid (VPA) for reversing a depressive-like behaviour and a cytoskeletal alteration in the hippocampus, the loss of the light neurofilament subunit (NF-L). Depressive-like behaviour was induced by inescapable stress. Animals were divided into four groups: two to assess the response to 21 days of treatment with 200 mg/kg (I.P.) of valproic acid, and two in which the treatment was interrupted and the effects of VPA were evaluated 90 days later. Depressive-like behaviour was evaluated by the quantification of escape movements in a swimming test. NF-L was quantified by immunohistochemistry in dentate gyrus and CA3 of hippocampus. VPA corrected the depressive-like behaviour and reversed the diminution of NF-L in the hippocampus. Ninety days after the end of the treatment, and in contrast to the results previously obtained with fluoxetine, no recurrence of the depressive-like behaviour was observed. Despite interruption of the treatment, a long-lasting effect of VPA was observed. A possible relationship between the effect on NF-L and the prevention of depressive-like behaviour recurrence could be suggested.

  13. [Influence of valproic acid (depakine I.V.) on human placenta metabolism--experimental model].

    Science.gov (United States)

    Semczuk-Sikora, Anna; Rogowska, Wanda; Semczuk, Marian

    2003-08-01

    The pregnancy in women with epilepsy is associated with an increased incidence of congenital malformations in offspring. Currently, anti-epileptic drugs (AEDs) are concerned to be a major etiologic factor of abnormal fetal development but the pathomechanism of teratogenicity of AEDs is complex and not well understood. The purpose of this study was to evaluate an influence of one of the AED-valproic acid (VPA) on placental metabolism (glucose consumption and lactate production). Term human placental cotyledons were perfused in vitro using a recycling perfusion of maternal and fetal circulations. A total 18 placentas were perfused either with 75 micrograms/ml of VPA (therapeutic dose) or with 225 micrograms/ml of VPA (toxic dose). Eight placentas were perfused with a medium without VPA and served as controls. During 2.5 h of experiment, both maternal and fetal glucose consumption and lactate production were measured every 30 minutes. The introduction of different concentrations of VPA into the perfusion system did not effect placental glucose consumption and lactate production rates in both maternal and fetal compartments. The teratogenic effect of valproic acid is not associated with metabolic disturbances of glucose or lactate in the placental tissue.

  14. Edaravone, a free radical scavenger, protects liver against valproic acid induced toxicity

    Directory of Open Access Journals (Sweden)

    Cakmak Neziha Hacihasanoglu

    2015-01-01

    Full Text Available Valproic acid (VPA, is a well established anticonvulsant drug that has been increasingly used in the treatment of many forms of generalized epilepsy. Edaravone (EDA; 3-methyl-1-phenyl-2-pyrazoline-5-one is a potent free radical scavenger. In this study, we aimed to investigate the effects of EDA on VPA-induced hepatic damage. Male Sprague Dawley rats were divided into four groups. Group I was control animals. Group II was control rats given valproic acid (500 mg kg-1 day for seven days. Group III was given only EDA (30 mg kg-1day for seven days. Group IV was given VPA+EDA (in same dose and time. EDA and VPA were given intraperitoneally. On the 8th day of experiment, blood samples and liver tissue were taken. Serum aspartate and alanine aminotransferase, alkaline phosphatase and bilirubin levels, liver myeloperoxidase, xanthine oxidase, adenosine deaminase, Na+/K+ATPase, sorbitol dehydrogenase, glutamate dehydrogenase, DT-diaphorase, arginase and thromboplastic activities, lipid peroxidation, protein carbonyl levels were increased whereas paraoxonase, biotinidase activities and glutathione levels were decreased in VPA group. Application of EDA with VPA protected against VPA-induced effects. These results demonstrated that administration of EDA is a potentially beneficial agent to reduce hepatic damage in VPA induced hepatotoxicity, probably by decreasing oxidative stress.

  15. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaofei; Zhu, Yanshuang [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); He, Huabin [Department of Orthopedics, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Lou, Lianqing; Ye, Weiwei; Chen, Yongxin [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Wang, Jinghe, E-mail: Xiaofeili2000@163.com [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China)

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  16. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    International Nuclear Information System (INIS)

    Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

    2013-01-01

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis

  17. Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells.

    Science.gov (United States)

    Langlands, Alistair J; Carroll, Thomas D; Chen, Yu; Näthke, Inke

    2018-02-15

    More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from Apc Min/+ mice recapitulate stages of intestinal polyposis in culture. They eventually form spherical cysts that reflect the competitive growth advantage of cells that have undergone loss of heterozygosity (LOH). We discovered that this emergence of cysts was inhibited by Chiron99021 and Valproic acid, which potentiates Wnt signalling. Chiron99021 and Valproic acid restrict the growth advantage of Apc mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of Apc mutant cells. As a proof of concept, we demonstrated that Chiron99021-treated Apc mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.

  18. Direct Determination of a Small-Molecule Drug, Valproic Acid, by an Electrically-Detected Microcantilever Biosensor for Personalized Diagnostics

    Directory of Open Access Journals (Sweden)

    Long-Sun Huang

    2015-01-01

    Full Text Available Direct, small-molecule determination of the antiepileptic drug, valproic acid, was investigated by a label-free, nanomechanical biosensor. Valproic acid has long been used as an antiepileptic medication, which is administered through therapeutic drug monitoring and has a narrow therapeutic dosage range of 50–100 μg·mL−1 in blood or serum. Unlike labeled and clinically-used measurement techniques, the label-free, electrical detection microcantilever biosensor can be miniaturized and simplified for use in portable or hand-held point-of-care platforms or personal diagnostic tools. A micromachined microcantilever sensor was packaged into the micro-channel of a fluidic system. The measurement of the antiepileptic drug, valproic acid, in phosphate-buffered saline and serum used a single free-standing, piezoresistive microcantilever biosensor in a thermally-controlled system. The measured surface stresses showed a profile over a concentration range of 50–500 μg·mL−1, which covered the clinically therapeutic range of 50–100 μg·mL−1. The estimated limit of detection (LOD was calculated to be 45 μg·mL−1, and the binding affinity between the drug and the antibody was measured at around 90 ± 21 μg·mL−1. Lastly, the results of the proposed device showed a similar profile in valproic acid drug detection with those of the clinically-used fluorescence polarization immunoassay.

  19. An Evaluation of Peripapillary Retinal Nerve Fiber Layer Thickness in Children With Epilepsy Receiving Treatment of Valproic Acid.

    Science.gov (United States)

    Dereci, Selim; Koca, Tuğba; Akçam, Mustafa; Türkyilmaz, Kemal

    2015-07-01

    We investigated the peripapillary retinal nerve fiber layer thickness with optical coherence tomography in epileptic children receiving valproic acid monotherapy. The study was conducted on children aged 8-16 years who were undergoing valproic acid monotherapy for epilepsy. The study group comprised a total of 40 children who met the inclusion criteria and 40 healthy age- and sex-matched children as a control group. Children with at least a 1-year history of epilepsy and taking 10-40 mg/kg/day treatment were included in the study. Peripapillary retinal nerve fiber layer thickness measurements were performed using Cirrus HD optical coherence tomography. All children and parents were informed about the study and informed consent was obtained from the parents of all the participants. The study group included 21 girls and 19 boys with a mean age of 10.6 ± 2.3 years. According to the results of optical coherence tomography measurements, the mean peripapillary retinal nerve fiber layer thickness was 91.6 ± 9.7 in the patient group and 95.5 ± 7.4 μm in the control group (P epilepsy who were receiving valproic acid monotherapy compared with healthy children. This situation can lead to undesirable results in terms of eye health. New studies are needed to investigate whether these findings are the result of epilepsy or can be attributed to valproic acid and whether there are adverse effects of valproic acid later in life. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. The Effect of Gallic Acid on Histopathologic Evaluation of Cerebellum in Valproic Acid-Induced Autism Animal Models

    Directory of Open Access Journals (Sweden)

    Parvin Samimi

    2016-06-01

    Full Text Available Autism spectrum disorder (ASD is counted as a worldwide public health problem. The possible causes of ASD are reactive oxygen species and free radicals. So, this study is aimed to evaluate the effects of Gallic acid, as an effective antioxidant, on histopathologic disorder of the cerebellum in valproic acid-induced autism animal models. 30 pregnant female rats were randomly divided into 5 groups, including: control, autism (or VAP and experimental 1, 2 and 3. Using a gavage needle, Gallic acid administered orally until about2 months of age. After the end of the treatment period, the rats were anesthetized with ether and their cerebellar tissues were removed for histopathologic studies. A significant decrease in the number of Purkinje and granular cells was observed in this study in VAP group compared to the control group (P≤0.05. A trend toward improvement was observed in the groups received 100 and 200 mg/kg of Gallic acid (P≤0.05. The results of this research revealed that Gallic acid reduces the side effects caused by valproic acid on cerebellar tissue of autistic rats. So, it should be considered for therapeutic goals.

  1. Should Pharmacies Be Included in Medication Reconciliation? A Report of Recurrent Valproic Acid Toxicity

    Directory of Open Access Journals (Sweden)

    B. Tate Cutshall

    2017-03-01

    Full Text Available Including outpatient pharmacies in the medication reconciliation process upon hospital discharge is not commonly performed. This case highlights the consequences of a patient refilling a discontinued prescription for valproic acid (VPA. We present a 32-year old male found unresponsive after ingesting delayed release divalproex sodium. Cerebral edema was visualized on magnetic resonance imaging. Hemodialysis and levo-carnitine treatment led to improved mental status, and VPA was discontinued. The same patient presented with VPA overdose eight months later after he continued to fill an outdated prescription. This case highlights consequences of VPA toxicity; it also demonstrates an opportunity to improve patient safety and high-value care by collaborating with outpatient pharmacies in the medication reconciliation process upon hospital discharge.

  2. A case of mania presenting with hypersexual behavior and gender dysphoria that resolved with valproic acid

    Directory of Open Access Journals (Sweden)

    Michelle R. Heare

    2016-11-01

    Full Text Available Hypersexuality and gender dysphoria have both been described in the literature as symptoms of mania. Hypersexuality is listed in the Diagnostic and Statistical Manual of Mental Disorders 5 as part of the diagnostic criteria for bipolar disorder. Gender dysphoria is less often described and its relation to mania remains unclear. This case report describes a young homosexual man presenting in a manic episode with co-morbid amphetamine abuse whose mania was marked by hypersexuality and the new onset desire to be a woman. Both of these symptoms resolved with the addition of valproic acid to antipsychotics. This case report presents the existing literature on hypersexuality and gender dysphoria in mania and describes a treatment option that has not been previously reported.

  3. Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

    Directory of Open Access Journals (Sweden)

    Berry Juliandi

    2015-12-01

    Full Text Available Prenatal exposure to valproic acid (VPA, an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.

  4. Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid

    DEFF Research Database (Denmark)

    Rinaldi, Tania; Silberberg, Gilad; Markram, Henry

    2008-01-01

    Exposure to valproic acid (VPA) during embryogenesis can cause several teratogenic effects, including developmental delays and in particular autism in humans if exposure occurs during the third week of gestation. We examined the postnatal effects of embryonic exposure to VPA on microcircuit...... properties of juvenile rat neocortex using in vitro electrophysiology. We found that a single prenatal injection of VPA on embryonic day 11.5 causes a significant enhancement of the local recurrent connectivity formed by neocortical pyramidal neurons. The study of the biophysical properties...... of these connections revealed weaker excitatory synaptic responses. A marked decrease of the intrinsic excitability of pyramidal neurons was also observed. Furthermore, we demonstrate a diminished number of putative synaptic contacts in connection between layer 5 pyramidal neurons. Local hyperconnectivity may render...

  5. Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

    Directory of Open Access Journals (Sweden)

    Lee SY

    2015-08-01

    Full Text Available Soo-Yun Lee,1 Wooseong Huh,2 Jin Ah Jung,3 Hye Min Yoo,2 Jae-Wook Ko,1,2 Jung-Ryul Kim2,4 1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 2Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, 3Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, 4Department of Clinical Research and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea Abstract: Valproic acid (VPA is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L. There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI] of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively. Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. Keywords: drug–drug interaction, pharmacokinetics

  6. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatraemia associated with valproic Acid : four case reports from the Netherlands and a case/non-case analysis of vigibase

    NARCIS (Netherlands)

    Beers, Erna; van Puijenbroek, Eugène P; Bartelink, Imke H; van der Linden, Carolien M J; Jansen, Paul A F

    The Netherlands Pharmacovigilance Centre Lareb received four cases of severe symptomatic hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) in association with valproic acid use, in which a causal relationship was suspected. This study describes these cases and gives

  7. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, Jennifer E [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen' s University, Kingston, Ontario, K7L 3N6 (Canada); Raymond, Angela M [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen' s University, Kingston, Ontario, K7L 3N6 (Canada); Winn, Louise M [Department of Pharmacology and Toxicology and School of Environmental Studies, Queen' s University, Kingston, Ontario, K7L 3N6 (Canada)

    2006-03-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-{kappa}B, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-{kappa}B, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P < 0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P < 0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P < 0.05). Folic acid also reduced VPA-induced alterations in p53, NF-{kappa}B, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-{kappa}B, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

  8. Radiochemically pure [1-14C]valproic acid--a mixture of labeled structural isomers

    International Nuclear Information System (INIS)

    Dickinson, R.G.; Wood, B.T.; Kluck, R.M.; Hooper, W.D.

    1986-01-01

    Ongoing studies of the disposition of valproic acid (VPA) and its glucuronide conjugate required the radiolabeled drug for greater sensitivity and tracing of oxidation metabolites. [1- 14 C]VPA hereinafter called LABEL (radiochemical purity greater than 98% as determined by paper and thin layer chromatography) was purchased from Amersham International, U.K. Quantitative analysis of VPA and VPA-glucuronide in bile and urine samples from rats given VPA and tracer LABEL by our standard gas chromatographic assay showed gross discrepancies with the results obtained by liquid scintillation counting of the same extracts. Examination of the purity of LABEL was therefore undertaken. Equilibration of LABEL between various organic-aqueous solvent pairs was identical to that of authentic VPA. However, gas chromatographic-mass spectrometric analysis of the trimethylsilyl derivative of LABEL revealed it to be a mixture of labeled 2-methylheptanoic acid (approximately 60%), 2-ethylhexanoic acid (approximately 30%), and 2-propylpentanoic acid (i.e., VPA, 5-10%). The origin of the isomers of VPA in LABEL was logically traced to the synthetic procedure--coupling of the Grignard reagent of (an isomeric mixture of 2-, 3-, and 4-) chloroheptane(s) with [ 14 C]carbon dioxide. This result highlights the inadequacy of the quality control procedures used and reinforces the necessity for caution in accepting the quoted purity of radiolabeled drugs

  9. Hyper-Connectivity and Hyper-Plasticity in the Medial Prefrontal Cortex in the Valproic Acid Animal Model of Autism

    OpenAIRE

    Rinaldi, Tania; Perrodin, Catherine; Markram, Henry

    2008-01-01

    The prefrontal cortex has been extensively implicated in autism to explain deficits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to significantly more neighbouring neurons than in controls. Th...

  10. Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid

    OpenAIRE

    Servadio, M; Melancia, F; Manduca, A; di Masi, A; Schiavi, S; Cartocci, V; Pallottini, V; Campolongo, P; Ascenzi, P; Trezza, V

    2016-01-01

    Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD. Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basi...

  11. Edaravone ameliorates the adverse effects of valproic acid toxicity in small intestine.

    Science.gov (United States)

    Oktay, S; Alev, B; Tunali, S; Emekli-Alturfan, E; Tunali-Akbay, T; Koc-Ozturk, L; Yanardag, R; Yarat, A

    2015-06-01

    Valproic acid (VPA) is a drug used for the treatment of epilepsy, bipolar psychiatric disorders, and migraine. Previous studies have reported an increased generation of reactive oxygen species and oxidative stress in the toxic mechanism of VPA. Edaravone, a free radical scavenger for clinical use, can quench free radical reaction by trapping a variety of free radical species. In this study, effect of edaravone on some small intestine biochemical parameters in VPA-induced toxicity was investigated. Thirty seven Sprague Dawley female rats were randomly divided into four groups. The groups include control group, edaravone (30 mg(-1) kg(-1) day(-1)) given group, VPA (0.5 g(-1) kg(-1) day(-1)) given group, VPA + edaravone (in same dose) given group. Edaravone and VPA were given intraperitoneally for 7 days. Biochemical parameters such as malondialdehyde, as an index of lipid peroxidation(LPO), sialic acid (SA), glutathione levels and glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, catalase, myeloperoxidase, alkaline phosphatase (ALP), and tissue factor (TF) activities were determined in small intestine samples by colorimetric methods. Decreased small intestine antioxidant enzyme activities, increased LPO and SA levels, and increased activities of ALP and TF were detected in the VPA group. Based on our results edaravone may be suggested to reverse the oxidative stress and inflammation due to VPA-induced small intestine toxicity. © The Author(s) 2014.

  12. Effects of royal jelly on genotoxicity and nephrotoxicity induced by valproic acid in albino mice

    Directory of Open Access Journals (Sweden)

    Sanaa R. Galaly

    2014-03-01

    Full Text Available Epilepsy is one of the most common neurological diseases affecting at least 50 million people worldwide. Valproic acid (VPA is a widely used antiepileptic medication for both generalized and partial seizures of epilepsy. The objective of the study was to investigate the anti-mutagenic and anti-histopathologic effects of royal jelly (RJ on VPA-induced genotoxicity and nephrotoxicity in male albino mice (Mus musculus. 80 Mice were used for 21 days; they were divided into eight groups, (G1 served as normal control group, G2 received VPA (100 mg/kg and (G3–G5 received RJ at doses 50, 100 and 200 mg/kg respectively. While (G6–G8 were administrated RJ simultaneously with VPA. In RJ treated mice at doses of 50 and 100 mg/kg, the kidney sections showed normal histological structure with non significant changes in chromosomal aberrations (CA and mitotic index (MI, while RJ at dose of 200 mg/kg showed mild inflammatory cells infiltration and hyperemic glomeruli but not highly significant changes in CA and MI. The cortex of VPA treated mice revealed congested glomeruli with inflammatory cells infiltration, and marked degeneration of almost structures of the glomeruli including some vacuoles in mesangial cells with dark mesangial substances on the ultrastructure level. Some proximal tubules showed degeneration of microvilli on the apical parts of some cells. Cells of the distal tubules attained obliterated lumen and vacuolated lining epithelium. The results also revealed that valproic acid induced a high frequency of CA in bone marrow cells of mice and MI was significantly decreased indicating bone marrow cytotoxicity. The treatment of mice with RJ at doses 50, 100 and 200 mg/kg for 21 days simultaneously with VPA resulted in abating the histological alterations in renal tissues with significant reduction in chromosomal aberrations, for doses of 50 and 100 mg/kg, and elevation in mitotic index (P < 0.05. RJ at doses 50 and 100 mg/kg appeared

  13. Dasatinib accelerates valproic acid-induced acute myeloid leukemia cell death by regulation of differentiation capacity.

    Directory of Open Access Journals (Sweden)

    Sook-Kyoung Heo

    Full Text Available Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.

  14. Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia.

    Science.gov (United States)

    Main, Stacey L; Kulesza, Randy J

    2017-01-06

    Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Soybean greatly reduces valproic acid plasma concentrations: A food–drug interaction study

    Science.gov (United States)

    Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-01-01

    The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents. PMID:24618639

  16. Soybean greatly reduces valproic acid plasma concentrations: a food-drug interaction study.

    Science.gov (United States)

    Marahatta, Anu; Bhandary, Bidur; Jeong, Seul-Ki; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-03-12

    The aim of this study was to investigate the effects of soy on the pharmacokinetics and pharmacodynamics of valproic acid (VPA). In a preclinical study, rats were pretreated with two different amounts of soy extract for five days (150 mg/kg and 500 mg/kg), which resulted in decreases of 57% and 65% in the Cmax of VPA, respectively. AUC of VPA decreased to 83% and 70% in the soy pretreatment groups. Interestingly, the excretion rate of VPA glucuronide (VPAG) was higher in the soy-fed groups. Levels of UDP-glucuronosyltransferase (UGT) UGT1A3, UGT1A6, UGT2B7 and UGT2B15 were elevated in the soy-treated group, and GABA concentrations were elevated in the brain after VPA administration. However, this was less pronounced in soy extract pretreated group than for the untreated group. This is the first study to report the effects of soy pretreatment on the pharmacokinetics and pharmacodynamics of VPA in rodents.

  17. Ciliary body toxicities of systemic oxcarbazepine and valproic acid treatments: electron microscopic study.

    Science.gov (United States)

    Göktaş, Güleser; Aktaş, Zeynep; Erdoğan, Deniz; Seymen, Cemile Merve; Karaca, Emine Esra; Cansu, Ali; Serdaroğlu, Ayşe; Kaplanoğlu, Gülnur Take

    2015-01-01

    Ciliary body is responsible for humour aqueous production in posterior chamber. Valproic acid (VPA) has been widely used for the treatment of epilepsy and other neuropsychiatric diseases such as bipolar disease and major depression. Oxcarbazepine (OXC) is a new anti-epileptic agent that has been used recently for childhood epilepsies such as VPA. In this study, we aimed to investigate the effects of VPA and OXC treatments used as antiepileptic in ciliary body by electron microscopy. In our study, 40 Wistar rats (21 days old) were divided equally into four groups which were applied saline (group 1), VPA (group 2), OXC (group 3) and VPA + OXC (group 4). The as-prepared ocular tissues were characterized by transmission electron microscopy (TEM) technique in scanning and transmission electron microscopy (SEM-TEM) (Carl Zeiss EVO LS10). The results confirmed that VPA caused dense ciliary body degeneration. Additionally, ciliary body degeneration in group 4 was supposed to be due to VPA treatment. Ciliary body damage and secondary outcomes should be considered in patients with long-term VPA therapy.

  18. Antifibrogenic role of valproic acid in streptozotocin induced diabetic rat penis.

    Science.gov (United States)

    Kutlu, O; Karaguzel, E; Gurgen, S G; Okatan, A E; Kutlu, S; Bayraktar, C; Kazaz, I O; Eren, H

    2016-05-01

    We investigated the therapeutic effects of valproic acid (VPA) on erectile dysfunction and reducing penile fibrosis in streptozocin (STZ)-induced diabetic rats. Eighteen male rats were divided into three experimental groups (Control, STZ-DM, STZ-DM plus VPA) and diabetes was induced by transperitoneal single dose STZ. Eight weeks after, VPA and placebo treatments were given according to groups for 15 days. All rats were anesthetised for the measurement of in vivo erectile response to cavernous nerve stimulation. Afterward penes were evaluated histologically in terms of immune labelling scores of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1). Slides were also evaluated in terms of collagen/smooth muscle ratio and penile apoptosis. After the treatment with VPA, erectile responses were found as improved when compared with STZ-DM rats but not statistically meaningful. eNOS and VEGF immune expressions diminished in penile corpora of STZ-DM rats and improved with VPA treatment. VPA led to decrease in TGF-β1 expression and collagen content of diabetic rats' penes. Penile apoptosis was not diminished with VPA. In conclusion, VPA treatment seems to be effective for reducing penile fibrosis in diabetic rats and more prolonged treatment period may enhance erectile functions. © 2015 Blackwell Verlag GmbH.

  19. Valproic acid improves the tolerance for the stress in learned helplessness rats.

    Science.gov (United States)

    Kobayashi, H; Iwata, M; Mitani, H; Yamada, T; Nakagome, K; Kaneko, K

    2012-04-01

    In this study, we investigated whether previously stressed rats with learned helplessness (LH) paradigm could recover from depressive-like behavior four weeks after the exposure, and also whether chronic treatment with valproic acid (VPA) could prevent behavioral despair due to the second stress on days 54 in these animals. Four weeks after induction of LH, we confirmed behavioral remission in the previously stressed rats. Two-way analysis of variance (ANOVA) performed with two factors, pretreatment (LH or Control) and drug (VPA or Saline), revealed a significant main effect of the drug on immobility time in forced swimming test. Post hoc test showed a shorter immobility time in the LH+VPA group than in the LH+Saline group. Immunohistochemical study of synapsin I showed a significant effect of drug by pretreatment interaction on immunoreactivity of synapsin I in the hippocampus: its expression levels in the regions were higher in the LH+VPA group than in the LH+Saline group. These results suggest that VPA could prevent the reappearance of stress-induced depressive-like behaviors in the rats recovering from prior stress, and that the drug-induced presynaptic changes in the expression of synapsin I in the hippocampus of LH animals might be related to improved tolerance toward the stress. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  20. Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.

    Science.gov (United States)

    Kim, Ji-Woon; Seung, Hana; Kim, Ki Chan; Gonzales, Edson Luck T; Oh, Hyun Ah; Yang, Sung Min; Ko, Mee Jung; Han, Seol-Heui; Banerjee, Sourav; Shin, Chan Young

    2017-02-01

    Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. pH-Dependant Antifungal Activity of Valproic Acid against the Human Fungal Pathogen Candida albicans

    Directory of Open Access Journals (Sweden)

    Julien Chaillot

    2017-10-01

    Full Text Available Current antifungal drugs suffer from limitations including toxicity, the emergence of resistance and decreased efficacy at low pH that are typical of human vaginal surfaces. Here, we have shown that the antipsychotic drug valproic acid (VPA exhibited a strong antifungal activity against both sensitive and resistant Candida albicans in pH condition similar to that encountered in vagina. VPA exerted a strong anti-biofilm activity and attenuated damage of vaginal epithelial cells caused by C. albicans. We also showed that VPA synergizes with the allylamine antifungal, Terbinafine. We undertook a chemogenetic screen to delineate biological processes that underlies VPA-sensitivity in C. albicans and found that vacuole-related genes were required to tolerate VPA. Confocal fluorescence live-cell imaging revealed that VPA alters vacuole integrity and support a model where alteration of vacuoles contributes to the antifungal activity. Taken together, this study suggests that VPA could be used as an effective antifungal against vulvovaginal candidiasis.

  2. Enhanced long term microcircuit plasticity in the valproic acid animal model of autism

    Directory of Open Access Journals (Sweden)

    Guilherme T Silva

    2009-06-01

    Full Text Available A single intra-peritoneal injection of valproic acid (VPA on embryonic day (ED 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a mini-column (<50μm. In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer V pyramidal cells in somatosensory cortex brain slices (PN 12-15, mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

  3. Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism.

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    Silva, Guilherme Testa; Le Bé, Jean-Vincent; Riachi, Imad; Rinaldi, Tania; Markram, Kamila; Markram, Henry

    2009-01-01

    A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (brain slices (PN 12-15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

  4. Serum Leptin Levels in Epileptic Patients Treated with Topiramate and Valproic Acid

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    İrem Fatma Uludağ

    2011-03-01

    Full Text Available OBJECTIVE: Leptin is considered to be a signal factor that regulates body weight and energy expenditure, and there is a strong correlation between serum leptin concentrations, body mass index, and body fat mass in humans. Our aim in this study was to evaluate the role of leptin in valproic acid (VPA and topiramate (TPM related weight changes in epileptic patients. METHODS: Body mass index is calculated and serum leptin and insulin levels are measured in 56 patients with epilepsy (40 patients taking VPA and 16 patients taking VPA and TPM and in 40 healty control subjects. RESULTS: Obesity was seen in 21 patients (52.5% in VPA treated group, in 15 patients (37.5% in the control group and in only one male (6.3% in VPA and TPM treated group. Body mass index was lower in the group treated with VPA and TPM (p<0.001. Serum leptin concentrations were correlated with the body mass index (r=0.49, p<0.001 and were significantly higher in obese subjects (p<0.001 and in women (p<0.001. Serum leptin levels were significantly lower in patients treated with VPA and TPM (p<0.05. CONCLUSION: High levels of serum leptin in patients taking VPA and significantly low levels of serum leptin in patients taking VPA and TPM in our study are in agreement with the hypotheses that weight changes induced with VPA and TPM are related with the alterations in serum leptin levels

  5. Serum Leptin Levels in Epileptic Patients Treated with Topiramate and Valproic Acid

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    İrem Fatma Uludağ

    2011-03-01

    Full Text Available OBJECTIVE: Leptin is considered to be a signal factor that regulates body weight and energy expenditure, and there is a strong correlation between serum leptin concentrations, body mass index, and body fat mass in humans. Our aim in this study was to evaluate the role of leptin in valproic acid (VPA and topiramate (TPM related weight changes in epileptic patients. METHODS: Body mass index is calculated and serum leptin and insulin levels are measured in 56 patients with epilepsy (40 patients taking VPA and 16 patients taking VPA and TPM and in 40 healty control subjects. RESULTS: Obesity was seen in 21 patients (52.5% in VPA treated group, in 15 patients (37.5% in the control group and in only one male (6.3% in VPA and TPM treated group. Body mass index was lower in the group treated with VPA and TPM (p<0.001. Serum leptin concentrations were correlated with the body mass index (r=0.49, p<0.001 and were significantly higher in obese subjects (p<0.001 and in women (p<0.001. Serum leptin levels were significantly lower in patients treated with VPA and TPM (p<0.05. CONCLUSION: High levels of serum leptin in patients taking VPA and significantly low levels of serum leptin in patients taking VPA and TPM in our study are in agreement with the hypotheses that weight changes induced with VPA and TPM are related with the alterations in serum leptin levels.

  6. Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors.

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    Griggs, Chanel A; Malm, Scott W; Jaime-Frias, Rosa; Smith, Catharine L

    2018-01-15

    Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop. In cells with an unsynchronized clock, VPA simultaneously upregulated the expression of genes encoding core circadian transcription factors that regulate the positive and negative limbs of the feedback loop. Using low dose glucocorticoid, we synchronized cultured fibroblast cells to a circadian oscillatory pattern. Whether VPA was added at the time of synchronization or 12h later at CT12, we found that VPA disrupted the oscillatory expression of multiple genes encoding essential transcription factors that regulate circadian rhythm. Therefore, we conclude that VPA has a potent effect on the circadian rhythm transcription-translation feedback loop that may be linked to negative VPA side effects in humans. Furthermore, our study suggests potential chronopharmacology implications of VPA usage. Copyright © 2017. Published by Elsevier Inc.

  7. Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid.

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    Juliandi, Berry; Abematsu, Masahiko; Sanosaka, Tsukasa; Tsujimura, Keita; Smith, Austin; Nakashima, Kinichi

    2012-01-01

    Within the developing mammalian cortex, neural progenitors first generate deep-layer neurons and subsequently more superficial-layer neurons, in an inside-out manner. It has been reported recently that mouse embryonic stem cells (mESCs) can, to some extent, recapitulate cortical development in vitro, with the sequential appearance of neurogenesis markers resembling that in the developing cortex. However, mESCs can only recapitulate early corticogenesis; superficial-layer neurons, which are normally produced in later developmental periods in vivo, are under-represented. This failure of mESCs to reproduce later corticogenesis in vitro implies the existence of crucial factor(s) that are absent or uninduced in existing culture systems. Here we show that mESCs can give rise to superficial-layer neurons efficiently when treated with valproic acid (VPA), a histone deacetylase inhibitor. VPA treatment increased the production of Cux1-positive superficial-layer neurons, and decreased that of Ctip2-positive deep-layer neurons. These results shed new light on the mechanisms of later corticogenesis. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  8. Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

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    Debeb, Bisrat G.; Xu Wei; Mok, Henry; Li Li; Robertson, Fredika; Ueno, Naoto T.; Reuben, Jim; Lucci, Anthony; Cristofanilli, Massimo; Woodward, Wendy A.

    2010-01-01

    Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.

  9. Valproic acid induces cutaneous wound healing in vivo and enhances keratinocyte motility.

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    Soung-Hoon Lee

    Full Text Available BACKGROUND: Cutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK signaling pathways. Valproic acid (VPA is a commonly used antiepileptic drug that acts on these signaling pathways; however, the effect of VPA on cutaneous wound healing is unknown. METHODS AND FINDINGS: We created full-thickness wounds on the backs of C3H mice and then applied VPA. After 7 d, we observed marked healing and reduced wound size in VPA-treated mice. In the neo-epidermis of the wounds, β-catenin and markers for keratinocyte terminal differentiation were increased after VPA treatment. In addition, α-smooth muscle actin (α-SMA, collagen I and collagen III in the wounds were significantly increased. VPA induced proliferation and suppressed apoptosis of cells in the wounds, as determined by Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining analyses, respectively. In vitro, VPA enhanced the motility of HaCaT keratinocytes by activating Wnt/β-catenin, ERK and phosphatidylinositol 3-kinase (PI3-kinase/Akt signaling pathways. CONCLUSIONS: VPA enhances cutaneous wound healing in a murine model and induces migration of HaCaT keratinocytes.

  10. Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression

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    Byler Timothy K

    2012-08-01

    Full Text Available Abstract Background Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein. Methods Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR. Results Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate. Conclusions Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.

  11. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.

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    Orr, J M; Abbott, F S; Farrell, K; Ferguson, S; Sheppard, I; Godolphin, W

    1982-05-01

    In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.

  12. A rapid and simple procedure for monitoring valproic acid by gas chromatography

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    Mohamed Said Mostafa

    2018-02-01

    Full Text Available Valproic acid (VPA, a widely used antiepileptic drug, has a narrow therapeutic range of 50-100 μg/mL and shows large individual variability. It is very important to monitor the trough VPA concentration using a reliable method. The aim of this study was to develop and validate a rapid gas chromatographic (GC technique for VPA quantification in human plasma and to compare it with the traditional immunoassay method. VPA extraction from human serum was efficient by dichloromethane and hydrochloric acid using octanoic acid as an internal standard. GC analysis was performed using a gas-chromatograph equipped with a flame ionization detector (GC/FID. VPA detection and quantification were accomplished isothermally at 135°C on a Gs-BP 100% dimethylpolysiloxane capillary column (10 m×0.53 mm ID, 2.65 μm film thickness, Supelco, Bellefonte, PA. Injection port and detector temperature were 280°C. Retention times of VPA and internal standard were 1.83 min and 2.33 min, respectively. The calibration curve was linear over the concentration range of 5-320 μg/mL, with a lower limit of detection of 1.25 μg/mL. The internal and inter-day precision was less than 5.3% and 6.1%, respectively, and the accuracy was below 2.8%. VPA recovery was 94.6%. A quick and accurate method for VPA determination in human plasma was developed and validated. It resulted sufficiently selective and sensitive.

  13. Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver

    International Nuclear Information System (INIS)

    Lee, Min-Ho; Kim, Mingoo; Lee, Byung-Hoon; Kim, Ju-Han; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-Il; Chung, Heekyoung; Kong, Gu; Lee, Mi-Ock

    2008-01-01

    Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P 1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid β-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity

  14. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

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    Maria Graziella Catalano

    2016-01-01

    Full Text Available Anaplastic thyroid cancer (ATC has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly and valproic acid (1,000 mg/day; the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11.

  15. Valproic acid prevents retinal degeneration in a murine model of normal tension glaucoma.

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    Kimura, Atsuko; Guo, Xiaoli; Noro, Takahiko; Harada, Chikako; Tanaka, Kohichi; Namekata, Kazuhiko; Harada, Takayuki

    2015-02-19

    Valproic acid (VPA) is widely used for treatment of epilepsy, mood disorders, migraines and neuropathic pain. It exerts its therapeutic benefits through modulation of multiple mechanisms including regulation of gamma-aminobutyric acid and glutamate neurotransmissions, activation of pro-survival protein kinases and inhibition of histone deacetylase. The evidence for neuroprotective properties associated with VPA is emerging. Herein, we investigated the therapeutic potential of VPA in a mouse model of normal tension glaucoma (NTG). Mice with glutamate/aspartate transporter gene deletion (GLAST KO mice) demonstrate progressive retinal ganglion cell (RGC) loss and optic nerve degeneration without elevated intraocular pressure, and exhibit glaucomatous pathology including glutamate neurotoxicity and oxidative stress in the retina. VPA (300mg/kg) or vehicle (PBS) was administered via intraperitoneal injection in GLAST KO mice daily for 2 weeks from the age of 3 weeks, which coincides with the onset of glaucomatous retinal degeneration. Following completion of the treatment period, the vehicle-treated GLAST KO mouse retina showed significant RGC death. Meanwhile, VPA treatment prevented RGC death and thinning of the inner retinal layer in GLAST KO mice. In addition, in vivo electrophysiological analyses demonstrated that visual impairment observed in vehicle-treated GLAST KO mice was ameliorated with VPA treatment, clearly establishing that VPA beneficially affects both histological and functional aspects of the glaucomatous retina. We found that VPA reduces oxidative stress induced in the GLAST KO retina and stimulates the cell survival signalling pathway associated with extracellular-signal-regulated kinases (ERK). This is the first study to report the neuroprotective effects of VPA in an animal model of NTG. Our findings raise intriguing possibilities that the widely prescribed drug VPA may be a novel candidate for treatment of glaucoma. Copyright © 2015 Elsevier

  16. Fluoxetine prevents the memory deficits and reduction in hippocampal cell proliferation caused by valproic acid.

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    Welbat, Jariya Umka; Sangrich, Preeyanuch; Sirichoat, Apiwat; Chaisawang, Pornthip; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanun; Wigmore, Peter

    2016-12-01

    Valproic acid (VPA), a commonly used antiepileptic drug, has been reported to cause cognitive impairments in patients. In a previous study, using a rodent model, we showed that VPA treatment impaired cognition which was associated with a reduction in the cell proliferation required for hippocampal neurogenesis. The antidepressant fluoxetine has been shown to increase hippocampal neurogenesis and to reverse the memory deficits found in a number of pathological conditions. In the present study we investigated the protective effects of fluoxetine treatment against the impairments in memory and hippocampal cell proliferation produced by VPA. Male Sprague Dawley rats received daily treatment with fluoxetine (10mg/kg) by oral gavage for 21days. Some rats were co-administered with VPA (300mg/kg, twice daily i.p. injections) for 14days from day 8 to day 21 of the fluoxetine treatment. Spatial memory was tested using the novel object location (NOL) test. The number of proliferating cells present in the sub granular zone of the dentate gyrus was quantified using Ki67 immunohistochemistry at the end of the experiment. Levels of the receptor Notch1, the neurotrophic factor BDNF and the neural differentiation marker DCX were determined by Western blotting. VPA-treated rats showed memory deficits, a decrease in the number of proliferating cells in the sub granular zone and decreases in the levels of Notch1 and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notch1 and BDNF were prevented in animals which had received both VPA and fluoxetine. Rats receiving fluoxetine alone did not show a significant difference in the number of proliferating cells or behavior compared to controls. These results demonstrated that the spatial memory deficits and reduction of cell proliferation produced by VPA can be ameliorated by the simultaneous administration of the antidepressant fluoxetine. Crown Copyright © 2016. Published by Elsevier B

  17. Teratology study of derivatives of tetramethylcyclopropyl amide analogues of valproic acid in mice.

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    Okada, Akinobu; Onishi, Yuko; Aoki, Yoshinobu; Yagen, Boris; Sobol, Eyal; Bialer, Meir; Fujiwara, Michio

    2006-06-01

    Although valproic acid (VPA) is used extensively for treating various kinds of epilepsies, it is well known that it causes neural tube and skeletal defects in both humans and animals. The amide and urea derivatives of the tetramethylcylcopropyl VPA analogue, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (N-methoxy-TMCD) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMC-urea), were synthesized and shown to have a more potent anticonvulsant activity than VPA. The objective of this study was to investigate the teratogenic effects of these compounds in NMRI mice. Pregnant NMRI mice were given a single subcutaneous injection of either VPA, N-methoxy-TMCD, or TMC-urea at 1.8 and 3.6 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18. First, the live fetuses were examined to detect any external malformations, then their skeletons were double-stained for bone and cartilage and subsequently examined. Significant increases in fetal losses and neural tube defects were observed with administration of VPA at 3.6 mmol/kg when compared to the vehicle control. In contrast, upon cesarean section, there were no significant differences between either N-methoxy-TMCD or TMC-urea and the control groups for any parameter. Skeletal examination revealed that a number of the abnormalities were induced by VPA dose-dependently at high rates of incidence. These abnormalities were mainly at the axial skeletal level. However, lower frequencies of skeletal abnormality were observed with N-methoxy-TMCD and TMC-urea than with VPA. In addition to their more potent antiepileptic activity, these findings clearly indicate that N-methoxy-TMCD and TMC-urea are distinctly less teratogenic than VPA in NMRI mice.

  18. Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats.

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    Chu, Weihua; Yuan, Jichao; Huang, Lei; Xiang, Xin; Zhu, Haitao; Chen, Fei; Chen, Yanyan; Lin, Jiangkai; Feng, Hua

    2015-07-01

    Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.

  19. Development to term of cloned cattle derived from donor cells treated with valproic acid.

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    Juliano Rodrigues Sangalli

    Full Text Available Cloning of mammals by somatic cell nuclear transfer (SCNT is still plagued by low efficiency. The epigenetic modifications established during cellular differentiation are a major factor determining this low efficiency as they act as epigenetic barriers restricting reprogramming of somatic nuclei. In this regard, most factors that promote chromatin decondensation, including histone deacetylase inhibitors (HDACis, have been found to increase nuclear reprogramming efficiency, making their use common to improve SCNT rates. Herein we used valproic acid (VPA in SCNT to test whether the treatment of nuclear donor cells with this HDACi improves pre- and post-implantation development of cloned cattle. We found that the treatment of fibroblasts with VPA increased histone acetylation without affecting DNA methylation. Moreover, the treatment with VPA resulted in increased expression of IGF2R and PPARGC1A, but not of POU5F1. However, when treated cells were used as nuclear donors no difference of histone acetylation was found after oocyte reconstruction compared to the use of untreated cells. Moreover, shortly after artificial activation the histone acetylation levels were decreased in the embryos produced with VPA-treated cells. With respect to developmental rates, the use of treated cells as donors resulted in no difference during pre- and post-implantation development. In total, five clones developed to term; three produced with untreated cells and two with VPA-treated cells. Among the calves from treated group, one stillborn calf was delivered at day 270 of gestation whereas the other one was delivered at term but died shortly after birth. Among the calves from the control group, one died seven days after birth whereas the other two are still alive and healthy. Altogether, these results show that in spite of the alterations in fibroblasts resulting from the treatment with VPA, their use as donor cells in SCNT did not improve pre- and post

  20. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

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    Barker, Christopher A., E-mail: barkerc@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Bishop, Andrew J.; Chang, Maria; Beal, Kathryn; Chan, Timothy A. [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-07-01

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.

  1. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

    International Nuclear Information System (INIS)

    Barker, Christopher A.; Bishop, Andrew J.; Chang, Maria; Beal, Kathryn; Chan, Timothy A.

    2013-01-01

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted

  2. Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero

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    Anwesha eBanerjee

    2014-11-01

    Full Text Available Autism Spectrum Disorders (ASD are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning. We therefore sought to further examine anxiety and emotional learning in an environmentally induced animal model of ASD that utilizes the administration of the known teratogen, valproic acid (VPA during gestation. Specifically we exposed dams to one of two different doses of VPA (500 and 600 mg/kg or vehicle on day 12.5 of gestation and examined the resultant progeny. Our data indicate that animals exposed to VPA in utero exhibit enhanced anxiety in the open field test and normal object recognition memory compared to control animals. Animals exposed to 500 mg/kg of VPA displayed normal acquisition of auditory fear conditioning, and exhibited reduced extinction of fear memory and normal litter survival rates as compared to control animals. We observed that animals exposed to 600 mg/kg of VPA exhibited a significant reduction in the acquisition of fear conditioning, a significant reduction in social interaction and a significant reduction in litter survival rates as compared to control animals. VPA (600 mg/kg exposed animals exhibited similar shock sensitivity and hearing as compared to control animals indicating the fear conditioning deficit observed in these animals was not likely due to sensory deficits, but rather due to deficits in learning or memory retrieval. In conclusion, considering that progeny from dams exposed to rather similar doses of VPA exhibit striking differences in emotional learning, the VPA model may serve as a useful tool to explore the molecular and cellular mechanisms that contribute to not only ASD, but also emotional learning.

  3. Environmental enrichment attenuates behavioral abnormalities in valproic acid-exposed autism model mice.

    Science.gov (United States)

    Yamaguchi, Hiroshi; Hara, Yuta; Ago, Yukio; Takano, Erika; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2017-08-30

    We recently demonstrated that prenatal exposure to valproic acid (VPA) at embryonic day 12.5 causes autism spectrum disorder (ASD)-like phenotypes such as hypolocomotion, anxiety-like behavior, social deficits and cognitive impairment in mice and that it decreases dendritic spine density in the hippocampal CA1 region. Previous studies show that some abnormal behaviors are improved by environmental enrichment in ASD rodent models, but it is not known whether environmental enrichment improves cognitive impairment. In the present study, we examined the effects of early environmental enrichment on behavioral abnormalities and neuromorphological changes in prenatal VPA-treated mice. We also examined the role of dendritic spine formation and synaptic protein expression in the hippocampus. Mice were housed for 4 weeks from 4 weeks of age under either a standard or enriched environment. Enriched housing was found to increase hippocampal brain-derived neurotrophic factor mRNA levels in both control and VPA-exposed mice. Furthermore, in VPA-treated mice, the environmental enrichment improved anxiety-like behavior, social deficits and cognitive impairment, but not hypolocomotion. Prenatal VPA treatment caused loss of dendritic spines in the hippocampal CA1 region and decreases in mRNA levels of postsynaptic density protein-95 and SH3 and multiple ankyrin repeat domains 2 in the hippocampus. These hippocampal changes were improved by the enriched housing. These findings suggest that the environmental enrichment improved most ASD-like behaviors including cognitive impairment in the VPA-treated mice by enhancing dendritic spine function. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma.

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    Mascaro-Cordeiro, Bruna; Oliveira, Indhira Dias; Tesser-Gamba, Francine; Pavon, Lorena Favaro; Saba-Silva, Nasjla; Cavalheiro, Sergio; Dastoli, Patrícia; Toledo, Silvia Regina Caminada

    2018-05-22

    Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines. Dose-response curve determined IC 50 values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes. The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation. MB tumors belonging to SHH molecular subgroup, with TP53 MUT , would be the ones that present high risk in relation to VA use during the treatment, while TP53 WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.

  5. Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally.

    Science.gov (United States)

    Barrett, Catherine E; Hennessey, Thomas M; Gordon, Katelyn M; Ryan, Steve J; McNair, Morgan L; Ressler, Kerry J; Rainnie, Donald G

    2017-01-01

    The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.

  6. Valproic acid potentiates curcumin-mediated neuroprotection in Lipopolysaccharide induced rats

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    Amira eZaky

    2014-10-01

    Full Text Available The etiology of neuroinflammation is complex and comprises multifactorial, involving both genetic and environmental factors during which diverse genetic and epigenetic modulations are implicated. Curcumin (Cur, and valproic acid (VPA, histone deacetylase 1 inhibitor, have neuroprotective effects. The present study was designed with an aim to investigate the ability of co-treatment of both compounds (Cur or VPA (200mg/kg for four weeks to augment neuroprotection and enhance brain recovery from intra-peritoneal (IP injection of (250 µg/kg lipopolysaccharide (LPS-stimulated neuroinflammatory condition on rat brain cortex. Cortex activation and the effects of combined treatment and production of proinflammatory mediators, COX-2, APE1 and nitric oxide/iNOS were investigated. Neuroinflammation development was assessed by histological analyses and by investigating associated indices (BACE1, APP, PSEN-1 and PSEN-2. Furthermore we measured the expression profile of let-7 miRNAs members a, b, c, e and f in all groups, a highly abundant regulator of gene expression in the CNS. Protein and mRNA levels of neuroinflammation markers COX-2, BACE1, APP and iNOS were also attenuated by combined therapy. On the other hand, assessment of the indicated five let-7 members, showed distinct expression profile pattern in the different groups. Let-7 a, b and c disappeared in the induced group, an effect that was partially suppressed by co-addition of either Cur or VPA. These data suggest that the combined treatment induced significantly the expression of the five members when compared to rats treated with Cur or VPA only as well as to self-recovery group, which indicates a possible benefit from the synergistic effect of Cur-VPA combination as therapeutic agents for neuroinflammation and its associated disorders. The mechanism elucidated here highlights the particular drug-induced expression profile of let-7 family as new targets for future pharmacological development.

  7. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1: An in Silico Approach

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    Mohamed A. Abdallah Elbadawi

    2015-02-01

    Full Text Available A new Plasmodium falciparum histone deacetylase1 (PfHDAC1 homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.

  8. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid

    DEFF Research Database (Denmark)

    Rinaldi, Tania; Kulangara, Karina; Antoniello, Katia

    2007-01-01

    as the commonly linked kinase calcium/calmodulin-dependent protein kinase II. Synaptic plasticity experiments between pairs of pyramidal neurons revealed an augmented postsynaptic form of long-term potentiation. These results indicate that VPA significantly enhances NMDA receptor-mediated transmission and causes......Valproic acid (VPA) is a powerful teratogen causing birth defects in humans, including autism spectrum disorder (ASD), if exposure occurs during the first trimester of embryogenesis. Learning and memory alterations are common symptoms of ASD, but underlying molecular and synaptic alterations remain...

  9. In vivo effects of naproxen, salicylic acid, and valproic acid on the pharmacokinetics of trichloroethylene and metabolites in rats.

    Science.gov (United States)

    Rouhou, Mouna Cheikh; Charest-Tardif, Ginette; Haddad, Sami

    2015-01-01

    It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure.

  10. Association between the blood concentrations of ammonia and carnitine/amino acid of schizophrenic patients treated with valproic acid.

    Science.gov (United States)

    Ando, Masazumi; Amayasu, Hideaki; Itai, Takahiro; Yoshida, Hisahiro

    2017-01-01

    Administration of valproic acid (VPA) is complicated with approximately 0.9% of patients developing hyperammonemia, but the pathogenesis of this adverse effect remains to be clarified. The aim of the present study was to search for mechanisms associated with VPA-induced hyperammonemia in the light of changes in serum amino acids concentrations associated with the urea cycle of schizophrenic patients. Blood samples (10 mL) were obtained from 37 schizophrenic patients receiving VPA for the prevention of violent behaviors in the morning after overnight fast. Blood concentrations of ammonia, VPA, free carnitine, acyl-carnitine, and 40 amino acids including glutamate and citrulline were measured for each patient. Univariate and multivariate regression analyses were performed to identify amino acids or concomitantly administered drugs that were associated with variability in the blood concentrations of ammonia. The blood ammonia level was positively correlated with the serum glutamate concentration ( r  = 0.44, p  < 0.01) but negatively correlated with glutamine ( r  = -0.41, p  = 0.01), citrulline ( r  = -0.42, p  = 0.01), and glycine concentrations ( r  = -0.54, p  < 0.01). It was also revealed that the concomitant administration of the mood stabilizers ( p  = 0.04) risperidone ( p  = 0.03) and blonanserin ( p  < 0.01) was positively associated with the elevation of the blood ammonia level. We hypothisized that VPA would elevate the blood ammonia level of schizophrenic patients. The observed changes in serum amino acids are compatible with urea cycle dysfunction, possibly due to reduced carbamoyl-phosphate synthase 1 (CPS1) activity. We conclude that VPA should be prudently prescribed to schizophrenic patients, particularly those receiving mood stabilizers or certain antipsychotics.

  11. All guns blazing: management and survival of massive valproic acid overdose – case report and literature review

    Directory of Open Access Journals (Sweden)

    Al Jawder S

    2018-01-01

    Full Text Available Shaikha Al Jawder,1 Eiman AlJishi,2 Shaikhah Al-Otaibi,2 Mohammed S Al-Shahrani3 1King Hamad University Hospital, Busaiteen, Bahrain; 2Emergency Medicine Department, 3Emergency and Critical Care Department, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Abstract: A 51-year-old woman, who intentionally ingested a massive dose of ~60 g of valproic acid which she was using as a mood stabilizer for bipolar affective disorder, presented within 30 minutes of ingestion to the emergency department. The patient was asymptomatic and was immediately started on decontamination therapy with activated charcoal (AC. Drug serum levels, liver functions, and ammonia levels were tested and followed up during treatment. Due to the massive ingestion and continuous rise in serum drug levels, the patient received regular multiple doses of AC, as well as l-carnitine for liver protection. The patient was started on extracorporeal therapy in the form of renal replacement therapy in the intensive care unit (ICU, followed by intermittent hemodialysis. Drug serum levels dropped significantly. Ammonia levels showed improvement with treatment. The patient was discharged from the ICU after 14 days of treatment. She was stable and in good condition with no residual hepatic or central nervous system (CNS manifestations. Keywords: valproic acid, multiple dose activated charcoal, l-carnitine, hemodialysis

  12. Increasing pro-survival factors within whole brain tissue of Sprague Dawley rats via intracerebral administration of modified valproic acid

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    Ryan C. Bates

    2015-08-01

    Full Text Available Neural tissue exposure to valproic acid (VPA increases several pro-survival phospho-proteins that can be used as biomarkers for indicating a beneficial drug response (pAktSer473, pGSK3βSer9, pErk1/2Thr202/Tyr204. Unfortunately, targeting VPA to neural tissue is a problem due to severe asymmetrical distribution, wherein the drug tends to remain in peripheral blood rather than localizing within the brain. Intracerebral delivery of an amide-linked VPA–PEG conjugate could address these issues by enhancing retention and promoting cerebro-global increases in pro-survival phospho-proteins. It is necessary to assay for the retained bioactivity of a PEGylated valproic acid molecule, along with locating an intracranial cannula placement that optimizes the increase of a known downstream biomarker for chronic VPA exposure. Here we show an acute injection of VPA–PEG conjugate within brain tissue increased virtually all of the assayed phospho-proteins, including well-known pro-survival factors. In contrast, an acute injection of VPA expectedly decreased signaling throughout the hour. Needle penetration into whole brain tissue is the intentional cause of trauma in this procedure. The trauma to brain tissue was observed to overcome known phospho-protein increases for unmodified VPA in the injected solution, while VPA–PEG conjugate appeared to induce significant increases in pro-survival phospho-proteins, despite the procedural trauma.

  13. Phase II open label study of valproic acid in spinal muscular atrophy.

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    Kathryn J Swoboda

    Full Text Available Preliminary in vitro and in vivo studies with valproic acid (VPA in cell lines and patients with spinal muscular atrophy (SMA demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS, electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP amplitudes and motor unit number estimation (MUNE, body composition and bone density via dual-energy X-ray absorptiometry (DEXA, and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

  14. Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup.

    Science.gov (United States)

    Ghannoum, Marc; Laliberté, Martin; Nolin, Thomas D; MacTier, Robert; Lavergne, Valery; Hoffman, Robert S; Gosselin, Sophie

    2015-06-01

    The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup presents its systematic review and clinical recommendations on the use of extracorporeal treatment (ECTR) in valproic acid (VPA) poisoning. The lead authors reviewed all of the articles from a systematic literature search, extracted the data, summarized the key findings, and proposed structured voting statements following a predetermined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Anonymous votes were compiled, returned, and discussed in person. A second vote was conducted to determine the final workgroup recommendations. The latest literature search conducted in November 2014 retrieved a total of 79 articles for final qualitative analysis, including one observational study, one uncontrolled cohort study with aggregate analysis, 70 case reports and case series, and 7 pharmacokinetic studies, yielding a very low quality of evidence for all recommendations. Clinical data were reported for 82 overdose patients while pharmaco/toxicokinetic grading was performed in 55 patients. The workgroup concluded that VPA is moderately dialyzable (level of evidence = B) and made the following recommendations: ECTR is recommended in severe VPA poisoning (1D); recommendations for ECTR include a VPA concentration > 1300 mg/L (9000 μmol/L)(1D), the presence of cerebral edema (1D) or shock (1D); suggestions for ECTR include a VPA concentration > 900 mg/L (6250 μmol/L)(2D), coma or respiratory depression requiring mechanical ventilation (2D), acute hyperammonemia (2D), or pH ≤ 7.10 (2D). Cessation of ECTR is indicated when clinical improvement is apparent (1D) or the serum VPA concentration is between 50 and 100 mg/L (350-700 μmol/L)(2D). Intermittent hemodialysis is the preferred ECTR in VPA poisoning (1D). If hemodialysis is not available, then intermittent hemoperfusion (1D) or continuous

  15. Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism

    DEFF Research Database (Denmark)

    Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen

    2014-01-01

    The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 day...

  16. New insights into the molecular and epigenetic effects of antitumor Pt(IV)-valproic acid conjugates in human ovarian cancer cells

    Czech Academy of Sciences Publication Activity Database

    Novohradský, Vojtěch; Zerzánková, Lenka; Štěpánková, Jana; Vrána, Oldřich; Raveendran, R.; Gibson, D.; Kašpárková, Jana; Brabec, Viktor

    2015-01-01

    Roč. 95, č. 3 (2015), s. 133-144 ISSN 0006-2952 R&D Projects: GA ČR(CZ) GA14-21053S; GA MŠk(CZ) LD14019 Institutional support: RVO:68081707 Keywords : HISTONE DEACETYLASE INHIBITORS * MALIGNANT PLEURAL MESOTHELIOMA * VALPROIC ACID Subject RIV: BO - Biophysics Impact factor: 5.091, year: 2015

  17. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

  18. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate: Evidence in Humans and Experimental Models

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    Noemí Cárdenas-Rodríguez

    2013-01-01

    Full Text Available It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity. This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS activation and the generation of reactive oxygen species (ROS. Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA, oxcarbazepine (OXC, and topiramate (TPM modulate oxidative stress.

  19. Comparison of clinical, magnetic resonance and evoked potentials data in a case of valproic-acid-related hyperammonemic coma

    International Nuclear Information System (INIS)

    Hantson, Philippe; Grandin, Cecile; Duprez, Thierry; Nassogne, Marie-Cecile; Guerit, Jean-Michel

    2005-01-01

    Magnetic resonance (MR) multimodality evoked potentials (MEPs) and clinical findings were correlated in a 47-year-old epileptic man in whom parenteral valproic acid (VPA) therapy induced severe comatose hyperammonemic encephalopathy without biological signs of hepatotoxicity (or hepatocytic dysfunction). Although the plasma VPA level remained within a normal therapeutic range, the ammoniemia increased to a toxic peak level at 411 μmol/l 24 h after symptom onset, requiring VPA therapy discontinuation. Brain MR monitoring demonstrated early cytotoxic edema evolving into delayed vasogenic edema and final brain atrophy. Concomitantly to abnormalities within the brainstem on MR images, an increase in brainstem conduction at MEPs and clinical disturbance of brainstem reflexes were observed at the initial phase of the disease course. Later, the resolution of the MR and MEPs abnormalities paralleled the clinical recovery of the reflexes. (orig.)

  20. Role of SMAD4 in the mechanism of valproic acid's inhibitory effect on prostate cancer cell invasiveness.

    Science.gov (United States)

    Jiang, Wei; Zheng, Yi; Huang, Zhongxian; Wang, Muwen; Zhang, Yinan; Wang, Zheng; Jin, Xunbo; Xia, Qinghua

    2014-05-01

    To investigate the influence of the histone deacetylase inhibitor valproic acid (VPA) on SMAD4 expression and invasive ability of prostate cancer cell lines. DU145 and PC3 cell lines were treated with 0, 2, and 5 mMol/l of VPA; invasion of DU145 and PC3 cells were then examined by transwell assay. Immunohistochemistry and Western blot were used to examine SMAD4 protein expression in DU145 and PC3 cells. Compared with controls, VPA significantly suppressed invasiveness in both PC3 and DU145 cells in a dose-dependent way (P AKT protein (which was regarded as an effective indicator here), and meanwhile, SMAD4 expression was down-regulated after VPA treatment in a dose-dependent manner in both DU145 (P SMAD4 enhancers could form a basis for a novel prostate cancer treatment.

  1. Comparison of clinical, magnetic resonance and evoked potentials data in a case of valproic-acid-related hyperammonemic coma

    Energy Technology Data Exchange (ETDEWEB)

    Hantson, Philippe [Universite Catholique de Louvain, Department of Intensive Care, Cliniques Saint-Luc, Brussels (Belgium); Grandin, Cecile; Duprez, Thierry [Universite Catholique de Louvain, Department of Neuroradiology, Cliniques Saint-Luc, Brussels (Belgium); Nassogne, Marie-Cecile [Universite Catholique de Louvain, Department of Pediatric Neurology, Cliniques Saint-Luc, Brussels (Belgium); Guerit, Jean-Michel [Universite Catholique de Louvain, Laboratory of Neurophysiology, Cliniques Saint-Luc, Brussels (Belgium)

    2005-01-01

    Magnetic resonance (MR) multimodality evoked potentials (MEPs) and clinical findings were correlated in a 47-year-old epileptic man in whom parenteral valproic acid (VPA) therapy induced severe comatose hyperammonemic encephalopathy without biological signs of hepatotoxicity (or hepatocytic dysfunction). Although the plasma VPA level remained within a normal therapeutic range, the ammoniemia increased to a toxic peak level at 411 {mu}mol/l 24 h after symptom onset, requiring VPA therapy discontinuation. Brain MR monitoring demonstrated early cytotoxic edema evolving into delayed vasogenic edema and final brain atrophy. Concomitantly to abnormalities within the brainstem on MR images, an increase in brainstem conduction at MEPs and clinical disturbance of brainstem reflexes were observed at the initial phase of the disease course. Later, the resolution of the MR and MEPs abnormalities paralleled the clinical recovery of the reflexes. (orig.)

  2. The effects of peritoneal dialysis on the single dose and steady state pharmacokinetics of valproic acid in a uremic epileptic child.

    Science.gov (United States)

    Orr, J M; Farrell, K; Abbott, F S; Ferguson, S; Godolphin, W J

    1983-01-01

    The pharmacokinetics of valproic acid (VPA) have been studied during peritoneal dialysis in a uremic male epileptic child following a single 500 mg dose and after multiple doses over 5 months (700 mg daily) of valproic acid as the syrup. Serum level decline was biphasic in both instances with a terminal half-life of 27.2 after the single dose and 10.2 h at steady-state. Total serum clearance was 0.0236 l/h/kg after the single dose and increased to 0.0408 l/h/kg after 5 months. Free (intrinsic) serum clearances were 0.1489 and 0.1518 l/h/kg and serum free fractions were 0.224 and 0.272 respectively for the single dose and steady-state studies. Peritoneal dialysis for periods of 12 or 24 h removed an average of 4.5% of the VPA dose.

  3. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells.

    Directory of Open Access Journals (Sweden)

    Soung-Hoon Lee

    Full Text Available Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA, a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP. VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX, a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.

  4. Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder.

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    Anshu, Kumari; Nair, Ajay Kumar; Kumaresan, U D; Kutty, Bindu M; Srinath, Shoba; Laxmi, T Rao

    2017-12-01

    Attention is foundational to efficient perception and optimal goal driven behavior. Intact attentional processing is crucial for the development of social and communication skills. Deficits in attention are therefore likely contributors to the core pathophysiology of autism spectrum disorder (ASD). Clinical evidence in ASD is suggestive of impairments in attention and its control, but the underlying mechanisms remain elusive. We examined sustained, spatially divided attention in a prenatal valproic acid (VPA) model of ASD using the 5-choice serial reaction time task (5-CSRTT). As compared to controls, male and female VPA rats had progressively lower accuracy and higher omissions with increasing attentional demands during 5-CSRTT training, and showed further performance decrements when subjected to parametric task manipulations. It is noteworthy that although VPA exposure induced attentional deficits in both sexes, there were task parameter specific sex differences. Importantly, we did not find evidence of impulsivity or motivational deficits in VPA rats but we did find reduced social preference, as well as sensorimotor deficits that suggest pre-attentional information processing impairments. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. To the best of our knowledge, this is the first study examining attentional functions in a VPA model. Our work underscores the need for studying both sexes in ASD animal models and validates the use of the VPA model in the quest for mechanistic understanding of aberrant attentional functions and for evaluating suitable therapeutic targets. Autism Res 2017, 10: 1929-1944. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics

  5. Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

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    Sharareh Eskandari

    2011-02-01

    Full Text Available Sharareh Eskandari1, Jaleh Varshosaz1, Mohsen Minaiyan2, Majid Tabbakhian11Department of Pharmaceutics, 2Department of Pharmacology, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, IranAbstract: The treatment of brain disorders is one of the greatest challenges in drug delivery because of a variety of main barriers in effective drug transport and maintaining therapeutic concentrations in the brain for a prolonged period. The objective of this study was delivery of valproic acid (VPA to the brain by intranasal route. For this purpose, nanostructured lipid carriers (NLCs were prepared by solvent diffusion method followed by ultrasonication and characterized for size, zeta potential, drug-loading percentage, and release. Six groups of rats each containing six animals received drug-loaded NLCs intraperitoneally (IP or intranasally. Brain responses were then examined by using maximal electroshock (MES. The hind limb tonic extension:flexion inhibition ratio was measured at 15-, 30-, 60-, 90-, and 120-minute intervals. The drug concentration was also measured in plasma and brain at the most protective point using gas chromatography method. The particle size of NLCs was 154 ± 16 nm with drug-loading percentage of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo results showed that there was a significant difference between protective effects of NLCs of VPA and control group 15, 30, 60, and 90 minutes after treatment via intranasal route (P < 0.05. Similar protective effect was observed in rats treated with NLCs of VPA in intranasal route and positive control in IP route (P > 0.05. Results of drug determination in brain and plasma showed that brain:plasma concentration ratio was much higher after intranasal administration of NLCs of VPA than the positive control group (IP route. In conclusion, intranasal administration of NLCs of VPA provided a better protection

  6. Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET

    International Nuclear Information System (INIS)

    Kim, Sung Won; Hooker, Jacob M.; Otto, Nicola; Win, Khaing; Muench, Lisa; Shea, Colleen; Carter, Pauline; King, Payton; Reid, Alicia E.; Volkow, Nora D.; Fowler, Joanna S.

    2013-01-01

    The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using 11 CO 2 and the appropriate Grignard reagents. [ 11 C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low ( VPA > PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [ 11 C]BA showed relatively high uptake in spleen and pancreas whereas [ 11 C]PBA showed high uptake in liver and heart. Notably, [ 11 C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects

  7. Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid.

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    Bhalla, Sheena; Joshi, Deval; Bhullar, Shaminder; Kasuga, Daniel; Park, Yeonhee; Kay, Christine N

    2013-07-01

    The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies. A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated. Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm(2) (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use. VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.

  8. Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism

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    Tania Rinaldi

    2008-10-01

    Full Text Available The prefrontal cortex has been extensively implicated in autism to explain deficits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to significantly more neighbouring neurons than in controls. These excitatory connections are more plastic displaying enhanced long-term potentiation of the strength of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms. We propose that a number of deficits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyper-functional prefrontal cortex.

  9. Synergistic apoptotic response between valproic acid and fludarabine in chronic lymphocytic leukaemia (CLL) cells involves the lysosomal protease cathepsin B

    International Nuclear Information System (INIS)

    Yoon, J-Y; Szwajcer, D; Ishdorj, G; Benjaminson, P; Xiao, W; Kumar, R; Johnston, J B; Gibson, S B

    2013-01-01

    Fludarabine, a nucleoside analogue, is commonly used in combination with other agents for the treatment of chronic lymphocytic leukaemia (CLL). In previous studies, valproic acid (VPA), an inhibitor of histone deacetylases, combined with fludarabine to synergistically increase apoptotic cell death in CLL cells. In the present study, we found that the combination of fludarabine and VPA decreases the level of the anti-apoptotic proteins Mcl-1 and XIAP in primary CLL cells. Treatment with fludarabine alone, or in combination with VPA, led to the loss of lysosome integrity, and chemical inhibition of the lysosomal protease cathepsin B, using CA074-Me, was sufficient to reduce apoptosis. VPA treatment increased cathepsin B levels and activities in primary CLL cells, thereby priming CLL cells for lysosome-mediated cell death. Six previously treated patients with relapsed CLL were treated with VPA, followed by VPA/fludarabine combination. The combined therapy resulted in reduced lymphocyte count in five out of six and reduced lymph node sizes in four out of six patients. In vivo VPA treatment increased histone-3 acetylation and cathepsin B expression levels. Thus, the synergistic apoptotic response with VPA and fludarabine in CLL is mediated by cathepsin B activation leading to a decrease in the anti-apoptotic proteins

  10. Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

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    Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

    2013-10-01

    The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  11. The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations.

    Science.gov (United States)

    Wu, Chien-Chih; Pai, Tsung-Yu; Hsiao, Fei-Yuan; Shen, Li-Jiuan; Wu, Fe-Lin Lin

    2016-10-01

    Carbapenem antibiotics (CBPMs) may significantly reduce the serum concentration of valproic acid (VPA), but the extent of this effect among various CBPMs is unknown. This study compared the extent and onset of the interactions among ertapenem, imipenem/cilastatin, and meropenem. A 5-year retrospective study was performed. Hospitalized patients over 18 years old who received VPA and a CBPM concurrently were enrolled via the pharmacy computer system. Patients who lacked VPA serum concentration measurements before or during CBPMs' use, had concurrent medication(s) that might interfere with VPA metabolism, or had a history of liver cirrhosis were excluded. Total VPA serum concentrations before and during CBPMs' use and after its discontinuation were recorded, and differences among various CBPMs were analyzed. Fifty-two patients were included in this analysis. Irrespective of the route of administration, VPA serum concentrations were subtherapeutic in 90% of the subjects during CBPMs' use. There was a significant decrease (P imipenem/cilastatin (N = 17), and meropenem (N = 26) groups, respectively. The effect of ertapenem and meropenem on VPA was significantly more expressed than that of imipenem/cilastatin (P imipenem/cilastatin. Because of the dramatic reduction of VPA serum concentration during CBPMs' use, concomitant use of VPA and CBPMs should be avoided.

  12. Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA.

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    Hirsch, Mauro Mozael; Deckmann, Iohanna; Fontes-Dutra, Mellanie; Bauer-Negrini, Guilherme; Della-Flora Nunes, Gustavo; Nunes, Walquiria; Rabelo, Bruna; Riesgo, Rudimar; Margis, Rogerio; Bambini-Junior, Victorio; Gottfried, Carmem

    2018-05-01

    Autism spectrum disorder (ASD) is characterized by difficulties in social interaction, communication and language, and restricted repertoire of activities and interests. The etiology of ASD remains unknown and no clinical markers for diagnosis were identified. Environmental factors, including prenatal exposure to valproic acid (VPA), may contribute to increased risk of developing ASD. MicroRNA (miRNA) are small noncoding RNA that regulate gene expression and are frequently linked to biological processes affected in neurodevelopmental disorders. In this work, we analyzed the effects of resveratrol (an antioxidant and anti-inflammatory molecule) on behavioral alterations of the VPA model of autism, as well as the levels of circulating miRNA. We also evaluated the same set of miRNA in autistic patients. Rats of the VPA model of autism showed reduced total reciprocal social interaction, prevented by prenatal treatment with resveratrol (RSV). The levels of miR134-5p and miR138-5p increased in autistic patients. Interestingly, miR134-5p is also upregulated in animals of the VPA model, which is prevented by RSV. In conclusion, our findings revealed important preventive actions of RSV in the VPA model, ranging from behavior to molecular alterations. Further evaluation of preventive mechanisms of RSV can shed light in important biomarkers and etiological triggers of ASD. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. In Vivo Screening Using Transgenic Zebrafish Embryos Reveals New Effects of HDAC Inhibitors Trichostatin A and Valproic Acid on Organogenesis.

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    Ling Li

    Full Text Available The effects of endocrine disrupting chemicals (EDCs on reproduction are well known, whereas their developmental effects are much less characterized. However, exposure to endocrine disruptors during organogenesis may lead to deleterious and permanent problems later in life. Zebrafish (Danio rerio transgenic lines expressing the green fluorescent protein (GFP in specific organs and tissues are powerful tools to uncover developmental defects elicited by EDCs. Here, we used seven transgenic lines to visualize in vivo whether a series of EDCs and other pharmaceutical compounds can alter organogenesis in zebrafish. We used transgenic lines expressing GFP in pancreas, liver, blood vessels, inner ear, nervous system, pharyngeal tooth and pectoral fins. This screen revealed that four of the tested chemicals have detectable effects on different organs, which shows that the range of effects elicited by EDCs is wider than anticipated. The endocrine disruptor tetrabromobisphenol-A (TBBPA, as well as the three drugs diclofenac, trichostatin A (TSA and valproic acid (VPA induced abnormalities in the embryonic vascular system of zebrafish. Moreover, TSA and VPA induced specific alterations during the development of pancreas, an observation that was confirmed by in situ hybridization with specific markers. Developmental delays were also induced by TSA and VPA in the liver and in pharyngeal teeth, resulting in smaller organ size. Our results show that EDCs can induce a large range of developmental alterations during embryogenesis of zebrafish and establish GFP transgenic lines as powerful tools to screen for EDCs effects in vivo.

  14. Valproic Acid Promotes Survival of Facial Motor Neurons in Adult Rats After Facial Nerve Transection: a Pilot Study.

    Science.gov (United States)

    Zhang, Lili; Fan, Zhaomin; Han, Yuechen; Xu, Lei; Liu, Wenwen; Bai, Xiaohui; Zhou, Meijuan; Li, Jianfeng; Wang, Haibo

    2018-04-01

    Valproic acid (VPA), a medication primarily used to treat epilepsy and bipolar disorder, has been applied to the repair of central and peripheral nervous system injury. The present study investigated the effect of VPA on functional recovery, survival of facial motor neurons (FMNs), and expression of proteins in rats after facial nerve trunk transection by functional measurement, Nissl staining, TUNEL, immunofluorescence, and Western blot. Following facial nerve injury, all rats in group VPA showed a better functional recovery, which was significant at the given time, compared with group NS. The Nissl staining results demonstrated that the number of FMNs survival in group VPA was higher than that in group normal saline (NS). TUNEL staining showed that axonal injury of facial nerve could lead to neuronal apoptosis of FMNs. But treatment of VPA significantly reduced cell apoptosis by decreasing the expression of Bax protein and increased neuronal survival by upregulating the level of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) expression in injured FMNs compared with group NS. Overall, our findings suggest that VPA may advance functional recovery, reduce lesion-induced apoptosis, and promote neuron survival after facial nerve transection in rats. This study provides an experimental evidence for better understanding the mechanism of injury and repair of peripheral facial paralysis.

  15. Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

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    Ali, Elham H A; Elgoly, Amany H Mahmoud

    2013-10-01

    The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

  16. Maternal DHA supplementation protects rat offspring against impairment of learning and memory following prenatal exposure to valproic acid.

    Science.gov (United States)

    Gao, Jingquan; Wu, Hongmei; Cao, Yonggang; Liang, Shuang; Sun, Caihong; Wang, Peng; Wang, Ji; Sun, Hongli; Wu, Lijie

    2016-09-01

    Docosahexaenoic acid (22:6n-3; DHA) is known to play a critical role in postnatal brain development. However, there have been no studies investigating the preventive effect of DHA on prenatal valproic acid (VPA)-induced behavioral and molecular alterations in offspring. The present study was to evaluate the neuroprotective effects in offspring using maternal feeding of DHA to rats exposed to VPA in pregnancy. In the present study, rats were exposed to VPA on day 12.5 of pregnancy; DHA was administered at the dosages of 100, 300 and 500 mg/kg/day for 3 weeks from day 1 to 21 of pregnancy. The results showed that maternal feeding of DHA to the prenatal exposed to VPA (1) prevented VPA-induced learning and memory impairment but did not change social-related behavior, (2) increased total DHA content in offspring plasma and hippocampus, (3) rescued VPA-induced neuronal loss and apoptosis of pyramidal cells in hippocampal CA1, (4) influenced the content of malondialdehyde and glutathione and the activities of superoxide dismutase and glutathione in the hippocampus, (5) altered levels of apoptosis-related proteins (Bcl-2, Bax and caspase-3) and inhibited the activity of caspase-3 in offspring hippocampus and (6) enhanced relative levels of p-CaMKII and p-CREB proteins in the hippocampus. These findings suggest that maternal feeding with DHA may prevent prenatal VPA-induced impairment of learning and memory, normalize several different molecules associated with oxidative stress and apoptosis in the hippocampus of offspring, and exert preventive effects on prenatal VPA-induced brain dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Cytochrome P-450-catalyzed desaturation of valproic acid in vitro. Species differences, induction effects, and mechanistic studies

    International Nuclear Information System (INIS)

    Rettie, A.E.; Boberg, M.; Rettenmeier, A.W.; Baillie, T.A.

    1988-01-01

    The cytochrome P-450-mediated desaturation of valproic acid (VPA) to its hepatotoxic metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), was examined in liver microsomes from rats, mice, rabbits and humans. The highest substrate turnover was found with microsomes from rabbits (44.2 +/- 2.7 pmol of product/nmol P-450/15 min), while lower activities were observed in preparations from human, mouse, and rat liver, in that order. Pretreatment of animals with phenobarbital led to enhanced rates of formation of 4-ene-VPA in vitro and yielded induction ratios for desaturation ranging from 2.5 to 8.4, depending upon the species. Comparative studies in the rat showed that phenobarbital is a more potent inducer of olefin formation than either phenytoin or carbamazepine. The mechanism of the desaturation reaction was studied by inter- and intramolecular deuterium isotope effect experiments, which demonstrated that removal of a hydrogen atom from the subterminal C-4 position of VPA is rate limiting in the formation of both 4-ene- and 4-hydroxy-VPA. Hydroxylation at the neighboring C-5 position, on the other hand, was highly sensitive to deuterium substitution at that site, but not to deuteration at C-4. Based on these findings, it is proposed that 4-ene- and 4-hydroxy-VPA are products of a common P-450-dependent metabolic pathway, in which a carbon-centered free radical at C-4 serves as the key intermediate. 5-Hydroxy-VPA, in contrast, derives from an independent hydroxylation reaction

  18. Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat.

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    Khan, Sabbir; Kumar, Sandeep; Jena, Gopabandhu

    2016-06-01

    Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  19. Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis.

    Science.gov (United States)

    Zimmermann, Fernanda Francine; Gaspary, Karina Vidarte; Leite, Carlos Eduardo; De Paula Cognato, Giana; Bonan, Carla Denise

    2015-01-01

    Changes in social behavior are associated with brain disorders, including mood disorders, stress, schizophrenia, Alzheimer's disease, and autism spectrum disorders (ASD). Autism is a complex neurodevelopmental disorder characterized by deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Zebrafish is one of the most social vertebrates used as a model in biomedical research, contributing to an understanding of the mechanisms that underlie social behavior. Valproic acid (VPA) is used as an anti-epileptic drug and mood stabilizer; however, prenatal VPA exposure in humans has been associated with an increased incidence of autism and it can also affect fetal brain development. Therefore, we conducted a behavioral screening at different periods of zebrafish development at 6, 30, 70, and 120dpf (days postfertilization) after VPA exposure in the early development stage to investigate social behavior, locomotion, aggression, and anxiety. VPA (48μM) exposure during the first 48hpf (hours postfertilization) did not promote changes on survival, morphology, and hatching rate at 24hpf, 48hpf, and 72hpf. The behavioral patterns suggest that VPA exposure induces changes in locomotor activity and anxiety at different developmental periods in zebrafish. Furthermore, a social interaction deficit is present at 70dpf and 120dpf. VPA exposure did not affect aggression in the adult stage at 70dpf and 120dpf. This is the first study that demonstrated zebrafish exposed to VPA during the first 48h of development exhibit deficits in social interaction, anxiety, and hyperactivity at different developmental periods. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Resveratrol Prevents Cellular and Behavioral Sensory Alterations in the Animal Model of Autism Induced by Valproic Acid

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    Mellanie Fontes-Dutra

    2018-05-01

    Full Text Available Autism spectrum disorder (ASD is characterized by impairments in both social communication and interaction and repetitive or stereotyped behaviors. Although its etiology remains unknown, genetic and environmental risk factors have been associated with this disorder, including the exposure to valproic acid (VPA during pregnancy. Resveratrol (RSV is an anti-inflammatory and antioxidant molecule known to prevent social impairments in the VPA animal model of autism. This study aimed to analyze the effects of prenatal exposure to VPA, as well as possible preventive effects of RSV, on sensory behavior, the localization of GABAergic parvalbumin (PV+ neurons in sensory brain regions and the expression of proteins of excitatory and inhibitory synapses. Pregnant rats were treated daily with RSV (3.6 mg/kg from E6.5 to E18.5 and injected with VPA (600 mg/kg in the E12.5. Male pups were analyzed in Nest Seeking (NS behavior and in whisker nuisance task (WNT. At P30, the tissues were removed and analyzed by immunofluorescence and western blotting. Our data showed for the first time an altered localization of PV+-neurons in primary sensory cortex and amygdala. We also showed a reduced level of gephyrin in the primary somatosensory area (PSSA of VPA animals. The treatment with RSV prevented all the aforementioned alterations triggered by VPA. Our data shed light on the relevance of sensory component in ASD and highlights the interplay between RSV and VPA animal model as an important tool to investigate the pathophysiology of ASD.

  1. The anti-epileptic drug valproic acid (VPA inhibits steroidogenesis in bovine theca and granulosa cells in vitro.

    Directory of Open Access Journals (Sweden)

    Claire Glister

    Full Text Available Valproic acid (VPA is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC and granulosa (GC cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P99% decrease; P<0.0001 with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05. VPA only reduced TC progesterone secretion induced by the highest (luteinizing LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001 by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001. The potent histone deacetylase (HDAC inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.

  2. Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia.

    Science.gov (United States)

    Sun, Rulin; Zhang, Santao; Hu, Wenjun; Lu, Xing; Lou, Ning; Yang, Zhende; Chen, Shaoyong; Zhang, Xiaoping; Yang, Hongmei

    2016-07-01

    Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia. Copyright © 2016 the American Physiological Society.

  3. The effect of ketogenic diet in an animal model of autism induced by prenatal exposure to valproic acid.

    Science.gov (United States)

    Castro, Kamila; Baronio, Diego; Perry, Ingrid Schweigert; Riesgo, Rudimar Dos Santos; Gottfried, Carmem

    2017-07-01

    Autism spectrum disorder (ASD) is characterized by impairments in social interaction and communication, and by restricted repetitive behaviors and interests. Its etiology is still unknown, but different environmental factors during pregnancy, such as exposure to valproic acid (VPA), are associated with high incidence of ASD in children. In this context, prenatal exposure to VPA in rodents has been used as a reliable model of ASD. Ketogenic diet (KD) is an alternative therapeutic option for refractory epilepsy; however, the effects of this approach in ASD-like behavior need to be evaluated. We conducted a behavioral assessment of the effects of KD in the VPA model of autism. Pregnant animals received a single-intraperitoneal injection of 600 mg/kg VPA, and their offspring were separated into four groups: (1) control group with standard diet (C-SD), (2) control group with ketogenic diet (C-KD), (3) VPA group with standard diet (VPA-SD), and (4) VPA group with ketogenic diet (VPA-KD). When compared with the control group, VPA animals presented increased social impairment, repetitive behavior and higher nociceptive threshold. Interestingly, the VPA group fed with KD presented improvements in social behavior. These mice displayed higher scores in sociability index and social novelty index when compared with the SD-fed VPA mice. VPA mice chronically exposed to a KD presented behavioral improvements; however, the mechanism by which KD improves ASD-like features needs to be further investigated. In conclusion, the present study reinforces the potential use of KD as a treatment for the core deficits of ASD.

  4. Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

    Science.gov (United States)

    He, Yingzi; Cai, Chengfu; Tang, Dongmei; Sun, Shan; Li, Huawei

    2014-01-01

    In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID:25431550

  5. S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice.

    Science.gov (United States)

    Ornoy, Asher; Weinstein-Fudim, Liza; Tfilin, Matanel; Ergaz, Zivanit; Yanai, Joseph; Szyf, Moshe; Turgeman, Gadi

    2018-01-16

    A common animal model of ASD is the one induced by valproic acid (VPA), inducing epigenetic changes and oxidative stress. We studied the possible preventive effect of the methyl donor for epigenetic enzymatic reactions, S-adenosine methionine (SAM), on ASD like behavioral changes and on redox potential in the brain and liver in this model. ICR albino mice were injected on postnatal day 4 with one dose of 300 mg/kg of VPA, with normal saline (controls) or with VPA and SAM that was given orally for 3 days at the dose of 30 mg/kg body weight. From day 50, we carried out neurobehavioral tests and assessment of the antioxidant status of the prefrontal cerebral cortex, liver assessing SOD and CAT activity, lipid peroxidation and the expression of antioxidant genes. Mice injected with VPA exhibited neurobehavioral deficits typical of ASD that were more prominent in males. Changes in the activity of SOD and CAT increased lipid peroxidation and changes in the expression of antioxidant genes were observed in the prefrontal cortex of VPA treated mice, more prominent in females, while ASD like behavior was more prominent in males. There were no changes in the redox potential of the liver. The co-administration of VPA and SAM alleviated most ASD like neurobehavioral symptoms and normalized the redox potential in the prefrontal cortex. Early postnatal VPA administration induces ASD like behavior that is more severe in males, while the redox status changes are more severe in females; SAM corrects both. VPA-induced ASD seems to result from epigenetic changes, while the redox status changes may be secondary. Copyright © 2018. Published by Elsevier Inc.

  6. Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder.

    Science.gov (United States)

    Wilson, C Brad; McLaughlin, Leslie D; Ebenezer, Philip J; Nair, Anand R; Francis, Joseph

    2014-07-15

    Reactive oxygen species (ROS) and pro-inflammatory cytokines (PIC) are upregulated in post-traumatic stress disorder (PTSD). Histone deacetylase inhibitors (HDACi) modify genetic transcription and can diminish ROS and PIC escalation. They can also modulate levels of neurotransmitters such as catecholamines and serotonin (5-HT). Thus, this study sought to analyze the effects of the HDACi valproic acid (VA) on oxidative stress, inflammation, and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. PTSD-like effects were induced in male Sprague-Dawley rats (n=6/group×4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1h on days 1, 11, and 40 of a 40-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, the treatment group (PTSD+VA) and control group (Control+VA) rats were given VA in their drinking water for 30 days. The rats were then euthanized and their brains were dissected to remove the hippocampus and prefrontal cortex (PFC). Whole blood was collected to assess systemic oxidative stress. ROS and PIC mRNA and protein elevation in the PTSD group were normalized with VA. Anxiety decreased in this group via improved performance on the elevated plus-maze (EPM). No changes were attributed to VA in the control group, and no improvements were noted in the vehicle groups. Results indicate VA can attenuate oxidative stress and inflammation, enhance fear extinction, and correct neurotransmitter aberrancies in a rat model of PTSD. Copyright © 2014. Published by Elsevier B.V.

  7. Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

    Directory of Open Access Journals (Sweden)

    Yingzi eHe

    2014-11-01

    Full Text Available In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, nonmammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well suited for studying hair cell development and regeneration. Histone deacetylase (HDAC activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA or valproic acid (VPA increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line.

  8. Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock

    DEFF Research Database (Denmark)

    Imam, Ayesha M; Jin, Guang; Duggan, Michael

    2013-01-01

    Traumatic brain injury (TBI) and hemorrhagic shock (HS) are major causes of trauma-related deaths and are especially lethal as a combined insult. Previously, we showed that early administration of fresh frozen plasma (FFP) decreased the size of the brain lesion and associated swelling in a swine...... model of combined TBI+HS. We have also shown separately that addition of valproic acid (VPA) to the resuscitation protocol attenuates inflammatory markers in the brain as well as the degree of TBI. The current study was performed to determine whether a combined FFP+VPA treatment strategy would exert...

  9. A simple and sensitive methodology for voltammetric determination of valproic acid in human blood plasma samples using 3-aminopropyletriethoxy silane coated magnetic nanoparticles modified pencil graphite electrode.

    Science.gov (United States)

    Zabardasti, Abedin; Afrouzi, Hossein; Talemi, Rasoul Pourtaghavi

    2017-07-01

    In this work, we have prepared a nano-material modified pencil graphite electrode for the sensing of valproic acid (VA) by immobilization 3-aminopropyletriethoxy silane coated magnetic nanoparticles (APTES-MNPs) on the pencil graphite surface (PGE). Electrochemical studies indicated that the APTES-MNPs efficiently increased the electron transfer kinetics between VA and the electrode and the free NH 2 groups of the APTES on the outer surface of magnetic nanoparticles can interact with carboxyl groups of VA. Based on this, we have proposed a sensitive, rapid and convenient electrochemical method for VA determination. Under the optimized conditions, the reduction peak current of VA is found to be proportional to its concentration in the range of 1.0 (±0.2) to 100.0 (±0.3) ppm with a detection limit of 0.4 (±0.1) ppm. The whole sensor fabrication process was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) methods with using [Fe(CN) 6 ] 3-/4- as an electrochemical redox indicator. The prepared modified electrode showed several advantages such as high sensitivity, selectivity, ease of preparation and good repeatability, reproducibility and stability. The proposed method was applied to determination of valproic acid in blood plasma samples and the obtained results were satisfactory accurate. Copyright © 2017. Published by Elsevier B.V.

  10. Harmful Interactions: Mixing Alcohol with Medicines

    Science.gov (United States)

    ... Depakene®, Depakote® Valproic acid Drowsiness, dizziness; tremors; increased risk for side effects, such as restlessness, impaired motor control; loss of appetite; stomach upset; irregular bowel movement; joint or muscle ...

  11. Evaluation of the efficacy of valproic acid and suberoylanilide hydroxamic acid (vorinostat in enhancing the effects of first-line tuberculosis drugs against intracellular Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Martin Rao

    2018-04-01

    Full Text Available Background: New tuberculosis (TB drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs valproic acid (VPA and suberoylanilide hydroxamic acid (SAHA to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis. Methods: M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH and rifampicin (RIF. The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU. Results: VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction, while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction and equalled that of INH (1.5-log CFU reduction. INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3 days vs. 6 days. Conclusions: VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted. Keywords: Mycobacterium tuberculosis, Adjunct host-directed therapy, Tuberculosis, Histone deacetylase inhibitors, Repurposed drugs

  12. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Krauze, Andra V. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Myrehaug, Sten D. [Department of Radiation Oncology, Lakeridge Health Durham Regional Cancer Centre, Oshawa, Ontario (Canada); Chang, Michael G.; Holdford, Diane J. [Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia (United States); Smith, Sharon; Shih, Joanna; Tofilon, Philip J. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Fine, Howard A. [New York University Langone Medical Center, New York, New York (United States); Camphausen, Kevin, E-mail: camphauk@mail.nih.gov [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States)

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  13. Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

    Science.gov (United States)

    Wei, Muyun; Mao, Shaowei; Lu, Guoliang; Li, Liang; Lan, Xiaopeng; Huang, Zhongxian; Chen, Yougen; Zhao, Miaoqing; Zhao, Yueran; Xia, Qinghua

    2018-04-17

    Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways. 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. VPA not only exhibits

  14. Valproic acid exposure decreases Cbp/p300 protein expression and histone acetyltransferase activity in P19 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lamparter, Christina L. [Department of Biomedical and Molecular Sciences, Graduate Program in Pharmacology and Toxicology, Queen' s University, Kingston, Ontario K7L 3N6 (Canada); Winn, Louise M., E-mail: winnl@queensu.ca [Department of Biomedical and Molecular Sciences, Graduate Program in Pharmacology and Toxicology, Queen' s University, Kingston, Ontario K7L 3N6 (Canada); School of Environmental Studies, Queen' s University, Kingston, Ontario K7L 3N6 (Canada)

    2016-09-01

    The teratogenicity of the antiepileptic drug valproic acid (VPA) is well established and its inhibition of histone deacetylases (HDAC) is proposed as an initiating factor. Recently, VPA-mediated HDAC inhibition was demonstrated to involve transcriptional downregulation of histone acetyltransferases (HATs), which was proposed to compensate for the increased acetylation resulting from HDAC inhibition. Cbp and p300 are HATs required for embryonic development and deficiencies in either are associated with congenital malformations and embryolethality. The objective of the present study was to characterize Cbp/p300 following VPA exposure in P19 cells. Consistent with previous studies, exposure to 5 mM VPA over 24 h induced a moderate decrease in Cbp/p300 mRNA, which preceded a strong decrease in total cellular protein mediated by ubiquitin-proteasome degradation. Nuclear Cbp/p300 protein was also decreased following VPA exposure, although to a lesser extent. Total cellular and nuclear p300 HAT activity was reduced proportionately to p300 protein levels, however while total cellular HAT activity also decreased, nuclear HAT activity was unaffected. Using the Cbp/p300 HAT inhibitor C646, we demonstrated that HAT inhibition similarly affected many of the same endpoints as VPA, including increased reactive oxygen species and caspase-3 cleavage, the latter of which could be attenuated by pre-treatment with the antioxidant catalase. C646 exposure also decreased NF-κB/p65 protein, which was not due to reduced mRNA and was not attenuated with catalase pre-treatment. This study provides support for an adaptive HAT response following VPA exposure and suggests that reduced Cbp/p300 HAT activity could contribute to VPA-mediated alterations. - Highlights: • VPA exposure in vitro downregulates Cbp/p300 mRNA and induces protein degradation. • Cbp/p300 histone acetyltransferase activity is similarly reduced with VPA exposure. • Inhibition of Cbp/p300 acetyltransferase activity

  15. Clinical Validation and Implications of Dried Blood Spot Sampling of Carbamazepine, Valproic Acid and Phenytoin in Patients with Epilepsy

    Science.gov (United States)

    Kong, Sing Teang; Lim, Shih-Hui; Lee, Wee Beng; Kumar, Pasikanthi Kishore; Wang, Hwee Yi Stella; Ng, Yan Lam Shannon; Wong, Pei Shieen; Ho, Paul C.

    2014-01-01

    To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r = 0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT−1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs. PMID:25255292

  16. Corrigendum to “Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain" [Neurosci.Lett. 580 (2014) 12–16] A possible new animal model of autism

    DEFF Research Database (Denmark)

    Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen

    2015-01-01

    The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20 mg/kg or 100 mg/kg) continuously during the last 9–12 d...

  17. Determination of acute lethal and chronic lethal dose thresholds of valproic acid using 3D spheroids constructed from the immortal human hepatocyte cell line HepG2/C3A

    DEFF Research Database (Denmark)

    Fey, S. J.; Wrzesinski, K.

    2013-01-01

    describe here a culture system based on 3D spheroid culture of immortal hepatocytes which can determine the toxicity of valproic acid (or structurally or functionally related molecules) in vitro. The spheroids were used to follow changes in ATP production, glucose uptake and adenylate kinase following...

  18. Gross hepatic changes in developing albino rats exposed to valproic acid

    International Nuclear Information System (INIS)

    Khan, M.; Khattak, S.T.; Elahi, M.

    2011-01-01

    Background: Valproid Acid (VPA) is a broad spectrum antiepileptic drug. Its use during pregnancy has been associated with congenital anomalies and hepatotoxicity. This study was designed to assess the effects of VPA on the gross structure of liver in developing albino rats exposed to the drug during various trimesters of pregnancy. Methods: In this experimental study 40 pregnant rats were divided into 4 equal groups A, B, C and D. Group A received VPA in a dose of 500 mg/Kg/day intraperitonealy (I/P) on days 3, 4 and 5 of gestation. Group B received the drug in a dose of 500 mg/Kg/day I/P on days 8, 9 and 10 of gestation. Group C received VPA in a dose of 500 mg/Kg/day I/P on days 16, 17 and 18 of gestation. Group D received no treatment and was kept as a control group. On day 21, the rats were euthanised by cervical dislocation. The liver of the foetuses were dissected out for the assessment of their gross structure. Results: Foetal liver of the experimental groups showed significant decrease in weight as well as relative tissue weight index (RTWI) as compared to the control group, although the gross appearance of the foetal liver was normal in all the groups. Conclusion: The use of VPA during various trimesters of pregnancy produces hepatotoxicity in the developing rats. So, the use of this drug during pregnancy should be carefully decided. (author)

  19. Data on social transmission of food preference in a model of autism induced by valproic acid and translational analysis of circulating microRNA

    Directory of Open Access Journals (Sweden)

    Mauro Mozael Hirsch

    2018-06-01

    Full Text Available This article contains data of Social Transmission of Food Preference in an animal model of autism and the evaluation of a set of microRNA analyzed in autistic patients and animal model of autism. The analyses of the absolute consumption of two flavored food by male rats prenatally exposed to valproic acid (VPA and treated with resveratrol (RSV, showed that VPA animals show a trend to eat less of the flavored food presented by a demonstrator rat. We also identified 13 microRNA with similar levels among rodents’ experimental groups, as well as 11 microRNA with no alterations between autistic and control subjects. Further evaluation of mechanisms of VPA and RSV actions on behavioral and molecular alterations can shed light in important biomarkers and etiological triggers of autistic spectrum disorders. Keywords: Autism, Social transmission of food preference, microRNA, Resveratrol, Translational research, Preclinical models, Valproate

  20. Randomized Phase II trial of paclitaxel plus valproic acid vs paclitaxel alone as second-line therapy for patients with advanced gastric cancer

    Directory of Open Access Journals (Sweden)

    Fushida S

    2015-04-01

    Full Text Available Sachio Fushida,1 Masahide Kaji,2 Katsunobu Oyama,1 Yasuo Hirono,3 Hideaki Nezuka,4 Toshiya Takeda,5 Tomoya Tsukada,1 Daisuke Fujimoto,3 Shigekazu Ohyama,6 Takashi Fujimura,7 Tetsuo Ohta1 On behalf of the Digestive Disease Support Organization (DDSO 1Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, 2Department of Surgery, Toyama Prefectural Central Hospital, Toyama, 3First Department of Surgery, Fukui University Hospital, Fukui, 4Department of Surgery, Yatsuo General Hospital, Toyama, 5Department of Surgery, Ishikawa Matto Central Hospital, Hakusan, 6Department of Surgery, Kanazawa Medical Center, Kanazawa, 7Toyama City Hospital, Toyama, Japan Abstract: The standard regimen of second-line chemotherapy for patients with unresectable gastric cancer has not been established. However, weekly paclitaxel (wPTX has become the preferable second-line chemotherapy in Japan. Histone deacetylase (HDAC inhibitors have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in gastric cancer cells. One HDAC inhibitor, valproic acid (VPA, also inhibits tumor growth by inducing apoptosis, and enhances the efficacy of paclitaxel in a mouse xenograft model of gastric cancer. wPTX plus VPA as a second-line chemotherapy is expected to improve survival in gastric cancer patients. A multicenter randomized Phase II study was conducted to compare the effects of wPTX plus VPA and wPTX alone. A total of 66 patients participated in this study. The primary end point of the study was overall survival, and secondary end points were progression-free survival, response rate, and assessment of peripheral neuropathy. Keywords: valproic acid, paclitaxel, second-line therapy, advanced gastric cancer 

  1. Music application alleviates short-term memory impairments through increasing cell proliferation in the hippocampus of valproic acid-induced autistic rat pups.

    Science.gov (United States)

    Lee, Sung-Min; Kim, Bo-Kyun; Kim, Tae-Woon; Ji, Eun-Sang; Choi, Hyun-Hee

    2016-06-01

    Autism is a neurodevelopmental disorder and this disorder shows impairment in reciprocal social interactions, deficits in communication, and restrictive and repetitive patterns of behaviors and interests. The effect of music on short-term memory in the view of cell proliferation in the hippocampus was evaluated using valproic acid-induced autistic rat pups. Animal model of autism was made by subcutaneous injection of 400-mg/kg valproic acid into the rat pups on the postnatal day 14. The rat pups in the music-applied groups were exposed to the 65-dB comfortable classic music for 1 hr once a day, starting postnatal day 15 and continued until postnatal day 28. In the present results, short-term memory was deteriorated by autism induction. The numbers of 5-bromo-2'-deoxyridine (BrdU)-positive, Ki-67-positive, and doublecortin (DCX)-positive cells in the hippocampal dentate gyrus were decreased by autism induction. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expressions in the hippocampus were also suppressed in the autistic rat pups. Music application alleviated short-term memory deficits with enhancing the numbers of BrdU-positive, Ki-67-positive, and DCX-positive cells in the autistic rat pups. Music application also enhanced BDNF and TrkB expressions in the autistic rat pups. The present study show that application of music enhanced hippocampal cell proliferation and alleviated short-term memory impairment through stimulating BDNF-TrkB signaling in the autistic rat pups. Music can be suggested as the therapeutic strategy to overcome the autism-induced memory deficits.

  2. Different effects of valproic acid on photoreceptor loss in Rd1 and Rd10 retinal degeneration mice.

    Science.gov (United States)

    Mitton, Kenneth P; Guzman, Alvaro E; Deshpande, Mrinalini; Byrd, David; DeLooff, Camryn; Mkoyan, Kristina; Zlojutro, Paul; Wallace, Adrianne; Metcalf, Brandon; Laux, Kirsten; Sotzen, Jason; Tran, Trung

    2014-01-01

    The histone-deacetylase inhibitor activity of valproic acid (VPA) was discovered after VPA's adoption as an anticonvulsant. This generated speculation for VPA's potential to increase the expression of neuroprotective genes. Clinical trials for retinitis pigmentosa (RP) are currently active, testing VPA's potential to reduce photoreceptor loss; however, we lack information regarding the effects of VPA on available mammalian models of retinal degeneration, nor do we know if retinal gene expression is perturbed by VPA in a predictable way. Thus, we examined the effects of systemic VPA on neurotrophic factor and Nrl-related gene expression in the mouse retina and compared VPA's effects on the rate of photoreceptor loss in two strains of mice, Pde6b(rd1/rd1) and Pde6b(rd10/rd10) . The expression of Bdnf, Gdnf, Cntf, and Fgf2 was measured by quantitative PCR after single and multiple doses of VPA (intraperitoneal) in wild-type and Pde6b(rd1/rd1) mice. Pde6b(rd1/rd1) mice were treated with daily doses of VPA during the period of rapid photoreceptor loss. Pde6b(rd10/rd10) mice were also treated with systemic VPA to compare in a partial loss-of-function model. Retinal morphology was assessed by virtual microscopy or spectral-domain optical coherence tomography (SD-OCT). Full-field and focal electroretinography (ERG) analysis were employed with Pde6b(rd10/rd10) mice to measure retinal function. In wild-type postnatal mice, a single VPA dose increased the expression of Bdnf and Gdnf in the neural retina after 18 h, while the expression of Cntf was reduced by 70%. Daily dosing of wild-type mice from postnatal day P17 to P28 resulted in smaller increases in Bdnf and Gdnf expression, normal Cntf expression, and reduced Fgf2 expression (25%). Nrl gene expression was decreased by 50%, while Crx gene expression was not affected. Rod-specific expression of Mef2c and Nr2e3 was decreased substantially by VPA treatment, while Rhodopsin and Pde6b gene expression was normal at P28. Daily

  3. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Skavland, J; Jørgensen, K M [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hadziavdic, K [Department of Informatics, University of Bergen, Bergen (Norway); Hovland, R [Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen (Norway); Jonassen, I [Department of Informatics, University of Bergen, Bergen (Norway); Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway); Bruserud, Ø; Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)

    2011-02-01

    Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

  4. The interplay between ventro striatal BDNF levels and the effects of valproic acid on the acquisition of ethanol-induced conditioned place preference in mice.

    Science.gov (United States)

    Dos Santos, Manuel Alves; Escudeiro, Sarah Sousa; Vasconcelos, Germana Silva; Matos, Natália Castelo Branco; de Souza, Marcos Romário Matos; Patrocínio, Manoel Cláudio Azevedo; Dantas, Leonardo Pimentel; Macêdo, Danielle; Vasconcelos, Silvânia Maria Mendes

    2017-11-01

    Alcohol addiction is a chronic, relapsing and progressive brain disease with serious consequences for health. Compulsive use of alcohol is associated with the capacity to change brain structures involved with the reward pathway, such as ventral striatum. Recent evidence suggests a role of chromatin remodeling in the pathophysiology of alcohol dependence and addictive-like behaviors. In addition, neuroadaptive changes mediated by the brain-derived neurotrophic factor (BDNF) seems to be an interesting pharmacological target for alcoholism treatment. In the present study, we evaluated the effects of the deacetylase inhibitor valproic acid (VPA) (300mg/kg) on the conditioned rewarding effects of ethanol using conditioned place preference (CPP) (15% v/v; 2g/kg). Ethanol rewarding effect was investigated using a biased protocol of CPP. BDNF levels were measured in the ventral striatum. Ethanol administration induced CPP. VPA pretreatment did not reduce ethanol-CPP acquisition. VPA pretreatment increased BDNF levels when compared to ethanol induced-CPP. VPA pretreatment increased BDNF levels even in saline conditioned mice. Taken together, our results indicate a modulatory effect of VPA on the BDNF levels in the ventral striatum. Overall, this study brings initial insights into the involvement of neurotrophic mechanisms in the ventral striatum in ethanol-induced addictive-like behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Valproic acid reduces hair loss and improves survival in patients receiving temozolomide-based radiation therapy for high-grade glioma.

    Science.gov (United States)

    Watanabe, Shinichi; Kuwabara, Yui; Suehiro, Satoshi; Yamashita, Daisuke; Tanaka, Mamoru; Tanaka, Akihiro; Ohue, Shiro; Araki, Hiroaki

    2017-03-01

    Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is also used to manage seizures in glioblastoma patients. HDAC inhibitors can protect normal cells and tissues from the deleterious effects of radiotherapy, and VPA is reported to improve the survival of glioblastoma patients receiving chemoradiation therapy. VPA also promotes hair growth, and thus has the potential to reduce the radiotherapy side effect of hair loss while improving the survival of patients with glioblastoma. The purpose of this study was to determine whether VPA use during radiotherapy for high-grade glioma is associated with decreased side effects of radiotherapy and an improvement in overall survival (OS) and progression-free survival (PFS). Medical records of 112 patients with high-grade glioma were retrospectively reviewed. We grouped patients by VPA use or non-use during radiotherapy, and evaluated hair loss, OS, and PFS. The radiation dose and fractionation at the onset of hair loss were 4 Gy and two fractions higher, respectively, in the VPA group compared with the VPA non-use group (P hair loss and improvement in survival. Hair loss prevention benefits patients suffering from the deleterious effects of radiation.

  6. Resting-state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign epilepsy with central-temporal spikes

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qirui; Zhang, Zhiqiang; Xu, Qiang; Wu, Han; Li, Zhipeng; Lu, Guangming [Nanjing University School of Medicine, Department of Medical Imaging, Jinling Hospital, Nanjing (China); Yang, Fang; Li, Qian [Nanjing University School of Medicine, Department of Neurology, Jinling Hospital, Nanjing (China); Hu, Zheng [Nanjing Children' s Hospital, Department of Neurology, Nanjing (China); Dante, Mantini [Faculty of Kinesiology and Rehabilitation Sciences, KU Leuven (Belgium); Li, Kai [Suzhou University, Laboratory of Molecular Medicine, Suzhou (China)

    2017-05-15

    Our aim was to investigate regional difference in brain activities in response to antiepileptic drug (AED) medications in benign epilepsy with central-temporal spikes (BECTS) using resting-state functional magnetic resonance imaging (fMRI). Fifty-seven patients with BECTS underwent resting-state fMRI scans after receiving either valproic acid (VPA) (n = 15), levetiracetam (LEV) (n = 21), or no medication (n = 21). fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared and were correlated with total doses of AED in the two medicated groups. Compared with patients on no-medication, patients receiving either VPA or LEV showed decreased ReHo in the central-temporal region, frontal cortex, and thalamus. In particular, the VPA group showed greater ReHo decrease in the thalamus and milder in cortices and caudate heads compared with the LEV group. In addition, the VPA group demonstrated a negative correlation between ReHo values in the central-temporal region and medication dose. Both VPA and LEV inhibit resting-state neural activity in the central-temporal region, which is the main epileptogenic focus of BECTS. VPA reduced brain activity in the cortical epileptogenic regions and thalamus evenly, whereas LEV reduced brain activity predominantly in the cortices. Interestingly, VPA showed a cumulative effect on inhibiting brain activity in the epileptogenic regions in BECTS. (orig.)

  7. Encapsulation of valproic acid and sodic phenytoin in ordered mesoporous SiO 2 solids for the treatment of temporal lobe epilepsy

    Science.gov (United States)

    López, T.; Basaldella, E. I.; Ojeda, M. L.; Manjarrez, J.; Alexander-Katz, R.

    2006-10-01

    Temporal lobe epilepsy is one of the most frequent types of human neurological diseases, and a variety of surgical procedures have been developed for the treatment of intractable cases. An alternative is the use of drug-containing reservoirs based on nanostructured materials of controlled pore sizes in order to deliver the drug without causing secondary effects. Ordered SiO 2 nanostructures were developed as drug reservoirs. The latter were prepared by the sol-gel process using tetraethyl orthosilicate TEOS as precursor to form the "sol" and P123 surfactant as the organic structure-directing agent. In addition to the nontoxic nature of amorphous silica, uniform and tunable pore sizes between 2.5 and 30 nm can be obtained in this way. The aim of this study is to investigate the potential of these materials for the storage and release of drugs in the brain. For that, we loaded valproic acid (VH) and sodic phenytoin (PH) molecules into an ordered mesoporous SiO 2 by impregnation and characterized the drug impregnated SiO 2 by standard physical and spectroscopic techniques to identify the parameters necessary to improve the capacity and quality of the reservoirs. Finally, a study of neurohistopathology of the effects of these reservoirs on brain tissue is presented.

  8. Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism.

    Science.gov (United States)

    Hara, Yuta; Ago, Yukio; Higuchi, Momoko; Hasebe, Shigeru; Nakazawa, Takanobu; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2017-11-01

    Recent studies have reported that oxytocin ameliorates behavioral abnormalities in both animal models and individuals with autism spectrum disorders (ASD). However, the mechanisms underlying the ameliorating effects of oxytocin remain unclear. In this study, we examined the effects of intranasal oxytocin on impairments in social interaction and recognition memory in an ASD mouse model in which animals are prenatally exposed to valproic acid (VPA). We found that a single intranasal administration of oxytocin restored social interaction deficits for up to 2h in mice prenatally exposed to VPA, but there was no effect on recognition memory impairments. Additionally, administration of oxytocin across 2weeks improved prenatal VPA-induced social interaction deficits for at least 24h. In contrast, there were no effects on the time spent sniffing in control mice. Immunohistochemical analysis revealed that intranasal administration of oxytocin increased c-Fos expression in the paraventricular nuclei (PVN), prefrontal cortex, and somatosensory cortex, but not the hippocampal CA1 and CA3 regions of VPA-exposed mice, suggesting the former regions may underlie the effects of oxytocin. These findings suggest that oxytocin attenuates social interaction deficits through the activation of higher cortical areas and the PVN in an ASD mouse model. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. In vitro interactions of amantadine hydrochloride, R-(-)-deprenyl hydrochloride and valproic acid sodium salt with antifungal agents against filamentous fungal species causing central nervous system infection.

    Science.gov (United States)

    Galgóczy, L; Tóth, Liliána; Virágh, M; Papp, T; Vágvölgyi, C S

    2012-12-01

    The mortality rates of fungal infections that affect the central nervous system are high in consequence of the absence of effective antifungal drugs with good penetration across the blood-brain barrier and the blood-cerebrospinal fluid barrier. In the present work in vitro antifungal activities of three good penetrating non-antifungal drugs (amantadine hydrochloride, R-(-)-deprenyl hydrochloride, valproic acid sodium salt) and their combinations with three antifungal agents (amphotericin B, itraconazole, terbinafine) were tested with broth microdilution method against eight fungal isolates belonging to Zygomycetes (Lichtheimia corymbifera, Rhizomucor miehei, Rhizopus microsporus var. rhizopodiformis, Saksenaeavasiformis) and Aspergillus genus (A. flavus, A. fumigatus, A. nidulans, A. terreus). These are known to be possible agents of central nervous fungal infections (CNFI). When used alone, the investigated nonantifungal drugs exerted slight antifungal effects. In their combinations with antifungal agents they acted antagonistically, additively and synergistically against zygomyceteous isolates. Primarily antagonistic interactions were revealed between the investigated drugs in case of Aspergilli, but additive and synergistic interactions were also observed. The additive and synergistic combinations allowed the usage of reduced concentrations of antifungal agents to inhibit the fungal growth in our study. These combinations would be a basis of an effective, less toxic therapy for treatment of CNFI.

  10. Morphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies.

    Science.gov (United States)

    Tashiro, Yasura; Oyabu, Akiko; Imura, Yoshio; Uchida, Atsuko; Narita, Naoko; Narita, Masaaki

    2011-06-01

    Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

  11. Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

    DEFF Research Database (Denmark)

    Gotfryd, Kamil; Skladchikova, Galina; Lepekhin, Eugene E

    2010-01-01

    lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3). Results: VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1......ABSTRACT: BACKGROUND: The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent. Methods: The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell....../2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK...

  12. Resting-state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign epilepsy with central-temporal spikes

    International Nuclear Information System (INIS)

    Zhang, Qirui; Zhang, Zhiqiang; Xu, Qiang; Wu, Han; Li, Zhipeng; Lu, Guangming; Yang, Fang; Li, Qian; Hu, Zheng; Dante, Mantini; Li, Kai

    2017-01-01

    Our aim was to investigate regional difference in brain activities in response to antiepileptic drug (AED) medications in benign epilepsy with central-temporal spikes (BECTS) using resting-state functional magnetic resonance imaging (fMRI). Fifty-seven patients with BECTS underwent resting-state fMRI scans after receiving either valproic acid (VPA) (n = 15), levetiracetam (LEV) (n = 21), or no medication (n = 21). fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared and were correlated with total doses of AED in the two medicated groups. Compared with patients on no-medication, patients receiving either VPA or LEV showed decreased ReHo in the central-temporal region, frontal cortex, and thalamus. In particular, the VPA group showed greater ReHo decrease in the thalamus and milder in cortices and caudate heads compared with the LEV group. In addition, the VPA group demonstrated a negative correlation between ReHo values in the central-temporal region and medication dose. Both VPA and LEV inhibit resting-state neural activity in the central-temporal region, which is the main epileptogenic focus of BECTS. VPA reduced brain activity in the cortical epileptogenic regions and thalamus evenly, whereas LEV reduced brain activity predominantly in the cortices. Interestingly, VPA showed a cumulative effect on inhibiting brain activity in the epileptogenic regions in BECTS. (orig.)

  13. Glutathione depletion by valproic acid in sandwich-cultured rat hepatocytes: Role of biotransformation and temporal relationship with onset of toxicity

    International Nuclear Information System (INIS)

    Kiang, Tony K.L.; Teng Xiaowei; Surendradoss, Jayakumar; Karagiozov, Stoyan; Abbott, Frank S.; Chang, Thomas K.H.

    2011-01-01

    The present study was conducted in sandwich-cultured rat hepatocytes to investigate the chemical basis of glutathione (GSH) depletion by valproic acid (VPA) and evaluate the role of GSH depletion in VPA toxicity. Among the synthetic metabolites of VPA investigated, 4-ene-VPA and (E)-2,4-diene-VPA decreased cellular levels of total GSH, but only (E)-2,4-diene-VPA was more effective and more potent than the parent drug. The in situ generated, cytochrome P450-dependent 4-ene-VPA did not contribute to GSH depletion by VPA, as suggested by the experiment with a cytochrome P450 inhibitor, 1-aminobenzotriazole, to decrease the formation of this metabolite. In support of a role for metabolites, alpha-F-VPA and octanoic acid, which do not undergo biotransformation to form a 2,4-diene metabolite, CoA ester, or glucuronide, did not deplete GSH. A time course experiment showed that GSH depletion did not occur prior to the increase in 2',7'-dichlorofluorescein (a marker of oxidative stress), the decrease in [2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] (WST-1) product formation (a marker of cell viability), or the increase in lactate dehydrogenase (LDH) release (a marker of necrosis) in VPA-treated hepatocytes. In conclusion, the cytochrome P450-mediated 4-ene-VPA pathway does not play a role in the in situ depletion of GSH by VPA, and GSH depletion is not an initiating event in VPA toxicity in sandwich-cultured rat hepatocytes.

  14. Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder.

    Science.gov (United States)

    Kim, Ki Chan; Kim, Pitna; Go, Hyo Sang; Choi, Chang Soon; Park, Jin Hee; Kim, Hee Jin; Jeon, Se Jin; Dela Pena, Ike Campomayor; Han, Seol-Heui; Cheong, Jae Hoon; Ryu, Jong Hoon; Shin, Chan Young

    2013-03-01

    Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA-exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between male and female rats in control condition. However, VPA-exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD-like behavioral phenotype, prenatally VPA-exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, post-synaptic marker proteins such as PSD-95 and α-CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of post-synapse in male but not in female at 4 weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged post-synaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased post-synaptic compartment, VPA-exposed male rats showed higher sensitivity to electric shock than VPA-exposed female rats. These results suggest that prenatally VPA-exposed rats show the male preponderance of ASD-like behaviors including defective social interaction similar to human autistic patients, which

  15. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    John T Kissel

    Full Text Available BACKGROUND: Multiple lines of evidence have suggested that valproic acid (VPA might benefit patients with spinal muscular atrophy (SMA. The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. METHODS: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend, timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP, handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. RESULTS: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. CONCLUSIONS: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

  16. Determination of valproic acid in human plasma using dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection

    Science.gov (United States)

    Fazeli-Bakhtiyari, Rana; Panahi-Azar, Vahid; Sorouraddin, Mohammad Hossein; Jouyban, Abolghasem

    2015-01-01

    Objective(s): Dispersive liquid-liquid microextraction coupled with gas chromatography (GC)-flame ionization detector was developed for the determination of valproic acid (VPA) in human plasma. Materials and Methods: Using a syringe, a mixture of suitable extraction solvent (40 µl chloroform) and disperser (1 ml acetone) was quickly added to 10 ml of diluted plasma sample containing VPA (pH, 1.0; concentration of NaCl, 4% (w/v)), resulting in a cloudy solution. After centrifugation (6000 rpm for 6 min), an aliquot (1 µl) of the sedimented organic phase was removed using a 1-µl GC microsyringe and injected into the GC system for analysis. One variable at a time optimization method was used to study various parameters affecting the extraction efficiency of target analyte. Then, the developed method was fully validated for its accuracy, precision, recovery, stability, and robustness. Results: Under the optimum extraction conditions, good linearity range was obtained for the calibration graph, with correlation coefficient higher than 0.998. Limit of detection and lower limit of quantitation were 3.2 and 6 μg/ml, respectively. The relative standard deviations of intra and inter-day analysis of examined compound were less than 11.5%. The relative recoveries were found in the range of 97 to 107.5%. Finally, the validated method was successfully applied to the analysis of VPA in patient sample. Conclusion: The presented method has acceptable levels of precision, accuracy and relative recovery and could be used for therapeutic drug monitoring of VPA in human plasma. PMID:26730332

  17. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid

    Directory of Open Access Journals (Sweden)

    Zanoteli Edmar

    2011-03-01

    Full Text Available Abstract Background Spinal muscular atrophy (SMA is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1 and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2. The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA, a histone deacetylase inhibitor. Methods Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC, the Hammersmith Functional Motor Scale (HFMS, and the Barthel Index. Results After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease. Trial Registration ClinicalTrials.gov: NCT01033331

  18. Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism.

    Science.gov (United States)

    Hara, Yuta; Ago, Yukio; Taruta, Atsuki; Katashiba, Keisuke; Hasebe, Shigeru; Takano, Erika; Onaka, Yusuke; Hashimoto, Hitoshi; Matsuda, Toshio; Takuma, Kazuhiro

    2016-09-01

    Rodents exposed prenatally to valproic acid (VPA) show autism-related behavioral abnormalities. We recently found that prenatal VPA exposure causes a reduction of dopaminergic activity in the prefrontal cortex of male, but not female, mice. This suggests that reduced prefrontal dopaminergic activity is associated with behavioral abnormalities in VPA-treated mice. In the present study, we examined whether the attention deficit/hyperactivity disorder drugs methylphenidate and atomoxetine (which increase dopamine release in the prefrontal cortex, but not striatum, in mice) could alleviate the behavioral abnormalities and changes in dendritic spine morphology induced by prenatal VPA exposure. We found that methylphenidate and atomoxetine increased prefrontal dopamine and noradrenaline release in VPA-treated mice. Acute treatment with methylphenidate or atomoxetine did not alleviate the social interaction deficits or recognition memory impairment in VPA-treated mice, while chronic treatment for 2 weeks did. Methylphenidate or atomoxetine for 2 weeks also improved the prenatal VPA-induced decrease in dendritic spine density in the prefrontal cortex. The effects of these drugs on behaviors and dendritic spine morphology were antagonized by concomitant treatment with the dopamine-D1 receptor antagonist SCH39166 or the dopamine-D2 receptor antagonist raclopride, but not by the α2 -adrenoceptor antagonist idazoxan. These findings suggest that chronic treatment with methylphenidate or atomoxetine improves abnormal behaviors and diminishes the reduction in spine density in VPA-treated mice via a prefrontal dopaminergic system-dependent mechanism. Autism Res 2016, 9: 926-939. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

  19. Modulation of sphingosine 1-phosphate (S1P) attenuates spatial learning and memory impairments in the valproic acid rat model of autism.

    Science.gov (United States)

    Wu, Hongmei; Zhang, Quanzhi; Gao, Jingquan; Sun, Caihong; Wang, Jia; Xia, Wei; Cao, Yonggang; Hao, Yanqiu; Wu, Lijie

    2018-03-01

    Autism spectrum disorders (ASD) are a set of pervasive neurodevelopmental disorders that manifest in early childhood, and it is growing up to be a major cause of disability in children. However, the etiology and treatment of ASD are not well understood. In our previous study, we found that serum levels of sphingosine 1-phosphate (S1P) were increased significantly in children with autism, indicating that S1P levels may be involved in ASD. The objective of this study was to identify a link between increased levels of S1P and neurobehavioral changes in autism. We utilized a valproic acid (VPA) -induced rat model of autism to evaluate the levels of S1P and the expression of sphingosine kinase (SphK), a key enzyme for S1P production, in serum and hippocampal tissue. Furthermore, we assessed cognitive functional changes and histopathological and neurochemical alterations in VPA-exposed rats after SphK blockade to explore the possible link between increased levels of S1P and neurobehavioral changes in autism. We found that SphK2 and S1P are upregulated in hippocampal tissue from VPA-exposed rats, while pharmacological inhibition of SphK reduced S1P levels, attenuated spatial learning and memory impairments, increased the expression of phosphorylated CaMKII and CREB and autophagy-related proteins, inhibited cytochrome c release, decreased the expression of apoptosis related proteins, and protected against neuronal loss in the hippocampus. We have demonstrated that an increased level of SphK2/S1P is involved in the spatial learning and memory impairments of autism, and this signaling pathway represents a novel therapeutic target and direction for future studies.

  20. Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington's disease.

    Science.gov (United States)

    Linares, Gabriel R; Chiu, Chi-Tso; Scheuing, Lisa; Leng, Yan; Liao, Hsiao-Mei; Maric, Dragan; Chuang, De-Maw

    2016-07-01

    Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG repeat expansions in the huntingtin gene. Although, stem cell-based therapy has emerged as a potential treatment for neurodegenerative diseases, limitations remain, including optimizing delivery to the brain and donor cell loss after transplantation. One strategy to boost cell survival and efficacy is to precondition cells before transplantation. Because the neuroprotective actions of the mood stabilizers lithium and valproic acid (VPA) induce multiple pro-survival signaling pathways, we hypothesized that preconditioning bone marrow-derived mesenchymal stem cells (MSCs) with lithium and VPA prior to intranasal delivery to the brain would enhance their therapeutic efficacy, and thereby facilitate functional recovery in N171-82Q HD transgenic mice. MSCs were treated in the presence or absence of combined lithium and VPA, and were then delivered by brain-targeted single intranasal administration to eight-week old HD mice. Histological analysis confirmed the presence of MSCs in the brain. Open-field test revealed that ambulatory distance and mean velocity were significantly improved in HD mice that received preconditioned MSCs, compared to HD vehicle-control and HD mice transplanted with non-preconditioned MSCs. Greater benefits on motor function were observed in HD mice given preconditioned MSCs, while HD mice treated with non-preconditioned MSCs showed no functional benefits. Moreover, preconditioned MSCs reduced striatal neuronal loss and huntingtin aggregates in HD mice. Gene expression profiling of preconditioned MSCs revealed a robust increase in expression of genes involved in trophic effects, antioxidant, anti-apoptosis, cytokine/chemokine receptor, migration, mitochondrial energy metabolism, and stress response signaling pathways. Consistent with this finding, preconditioned MSCs demonstrated increased survival after transplantation into the brain compared to non-preconditioned cells

  1. Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.

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    Eric J Hill

    Full Text Available Mood stabilising drugs such as lithium (LiCl and valproic acid (VPA are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4, neurons (Neurofilament M, astrocytes (GFAP or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.

  2. Effects of valproic acid and pioglitazone on cell cycle progression and proliferation of T-cell acute lymphoblastic leukemia Jurkat cells

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    Marie Saghaeian Jazi

    2016-07-01

    Full Text Available Objective(s: T-cell acute lymphoblastic leukemia (T-ALL is an aggressive hematologic malignant tumor. Administration of chemical compounds influencing apoptosis and T cell development has been discussed as promising novel therapeutic strategies. Valproic acid (VPA as a recently emerged anti-neoplastic histone deacetylase (HDAC inhibitor and pioglitazone (PGZ as a high-affinity peroxisome proliferator-activated receptor-gamma (PPARγ agonist have been shown to induce apoptosis and cell cycle arrest in different studies. Here, we aimed to investigate the underlying molecular mechanisms involved in anti-proliferative effects of these compounds on human Jurkat cells. Materials and Methods: Treated cells were evaluated for cell cycle progression and apoptosis using flowcytometry and MTT viability assay. Real-time RT-PCR was carried out to measure the alterations in key genes associated with cell death and cell cycle arrest. Results: Our findings illustrated that both VPA and PGZ can inhibit Jurkat E6.1 cells in vitro after   24 hr; however, PGZ 400 μM presents the most anti-proliferative effect. Interestingly, treated cells have been arrested in G2/M with deregulated cell division cycle 25A (Cdc25A phosphatase and cyclin-dependent kinase inhibitor 1B (CDKN1B or p27 expression. Expression of cyclin D1 gene was inhibited when DNA synthesis entry was declined. Cell cycle deregulation in PGZ and VPA-exposed cells generated an increase in the proportion of aneuploid cell population, which has not reported before. Conclusion: These findings define that anti-proliferative effects of PGZ and VPA on Jurkat cell line are mediated by cell cycle deregulation. Thus, we suggest PGZ and VPA may relieve potential therapeutic application against apoptosis-resistant malignancies.

  3. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

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    Kathryn J Swoboda

    2010-08-01

    Full Text Available Valproic acid (VPA has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1 and an ambulatory group of "walkers" (cohort 2. Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51. Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409. Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03 compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007.This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that

  4. Systemic administration of valproic acid and zonisamide promotes the survival and differentiation of induced pluripotent stem cell–derived dopaminergic neurons

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    Tatsuya eYoshikawa

    2013-02-01

    Full Text Available Cell replacement therapy using embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs is a promising strategy for the treatment of neurologic diseases such as Parkinson’s disease (PD. However, a limiting factor for effective cell transplantation is the low survival rate of grafted cells, especially neurons. In this study, we modified the host environment and investigated whether the simultaneous administration of soluble factors can improve the survival and differentiation of murine iPSC-derived dopaminergic (DA neurons in host brains. With the goal of applying this technology in clinical settings in the near future, we selected drugs that were already approved for clinical use. The drugs included two commonly used anticonvulsants, valproic acid (VPA and zonisamide (ZNS, and estradiol (E2, also known as biologically active estrogen. Following neural induction of murine iPSCs, we collected neural progenitor cells by sorting PSA-NCAM+ cells, then treated the PSA-NCAM+ cells with drugs for four days. An immunofluorescence study revealed that 0.01 mM and 0.1 mM of VPA and 10 nM of E2 increased the percentage of tyrosine hydroxylase+ (TH: a DA neuron marker cells in vitro. Furthermore, 0.1 mM of VPA increased the percentage of TH+ cells that simultaneously express the midbrain markers FOXA2 and NURR1. Next, in order to determine the effects of the drugs in vivo, the iPSC-derived NPCs were transplanted into the striata of intact SD rats. The animals received intraperitoneal injections of one of the drugs for four weeks, then were subjected to an immunofluorescence study. VPA administration (150 mg/kg/daily increased the number of NeuN+ postmitotic neurons and TH+ DA neurons in the grafts. Furthermore, VPA (150 mg/kg/daily and ZNS (30 mg/kg/daily increased the number of TH+FOXA2+ midbrain DA neurons. These results suggest that the systemic administration of VPA and ZNS may improve the efficiency of cell replacement therapy using i

  5. Effects of valproic acid and dexamethasone administration on early bio-markers and gene expression profile in acute kidney ischemia-reperfusion injury in the rat.

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    Ryan W Speir

    Full Text Available Renal ischemia-reperfusion (IR causes acute kidney injury (AKI with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group received Valproic Acid (150 mg/kg; VPA, Dexamethasone (3 mg/kg; Dex or Vehicle (saline intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL at 24 h was reduced (P<0.05 in VPA (2.7±1.8 and Dex (2.3±1.2 compared to Vehicle (3.8±0.5 group. At 3 h, urine albumin (mg/mL was higher in Vehicle (1.47±0.10, VPA (0.84±0.62 and Dex (1.04±0.73 compared to naïve (uninjured/untreated control (0.14±0.26 group. At 24 h post-IR urine lipocalin-2 (μg/mL was higher (P<0.05 in VPA, Dex and Vehicle groups (9.61-11.36 compared to naïve group (0.67±0.29; also, kidney injury molecule-1 (KIM-1; ng/mL was higher (P<0.05 in VPA, Dex and Vehicle groups (13.7-18.7 compared to naïve group (1.7±1.9. Histopathology demonstrated reduced (P<0.05 ischemic injury in the renal cortex in VPA (Grade 1.6±1.5 compared to Vehicle (Grade 2.9±1.1. Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI.

  6. DNA Methylation Changes in Valproic Acid-Treated HeLa Cells as Assessed by Image Analysis, Immunofluorescence and Vibrational Microspectroscopy.

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    Giovana M B Veronezi

    Full Text Available Valproic acid (VPA, a well-known histone deacetylase inhibitor, has been reported to affect the DNA methylation status in addition to inducing histone hyperacetylation in several cell types. In HeLa cells, VPA promotes histone acetylation and chromatin remodeling. However, DNA demethylation was not checked in this cell model for standing effects longer than those provided by histone acetylation, which is a rapid and transient phenomenon. Demonstration of VPA-induced DNA demethylation in HeLa cells would contribute to understanding the effect of VPA on an aggressive tumor cell line. In the present work, DNA demethylation in VPA-treated HeLa cells was assessed by image analysis of chromatin texture, the abundance of 5-methylcytosine (5mC immunofluorescence signals and Fourier transform-infrared (FT-IR microspectroscopy centered on spectral regions related to the vibration of-CH3 groups. Image analysis indicated that increased chromatin unpacking promoted by a 4-h-treatment with 1.0 mM VPA persisted for 24 h in the absence of the drug, suggesting the occurrence of DNA demethylation that was confirmed by decreased 5mC immunofluorescence signals. FT-IR spectra of DNA samples from 1 mM or 20 mM VPA-treated cells subjected to a peak fitting analysis of the spectral window for-CH3 stretching vibrations showed decreased vibrations and energy of these groups as a function of the decreased abundance of 5mC induced by increased VPA concentrations. Only the 20 mM-VPA treatment caused an increase in the ratio of -CH3 bending vibrations evaluated at 1375 cm-1 in relation to in-plane vibrations of overall cytosines evaluated at 1492 cm-1. CH3 stretching vibrations showed to be more sensitive than-CH3 bending vibrations, as detected with FT-IR microspectroscopy, for studies aiming to associate vibrational spectroscopy and changes in DNA 5mC abundance.

  7. Anti-inflammatory and Anti-apoptotic Effect of Valproic Acid and Doxycycline Independent from MMP Inhibition in Early Radiation Damage

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    Ferda Hoşgörler

    2016-10-01

    Full Text Available Background: Matrix metalloproteinase (MMP inhibitors decrease inflammation in normal tissues and suppress cancer progress in normal tissues. Valproic acid (VA and doxycycline (DX are MMP inhibitors that have radio-protective effects. Their ability to inhibit MMPs in irradiated tissue is unknown and the role of MMPs in radio-protective effects has not been tested to date. Aims: The purpose of this study was to examine whether administration of VA and DX to rats before irradiation affects tissue inflammation and apoptosis in the early phase of radiation, and whether the effect of these drugs is mediated by MMP inhibition. Study Design: Animal experimentation. Methods: Twenty-six Wistar rats were randomized into four groups: control (CTRL, radiation (RT, VA plus radiation (VA+RT, and DX plus radiation (DX+RT.Three study groups were exposed to a single dose of abdominal 10 Gy gamma radiation; the CTRL group received no radiation. Single doses of VA 300 mg/kg and DX 100 mg/kg were administered to each rat before radiation and all rats were sacrificed 8 hours after irradiation, at which point small intestine tissue samples were taken for analyses. Levels of inflammatory cytokines (TNF-α, IL-1β, and IL-6 and matrix metalloproteinases (MMP-2 and MMP 9 were measured by ELISA, MMP activities were measured by gelatin and casein zymography and apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: VA decreased the levels of TNF-α and IL-1β proteins insignificantly and decreased apoptosis significantly in the irradiated tissue, but did not inhibit MMPs. In contrast, VA protected the basal MMP activities, which decreased in response to irradiation. No effect of DX was observed on the levels of inflammatory cytokines or activities of MMPs in the early phases of radiation apoptosis. Conclusion: Our findings indicated that VA protects against inflammation and apoptosis, and DX exhibits anti-apoptotic effects in

  8. Corrigendum to “Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain" [Neurosci.Lett. 580 (2014) 12–16] A possible new animal model of autism

    DEFF Research Database (Denmark)

    Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen

    2015-01-01

    The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20 mg/kg or 100 mg/kg) continuously during the last 9......–12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fraction at or and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups....... Pups exposed to 100 mg/kg, but not to 20 mg/kg VPA displayed a significant (p brain development by disturbing neocortical organization...

  9. Insuficiência aguda hepática associada ao ácido valpróico na infância: relato de três casos Acute hepatic failure with valproic acid in children: report of three cases

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    Sérgio A. Antoniuk

    1996-12-01

    Full Text Available Relatamos três casos da insuficiência aguda hepática associada ao uso de ácido valpróico (AVP em crianças epilépticas. A idade variou de 2 anos e 8 meses a 5 anos e 1 mês. Todos os pacientes apresentavam epilepsia de difícil controle e dois deles tinham desenvolvimento psicomotor severamente comprometido. O AVP foi usado em associação com outros antiepilépticos (carbamazepina em dois, fenobarbital em um. Todos os pacientes apresentaram sinais clínicos de insuficiência hepática.Vômitos, edema e icterícia foram os sinais iniciais. Febre ocorreu em dois pacientes. Os exames laboratoriais mostraram transaminases pouco aumentadas (inferiores a 194 U/l e níveis de bilirrubina entre 5,5 e 19,8 mg%. Um dos pacientes usava a droga há 12 meses e os dois outros, há menos de 6 meses. Dois pacientes apresentaram resolução do quadro hepático após a retirada da droga e um faleceu. Com este relato, salientamos a toxicidade do AVP em crianças epilépticas mesmo acima de dois anos de idade, principalmente em uso de politerapia, com comprometimento neurológico, e que o quadro pode ser reversível com a retirada da droga.We report the cases of three epileptic children who developed hepatotoxicity induced by valproic acid. Two patients had developmental delay. Including the one who died, all patients were receiving polytherapy (carbamazepine in two and phenobarbital in one. The patients age ranged from 2 years and 8 months to 5 years and 1 month. The onset of hepatic complications occurred within 6 months of valproate therapy in two patients and 12 months in one. All patients developed the classical clinical signs of hepatotoxicity. Vomiting, edema and jaundice were the initial symptoms. Fever occurred in two patients. The serum levels of glutamic oxaloacetic transaminase were mildly elevated with a maximum of 194 IU. The bilirubin levels ranged from 5.5 to 19.8 mg%. Two patients recovered clinically and showed normalization of the

  10. Differences in immunolocalization of Kim-1, RPA-1, and RPA-2 in kidneys of gentamicin-, cisplatin-, and valproic acid-treated rats: potential role of iNOS and nitrotyrosine.

    Science.gov (United States)

    Zhang, Jun; Goering, Peter L; Espandiari, Parvaneh; Shaw, Martin; Bonventre, Joseph V; Vaidya, Vishal S; Brown, Ronald P; Keenan, Joe; Kilty, Cormac G; Sadrieh, Nakissa; Hanig, Joseph P

    2009-08-01

    The present study compared the immunolocalization of Kim-1, renal papillary antigen (RPA)-1, and RPA-2 with that of inducible nitric oxide synthase (iNOS) and nitrotyrosine in kidneys of gentamicin sulfate (Gen)- and cisplatin (Cis)-treated rats. The specificity of acute kidney injury (AKI) biomarkers, iNOS, and nitrotyrosine was evaluated by dosing rats with valproic acid (VPA). Sprague-Dawley (SD) rats were injected subcutaneously (sc) with 100 mg/kg/day of Gen for six or fourteen days; a single intraperitoneal (ip) dose of 1, 3, or 6 mg/kg of Cis; or 650 mg/kg/day of VPA (ip) for four days. In Gen-treated rats, Kim-1 was expressed in the epithelial cells, mainly in the S1/S2 segments but less so in the S3 segment, and RPA-1 was increased in the epithelial cells of collecting ducts (CD) in the cortex. Spatial expression of iNOS or nitrotyrosine with Kim-1 or RPA-1 was detected. In Cis-treated rats, Kim-1 was expressed only in the S3 segment cells, and RPA-1 and RPA-2 were increased in the epithelial cells of medullary CD or medullary loop of Henle (LH), respectively. Spatial expression of iNOS or nitrotyrosine with RPA-1 or RPA-2 was also identified. These findings suggest that peroxynitrite formation may be involved in the pathogenesis of Gen and Cis nephrotoxicity and that Kim-1, RPA-1, and RPA-2 have the potential to serve as site-specific biomarkers for Gen or Cis AKI.

  11. Extracorporeal treatment for valproic acid poisoning

    DEFF Research Database (Denmark)

    Ghannoum, Marc; Laliberté, Martin; Nolin, Thomas D

    2015-01-01

    . The workgroup concluded that VPA is moderately dialyzable (level of evidence = B) and made the following recommendations: ECTR is recommended in severe VPA poisoning (1D); recommendations for ECTR include a VPA concentration > 1300 mg/L (9000 μmol/L)(1D), the presence of cerebral edema (1D) or shock (1D......); suggestions for ECTR include a VPA concentration > 900 mg/L (6250 μmol/L)(2D), coma or respiratory depression requiring mechanical ventilation (2D), acute hyperammonemia (2D), or pH ≤ 7.10 (2D). Cessation of ECTR is indicated when clinical improvement is apparent (1D) or the serum VPA concentration is between...... 50 and 100 mg/L (350-700 μmol/L)(2D). Intermittent hemodialysis is the preferred ECTR in VPA poisoning (1D). If hemodialysis is not available, then intermittent hemoperfusion (1D) or continuous renal replacement therapy (2D) is an acceptable alternative. CONCLUSIONS: VPA is moderately dialyzable...

  12. Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham´s chorea: clinical follow-up of 18 patients Comparación de la eficacia de carbamazepina, haloperidol y acido valproico en el tratamiento de niños con corea de Sydenham: seguimiento clínico de 18 pacientes

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    Joaquín Peña

    2002-06-01

    Full Text Available In order to compare and contrast the efficacy of haloperidol, carbamazepine, and valproic acid in the treatment of Sydenham´s chorea a prospective study including 18 cases of this disorder was undertaken. Age of patients ranged from 7 to 15 years. Ten children were female and 8 were male. All but one had generalized, either symmetric or asymmetric chorea. The patients were divided in three equal groups, and were given a standardized dose of each of the drugs built-up over a week. Following therapy, the six children receiving valproic acid showed remarkable improvement, without side effects. Five patients receiving carbamazepine showed improvement without side effects. Only three of the patients that received haloperidol improved. In the 4 cases that did not show clinical improvement after one week of treatment, therapy with valproic acid led to disappearance of the symptoms in a lapse that ranged from 4 to 7 days. Recurrence related to discontinuation of treatment was observed in two patients. In view of the present results we recommend valproic acid as the first choice drug to treat Sydenham chorea.A fin de comparar y contrastar la eficacia de haloperidol, carbamazepina y ácido valproico en el tratamiento de la corea de Sydenham, se realizó un estudio prospectivo que incluyó 18 casos de esta patología. La edad de los pacientes varió de 7 a 15 años. Diez de los niños eran varones y el resto hembras. A excepción de uno de ellos, todos tenían corea generalizada, simétrica ó asimétrica. Los pacientes fueron divididos en tres grupos iguales, a cada uno de los cuales se le administró una dosis estandarizada de los medicamentos mencionados durante una semana. Luego del tratamiento, los seis pacientes que recibieron ácido valproico mostraron mejoría notable sin efectos colaterales. Cinco de los seis pacientes que recibieron carbamazepina exhibieron mejoría sin efectos colaterales. Solo tres de los pacientes que recibieron haloperidol

  13. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy

    International Nuclear Information System (INIS)

    Grishina, Olga; Schmoor, Claudia; Döhner, Konstanze; Hackanson, Björn; Lubrich, Beate; May, Annette M.; Cieslik, Caroline; Müller, Michael J.; Lübbert, Michael

    2015-01-01

    Acute myeloid leukemia (AML) is predominantly a disease of older patients with a poor long-term survival. Approval of decitabine (DAC) in the European Union (EU) in 2012 for the treatment of patients with AML ≥65 years marks the potential for hypomethylating agents in elderly AML. Nevertheless the situation is dissatisfactory and the quest for novel treatment approaches, including combination epigenetic therapy is actively ongoing. The given randomized trial should be helpful in investigating the question whether combinations of DAC with the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and/or all-trans retinoic acid (ATRA), which in vitro show a very promising synergism, are superior to the DAC monotherapy. The accompanying translational research project will contribute to find surrogate molecular end points for drug efficacy and better tailor epigenetic therapy. An additional aim of the study is to investigate the prognostic value of geriatric assessments for elderly AML patients treated non-intensively. DECIDER is a prospective, randomized, observer blind, parallel group, multicenter, Phase II study with a 2x2 factorial design. The primary endpoint is objective best overall response (complete remission (CR) and partial remission (PR)). The target population is AML patients aged 60 years or older and unfit for standard induction chemotherapy. Patients are randomized to one of the four treatment groups: DAC alone or in combination with VPA or ATRA or with both add-on drugs. One interim safety analysis was planned and carried out with the objective to stop early one or more of the treatment arms in case of an unacceptable death rate. This analysis showed that in all treatment arms the critical stopping rule was not reached. No important safety issues were observed. The Data Monitoring Committee (DMC) recommended continuing the study as planned. The first patient was included in December 2011. A total of 189 out of 200 planned patients were randomized

  14. Valproic acid modulates platelet and coagulation function ex vivo

    DEFF Research Database (Denmark)

    Bambakidis, Ted; Dekker, Simone E; Halaweish, Ihab

    2017-01-01

    of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI...

  15. Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs ...

    African Journals Online (AJOL)

    Epilepsy Drugs: Synthesis, Characterization and In-vitro ... The release of VPA from polymeric prodrugs was studied using cellophane ... pharmacokinetics and accessibility in market [8]. ..... between the drug and polymer chain can affect.

  16. Novel Polymeric Prodrugs of Valproic Acid as Anti- Epilepsy Drugs ...

    African Journals Online (AJOL)

    The release of VPA from polymeric prodrugs was studied using cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1, 7 and 10) at 37 oC. The quantity of released drug was detected by ultraviolet (UV) spectroscopy. Results: 1H-NMR and elemental analyses data for calculating mole composition of ...

  17. Avelumab With Valproic Acid in Virus-associated Cancer

    Science.gov (United States)

    2018-06-11

    Cancer That is Associated With a Chronic Viral Infection; p16 Positive SCCHN; Squamous Cell Carcinoma of the Cervix; p16 Positive Squamous Cell Carcinoma of the Vagina or Vulva; p16 Positive Squamous Cell Carcinoma of the Penis; p16 Positive Squamous Cell Carcinoma of the Anus or Anal Canal; EBER Positive NPC; EBER Positive Hodgkins and Non-hodgkins Lymphona

  18. A case of fetal valproate syndrome with new features expanding the phenotype

    International Nuclear Information System (INIS)

    Seidahmed, Mohammed Z.; Miqdad, Abeer M.; AlDohami, Hessa S.; Shareefi, Osama M.

    2009-01-01

    Fetal valproate syndrome (FVS) is a well-recognized constellation of dysmorphic features, and neurodevelopmental retardation that results from prenatal exposure to the anticonvulsant valproic acid. In this report, we describe a case with typical features of FVS. A 23-year-old lady with post-traumatic epilepsy controlled by sodium valproate (Depakene) 500 mg twice daily throughout pregnancy as monotherapy, gave birth to a female baby with facial features characteristic of FVS, and severe radial ray reduction. She also had wide-spaced nipples and short neck, features not described before. Sodium valproate, a widely used anticonvulsant and mood regulator, is a well-recognized teratogen that can result in severe limb deformities, craniosynostosis, neural tube defects and neurodevelopmental retardation. Therefore, we recommend that valproic acid must be avoided during pregnancy, as new generation of anticonvulsant drugs have emerged into the market. (author)

  19. The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy.

    Science.gov (United States)

    Choi, Chang Soon; Gonzales, Edson Luck; Kim, Ki Chan; Yang, Sung Min; Kim, Ji-Woon; Mabunga, Darine Froy; Cheong, Jae Hoon; Han, Seol-Heui; Bahn, Geon Ho; Shin, Chan Young

    2016-11-07

    Autism spectrum disorder (ASD) is a heterogeneously pervasive developmental disorder in which various genetic and environmental factors are believed to underlie its development. Recently, epigenetics has been suggested as a novel concept for ASD aetiology with a proposition that epigenetic marks can be transgenerationally inherited. Based on this assumption of epigenetics, we investigated the transgenerational inheritance of ASD-like behaviours and their related synaptic changes in the VPA animal model of ASD. The first generation (F1) VPA-exposed offspring exhibited autistic-like impaired sociability and increased marble burying. They also showed increased seizure susceptibility, hyperactivity and decreased anxiety. We mated the VPA-exposed F1 male offspring with naïve females to produce the second generation (F2), and then similarly mated the F2 to deliver the third generation (F3). Remarkably, the autism-like behavioural phenotypes found in F1 persisted to the F2 and F3. Additionally, the frontal cortices of F1 and F3 showed some imbalanced expressions of excitatory/inhibitory synaptic markers, suggesting a transgenerational epigenetic inheritance. These results open the idea that E/I imbalance and ASD-like behavioural changes induced by environmental insults in mice can be epigenetically transmitted, at least, to the third generation. This study could help explain the unprecedented increase in ASD prevalence.

  20. Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation

    NARCIS (Netherlands)

    Abdul Roda, Mojtaba; Sadik, Mariam; Gaggar, Amit; Hardison, Matthew T; Jablonsky, Michael J; Braber, Saskia; Blalock, James Edwin; Redegeld, Frank A; Folkerts, Gert; Jackson, Patricia L

    2014-01-01

    A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by

  1. Valproic Acid Decreases the Reparation Capacity of Irradiated MOLT-4 Cells

    Czech Academy of Sciences Publication Activity Database

    Muthna, D.; Vávrová, J.; Lukášová, Emilie; Tichý, Adam; Knížek, J.; Köhlerová, R.; Mazánková, N.; Řezáčová, M.

    2012-01-01

    Roč. 46, č. 1 (2012), s. 110-116 ISSN 0026-8933 Institutional support: RVO:68081707 Keywords : HISTONE DEACETYLASE INHIBITOR * ENHANCES RADIATION SENSITIVITY * TRANSFORMED-CELLS Subject RIV: BO - Biophysics Impact factor: 0.637, year: 2012

  2. Metabolic syndrome and anticonvulsants: A comparative study of valproic acid and carbamazepine.

    Science.gov (United States)

    Rakitin, Aleksei; Kõks, Sulev; Haldre, Sulev

    2016-05-01

    The aim of this study was to compare the risk of metabolic syndrome (MS) and evaluate related factors for MS among people with epilepsy treated with valproate (VPA) or carbamazepine (CBZ). A total of 213 adult patients with epilepsy treated with VPA (n=118) or CBZ (n=95) monotherapy were included in the study. Participants were evaluated for the presence of MS, diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. In the multiple logistic regression analysis, the risk of MS in CBZ- and VPA-treated patients was similar (odds ratio [OR]=0.99; 95% confidence interval [CI], 0.43-2.26; P=0.979). A lower proportion of CBZ-treated patients had abnormally low levels of high-density lipoprotein cholesterol (OR=0.10; 95% CI, 0.02-0.42; P=0.002), whereas a lower proportion of VPA-treated patients had abnormally high concentrations of fasting blood glucose (OR=0.30; 95% CI, 0.13-0.69; P=0.004). Females treated with VPA tended to have a higher risk of MS (OR=1.48; 95% CI, 0.50-4.41; P=0.485) compared to males (OR=0.74; 95% CI, 0.28-1.96; P=0.551), although this difference was not statistically significant. Although the overall risk of MS was similar in patients with epilepsy who were treated with VPA or CBZ, the distribution of MS components differed between treatment groups. Patients treated with CBZ or VPA less frequently had decreased high-density lipoprotein cholesterol levels or increased blood glucose concentrations, respectively. Females on VPA treatment could be at higher risk of MS than males. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  3. Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients

    Science.gov (United States)

    Tartara, A.; Galimberti, C.A.; Manni, R.; Parietti, L.; Zucca, C.; Baasch, H.; Caresia, L.; Mück, W.; Barzaghi, N.; Gatti, G.; Perucca, E.

    1991-01-01

    1 The single dose pharmacokinetics of orally administered nimodipine (60 mg) were investigated in normal subjects and in two groups of epileptic patients receiving chronic treatment with hepatic microsomal enzyme-inducing anticonvulsants (carbamazepine, phenobarbitone or phenytoin) and sodium valproate, respectively. 2 Compared with the values found in the control group, mean areas under the plasma nimodipine concentration curve were lowered by about seven-fold (P anticonvulsants and increased by about 50% (P < 0.05) in patients taking sodium valproate. 3 Nimodipine half-lives were shorter in enzyme-induced patients than in controls (3.9 ± 2.0 h vs 9.1 ± 3.4 h, means ± s.d., P < 0.01), but this difference could be artifactual since in the patients drug concentrations declined rapidly below the limit of assay, thus preventing identification of a possible slower terminal phase. In valproate-treated patients, half-lives (8.2 ± 1.8 h) were similar to those found in controls. PMID:1777370

  4. A Case of Mania Presenting with Hypersexual Behavior and Gender Dysphoria that Resolved with Valproic Acid

    OpenAIRE

    Heare, Michelle R.; Barsky, Maria; Faziola, Lawrence R.

    2016-01-01

    Hypersexuality and gender dysphoria have both been described in the literature as symptoms of mania. Hypersexuality is listed in the Diagnostic and Statistical Manual of Mental Disorders 5 as part of the diagnostic criteria for bipolar disorder. Gender dysphoria is less often described and its relation to mania remains unclear. This case report describes a young homosexual man presenting in a manic episode with co-morbid amphetamine abuse whose mania was marked by hypersexuality and the new o...

  5. Cell motility is inhibited by the antiepileptic compound, valproic acid and its teratogenic analogues

    DEFF Research Database (Denmark)

    Walmod, P S; Foley, A; Berezin, A

    1998-01-01

    -term recordings and measurements of mean-cell speed, the reduction in the motile behaviour was shown to correlate with the teratogenic potency of the tested compounds. The observed effects of VPA on cell motility was independent of the employed L-cell clone, and could be reproduced in cells containing...... the neuronal marker NCAM and in the neuronal cell line N2a. Furthermore, the observed effect was independent of culture substratum, being observed for L-cells grown on fibronectin as well as on plastic. Immunofluorescence microscopy revealed that VPA-treatment of mouse L-cells caused a redistribution of F...

  6. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.

    Science.gov (United States)

    Cipriani, Andrea; Reid, Keith; Young, Allan H; Macritchie, Karine; Geddes, John

    2013-10-17

    Bipolar disorder is a recurrent illness that is amongst the top 30 causes of disability worldwide and is associated with significant healthcare costs. In the past, emphasis was placed solely on the treatment of acute episodes of bipolar disorder; recently, the importance of episode prevention and of minimisation of iatrogenicity has been recognised. For many years, lithium was the only mood stabiliser in common use, and it remains an agent of first choice in the preventative treatment of bipolar disorder. However, an estimated 20% to 40% of patients may not respond adequately to lithium. Valproate is an anticonvulsant drug that has been shown to be effective in acute mania and is frequently used in maintenance treatment of bipolar disorder. When the acceptability of long-term treatment is considered, together with efficacy, the adverse event profile of a medication is also important. This is an update of a Cochrane review first published in 2001 and last updated in 2009. 1. To determine the efficacy of valproate continuation and maintenance treatment:a) in preventing or attenuating manic, depressive and mixed episodes of bipolar disorder;b) in preventing or attenuating episodes of bipolar disorder in patients with rapid cycling disorder; and; c) in improving patients' general health and social functioning, as measured by global clinical impression, employment and marital stability.2. To review the acceptability to patients of long-term valproate treatment, as measured by numbers of dropouts and reasons for dropping out, by compliance and by reference to patients' expressed views regarding treatment.3. To investigate the adverse effects of valproate treatment (including general prevalence of side effects) and overall mortality rates. Search of the Cochrane Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) (to January 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE, (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). No language restrictions were applied. Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing valproate and experts in this field were contacted for supplemental data. Randomised controlled trials allocating participants with bipolar disorder to long-term treatment with valproate or any other mood stabiliser, or antipsychotic drugs, or placebo. Maintenance treatment was defined as treatment instituted specifically or mainly to prevent further episodes of illness. Three review authors independently extracted data. A double-entry procedure was employed by two review authors. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. For dichotomous data, risk ratios were calculated with 95% confidence intervals (CIs). For statistically significant results, we calculated the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH). For continuous data, mean differences (MDs) or standardised mean differences (SMDs) were calculated along with 95% CIs. MDs were used when the same scale was used to measure an outcome; SMDs were employed when different scales were used to measure the same outcome. The primary analysis used a fixed-effect model. Binary outcomes were calculated on a strict intention-to-treat (ITT) basis; dropouts were included in this analysis. When data were missing and the method of "last observation carried forward" (LOCF) had been used to do an ITT analysis, then the LOCF data were used. Six randomised controlled trials (overall 876 participants) lasting 6 to 24 months were included. Two studies (overall 312 participants) compared valproate with placebo, four studies (overall 618 participants) valproate with lithium, one study (overall 23 participants) valproate with olanzapine and one study (overall 220 participants) valproate with the combination of valproate plus lithium. In terms of study quality, most studies reported the methods used to generate random sequence; however, only one study reported enough details on allocation concealment. Four of six included studies described their design as "double blind", but only two trials reported full details about blinding. Valproate was more effective than placebo in preventing study withdrawal due to any mood episode (RR 0.68, 95% CI 0.49 to 0.93; NNTB 8), but no difference in efficacy was found between valproate and lithium (RR 1.02, 95% CI 0.87 to 1.20). Valproate was associated with fewer participants dropping out of treatment for any cause when compared with placebo or lithium (RR 0.82, 95% CI 0.71 to 0.95 and RR 0.87, 95% CI 0.77 to 0.98, respectively). However, combination therapy with lithium plus valproate was more likely to prevent relapse than was monotherapy with valproate (RR 0.78, 95% CI 0.63 to 0.96). Significant differences in adverse event frequencies were found, and lithium was associated with more frequent diarrhoea, polyuria, increased thirst and enuresis, whereas valproate was associated with increased sedation and infection. Limited evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. Clinicians and patients should consider acceptability and tolerability profile when choosing between lithium and valproate-their combination or other agents-as long-term treatment for bipolar disorder.

  7. Valproic Acid Increases CD133 Positive Cells that Show Low Sensitivity to Cytostatics in Neuroblastoma

    Czech Academy of Sciences Publication Activity Database

    Khalil, M.A.; Hraběta, J.; Groh, T.; Procházka, Pavel; Doktorová, H.; Eckschlager, T.

    2016-01-01

    Roč. 11, č. 9 (2016), e0162916 E-ISSN 1932-6203 R&D Projects: GA ČR GAP301/12/1734 Institutional support: RVO:68378041 Keywords : cancer stem-cells * histone deacetylase * colon-cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.806, year: 2016

  8. The effects of valproic acid on the mRNA expression of Natriuretic ...

    African Journals Online (AJOL)

    Mona Hajikazemi

    2017-04-28

    Apr 28, 2017 ... and KCNQ1 among VPA-treated colon cancer cells. Materials and methods: Human ... cause of cancer death in the United States.1 Modification of histones is an epigenetic pro- ..... target for prostate cancer. Mol Cancer. 2011 ...

  9. Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model.

    Science.gov (United States)

    Hara, Yuta; Takuma, Kazuhiro; Takano, Erika; Katashiba, Keisuke; Taruta, Atsuki; Higashino, Kosuke; Hashimoto, Hitoshi; Ago, Yukio; Matsuda, Toshio

    2015-08-01

    Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0 mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increases in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation.

    Science.gov (United States)

    Yu, In Tag; Park, Jin-Yong; Kim, Sung Hyun; Lee, Jeong-Sik; Kim, Yong-Seok; Son, Hyeon

    2009-02-01

    Valproate (VPA) influences the proliferation and differentiation of neuronal cells. However, little is known about the downstream events, such as alterations in gene transcription, that are associated with cell fate choice. To determine whether VPA plays an instructive role in cell fate choice during hippocampal neurogenesis, the expression of genes involved in the cell cycle and neuronal differentiation was investigated. Treatment with VPA during the progenitor stages resulted in strong inhibition of cell proliferation and induction of neuronal differentiation, accompanied by increases in the expression of proneural transcription factors and in neuronal cell numbers. The increased expression of Ngn1, Math1 and p15 points to a shift towards neuronal fate in response to histone deacetylase inhibitors (HDACi). Chromatin immunoprecipitation (ChIP) analysis showed that acetylated histone H4 (Ac-H4) was associated with the Ngn1, Math1 and p15 promoters in cultured hippocampal neural progenitor cells. VPA-induced hippocampal neurogenesis was also accompanied by association of Ac-H4 with the Ngn1 promoter in hippocampal extracts. The discovery of an association between HDACi and the Ngn1, Math1 and p15 promoters extends the importance of HDAC inhibition as a key regulator of neuronal differentiation at the transcriptional level.

  11. The effect of valproic acid and oxcarbazepine on the distribution of adhesion molecules in embryo implantation

    International Nuclear Information System (INIS)

    Gürgen, Seren Gülşen; Erdoğan, Deniz; Coşkun, Zafer Kutay; Cansu, Ali

    2012-01-01

    This study was intended to investigate the effect of valproate (VPA) and oxcarbazepine (OXC) on embryo implantation in terms of extracellular matrix protein distribution. Thirty female rats (Wistar albino) were assigned to three groups of 10 animals each. Group 1 was administered two doses of saline solution, group 2, two doses of VPA at 300 mg/kg/day and group 3, two doses of OXC at 100 mg/kg/day, for a period of 3 months. Female rats with vaginal plugs mated with males for one night were placed into separate cages. Day of mating was taken as day 0, and implantation areas were obtained with rats being sacrificed on the morning of day 7. Immunohistochemical staining and electron microscopic protocols were then applied. At electron microscopic evaluation, extraembryonic endoderm and ectoderm layers could not be distinguished in semi-thin sections in the VPA group, while they were partially differentiated in the OXC group. At immunohistochemical staining, laminin was observed in the primary embryonic endoderm cell visceral and parietal layers, the uterine luminal epithelial cells and the secondary decidual zone in the control group. In the VPA group, it was weakly expressed in some embryo trophoectoderm cells and uterine luminal epithelial cells and moderately in some decidual cells. In the OXC group, it was moderately expressed in some trophoectoderm and decidual cells. Collagen IV was localized in the ectoplacental cone cells and secondary decidual zone and weak in the luminal epithelial cells in the control group. In the VPA and OXC groups, collagen IV was negative in all embryonic and maternal structures in the VPA and OXC groups. Vimentin was moderately expressed in the luminal epithelium and strongly expressed in the primary decidual zone and ectoplacental cone cells in the control group. In the VPA group, it was negative in the embryo trophoectoderm, decidual and uterine luminal epithelial cells, while in the OXC group it was moderately localized in the ectoplacental cone cells. The use of VPA and OXC has a negative effect on the expression of extracellular matrix proteins that play a key role in embryo implantation in young rats. This may lead to pregnancies ending in failure.

  12. Antiepileptic teratogen valproic acid (VPA) modulates organisation and dynamics of the actin cytoskeleton

    DEFF Research Database (Denmark)

    Walmod, P S; Skladchikova, G; Kawa, A

    1999-01-01

    for the VPA mediated inhibition of motility. In addition it is shown that the actomyosin cytoskeleton of VPA-treated cells was capable of contraction upon exposure to ATP, indicating that the reduced motility of VPA-treated cells was not caused by an inhibition of actomyosin contraction. On the other hand...... state. These findings indicate that VPA affects cell morphology and motility through interference with the dynamics of the actin cytoskeleton....

  13. The effects of valproic acid on the mRNA expression of Natriuretic ...

    African Journals Online (AJOL)

    Mona Hajikazemi

    2017-04-28

    Apr 28, 2017 ... Real Time RT-PCR was used to quantify differential mRNA expression of NPR-A and KCNQ1 genes. Two-way ANOVA and bonferroni post-tests were used to analyze data statistically. Results: We showed that VPA treatment inhibits the growth of SW-480 cells more efficiently compared to. HT-29. NPR-A ...

  14. The effects of valproic acid on the mRNA expression of Natriuretic ...

    African Journals Online (AJOL)

    Conclusion: The alteration of NPR-A and KCNQ1 genes were more ordered among SW-480 cancer cells. The expressional changes of KCNQ1 and NPR-A among VPA treated human colon cancer cells follow the same pattern in similar combinations. VPA could regulate the expression of KCNQ1 through altering the mRNA ...

  15. Different Resuscitation Strategies and Novel Pharmacologic Treatment with Valproic Acid in Traumatic Brain Injury

    Science.gov (United States)

    2017-07-25

    Fluid resuscitation Prompt fluid resuscitation is the first-line therapy to restore the lost intra- vascular volume. As blood products are often...Increased cell survival, and decreased apoptosis and necrosis TBI animal model Dekker et al., 2014b Spinal cord injury animal model Abdanipour et al...AL. were mapped to, among others, pathways related to cell death, apopto- sis, and necrosis (Dekker, 2014b). These findings support our hypothe- sis

  16. VALPROIC ACID-INDUCED BRAIN DAMAGE IN RATS AS A MODEL FOR AUTISM. (R824758)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  17. The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation

    NARCIS (Netherlands)

    Walasek, Marta A.; Bystrykh, Leonid; van den Boom, Vincent; Olthof, Sandra; Ausema, Albertina; Ritsema, Martha; Huls, Gerwin; de Haan, Gerald; van Os, Ronald

    2012-01-01

    Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small

  18. Gastric Varices with Remarkable Collateral Veins in Valpronic Acid-Induced Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Y. Hattori

    2008-08-01

    Full Text Available Valproic acid (VPA is a commonly prescribed and approved treatment for epilepsy, including Angelman syndrome, throughout the world. However, the long-term administration of drugs like VPA is associated with the possible development of gastric varices and splenic obstruction as a result of chronic pancreatitis. Such cases can be difficult to treat using endoscopy or interventional radiology because of hemodynamic abnormalities; therefore, surgical treatment is often necessary.

  19. Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic Acid animal model of autism

    DEFF Research Database (Denmark)

    Rinaldi, Tania; Perrodin, Catherine; Markram, Henry

    2008-01-01

    of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions...

  20. Quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid

    NARCIS (Netherlands)

    Piepers, Sanne; Cobben, Jan-Maarten; Sodaar, Peter; Jansen, Marc D.; Wadman, Renske I.; Meester-Delver, Ann; Poll-The, Bwee Tien; Lemmink, Henny H.; Wokke, John H. J.; van der Pol, W.-Ludo; van den Berg, Leonard H.

    2011-01-01

    Spinal muscular atrophy (SMA) is caused by the homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene produces small amounts of full-length mRNA and functional SMN protein, due to a point mutation in a critical splicing site. Increasing SMN protein production by

  1. Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity

    International Nuclear Information System (INIS)

    Di Renzo, Francesca; Cappelletti, Graziella; Broccia, Maria L.; Giavini, Erminio; Menegola, Elena

    2007-01-01

    Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice were treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 h after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor α = 0.51 and maximum velocity by a factor β = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations

  2. Systemic administration of valproic acid and zonisamide promotes the survival and differentiation of induced pluripotent stem cell–derived dopaminergic neurons

    OpenAIRE

    Tatsuya eYoshikawa; Tatsuya eYoshikawa; Tatsuya eYoshikawa; Bumpei eSamata; Bumpei eSamata; Aya eOgura; Aya eOgura; Susumu eMiyamoto; Jun eTakahashi; Jun eTakahashi; Jun eTakahashi

    2013-01-01

    Cell replacement therapy using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) is a promising strategy for the treatment of neurologic diseases such as Parkinson’s disease (PD). However, a limiting factor for effective cell transplantation is the low survival rate of grafted cells, especially neurons. In this study, we modified the host environment and investigated whether the simultaneous administration of soluble factors can improve the survival and differentiation of...

  3. Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock

    DEFF Research Database (Denmark)

    Dekker, Simone E; Sillesen, Martin; Bambakidis, Ted

    2014-01-01

    synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. MATERIALS AND METHODS: Ten swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were...... neuroprotective effects of VPA may be due to a conservation of platelet function as measured by a higher platelet activation response after resuscitation....... left in shock for 2 h before resuscitation with either FFP or FFP + VPA (300 mg/kg). Serum levels of platelet activation markers transforming growth factor beta, CD40 L, P-selectin, and platelet endothelial cell adhesion molecule (PECAM) 1 were measured at baseline, postresuscitation, and after a 6-h...

  4. The pharmacokinetics of oxcarbazepine and its active metabolite 10-hydroxy-carbazepine in healthy subjects and in epileptic patients treated with phenobarbitone or valproic acid.

    Science.gov (United States)

    Tartara, A; Galimberti, C A; Manni, R; Morini, R; Limido, G; Gatti, G; Bartoli, A; Strada, G; Perucca, E

    1993-01-01

    The kinetics of oxcarbazepine (OXC) and its active metabolite 10-hydroxy-carbazepine (10-OH-CZ) after a single oral OXC dose (600 mg) were compared in healthy control subjects and in epileptic patients treated with phenobarbitone or sodium valproate (n = 8 in each group). In all groups, serum 10-OH-CZ concentrations were much higher than those of the parent drug. In patients on valproate, the kinetics of OXC and 10-OH-CZ did not differ significantly from those observed in controls. In patients on phenobarbitone, AUC values of both OXC and 10-OH-CZ were lower than in controls (2.9 +/- 0.4 vs 5.1 +/- 0.7 microg ml(-1) h and 89 +/- 7 vs 119 +/- 10 microg ml(-1) h respectively, means +/- s.e. mean, P effect is unlikely to be of great clinical significance. PMID:12959317

  5. Efficacy and safety of valproic acid versus haloperidol in patients with acute agitation: results of a randomized, double-blind, parallel-group trial.

    Science.gov (United States)

    Asadollahi, Shadi; Heidari, Kamran; Hatamabadi, Hamidreza; Vafaee, Reza; Yunesian, Somayeh; Azadbakht, Alireza; Mirmohseni, Ladan

    2015-05-01

    The objective of this study was to compare the efficacy of valproate versus haloperidol in decreasing the agitation level in affected patients in the emergency department. We assigned 80 acutely agitated patients to receive either intravenous sodium valproate (20 mg/kg) or intramuscular haloperidol (5 mg/1 ml). Agitation was measured at baseline and 30 min after the first injection using the Agitation-Calmness Evaluation Scale (ACES), the Positive and Negative Syndrome Scale-Excited Component subscale, and the Agitated Behavior Scale. For 80 patients treated with sodium valproate, the mean ± SD dosage was 1541.5 ± 286 mg (range 940-2400). The mean postintervention ACES scores from baseline to 30 min after drug injection were 4.73 (SD = 1.93) for the valproate group and 5.45 (SD = 2.09) for the haloperidol group (P = 0.028). No significant differences were observed in terms of the mean changes 30 min after the intervention for two additional agitation scales. A larger proportion of patients in the haloperidol group experienced intense sedation (36.2%, P haloperidol in reducing agitation, with a better safety profile.

  6. Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL

    Directory of Open Access Journals (Sweden)

    Han Seol

    2011-07-01

    Full Text Available Abstract Background At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. Methods Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C. diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay. Results In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. Conclusion To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally critical periods through the degradation of IκBα and the activation of NF-κB signaling. The reduced NPCs death might underlie the neurodevelopmental defects collectively called fetal valproate syndrome, which shows symptoms such as mental retardation and autism-like behavior.

  7. Valproic acid silencing of ascl1b/Ascl1 results in the failure of serotonergic differentiation in a zebrafish model of fetal valproate syndrome

    Directory of Open Access Journals (Sweden)

    John Jacob

    2014-01-01

    Full Text Available Fetal valproate syndrome (FVS is caused by in utero exposure to the drug sodium valproate. Valproate is used worldwide for the treatment of epilepsy, as a mood stabiliser and for its pain-relieving properties. In addition to birth defects, FVS is associated with an increased risk of autism spectrum disorder (ASD, which is characterised by abnormal behaviours. Valproate perturbs multiple biochemical pathways and alters gene expression through its inhibition of histone deacetylases. Which, if any, of these mechanisms is relevant to the genesis of its behavioural side effects is unclear. Neuroanatomical changes associated with FVS have been reported and, among these, altered serotonergic neuronal differentiation is a consistent finding. Altered serotonin homeostasis is also associated with autism. Here we have used a chemical-genetics approach to investigate the underlying molecular defect in a zebrafish FVS model. Valproate causes the selective failure of zebrafish central serotonin expression. It does so by downregulating the proneural gene ascl1b, an ortholog of mammalian Ascl1, which is a known determinant of serotonergic identity in the mammalian brainstem. ascl1b is sufficient to rescue serotonin expression in valproate-treated embryos. Chemical and genetic blockade of the histone deacetylase Hdac1 downregulates ascl1b, consistent with the Hdac1-mediated silencing of ascl1b expression by valproate. Moreover, tonic Notch signalling is crucial for ascl1b repression by valproate. Concomitant blockade of Notch signalling restores ascl1b expression and serotonin expression in both valproate-exposed and hdac1 mutant embryos. Together, these data provide a molecular explanation for serotonergic defects in FVS and highlight an epigenetic mechanism for genome-environment interaction in disease.

  8. Effect of valproic acid and injury on lesion size and endothelial glycocalyx shedding in a rodent model of isolated traumatic brain injury

    DEFF Research Database (Denmark)

    Jepsen, Cecilie Heerdegen; deMoya, Marc A; Perner, Anders

    2014-01-01

    were analyzed for sSDC-1, and lesion size was determined on Nissl-stained cryosections. RESULTS: sSDC-1 was significantly elevated in injured compared with uninjured animals at 3 hours (p = 0.0009) and 6 hours (p = 0.0007) after injury. This effect was significantly more pronounced in the animals...

  9. Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder.

    Science.gov (United States)

    Yoshimi, Noriko; Futamura, Takashi; Kakumoto, Keiji; Salehi, Alireza M; Sellgren, Carl M; Holmén-Larsson, Jessica; Jakobsson, Joel; Pålsson, Erik; Landén, Mikael; Hashimoto, Kenji

    2016-06-01

    Bipolar disorder (BD) is a severe and debilitating psychiatric disorder. However, the precise biological basis remains unknown, hampering the search for novel biomarkers. We performed a metabolomics analysis to discover novel peripheral biomarkers for BD. We quantified serum levels of 116 metabolites in mood-stabilized male BD patients (n = 54) and age-matched male healthy controls (n = 39). After multivariate logistic regression, serum levels of pyruvate, N-acetylglutamic acid, α-ketoglutarate, and arginine were significantly higher in BD patients than in healthy controls. Conversely, serum levels of β-alanine, and serine were significantly lower in BD patients than in healthy controls. Chronic (4-weeks) administration of lithium or valproic acid to adult male rats did not alter serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, or arginine, but lithium administration significantly increased serum levels of α-ketoglutarate. The metabolomics analysis demonstrated altered serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, and arginine in BD patients. The present findings suggest that abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism play a role in the pathogenesis of BD.

  10. Aspartic acid

    Science.gov (United States)

    ... we eat. Aspartic acid is also called asparaginic acid. Aspartic acid helps every cell in the body work. It ... release Normal nervous system function Plant sources of aspartic acid include: avocado, asparagus, and molasses. Animal sources of ...

  11. Transport of monocarboxylic acids at the blood-brain barrier: Studies with monolayers of primary cultured bovine brain capillary endothelial cells

    International Nuclear Information System (INIS)

    Terasaki, T.; Takakuwa, S.; Moritani, S.; Tsuji, A.

    1991-01-01

    The kinetics and mechanism of the transport of monocarboxylic acids (MCAs) were studied by using primary cultured bovine brain capillary endothelial cells. Concentration-dependent uptake of acetic acid was observed, and the kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 3.41 ± 1.87 mM, the maximum uptake rate, Jmax, was 144.7 ± 55.7 nmol/mg of protein/min and the nonsaturable first-order rate constant, Kd, was 6.66 ± 1.98 microliters/mg of protein/min. At medium pH below 7.0, the uptake rate of [3H]acetic acid increased markedly with decreasing medium pH, whereas pH-independent uptake was observed in the presence of 10 mM acetic acid. An energy requirement for [3H]acetic acid uptake was also demonstrated, because metabolic inhibitors (2,4-dinitrophenol and rotenone) reduced significantly the uptake rate (P less than .05). Carbonylcyanide-p-trifluoro-methoxyphenylhydrazone, a protonophore, inhibited significantly the uptake of [3H]acetic acid at medium pH of 5.0 and 6.0, whereas 4,4'-diisothiocyanostilben-2,2'-disulfonic acid did not. Several MCAs inhibited significantly the uptake rate of [3H]acetic acid, whereas di- and tricarboxylic acids did not. The uptake of [3H]acetic acid was competitively inhibited by salicylic acid, with an inhibition constant, Ki, of 3.60 mM, suggesting a common transport system between acetic acid and salicylic acid. Moreover, at the medium pH of 7.4, salicylic acid and valproic acid inhibited significantly the uptake of [3H]acetic acid, demonstrating that the transport of MCA drugs could also be ascribed to the MCA transport system at the physiologic pH

  12. Decrease of intracellular pH as possible mechanism of embryotoxicity of glycol ether alkoxyacetic acid metabolites

    International Nuclear Information System (INIS)

    Louisse, Jochem; Bai Yanqing; Verwei, Miriam; Sandt, Johannes J.M. van de; Blaauboer, Bas J.; Rietjens, Ivonne M.C.M.

    2010-01-01

    Embryotoxicity of glycol ethers is caused by their alkoxyacetic acid metabolites, but the mechanism underlying the embryotoxicity of these acid metabolites is so far not known. The present study investigates a possible mechanism underlying the embryotoxicity of glycol ether alkoxyacetic acid metabolites using the methoxyacetic acid (MAA) metabolite of ethylene glycol monomethyl ether as the model compound. The results obtained demonstrate an MAA-induced decrease of the intracellular pH (pH i ) of embryonic BALB/c-3T3 cells as well as of embryonic stem (ES)-D3 cells, at concentrations that affect ES-D3 cell differentiation. These results suggest a mechanism for MAA-mediated embryotoxicity similar to the mechanism of embryotoxicity of the drugs valproic acid and acetazolamide (ACZ), known to decrease the pH i in vivo, and therefore used as positive controls. The embryotoxic alkoxyacetic acid metabolites ethoxyacetic acid, butoxyacetic acid and phenoxyacetic acid also caused an intracellular acidification of BALB/c-3T3 cells at concentrations that are known to inhibit ES-D3 cell differentiation. Two other embryotoxic compounds, all-trans-retinoic acid and 5-fluorouracil, did not decrease the pH i of embryonic cells at concentrations that affect ES-D3 cell differentiation, pointing at a different mechanism of embryotoxicity of these compounds. MAA and ACZ induced a concentration-dependent inhibition of ES-D3 cell differentiation, which was enhanced by amiloride, an inhibitor of the Na + /H + -antiporter, corroborating an important role of the pH i in the embryotoxic mechanism of both compounds. Together, the results presented indicate that a decrease of the pH i may be the mechanism of embryotoxicity of the alkoxyacetic acid metabolites of the glycol ethers.

  13. Discriminative power of an assay for automated in vitro screening of teratogens

    DEFF Research Database (Denmark)

    Walmod, Peter S; Gravemann, Ute; Nau, Heinz

    2004-01-01

    -trans-retinoic acid, pentyl-4-yn-valproic acid, saccharin, salicylic acid and valproic acid. All compounds, with the exception of dimethadione inhibited proliferation in a linear dose-dependent manner, and there were statistically significant compound class-dependent differences between the IC(50)-values...... to teratogenicity were: 5-bromo-2(')-deoxyuridine, 6-aminonicotinamide, acrylamide, boric acid, D-(+)-camphor, dimethadione, dimethyl phthalate, diphenhydramine, hydroxyurea, isobutyl-ethyl-valproic acid, lithium chloride, methyl mercury chloride, methotrexate, methoxyacetic acid, penicillin G, all...

  14. Acid Rain

    Science.gov (United States)

    Bricker, Owen P.; Rice, Karen C.

    1995-01-01

    Although acid rain is fading as a political issue in the United States and funds for research in this area have largely disappeared, the acidity of rain in the Eastern United States has not changed significantly over the last decade, and it continues to be a serious environmental problem. Acid deposition (commonly called acid rain) is a term applied to all forms of atmospheric deposition of acidic substances - rain, snow, fog, acidic dry particulates, aerosols, and acid-forming gases. Water in the atmosphere reacts with certain atmospheric gases to become acidic. For example, water reacts with carbon dioxide in the atmosphere to produce a solution with a pH of about 5.6. Gases that produce acids in the presence of water in the atmosphere include carbon dioxide (which converts to carbonic acid), oxides of sulfur and nitrogen (which convert to sulfuric and nitric acids}, and hydrogen chloride (which converts to hydrochloric acid). These acid-producing gases are released to the atmosphere through natural processes, such as volcanic emissions, lightning, forest fires, and decay of organic matter. Accordingly, precipitation is slightly acidic, with a pH of 5.0 to 5.7 even in undeveloped areas. In industrialized areas, most of the acid-producing gases are released to the atmosphere from burning fossil fuels. Major emitters of acid-producing gases include power plants, industrial operations, and motor vehicles. Acid-producing gases can be transported through the atmosphere for hundreds of miles before being converted to acids and deposited as acid rain. Because acids tend to build up in the atmosphere between storms, the most acidic rain falls at the beginning of a storm, and as the rain continues, the acids "wash out" of the atmosphere.

  15. Amino acids

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002222.htm Amino acids To use the sharing features on this page, please enable JavaScript. Amino acids are organic compounds that combine to form proteins . ...

  16. Ascorbic Acid

    Science.gov (United States)

    Ascorbic acid is used to prevent and treat scurvy, a disease caused by a lack of vitamin C in ... Ascorbic acid comes in extended-release (long-acting) capsules and tablets, lozenges, syrup, chewable tablets, and liquid drops to ...

  17. Aminocaproic Acid

    Science.gov (United States)

    Aminocaproic acid is used to control bleeding that occurs when blood clots are broken down too quickly. This type ... the baby is ready to be born). Aminocaproic acid is also used to control bleeding in the ...

  18. Ethacrynic Acid

    Science.gov (United States)

    Ethacrynic acid, a 'water pill,' is used to treat swelling and fluid retention caused by various medical problems. It ... Ethacrynic acid comes as a tablet to take by mouth. It is usually taken once or twice a day ...

  19. Well acidizing

    Energy Technology Data Exchange (ETDEWEB)

    Street, E H

    1980-01-23

    The apparatus relates in particular to a well-treating process in which an aqueous acid solution having a pH of < 2 is injected into a subterranean reservoir in a manner such that materials that contain ferric ions are present in the acid and, as the acid reacts within the reservoir and attains a pH exceeding 3, tend to be precipitated as ferric ion-containing solid materials that may plug the pores of the reservoir. Such a precipitation is prevented by dissolving in the acid solution an amount of 5-sulfosalicylic acid which is at least sufficient to sequester significant proportions of ferric ions when the pH of the acid is from 0.5 to 3 but is less than enough to cause a significant salting-out of solid materials, and an amount of citric acid which is at least sufficient to sequester significant proportions of ferric ions when the pH of the acid is from 3 to 6 but is less than enough to precipitate a significant amount of calcium citrate. The amount of the 5-sulfosalicylic acid may be from 0.01 to 0.05 moles/l and the amount of citric acid is from 0.001 to 0.009 moles/l. 11 claims.

  20. Ibotenic acid and thioibotenic acid

    DEFF Research Database (Denmark)

    Hermit, Mette B; Greenwood, Jeremy R; Nielsen, Birgitte

    2004-01-01

    In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines....... Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid...... with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid...

  1. Formic acid

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, H; Laing, B

    1921-12-03

    The production of formic acid by the oxidation of methane with a metallic oxide or by the interaction of carbon monoxide and water vapor in the presence of a catalyst, preferably a metallic oxide, is described along with the destructive distillation of carbonaceous material in the preesnce of formic acid vapor for the purpose of increasing the yield of condensible hydrocarbons.

  2. Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder.

    Science.gov (United States)

    Modi, Hiren R; Ma, Kaizong; Chang, Lisa; Chen, Mei; Rapoport, Stanley I

    2017-08-01

    Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro. Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro. VCD like VPA will reduce brain AA turnover in unanaesthetized rats. A therapeutically relevant (50mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1- 14 C]AA in unanaesthetized rats for 10min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. VCD's ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD. Published by Elsevier B.V.

  3. Lipoic Acid

    Directory of Open Access Journals (Sweden)

    Ramazan Tetikcok

    2015-09-01

    Full Text Available Lipoic acid, which is defined as a miralce antioxidan, is used by many departments. Eventhough clinical using data are very limited , it is used in treatment of diabetic neuropathy, physical therapy and rehabilitation clinic, dermatology clinic, geriatric clinics. It has usage area for cosmetic purposes. Although there are reports there are the direction of the effectiveness in these areas, the works done are not enough. Today lipoic acid , used in many areas ,is evaluated as universal antioxidant [J Contemp Med 2015; 5(3.000: 206-209

  4. Mefenamic Acid

    Science.gov (United States)

    Mefenamic acid comes as a capsule to take by mouth. It is usually taken with food every 6 hours as needed for up to 1 week. Follow ... pain vomit that is bloody or looks like coffee grounds black, tarry, or bloody stools slowed breathing ...

  5. Acid rain. Les pluies acides

    Energy Technology Data Exchange (ETDEWEB)

    Curren, T

    1979-11-28

    This report was produced for the use of Members of Parliament and House of Commons committees. The document describes the formation of acid rain, emissions of acidifying pollutants in North America, the growth of the problem and its environmental effects on aquatic and terrestrial ecosystems, human health and man-made structures. Areas of Canada which are most susceptible are identified. Actions taken by Parliament are given, including the formation of a sub-committee on acid rain and the passing of Bill C-51 in 1980 to amend the Clean Air Act, bringing it closer to a similar law in the U.S. A chronology of government responses to acid rain at the international, national and provincial level, is given. The most recent government actions included the passing of the US Clean Air Act by the Senate, the amending of the act into law, and commencement of negotiations to develop a Canada-US Air Quality Accord. 10 refs.

  6. Long-Term Intake of Uncaria rhynchophylla Reduces S100B and RAGE Protein Levels in Kainic Acid-Induced Epileptic Seizures Rats

    Directory of Open Access Journals (Sweden)

    Nou-Ying Tang

    2017-01-01

    Full Text Available Epileptic seizures are crucial clinical manifestations of recurrent neuronal discharges in the brain. An imbalance between the excitatory and inhibitory neuronal discharges causes brain damage and cell loss. Herbal medicines offer alternative treatment options for epilepsy because of their low cost and few side effects. We established a rat epilepsy model by injecting kainic acid (KA, 12 mg/kg, i.p. and subsequently investigated the effect of Uncaria rhynchophylla (UR and its underlying mechanisms. Electroencephalogram and epileptic behaviors revealed that the KA injection induced epileptic seizures. Following KA injection, S100B levels increased in the hippocampus. This phenomenon was attenuated by the oral administration of UR and valproic acid (VA, 250 mg/kg. Both drugs significantly reversed receptor potentiation for advanced glycation end product proteins. Rats with KA-induced epilepsy exhibited no increase in the expression of metabotropic glutamate receptor 3, monocyte chemoattractant protein 1, and chemokine receptor type 2, which play a role in inflammation. Our results provide novel and detailed mechanisms, explaining the role of UR in KA-induced epileptic seizures in hippocampal CA1 neurons.

  7. Long-Term Intake of Uncaria rhynchophylla Reduces S100B and RAGE Protein Levels in Kainic Acid-Induced Epileptic Seizures Rats.

    Science.gov (United States)

    Tang, Nou-Ying; Lin, Yi-Wen; Ho, Tin-Yun; Cheng, Chin-Yi; Chen, Chao-Hsiang; Hsieh, Ching-Liang

    2017-01-01

    Epileptic seizures are crucial clinical manifestations of recurrent neuronal discharges in the brain. An imbalance between the excitatory and inhibitory neuronal discharges causes brain damage and cell loss. Herbal medicines offer alternative treatment options for epilepsy because of their low cost and few side effects. We established a rat epilepsy model by injecting kainic acid (KA, 12 mg/kg, i.p.) and subsequently investigated the effect of Uncaria rhynchophylla (UR) and its underlying mechanisms. Electroencephalogram and epileptic behaviors revealed that the KA injection induced epileptic seizures. Following KA injection, S100B levels increased in the hippocampus. This phenomenon was attenuated by the oral administration of UR and valproic acid (VA, 250 mg/kg). Both drugs significantly reversed receptor potentiation for advanced glycation end product proteins. Rats with KA-induced epilepsy exhibited no increase in the expression of metabotropic glutamate receptor 3, monocyte chemoattractant protein 1, and chemokine receptor type 2, which play a role in inflammation. Our results provide novel and detailed mechanisms, explaining the role of UR in KA-induced epileptic seizures in hippocampal CA1 neurons.

  8. Uncaria rhynchophylla and Rhynchophylline inhibit c-Jun N-terminal kinase phosphorylation and nuclear factor-kappaB activity in kainic acid-treated rats.

    Science.gov (United States)

    Hsieh, Ching-Liang; Ho, Tin-Yun; Su, Shan-Yu; Lo, Wan-Yu; Liu, Chung-Hsiang; Tang, Nou-Ying

    2009-01-01

    Our previous studies have shown that Uncaria rhynchophylla (UR) can reduce epileptic seizures. We hypothesized that UR and its major component rhynchophylline (RH), reduce epileptic seizures in rats treated with kainic acid (KA) by inhibiting nuclear factor-kappaB (NF-kappaB) and activator-protein-1 (AP-1) activity, and by eliminating superoxide anions. Therefore, the level of superoxide anions and the DNA binding activities of NF-kappaB and AP-1 were measured. Sprague-Dawley (SD) rats were pre-treated with UR (1.0 g/kg, i.p.), RH (0.25 mg/kg, i.p.), or valproic acid (VA, 250 mg/kg, i.p.) for 3 days and then KA was administered intra-peritoneal (i.p.). The results indicated that UR, RH, and VA can reduce epileptic seizures and the level of superoxide anions in the blood. Furthermore, KA was demonstrated to induce the DNA binding activities of NF-kappaB and AP-1. However, these inductions were inhibited by pre-treatment with UR, RH, or VA for 3 days. Moreover, UR and RH were shown to be involved in the suppression of c-Jun N-terminal kinase (JNK) phosphorylation. This study suggested that UR and RH have antiepileptic effects in KA-induced seizures and are associated with the regulation of the innate immune system via a reduction in the level of superoxide anions, JNK phosphorylation, and NF-kappaB activation.

  9. Teratology study of amide derivatives of branched aliphatic carboxylic acids with 4-aminobenzensulfonamide in NMRI mice.

    Science.gov (United States)

    Onishi, Yuko; Okada, Akinobu; Noyori, Hiroko; Okamura, Ai; Hen, Naama; Yagen, Boris; Bialer, Meir; Fujiwara, Michio

    2013-08-01

    Valproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (MSP), 2-ethyl-N-(4-sulfamoyl-phenyl)-butyramide (ESB), 2-ethyl-4-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (EMSP), and 2-ethyl-N-(4-sulfamoyl-benzyl)-butyramide (ESBB), have shown more potent anticonvulsant activity than VPA in preclinical testing. Here, we investigated the teratogenic effects of these analogous compounds of VPA in NMRI mice. Pregnant NMRI mice were given a single subcutaneous injection of either VPA at 1.8 or 3.6 mmol/kg, or MSP, ESB, EMSP, or ESBB at 1.8, 3.6, or 4.8 mmol/kg on gestation day (GD) 8. Cesarean section was performed on GD 18, and the live fetuses were examined for external and skeletal malformations. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at dose levels up to 4.8 mmol/kg (except for a single case of exencephaly at 4.8 mmol/kg MSP). Skeletal examination showed several abnormalities mainly at the axial skeletal level with VPA at 1.8 mmol/kg. Fused vertebrae and/or fused ribs were also observed with MSP, ESB, EMSP, and ESBB, they were less severe and seen at a lower incidence that those induced by VPA at the same dose level. In addition to exerting more potent preclinical antiepileptic activity, teratology comparison indicates that aminobenzensulfonamide analogs are generally more weakly teratogenic than VPA. © 2013 Wiley Periodicals, Inc.

  10. Levulinic acid

    Directory of Open Access Journals (Sweden)

    Barbara Hachuła

    2013-09-01

    Full Text Available The title compound (systematic name: 4-oxopentanoic acid, C5H8O3, is close to planar (r.m.s. deviation = 0.0762 Å. In the crystal, the molecules interact via O—H...O hydrogen bonds in which the hydroxy O atoms act as donors and the ketone O atoms in adjacent molecules as acceptors, forming C(7 chains along [20-1].

  11. Understanding Acid Rain

    Science.gov (United States)

    Damonte, Kathleen

    2004-01-01

    The term acid rain describes rain, snow, or fog that is more acidic than normal precipitation. To understand what acid rain is, it is first necessary to know what an acid is. Acids can be defined as substances that produce hydrogen ions (H+), when dissolved in water. Scientists indicate how acidic a substance is by a set of numbers called the pH…

  12. The acidic functional groups of humic acid

    Energy Technology Data Exchange (ETDEWEB)

    Shanxiang, Li; Shuhe, Sun; Zhai Zongxi, Wu Qihu

    1983-09-01

    The acidic functional groups content, pK value, DELTAH and DELTAS of humic acid (HA) and nitro-humic acid (NHA) were determined by potentiometry, conductometry and calorimetric titration. The thermodynamic parameters of carboxylic groups and phenolic hydroxyl groups of humic acid are similar to that of simple hydroxy-benzoic acid. The configuration sites of acidic functional groups in humic acid from different coals are different. The carbonyl groups on aromatic rings are probably ortho to phenolic -OH for HA and NHA extracted from Huangxian's brown coal and Japanese lignite, while those from Lingshi's weathered coal are not. The weak -COOH groups of the latter possess higher chemical activity. The -COOH content in HA increases, phenolic -OH group decreases and the chemical acidity of acidic functional groups increases when HA is oxidized by nitric acid. (14 refs.)

  13. Okadaic acid

    DEFF Research Database (Denmark)

    Danielsen, E Michael; Hansen, Gert H; Severinsen, Mai C K

    2014-01-01

    are the hallmark of phospholipidosis, a pathological condition characterized by lysosomal phospholipid accumulation. Phospholipidosis is observed in acquired lysosomal storage diseases and is induced by a large number of cationic amphiphilic drugs. Unlike the latter, however, OA does not act by accumulating...... in acidic organelles, implying a different toxic mechanism of action. We propose that rapid induction of LBs, an indicator of phospholipidosis, should be included in the future toxicity profile of OA....... hyper protein phosphorylation, but no detectable loss of cell polarity or cytoskeletal integrity of the enterocytes. Using a fluorescent membrane marker, FM dye, endocytosis from the brush border was affected by the toxin. Although constitutive uptake into subapical terminal web-localized early...

  14. Histone deactylase gene expression profiles are associated with outcomes in blunt trauma patients

    DEFF Research Database (Denmark)

    Sillesen, Martin; Bambakidis, Ted; Dekker, Simone E

    2016-01-01

    BACKGROUND: Treatment with histone deacetylase (HDAC) inhibitors, such as valproic acid, increases survival in animal models of trauma and sepsis. Valproic acid is a pan-inhibitor that blocks most of the known HDAC isoforms. Targeting individual HDAC isoforms may increase survival and reduce...

  15. Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

    Science.gov (United States)

    Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

    2016-04-15

    This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Copyright © 2016. Published by Elsevier Ltd.

  16. Antiepileptic Effect of Uncaria rhynchophylla and Rhynchophylline Involved in the Initiation of c-Jun N-Terminal Kinase Phosphorylation of MAPK Signal Pathways in Acute Seizures of Kainic Acid-Treated Rats

    Directory of Open Access Journals (Sweden)

    Hsin-Cheng Hsu

    2013-01-01

    Full Text Available Seizures cause inflammation of the central nervous system. The extent of the inflammation is related to the severity and recurrence of the seizures. Cell surface receptors are stimulated by stimulators such as kainic acid (KA, which causes intracellular mitogen-activated protein kinase (MAPK signal pathway transmission to coordinate a response. It is known that Uncaria rhynchophylla (UR and rhynchophylline (RP have anticonvulsive effects, although the mechanisms remain unclear. Therefore, the purpose of this study is to develop a novel strategy for treating epilepsy by investigating how UR and RP initiate their anticonvulsive mechanisms. Sprague-Dawley rats were administered KA (12 mg/kg, i.p. to induce seizure before being sacrificed. The brain was removed 3 h after KA administration. The results indicate that pretreatment with UR (1.0 g/kg, RP (0.25 mg/kg, and valproic acid (VA, 250 mg/kg for 3 d could reduce epileptic seizures and could also reduce the expression of c-Jun aminoterminal kinase phosphorylation (JNKp of MAPK signal pathways in the cerebral cortex and hippocampus brain tissues. Proinflammatory cytokines interleukin (IL-1β, IL-6, and tumor necrosis factor-α remain unchanged, indicating that the anticonvulsive effect of UR and RP is initially involved in the JNKp MAPK signal pathway during the KA-induced acute seizure period.

  17. Antiepileptic Effect of Uncaria rhynchophylla and Rhynchophylline Involved in the Initiation of c-Jun N-Terminal Kinase Phosphorylation of MAPK Signal Pathways in Acute Seizures of Kainic Acid-Treated Rats.

    Science.gov (United States)

    Hsu, Hsin-Cheng; Tang, Nou-Ying; Liu, Chung-Hsiang; Hsieh, Ching-Liang

    2013-01-01

    Seizures cause inflammation of the central nervous system. The extent of the inflammation is related to the severity and recurrence of the seizures. Cell surface receptors are stimulated by stimulators such as kainic acid (KA), which causes intracellular mitogen-activated protein kinase (MAPK) signal pathway transmission to coordinate a response. It is known that Uncaria rhynchophylla (UR) and rhynchophylline (RP) have anticonvulsive effects, although the mechanisms remain unclear. Therefore, the purpose of this study is to develop a novel strategy for treating epilepsy by investigating how UR and RP initiate their anticonvulsive mechanisms. Sprague-Dawley rats were administered KA (12 mg/kg, i.p.) to induce seizure before being sacrificed. The brain was removed 3 h after KA administration. The results indicate that pretreatment with UR (1.0 g/kg), RP (0.25 mg/kg), and valproic acid (VA, 250 mg/kg) for 3 d could reduce epileptic seizures and could also reduce the expression of c-Jun aminoterminal kinase phosphorylation (JNKp) of MAPK signal pathways in the cerebral cortex and hippocampus brain tissues. Proinflammatory cytokines interleukin (IL)-1 β , IL-6, and tumor necrosis factor- α remain unchanged, indicating that the anticonvulsive effect of UR and RP is initially involved in the JNKp MAPK signal pathway during the KA-induced acute seizure period.

  18. [Teichoic acids from lactic acid bacteria].

    Science.gov (United States)

    Livins'ka, O P; Harmasheva, I L; Kovalenko, N K

    2012-01-01

    The current view of the structural diversity of teichoic acids and their involvement in the biological activity of lactobacilli has been reviewed. The mechanisms of effects of probiotic lactic acid bacteria, in particular adhesive and immunostimulating functions have been described. The prospects of the use of structure data of teichoic acid in the assessment of intraspecific diversity of lactic acid bacteria have been also reflected.

  19. Plasma amino acids

    Science.gov (United States)

    Amino acids blood test ... types of methods used to determine the individual amino acid levels in the blood. ... test is done to measure the level of amino acids in the blood. An increased level of a ...

  20. Uric acid - urine

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003616.htm Uric acid urine test To use the sharing features on ... are no risks with this test. Images Uric acid test Uric acid crystals References Burns CM, Wortmann RL. Clinical ...

  1. Uric acid test (image)

    Science.gov (United States)

    Uric acid urine test is performed to check for the amount of uric acid in urine. Urine is collected over a 24 ... for testing. The most common reason for measuring uric acid levels is in the diagnosis or treatment of ...

  2. Methylmalonic acid blood test

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003565.htm Methylmalonic acid blood test To use the sharing features on this page, please enable JavaScript. The methylmalonic acid blood test measures the amount of methylmalonic acid in the ...

  3. Facts about Folic Acid

    Science.gov (United States)

    ... Information For… Media Policy Makers Facts About Folic Acid Language: English (US) Español (Spanish) Recommend on Facebook ... of the baby’s brain and spine. About folic acid Folic acid is a B vitamin. Our bodies ...

  4. Acid distribution in phosphoric acid fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Okae, I.; Seya, A.; Umemoto, M. [Fuji Electric Co., Ltd., Chiba (Japan)

    1996-12-31

    Electrolyte acid distribution among each component of a cell is determined by capillary force when the cell is not in operation, but the distribution under the current load conditions had not been clear so far. Since the loss of electrolyte acid during operation is inevitable, it is necessary to store enough amount of acid in every cell. But it must be under the level of which the acid disturbs the diffusion of reactive gases. Accordingly to know the actual acid distribution during operation in a cell is very important. In this report, we carried out experiments to clarify the distribution using small single cells.

  5. Activation and Repression of Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycles by Short- and Medium-Chain Fatty Acids

    Science.gov (United States)

    Gorres, Kelly L.; Daigle, Derek; Mohanram, Sudharshan

    2014-01-01

    ABSTRACT The lytic cycles of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are induced in cell culture by sodium butyrate (NaB), a short-chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitor. Valproic acid (VPA), another SCFA and an HDAC inhibitor, induces the lytic cycle of KSHV but blocks EBV lytic reactivation. To explore the hypothesis that structural differences between NaB and VPA account for their functional effects on the two related viruses, we investigated the capacity of 16 structurally related short- and medium-chain fatty acids to promote or prevent lytic cycle reactivation. SCFAs differentially affected EBV and KSHV reactivation. KSHV was reactivated by all SCFAs that are HDAC inhibitors, including phenylbutyrate. However, several fatty acid HDAC inhibitors, such as isobutyrate and phenylbutyrate, did not reactivate EBV. Reactivation of KSHV lytic transcripts could not be blocked completely by any fatty acid tested. In contrast, several medium-chain fatty acids inhibited lytic activation of EBV. Fatty acids that blocked EBV reactivation were more lipophilic than those that activated EBV. VPA blocked activation of the BZLF1 promoter by NaB but did not block the transcriptional function of ZEBRA. VPA also blocked activation of the DNA damage response that accompanies EBV lytic cycle activation. Properties of SCFAs in addition to their effects on chromatin are likely to explain activation or repression of EBV. We concluded that fatty acids stimulate the two related human gammaherpesviruses to enter the lytic cycle through different pathways. IMPORTANCE Lytic reactivation of EBV and KSHV is needed for persistence of these viruses and plays a role in carcinogenesis. Our direct comparison highlights the mechanistic differences in lytic reactivation between related human oncogenic gammaherpesviruses. Our findings have therapeutic implications, as fatty acids are found in the diet and produced by the human microbiota

  6. The Teratogenicity and the Action Mechanism of Gallic Acid Relating with Brain and Cervical Muscles

    Science.gov (United States)

    Hsieh, Chiu Lan; Lin, Chien-Hong; Chen, Kuan Chou; Peng, Chiung-Chi; Peng, Robert Y.

    2015-01-01

    Gallic acid (3,4,5-trihydroxybenzoic acid) (GA) and other flavanoids are extensively used in nutraceuticals because of their antioxidant and antiinflammatory properties. While examining whether GA is effective in alleviating valproic-acid-induced teratogenesis in a chicken embryo model (CEM), we observed embryo hemorrhage and liposis in the musculi longissimus cervicis. We conducted this study to determine whether GA is inherently teratogenic and the extent to which the risk can be transferred to fetuses. A CEM was used to administer GA at 2, 6, 10, and 14 μM. GA at 2 μM did not exhibit cytotoxicity. At 6, 10, and 14 μM, GA caused severe decreases in body and liver weights, causing -5.6%, -21.3%, and -27.5% body weights and 4.0, 3.8, and 3.2-g, liver weights, respectively, in day-1 chicks. The optimal alive birth rate (or damaging rate) reached 33.3%, 39.4%, and 29.2% at 6, 10, and 14 μM GA, respectively. The damaged tissue was primarily cervical muscle (musculi longissimus cervicis), as evidenced by liposis, Zenker’s necrosis, and hemolysis. The erythrocyte, hemoglobin, eosinophil, lymphocyte, and monocyte counts were severely reduced and PPAR-α was downregulated, whereas the Ras/Raf/JAK/STAT pathway was upregulated. The GA dose required to induce teratogenesis was ≥ 6 μM (1.02 mg/kg), which can be easily consumed by pregnant women in typical teas such as Chinese Pu-’Er and Chinese black teas, indicating a potential risk to human fetuses. GA at doses ≥ 1.02 mg/kg of body weight potentially causes characteristic cerebral hemolysis and liposis in the musculi longissimus cervicis. The mechanism of action of GA is multidisciplinary: The liposis can be ascribed to downregulation of PPAR-α; the erythrocyte hemolysis can be attributed to its unique autooxidative and prooxidant behavior and the inhibition of carbonic anhydrase; and the proliferation and differentiation deficits can be attributed to the upregulation of the Ras/Raf/JAK/STAT pathway. PMID

  7. Citric acid urine test

    Science.gov (United States)

    Urine - citric acid test; Renal tubular acidosis - citric acid test; Kidney stones - citric acid test; Urolithiasis - citric acid test ... No special preparation is necessary for this test. But the results ... test is usually done while you are on a normal diet. Ask your ...

  8. Acid Deposition Phenomena

    International Nuclear Information System (INIS)

    Ramadan, A.E.K.

    2004-01-01

    Acid deposition, commonly known as acid rain, occurs when emissions from the combustion of fossil fuels and other industrial processes undergo complex chemical reactions in the atmosphere and fall to the earth as wet deposition (rain, snow, cloud, fog) or dry deposition (dry particles, gas). Rain and snow are already naturally acidic, but are only considered problematic when less than a ph of 5.0 The main chemical precursors leading to acidic conditions are atmospheric concentrations of sulfur dioxide (SO 2 ) and nitrogen oxides (NO x ). When these two compounds react with water, oxygen, and sunlight in the atmosphere, the result is sulfuric (H 2 SO 4 ) and nitric acids (HNO 3 ), the primary agents of acid deposition which mainly produced from the combustion of fossil fuel and from petroleum refinery. Airborne chemicals can travel long distances from their sources and can therefore affect ecosystems over broad regional scales and in locations far from the sources of emissions. According to the concern of petroleum ministry with the environment and occupational health, in this paper we will discussed the acid deposition phenomena through the following: Types of acidic deposition and its components in the atmosphere Natural and man-made sources of compounds causing the acidic deposition. Chemical reactions causing the acidic deposition phenomenon in the atmosphere. Factors affecting level of acidic deposition in the atmosphere. Impact of acid deposition. Procedures for acidic deposition control in petroleum industry

  9. Collecting Samples for Testing

    Science.gov (United States)

    ... Creatinine Ratio Valproic Acid Vancomycin Vanillylmandelic Acid (VMA) VAP Vitamin A Vitamin B12 and Folate Vitamin D ... that used for CSF in that they require aspiration of a sample of the fluid through a ...

  10. Acid Lipase Disease

    Science.gov (United States)

    ... of Neurological Disorders and Stroke conducts and supports research to understand lipid storage diseases such as acid lipase deficiency and ... of Neurological Disorders and Stroke conducts and supports research to understand lipid storage diseases such as acid lipase deficiency and ...

  11. Lactic acid test

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003507.htm Lactic acid test To use the sharing features on this page, please enable JavaScript. Lactic acid is mainly produced in muscle cells and red ...

  12. Amino Acid Metabolism Disorders

    Science.gov (United States)

    ... this process. One group of these disorders is amino acid metabolism disorders. They include phenylketonuria (PKU) and maple syrup urine disease. Amino acids are "building blocks" that join together to form ...

  13. Folic Acid and Pregnancy

    Science.gov (United States)

    ... Fitness Diseases & Conditions Infections Drugs & Alcohol School & Jobs Sports Expert Answers (Q&A) Staying Safe Videos for Educators Search English Español Folic Acid and Pregnancy KidsHealth / For Parents / Folic Acid and Pregnancy Print ...

  14. Omega-6 Fatty Acids

    Science.gov (United States)

    Omega-6 fatty acids are types of fats. Some types are found in vegetable oils, including corn, evening primrose seed, safflower, and soybean oils. Other types of omega-6 fatty acids are found in black currant seed, borage seed, ...

  15. Hydrochloric acid poisoning

    Science.gov (United States)

    Hydrochloric acid is a clear, poisonous liquid. It is highly corrosive, which means it immediately causes severe damage, such ... poisoning due to swallowing or breathing in hydrochloric acid. This article is for information only. Do NOT ...

  16. Aminolevulinic Acid Topical

    Science.gov (United States)

    Aminolevulinic acid is used in combination with photodynamic therapy (PDT; special blue light) to treat actinic keratoses (small crusty ... skin cancer) of the face or scalp. Aminolevulinic acid is in a class of medications called photosensitizing ...

  17. Zoledronic Acid Injection

    Science.gov (United States)

    Zoledronic acid (Reclast) is used to prevent or treat osteoporosis (condition in which the bones become thin and weak ... of life,' end of regular menstrual periods). Zoledronic acid (Reclast) is also used to treat osteoporosis in ...

  18. Azelaic Acid Topical

    Science.gov (United States)

    Azelaic acid gel and foam is used to clear the bumps, lesions, and swelling caused by rosacea (a skin ... redness, flushing, and pimples on the face). Azelaic acid cream is used to treat the pimples and ...

  19. Aminocaproic Acid Injection

    Science.gov (United States)

    Aminocaproic acid injection is used to control bleeding that occurs when blood clots are broken down too quickly. This ... the baby is ready to be born). Aminocaproic acid injection is also used to control bleeding in ...

  20. Deoxycholic Acid Injection

    Science.gov (United States)

    Deoxycholic acid injection is used to improve the appearance and profile of moderate to severe submental fat ('double chin'; fatty tissue located under the chin). Deoxycholic acid injection is in a class of medications called ...

  1. Amino acids and proteins

    NARCIS (Netherlands)

    van Goudoever, Johannes B.; Vlaardingerbroek, Hester; van den Akker, Chris H.; de Groof, Femke; van der Schoor, Sophie R. D.

    2014-01-01

    Amino acids and protein are key factors for growth. The neonatal period requires the highest intake in life to meet the demands. Those demands include amino acids for growth, but proteins and amino acids also function as signalling molecules and function as neurotransmitters. Often the nutritional

  2. Acid Rain Study Guide.

    Science.gov (United States)

    Hunger, Carolyn; And Others

    Acid rain is a complex, worldwide environmental problem. This study guide is intended to aid teachers of grades 4-12 to help their students understand what acid rain is, why it is a problem, and what possible solutions exist. The document contains specific sections on: (1) the various terms used in conjunction with acid rain (such as acid…

  3. Immunoglobulin and fatty acids

    DEFF Research Database (Denmark)

    2009-01-01

    The present invention relates to a composition comprising 0.1-10 w/w % immunoglobulin (Ig), 4-14 w/w % saturated fatty acids, 4-14 w/w % mono-unsaturated fatty acids and 0-5 w/w % poly-unsaturated fatty acids, wherein the weight percentages are based on the content of dry matter in the composition...

  4. The Acid Rain Reader.

    Science.gov (United States)

    Stubbs, Harriett S.; And Others

    A topic which is often not sufficiently dealt with in elementary school textbooks is acid rain. This student text is designed to supplement classroom materials on the topic. Discussed are: (1) "Rain"; (2) "Water Cycle"; (3) "Fossil Fuels"; (4) "Air Pollution"; (5) "Superstacks"; (6) "Acid/Neutral/Bases"; (7) "pH Scale"; (8) "Acid Rain"; (9)…

  5. Stomach acid test

    Science.gov (United States)

    Gastric acid secretion test ... of the cells in the stomach to release acid. The stomach contents are then removed and analyzed. ... 3.5). These numbers are converted to actual acid production in units of milliequivalents per hour (mEq/ ...

  6. Acidic Ionic Liquids.

    Science.gov (United States)

    Amarasekara, Ananda S

    2016-05-25

    Ionic liquid with acidic properties is an important branch in the wide ionic liquid field and the aim of this article is to cover all aspects of these acidic ionic liquids, especially focusing on the developments in the last four years. The structural diversity and synthesis of acidic ionic liquids are discussed in the introduction sections of this review. In addition, an unambiguous classification system for various types of acidic ionic liquids is presented in the introduction. The physical properties including acidity, thermo-physical properties, ionic conductivity, spectroscopy, and computational studies on acidic ionic liquids are covered in the next sections. The final section provides a comprehensive review on applications of acidic ionic liquids in a wide array of fields including catalysis, CO2 fixation, ionogel, electrolyte, fuel-cell, membrane, biomass processing, biodiesel synthesis, desulfurization of gasoline/diesel, metal processing, and metal electrodeposition.

  7. Process for the preparation of lactic acid and glyceric acid

    Science.gov (United States)

    Jackson, James E [Haslett, MI; Miller, Dennis J [Okemos, MI; Marincean, Simona [Dewitt, MI

    2008-12-02

    Hexose and pentose monosaccharides are degraded to lactic acid and glyceric acid in an aqueous solution in the presence of an excess of a strongly anionic exchange resin, such as AMBERLITE IRN78 and AMBERLITE IRA400. The glyceric acid and lactic acid can be separated from the aqueous solution. Lactic acid and glyceric acid are staple articles of commerce.

  8. Amino acids in the sedimentary humic and fulvic acids

    Digital Repository Service at National Institute of Oceanography (India)

    Sardessai, S.

    acids in the coastal Arabian Sea sediments: whereas amino acids content of fulvic acids was lower than that of humic acids in the coastal sediments of Bay of Bengal. Slope sedimentary humic acids were relatively enriched in amino acids as compared...

  9. 78 FR 20029 - Castor Oil, Polymer With Adipic Acid, Linoleic Acid, Oleic Acid and Ricinoleic Acid; Tolerance...

    Science.gov (United States)

    2013-04-03

    ..., Polymer With Adipic Acid, Linoleic Acid, Oleic Acid and Ricinoleic Acid; Tolerance Exemption AGENCY... from the requirement of a tolerance for residues of castor oil, polymer with adipic acid, linoleic acid... pesticide formulation. Advance Polymer Technology submitted a petition to EPA under the Federal Food, Drug...

  10. Bile acid sequestrants

    DEFF Research Database (Denmark)

    Hansen, Morten; Sonne, David P; Knop, Filip K

    2014-01-01

    Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid...... and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption...... of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose...

  11. Citric Acid Alternative to Nitric Acid Passivation

    Science.gov (United States)

    Lewis, Pattie L. (Compiler)

    2013-01-01

    The Ground Systems Development and Operations GSDO) Program at NASA John F. Kennedy Space Center (KSC) has the primary objective of modernizing and transforming the launch and range complex at KSC to benefit current and future NASA programs along with other emerging users. Described as the launch support and infrastructure modernization program in the NASA Authorization Act of 2010, the GSDO Program will develop and implement shared infrastructure and process improvements to provide more flexible, affordable, and responsive capabilities to a multi-user community. In support of the GSDO Program, the purpose of this project is to demonstratevalidate citric acid as a passivation agent for stainless steel. Successful completion of this project will result in citric acid being qualified for use as an environmentally preferable alternative to nitric acid for passivation of stainless steel alloys in NASA and DoD applications.

  12. USGS Tracks Acid Rain

    Science.gov (United States)

    Gordon, John D.; Nilles, Mark A.; Schroder, LeRoy J.

    1995-01-01

    The U.S. Geological Survey (USGS) has been actively studying acid rain for the past 15 years. When scientists learned that acid rain could harm fish, fear of damage to our natural environment from acid rain concerned the American public. Research by USGS scientists and other groups began to show that the processes resulting in acid rain are very complex. Scientists were puzzled by the fact that in some cases it was difficult to demonstrate that the pollution from automobiles and factories was causing streams or lakes to become more acidic. Further experiments showed how the natural ability of many soils to neutralize acids would reduce the effects of acid rain in some locations--at least as long as the neutralizing ability lasted (Young, 1991). The USGS has played a key role in establishing and maintaining the only nationwide network of acid rain monitoring stations. This program is called the National Atmospheric Deposition Program/National Trends Network (NADP/NTN). Each week, at approximately 220 NADP/NTN sites across the country, rain and snow samples are collected for analysis. NADP/NTN site in Montana. The USGS supports about 72 of these sites. The information gained from monitoring the chemistry of our nation's rain and snow is important for testing the results of pollution control laws on acid rain.

  13. Acidity of hydroxamic acids and amides

    Czech Academy of Sciences Publication Activity Database

    Böhm, S.; Exner, Otto

    2003-01-01

    Roč. 1, č. 7 (2003), s. 1176-1180 ISSN 1477-0520 R&D Projects: GA AV ČR IAA4072005 Institutional research plan: CEZ:AV0Z4055905 Keywords : hydroxamic acids * DFT calculations * isodesmic reactions Subject RIV: CC - Organic Chemistry

  14. Fusidic acid in dermatology

    DEFF Research Database (Denmark)

    Schöfer, Helmut; Simonsen, Lene

    1995-01-01

    Studies on the clinical efficacy of fusidic acid in skin and soft-tissue infections (SSTIs), notably those due to Staphylococcus aureus, are reviewed. Oral fusidic acid (tablets dosed at 250 mg twice daily, or a suspension for paediatric use at 20 mg/kg/day given as two daily doses) has shown goo...

  15. Characterization of acid tars

    International Nuclear Information System (INIS)

    Leonard, Sunday A.; Stegemann, Julia A.; Roy, Amitava

    2010-01-01

    Acid tars from the processing of petroleum and petrochemicals using sulfuric acid were characterized by gas chromatography/mass spectrometry (GC/MS), inductively coupled plasma/optical emission spectrometry (ICP/OES), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectrometry, and scanning electron microscopy/energy dispersive X-ray (SEM/EDX) micro-analysis. Leaching of contaminants from the acid tars in 48 h batch tests with distilled water at a liquid-to-solid ratio 10:1 was also studied. GC/MS results show that the samples contained aliphatic hydrocarbons, cyclic hydrocarbons, up to 12 of the 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs), and numerous other organic groups, including organic acids (sulfonic acids, carboxylic acids and aromatic acids), phenyl, nitrile, amide, furans, thiophenes, pyrroles, and phthalates, many of which are toxic. Metals analysis shows that Pb was present in significant concentration. DSC results show different transition peaks in the studied samples, demonstrating their complexity and variability. FTIR analysis further confirmed the presence of the organic groups detected by GC/MS. The SEM/EDX micro-analysis results provided insight on the surface characteristics of the samples and show that contaminants distribution was heterogeneous. The results provide useful data on the composition, complexity, and variability of acid tars; information which hitherto have been scarce in public domain.

  16. Characterization of acid tars

    Energy Technology Data Exchange (ETDEWEB)

    Leonard, Sunday A., E-mail: sunday.leonard@ucl.ac.uk [Department of Civil Environmental and Geomatic Engineering, University College London, Chadwick Building, Gower Street, London, WC1E 6BT (United Kingdom); Stegemann, Julia A. [Department of Civil Environmental and Geomatic Engineering, University College London, Chadwick Building, Gower Street, London, WC1E 6BT (United Kingdom); Roy, Amitava [J. Bennett Johnston, Sr., Centre for Advance Microstructures and Devices (CAMD), 6980 Jefferson Highway, Louisiana State University, Baton Rouge, LA, 70806 (United States)

    2010-03-15

    Acid tars from the processing of petroleum and petrochemicals using sulfuric acid were characterized by gas chromatography/mass spectrometry (GC/MS), inductively coupled plasma/optical emission spectrometry (ICP/OES), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectrometry, and scanning electron microscopy/energy dispersive X-ray (SEM/EDX) micro-analysis. Leaching of contaminants from the acid tars in 48 h batch tests with distilled water at a liquid-to-solid ratio 10:1 was also studied. GC/MS results show that the samples contained aliphatic hydrocarbons, cyclic hydrocarbons, up to 12 of the 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs), and numerous other organic groups, including organic acids (sulfonic acids, carboxylic acids and aromatic acids), phenyl, nitrile, amide, furans, thiophenes, pyrroles, and phthalates, many of which are toxic. Metals analysis shows that Pb was present in significant concentration. DSC results show different transition peaks in the studied samples, demonstrating their complexity and variability. FTIR analysis further confirmed the presence of the organic groups detected by GC/MS. The SEM/EDX micro-analysis results provided insight on the surface characteristics of the samples and show that contaminants distribution was heterogeneous. The results provide useful data on the composition, complexity, and variability of acid tars; information which hitherto have been scarce in public domain.

  17. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2003-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  18. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  19. Peptide Nucleic Acids (PNA)

    DEFF Research Database (Denmark)

    2002-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  20. Peptide Nucleic Acids

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds known as peptide nucleic acids, bind complementary DNA and RNA strands, and generally do so more strongly than the corresponding DNA or RNA strands while exhibiting increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from...

  1. Folic acid in diet

    Science.gov (United States)

    ... regularly removed from the body through urine, so excess amounts do not build up in the body. You should not get more than 1000 mcg per day of folic acid. Using higher levels of folic acid can mask vitamin B12 deficiency.

  2. Peptide Nucleic Acid Synthons

    DEFF Research Database (Denmark)

    2004-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary ssDNA and RNA strands more strongly than a corresponding DNA. The peptide nucleic acids generally comprise ligands such as naturally occurring DNA bases attached to a peptide backbone through a suitable linker....

  3. Locked nucleic acid

    DEFF Research Database (Denmark)

    Jepsen, Jan Stenvang; Sørensen, Mads D; Wengel, Jesper

    2004-01-01

    Locked nucleic acid (LNA) is a class of nucleic acid analogs possessing very high affinity and excellent specificity toward complementary DNA and RNA, and LNA oligonucleotides have been applied as antisense molecules both in vitro and in vivo. In this review, we briefly describe the basic...

  4. Halogenated fatty acids

    DEFF Research Database (Denmark)

    Mu, Huiling; Wesén, Clas; Sundin, Peter

    1997-01-01

    Chlorinated fatty acids have been found to be major contributors to organohalogen compounds in fish, bivalves, jellyfish, and lobster, and they have been indicated to contribute considerably to organohalogens in marine mammals. Brominated fatty acids have been found in marine sponges. Also...

  5. Amino Acid Crossword Puzzle

    Science.gov (United States)

    Sims, Paul A.

    2011-01-01

    Learning the 20 standard amino acids is an essential component of an introductory course in biochemistry. Later in the course, the students study metabolism and learn about various catabolic and anabolic pathways involving amino acids. Learning new material or concepts often is easier if one can connect the new material to what one already knows;…

  6. Phosphates and phosphoric acid

    Energy Technology Data Exchange (ETDEWEB)

    Becker, P [Compagnie Francaise de l' Azote, Paris (France)

    1983-01-01

    In chapter 8.5 the following aspects of uranium recovery are treated: basis of extraction process, extraction principle, solvents, strength of the acid to be treated, technology, main processes in use, impact of uranium recovery on phosphoric acid plants, and economics of uranium recovery plants.

  7. Omega-3 Fatty Acids

    Science.gov (United States)

    Omega-3 fatty acids are used together with lifestyle changes (diet, weight-loss, exercise) to reduce the amount of triglycerides (a fat- ... in people with very high triglycerides. Omega-3 fatty acids are in a class of medications called antilipemic ...

  8. Chlorogenic acid and caffeic acid are absorbed in humans

    NARCIS (Netherlands)

    Olthof, Margreet R.; Hollman, Peter C H; Katan, Martijn B.

    2001-01-01

    Chlorogenic acid, an ester of caffeic acid and quinic acid, is a major phenolic compound in coffee; daily intake in coffee drinkers is 0.5-1 g. Chlorogenic acid and caffeic acid are antioxidants in vitro and might therefore contribute to the prevention of cardiovascular disease. However, data on the

  9. Enzymatic formation of hexadecenoic acid from palmitic acid

    International Nuclear Information System (INIS)

    Nakano, Masao; Fujino, Yasuhiko

    1975-01-01

    Desaturation of palmitic acid was investigated in an enzyme system prepared from rat liver. 2-trans-Hexadecenoic acid as well as 9-cis-gexadecenoic acid (palmitoleic acid) were found to be formed as monoenoic acid in this system. (author)

  10. Lewis Acidic Ionic Liquids.

    Science.gov (United States)

    Brown, Lucy C; Hogg, James M; Swadźba-Kwaśny, Małgorzata

    2017-08-21

    Until very recently, the term Lewis acidic ionic liquids (ILs) was nearly synonymous with halometallate ILs, with a strong focus on chloroaluminate(III) systems. The first part of this review covers the historical context in which these were developed, speciation of a range of halometallate ionic liquids, attempts to quantify their Lewis acidity, and selected recent applications: in industrial alkylation processes, in supported systems (SILPs/SCILLs) and in inorganic synthesis. In the last decade, interesting alternatives to halometallate ILs have emerged, which can be divided into two sub-sections: (1) liquid coordination complexes (LCCs), still based on halometallate species, but less expensive and more diverse than halometallate ionic liquids, and (2) ILs with main-group Lewis acidic cations. The two following sections cover these new liquid Lewis acids, also highlighting speciation studies, Lewis acidity measurements, and applications.

  11. Acidity in rainfall

    International Nuclear Information System (INIS)

    Tisue, G.T.; Kacoyannakis, J.

    1975-01-01

    The reported increasing acidity of rainfall raises many interesting ecological and chemical questions. In spite of extensive studies in Europe and North America there are, for example, great uncertainties in the relative contributions of strong and weak acids to the acid-base properties of rainwater. Unravelling this and similar problems may require even more rigorous sample collection and analytical procedures than previously employed. Careful analysis of titration curves permits inferences to be made regarding chemical composition, the possible response of rainwater to further inputs of acidic components to the atmosphere, and the behavior to be expected when rainwater interacts with the buffers present in biological materials and natural waters. Rainwater samples collected during several precipitation events at Argonne National Laboratory during October and November 1975 have been analyzed for pH, acid and base neutralizing properties, and the ions of ammonium, nitrate, chloride, sulfate, and calcium. The results are tabulated

  12. Conjugated Fatty Acid Synthesis

    Science.gov (United States)

    Rawat, Richa; Yu, Xiao-Hong; Sweet, Marie; Shanklin, John

    2012-01-01

    Conjugated linolenic acids (CLNs), 18:3 Δ9,11,13, lack the methylene groups found between the double bonds of linolenic acid (18:3 Δ9,12,15). CLNs are produced by conjugase enzymes that are homologs of the oleate desaturases FAD2. The goal of this study was to map the domain(s) within the Momordica charantia conjugase (FADX) responsible for CLN formation. To achieve this, a series of Momordica FADX-Arabidopsis FAD2 chimeras were expressed in the Arabidopsis fad3fae1 mutant, and the transformed seeds were analyzed for the accumulation of CLN. These experiments identified helix 2 and the first histidine box as a determinant of conjugase product partitioning into punicic acid (18:3 Δ9cis,11trans,13cis) or α-eleostearic acid (18:3 Δ9cis,11trans,13trans). This was confirmed by analysis of a FADX mutant containing six substitutions in which the sequence of helix 2 and first histidine box was converted to that of FAD2. Each of the six FAD2 substitutions was individually converted back to the FADX equivalent identifying residues 111 and 115, adjacent to the first histidine box, as key determinants of conjugase product partitioning. Additionally, expression of FADX G111V and FADX G111V/D115E resulted in an approximate doubling of eleostearic acid accumulation to 20.4% and 21.2%, respectively, compared with 9.9% upon expression of the native Momordica FADX. Like the Momordica conjugase, FADX G111V and FADX D115E produced predominantly α-eleostearic acid and little punicic acid, but the FADX G111V/D115E double mutant produced approximately equal amounts of α-eleostearic acid and its isomer, punicic acid, implicating an interactive effect of residues 111 and 115 in punicic acid formation. PMID:22451660

  13. Glycosyltransferase glycosylating flavokermesic acid and/or kermesic acid

    DEFF Research Database (Denmark)

    2016-01-01

    An isolated glycosyltransferase (GT) polypeptide capable of: (I) : conjugating glucose to flavokermesic acid (FK); and/or (II) : conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid.......An isolated glycosyltransferase (GT) polypeptide capable of: (I) : conjugating glucose to flavokermesic acid (FK); and/or (II) : conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid....

  14. GLYCOSYLTRANSFERASE GLYCOSYLATING FLAVOKERMESIC ACID AND/OR KERMESIC ACID

    DEFF Research Database (Denmark)

    2015-01-01

    An isolated glycosyltransferase (GT) polypeptide capable of: (I): conjugating glucose to flavokermesic acid (FK); and/or (II): conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid.......An isolated glycosyltransferase (GT) polypeptide capable of: (I): conjugating glucose to flavokermesic acid (FK); and/or (II): conjugating glucose to kermesic acid (KA) and use of this GT to e.g. make Carminic acid....

  15. Association between consistent purchase of anticonvulsants or lithium and suicide risk: a longitudinal cohort study from Denmark, 1995-2001

    DEFF Research Database (Denmark)

    Smith, Eric G; Søndergård, Lars; Lopez, Ana Garcia

    2009-01-01

    BACKGROUND: Prior studies suggest anticonvulsants purchasers may be at greater risk of suicide than lithium purchasers. METHODS: Longitudinal, retrospective cohort study of all individuals in Denmark purchasing anticonvulsants (valproic acid, carbamazepine, oxcarbazepine or lamotrigine) (n=9952...

  16. Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation

    DEFF Research Database (Denmark)

    Rekling, Jens C

    2003-01-01

    cell death induced by OGD. The newer anticonvulsants carbamazepine, felbamate, lamotrigine, tiagabine, and oxcarbazepine also had significant neuroprotective effects, but gabapentin, valproic acid (10 mM), levetiracetam and retigabine were not neuroprotective at a concentration up to 300 micro...

  17. Waht is 'molybdic acid' or 'polymolybdic acid'?

    International Nuclear Information System (INIS)

    Tytko, K.H.; Baethe, G.; Mehmke, K.

    1987-01-01

    According to a comparative study of the literature, supplemented by well-aimed experimental investigations and equilibrium calculations, the terms 'molybdic acid' or 'polymolybdic acid', used for many substances, species, or solutions in the literature, are applicable to a species, a solution, and two solids: a) The monomeric molybdic acid, most probably having the formula MoO 2 (OH) 2 (H 2 O) 2 (= H 2 MoO 4 , aq), exists in (aqueous) solution only and never exceeds a concentration of ∼ 10 -3 M since at higher concentrations it reacts with other monomeric molybdenum(VI) species to give anionic or cationic polymers. b) A concentrated (> 0.1 M Mo VI ) aqueous molybdate solution of degree of acidification P = 2 (realized, e.g., by a solution of one of the Mo VI oxides; by any molybdate solutions whose cations have been exchanged by H 2 O + on a cation exchanger; by suitable acidification of a molybdate solution) contains 8 H 3 O + and the well-known polyanion Mo 36 O 112 (H 2 O) 16 8- exactly in the stoichiometric proportions. c) A glassy substance, obtained from an alkali metal salt-free solution prepared acording to (b), refers to the compound (H 3 O) 8 [Mo 36 O 112 (H 2 O) 16 ] · xH 2 O, x = 25 - 29. d) A solid having the ideal composition [(H 3 O)Mo 5 O 15 (OH)H 2 O · H 2 O] ∞ consists of a polymolybdate skeleton (the well-known 'decamolybdate' structure), in the tunnels of which H 3 O + and H 2 O are intercalated. The structure is very unstable if only H 3 O + cations are present, but it is enormously stabilized by a partial exchange of H 3 O + by certain alkali or alkaline earth metal cations. For the compounds MoO 3 , MoO 3 ·H 2 O, and MoO 3 · 2 H 2 O the term 'molybdic acid' is unjustified. The commercial product 'molybdic acid, ∼ 85% MoO 3 ' is the well-known polymolybdate (NH 4 ) 2 O · 4 MoO 3 with a layer structure of the polyanion. 84 refs. (author)

  18. Amino acid racemisation dating

    International Nuclear Information System (INIS)

    Murray-Wallace, C.V.

    1999-01-01

    The potential of the time-dependent amino acid racemisation reaction as a method of age assessment was first reported by Hare and Abelson (1968). They noted that in specimens of the bivalve mollusc Mercenaria sp., greater concentrations of amino acids in the D-configuration with increasing fossil age. Hare and Abelson (1968) also reported negligible racemisation in a modern specimen of Mecanaria sp. On this basis they suggested that the extent of amino acid racemisation (epimerisation in the case of isoleucine) may be used to assess the age of materials within and beyond the range of radiocarbon dating. For the past thirty years amino acid racemisation has been extensively applied in Quaternary research as a method of relative and numeric dating, and a particularly large literature has emerged on the subject

  19. Amino Acids and Chirality

    Science.gov (United States)

    Cook, Jamie E.

    2012-01-01

    Amino acids are among the most heavily studied organic compound class in carbonaceous chondrites. The abundance, distributions, enantiomeric compositions, and stable isotopic ratios of amino acids have been determined in carbonaceous chondrites fi'om a range of classes and petrographic types, with interesting correlations observed between these properties and the class and typc of the chondritcs. In particular, isomeric distributions appear to correlate with parent bodies (chondrite class). In addition, certain chiral amino acids are found in enantiomeric excess in some chondrites. The delivery of these enantiomeric excesses to the early Earth may have contributed to the origin of the homochirality that is central to life on Earth today. This talk will explore the amino acids in carbonaceous chondritcs and their relevance to the origin of life.

  20. Acid Mine Drainage Treatment

    National Research Council Canada - National Science Library

    Fripp, Jon

    2000-01-01

    .... Acid mine drainage (AMD) can have severe impacts to aquatic resources, can stunt terrestrial plant growth and harm wetlands, contaminate groundwater, raise water treatment costs, and damage concrete and metal structures...

  1. Amoxicillin and Clavulanic Acid

    Science.gov (United States)

    ... in a class of medications called penicillin-like antibiotics. It works by stopping the growth of bacteria. Clavulanic acid ... It works by preventing bacteria from destroying amoxicillin. Antibiotics will not work for colds, flu, or other viral infections.

  2. Alpha Hydroxy Acids

    Science.gov (United States)

    ... or tenderness (8), chemical burns (6), and increased sunburn (3). The frequency of such reports for skin ... bear a statement that conveys the following information: Sunburn Alert: This product contains an alpha hydroxy acid ( ...

  3. Azetidinic amino acids

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Bunch, Lennart; Chopin, Nathalie

    2005-01-01

    A set of ten azetidinic amino acids, that can be envisioned as C-4 alkyl substituted analogues of trans-2-carboxyazetidine-3-acetic acid (t-CAA) and/or conformationally constrained analogues of (R)- or (S)-glutamic acid (Glu) have been synthesized in a diastereo- and enantiomerically pure form from...... of two diastereoisomers that were easily separated and converted in two steps into azetidinic amino acids. Azetidines 35-44 were characterized in binding studies on native ionotropic Glu receptors and in functional assays at cloned metabotropic receptors mGluR1, 2 and 4, representing group I, II and III...... beta-amino alcohols through a straightforward five step sequence. The key step of this synthesis is an original anionic 4-exo-tet ring closure that forms the azetidine ring upon an intramolecular Michael addition. This reaction was proven to be reversible and to lead to a thermodynamic distribution...

  4. [Acids in coffee. XI. The proportion of individual acids in the total titratable acid].

    Science.gov (United States)

    Engelhardt, U H; Maier, H G

    1985-07-01

    22 acids in ground roast coffees and instant coffees were determined by GLC of their silyl derivatives (after preseparation by gel electrophoresis) or isotachophoresis. The contribution to the total acidity (which was estimated by titration to pH 8 after cation exchange of the coffee solutions) was calculated for each individual acid. The mentioned acids contribute with 67% (roast coffee) and 72% (instant coffee) to the total acidity. In the first place citric acid (12.2% in roast coffee/10.7% in instant coffee), acetic acid (11.2%/8.8%) and the high molecular weight acids (8%/9%) contribute to the total acidity. Also to be mentioned are the shares of chlorogenic acids (9%/4.8%), formic acid (5.3%/4.6%), quinic acid (4.7%/5.9%), malic acid (3.9%/3%) and phosphoric acid (2.5%/5.2%). A notable difference in the contribution to total acidity between roast and instant coffee was found for phosphoric acid and pyrrolidonecarboxylic acid (0.7%/1.9%). It can be concluded that those two acids are formed or released from e.g. their esters in higher amounts than other acids during the production of instant coffee.

  5. Portable nucleic acid thermocyclers.

    Science.gov (United States)

    Almassian, David R; Cockrell, Lisa M; Nelson, William M

    2013-11-21

    A nucleic acid thermal cycler is considered to be portable if it is under ten pounds, easily carried by one individual, and battery powered. Nucleic acid amplification includes both polymerase chain reaction (e.g. PCR, RT-PCR) and isothermal amplification (e.g. RPA, HDA, LAMP, NASBA, RCA, ICAN, SMART, SDA). There are valuable applications for portable nucleic acid thermocyclers in fields that include clinical diagnostics, biothreat detection, and veterinary testing. A system that is portable allows for the distributed detection of targets at the point of care and a reduction of the time from sample to answer. The designer of a portable nucleic acid thermocycler must carefully consider both thermal control and the detection of amplification. In addition to thermal control and detection, the designer may consider the integration of a sample preparation subsystem with the nucleic acid thermocycler. There are a variety of technologies that can achieve accurate thermal control and the detection of nucleic acid amplification. Important evaluation criteria for each technology include maturity, power requirements, cost, sensitivity, speed, and manufacturability. Ultimately the needs of a particular market will lead to user requirements that drive the decision between available technologies.

  6. Fatty Acid Biosynthesis IX

    DEFF Research Database (Denmark)

    Carey, E. M.; Hansen, Heinz Johs. Max; Dils, R.

    1972-01-01

    # 1. I. [I-14C]Acetate was covalently bound to rabbit mammary gland fatty acid synthetase by enzymic transacylation from [I-14C]acetyl-CoA. Per mole of enzyme 2 moles of acetate were bound to thiol groups and up to I mole of acetate was bound to non-thiol groups. # 2. 2. The acetyl-fatty acid...... synthetase complex was isolated free from acetyl-CoA. It was rapidly hydrolysed at 30°C, but hydrolysis was greatly diminished at o°C and triacetic lactone synthesis occurred. In the presence of malonyl-CoA and NADPH, all the acetate bound to fatty acid synthetase was incorporated into long-chain fatty acids....... Hydrolysis of bound acetate and incorporation of bound acetate into fatty acids were inhibited to the same extent by guanidine hydrochloride. # 3. 3. Acetate was also covalently bound to fatty acid synthetase by chemical acetylation with [I-14C]acetic anhydride in the absence of CoASH. A total of 60 moles...

  7. Acidification and Acid Rain

    Science.gov (United States)

    Norton, S. A.; Veselã½, J.

    2003-12-01

    Air pollution by acids has been known as a problem for centuries (Ducros, 1845; Smith, 1872; Camuffo, 1992; Brimblecombe, 1992). Only in the mid-1900s did it become clear that it was a problem for more than just industrially developed areas, and that precipitation quality can affect aquatic resources ( Gorham, 1955). The last three decades of the twentieth century saw tremendous progress in the documentation of the chemistry of the atmosphere, precipitation, and the systems impacted by acid atmospheric deposition. Chronic acidification of ecosystems results in chemical changes to soil and to surface waters and groundwater as a result of reduction of base cation supply or an increase in acid (H+) supply, or both. The most fundamental changes during chronic acidification are an increase in exchangeable H+ or Al3+ (aluminum) in soils, an increase in H+ activity (˜concentration) in water in contact with soil, and a decrease in alkalinity in waters draining watersheds. Water draining from the soil is acidified and has a lower pH (=-log [H+]). As systems acidify, their biotic community changes.Acidic surface waters occur in many parts of the world as a consequence of natural processes and also due to atmospheric deposition of strong acid (e.g., Canada, Jeffries et al. (1986); the United Kingdom, Evans and Monteith (2001); Sweden, Swedish Environmental Protection Board (1986); Finland, Forsius et al. (1990); Norway, Henriksen et al. (1988a); and the United States (USA), Brakke et al. (1988)). Concern over acidification in the temperate regions of the northern hemisphere has been driven by the potential for accelerating natural acidification by pollution of the atmosphere with acidic or acidifying compounds. Atmospheric pollution ( Figure 1) has resulted in an increased flux of acid to and through ecosystems. Depending on the ability of an ecosystem to neutralize the increased flux of acidity, acidification may increase only imperceptibly or be accelerated at a rate that

  8. Why is hydrofluoric acid a weak acid?

    Science.gov (United States)

    Ayotte, Patrick; Hébert, Martin; Marchand, Patrick

    2005-11-08

    The infrared vibrational spectra of amorphous solid water thin films doped with HF at 40 K reveal a strong continuous absorbance in the 1000-3275 cm(-1) range. This so-called Zundel continuum is the spectroscopic hallmark for aqueous protons. The extensive ionic dissociation of HF at such low temperature suggests that the reaction enthalpy remains negative down to 40 K. These observations support the interpretation that dilute HF aqueous solutions behave as weak acids largely due to the large positive reaction entropy resulting from the structure making character of the hydrated fluoride ion.

  9. Acid Rain, pH & Acidity: A Common Misinterpretation.

    Science.gov (United States)

    Clark, David B.; Thompson, Ronald E.

    1989-01-01

    Illustrates the basis for misleading statements about the relationship between pH and acid content in acid rain. Explains why pH cannot be used as a measure of acidity for rain or any other solution. Suggests that teachers present acidity and pH as two separate and distinct concepts. (RT)

  10. [Lipid synthesis by an acidic acid tolerant Rhodotorula glutinis].

    Science.gov (United States)

    Lin, Zhangnan; Liu, Hongjuan; Zhang, Jian'an; Wang, Gehua

    2016-03-01

    Acetic acid, as a main by-product generated in the pretreatment process of lignocellulose hydrolysis, significantly affects cell growth and lipid synthesis of oleaginous microorganisms. Therefore, we studied the tolerance of Rhodotorula glutinis to acetic acid and its lipid synthesis from substrate containing acetic acid. In the mixed sugar medium containing 6 g/L glucose and 44 g/L xylose, and supplemented with acetic acid, the cell growth was not:inhibited when the acetic acid concentration was below 10 g/L. Compared with the control, the biomass, lipid concentration and lipid content of R. glutinis increased 21.5%, 171% and 122% respectively when acetic acid concentration was 10 g/L. Furthermore, R. glutinis could accumulate lipid with acetate as the sole carbon source. Lipid concentration and lipid yield reached 3.20 g/L and 13% respectively with the initial acetic acid concentration of 25 g/L. The lipid composition was analyzed by gas chromatograph. The main composition of lipid produced with acetic acid was palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid, including 40.9% saturated fatty acids and 59.1% unsaturated fatty acids. The lipid composition was similar to that of plant oil, indicating that lipid from oleaginous yeast R. glutinis had potential as the feedstock of biodiesel production. These results demonstrated that a certain concentration of acetic acid need not to be removed in the detoxification process when using lignocelluloses hydrolysate to produce microbial lipid by R. glutinis.

  11. Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids

    DEFF Research Database (Denmark)

    Conti, Paola; De Amici, Marco; Joppolo Di Ventimiglia, Samuele

    2003-01-01

    Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them...

  12. Chemistry and electrochemistry in trifluoroacetic acid. Comparison with acetic acid

    International Nuclear Information System (INIS)

    Petit, Gerard

    1972-01-01

    As the trifluoroacetic acid is, with the acetic acid, one of most often used carboxylic acids as solvent, notably in organic chemistry, this research thesis addresses some relatively simple complexing and redox reactions to highlight the peculiar feature of this acid, and to explain its very much different behaviour with respect to acetic acid. The author develops the notion of acidity level in solvents of low dielectric constant. The second part addresses a specific solvent: BF 3 (CH 3 COOH) 2 . The boron trifluoride strengthens the acidity of acetic acid and modifies its chemical and physical-chemical properties. In the third part, the author compares solvent properties of CF 3 COOH and CH 3 COOH. Noticed differences explain why the trifluoroacetic acid is a more interesting reaction environment than acetic acid for reactions such as electrophilic substitutions or protein solubilisation [fr

  13. Domoic Acid Epileptic Disease

    Directory of Open Access Journals (Sweden)

    John S. Ramsdell

    2014-03-01

    Full Text Available Domoic acid epileptic disease is characterized by spontaneous recurrent seizures weeks to months after domoic acid exposure. The potential for this disease was first recognized in a human case study of temporal lobe epilepsy after the 1987 amnesic shellfish-poisoning event in Quebec, and was characterized as a chronic epileptic syndrome in California sea lions through investigation of a series of domoic acid poisoning cases between 1998 and 2006. The sea lion study provided a breadth of insight into clinical presentations, unusual behaviors, brain pathology, and epidemiology. A rat model that replicates key observations of the chronic epileptic syndrome in sea lions has been applied to identify the progression of the epileptic disease state, its relationship to behavioral manifestations, and to define the neural systems involved in these behavioral disorders. Here, we present the concept of domoic acid epileptic disease as a delayed manifestation of domoic acid poisoning and review the state of knowledge for this disease state in affected humans and sea lions. We discuss causative mechanisms and neural underpinnings of disease maturation revealed by the rat model to present the concept for olfactory origin of an epileptic disease; triggered in dendodendritic synapases of the olfactory bulb and maturing in the olfactory cortex. We conclude with updated information on populations at risk, medical diagnosis, treatment, and prognosis.

  14. Citric acid by fermentation

    Energy Technology Data Exchange (ETDEWEB)

    El-Sayed, R M

    1978-11-30

    Citric acid is produced in 2 stages, in the first of which Escherichia coli KG93 F-is cultured on a substrate consisting of whey permeate to which phosphate and nitrate or urea is added. In the second stage, Hansenula wickerhamii CBS 4308 is cultured on the culture solution from the first stage and the citric acid isolated in the usual manner. Thus, a whey permeate comprising fat 0.20, protein 0.05, lactose 5.0, lactic acid 0.1, and salts 0.6% (Ca 0.06, P 0.06, K 0.16, N 0.03, and NaCl 0.3%) was amended with 1.2 g phosphate/L and 1.0 g NO/sub 3/sup -///L. After introducing the whey permeate into a continuous fermentor, it was inoculated with E. coli K693 F- and allowed to incubate at 37/sup 0/ and pH 7 (Maintained with NH/sub 3/ gas) for 12 h with aeration, thereby producing concentration pyruvic acid. After an additional 6 h cultivation without aeration, the broth was transferred to another fermentor and there inoculated with H. wickerhamii CBS 4308. The second cultivation step was carried out at 30/sup 0/ and a pH of 5 for 24 h with the pH stabilized by NH/sub 3/ gas. To the second stage culture, 0.3 g Fe(CN)/sup 4 -//L was added. The yield of pyruvic acid in the first stage was 32 g/L and the final yield of citric acid was 43 g/L.

  15. 2-arylureidobenzoic acids

    DEFF Research Database (Denmark)

    Valgeirsson, Jon; Nielsen, Elsebet Ø; Peters, Dan

    2003-01-01

    A series of 2-arylureidobenzoic acids (AUBAs) was prepared by a short and effective synthesis, and the pharmacological activity at glutamate receptors was evaluated in vitro and in vivo. The compounds showed noncompetitive antagonistic activity at the kainate receptor subtype GluR5. The most potent...... on the benzoic acid moiety (ring A), whereas ring B tolerated a variety of substituents, but with a preference for lipophilic substituents. The most potent compounds had a 4-chloro substituent on ring A and 3-chlorobenzene (6b), 2-naphthalene (8h), or 2-indole (8k) as ring B and had IC(50) values of 1.3, 1...

  16. Whither Acid Rain?

    Directory of Open Access Journals (Sweden)

    Peter Brimblecombe

    2000-01-01

    Full Text Available Acid rain, the environmental cause célèbre of the 1980s seems to have vanished from popular conscience. By contrast, scientific research, despite funding difficulties, has continued to produce hundreds of research papers each year. Studies of acid rain taught much about precipitation chemistry, the behaviour of snow packs, long-range transport of pollutants and new issues in the biology of fish and forested ecosystems. There is now evidence of a shift away from research in precipitation and sulfur chemistry, but an impressive theoretical base remains as a legacy.

  17. The Acid-Base Titration of a Very Weak Acid: Boric Acid

    Science.gov (United States)

    Celeste, M.; Azevedo, C.; Cavaleiro, Ana M. V.

    2012-01-01

    A laboratory experiment based on the titration of boric acid with strong base in the presence of d-mannitol is described. Boric acid is a very weak acid and direct titration with NaOH is not possible. An auxiliary reagent that contributes to the release of protons in a known stoichiometry facilitates the acid-base titration. Students obtain the…

  18. Catalytic acetoxylation of lactic acid to 2-acetoxypropionic acid, en route to acrylic acid

    NARCIS (Netherlands)

    Beerthuis, R.; Granollers, M.; Brown, D.R.; Salavagione, H.J.; Rothenberg, G.; Shiju, N.R.

    2015-01-01

    We present an alternative synthetic route to acrylic acid, starting from the platform chemical lactic acid and using heterogeneous catalysis. To improve selectivity, we designed an indirect dehydration reaction that proceeds via acetoxylation of lactic acid to 2-acetoxypropionic acid. This

  19. Comparison of Buffer Effect of Different Acids During Sandstone Acidizing

    International Nuclear Information System (INIS)

    Shafiq, Mian Umer; Mahmud, Hisham Khaled Ben; Hamid, Mohamed Ali

    2015-01-01

    The most important concern of sandstone matrix acidizing is to increase the formation permeability by removing the silica particles. To accomplish this, the mud acid (HF: HCl) has been utilized successfully for many years to stimulate the sandstone formations, but still it has many complexities. This paper presents the results of laboratory investigations of different acid combinations (HF: HCl, HF: H 3 PO 4 and HF: HCOOH). Hydrofluoric acid and fluoboric acid are used to dissolve clays and feldspar. Phosphoric and formic acids are added as a buffer to maintain the pH of the solution; also it allows the maximum penetration of acid into the core sample. Different tests have been performed on the core samples before and after the acidizing to do the comparative study on the buffer effect of these acids. The analysis consists of permeability, porosity, color change and pH value tests. There is more increase in permeability and porosity while less change in pH when phosphoric and formic acids were used compared to mud acid. From these results it has been found that the buffer effect of phosphoric acid and formic acid is better than hydrochloric acid. (paper)

  20. Usnic acid controls the acidity tolerance of lichens

    International Nuclear Information System (INIS)

    Hauck, Markus; Juergens, Sascha-Rene

    2008-01-01

    The hypotheses were tested that, firstly, lichens producing the dibenzofuran usnic acid colonize substrates characterized by specific pH ranges, secondly, this preferred pH is in a range where soluble usnic acid and its corresponding anion occur in similar concentrations, and thirdly, usnic acid makes lichens vulnerable to acidity. Lichens with usnic acid prefer an ambient pH range between 3.5 and 5.5 with an optimum between 4.0 and 4.5. This optimum is close to the pK a1 value of usnic acid of 4.4. Below this optimum pH, dissolved SO 2 reduces the chlorophyll fluorescence yield more in lichens with than without their natural content of usnic acid. This suggests that usnic acid influences the acidity tolerance of lichens. The putative mechanism of the limited acidity tolerance of usnic acid-containing lichens is the acidification of the cytosol by molecules of protonated usnic acid shuttling protons through the plasma membrane at an apoplastic pH a1 . - Combined field and experimental data suggest that usnic acid makes lichens sensitive to acidity at pH <3.5

  1. [Studies on interaction of acid-treated nanotube titanic acid and amino acids].

    Science.gov (United States)

    Zhang, Huqin; Chen, Xuemei; Jin, Zhensheng; Liao, Guangxi; Wu, Xiaoming; Du, Jianqiang; Cao, Xiang

    2010-06-01

    Nanotube titanic acid (NTA) has distinct optical and electrical character, and has photocatalysis character. In accordance with these qualities, NTA was treated with acid so as to enhance its surface activity. Surface structures and surface groups of acid-treated NTA were characterized and analyzed by Transmission Electron Microscope (TEM) and Fourier Transform Infrared Spectrometry (FT-IR). The interaction between acid-treated NTA and amino acids was investigated. Analysis results showed that the lengths of acid-treated NTA became obviously shorter. The diameters of nanotube bundles did not change obviously with acid-treating. Meanwhile, the surface of acid-treated NTA was cross-linked with carboxyl or esterfunction. In addition, acid-treated NTA can catch amino acid residues easily, and then form close combination.

  2. A Direct, Biomass-Based Synthesis of Benzoic Acid: Formic Acid-Mediated Deoxygenation of the Glucose-Derived Materials Quinic Acid and Shikimic Acid

    Energy Technology Data Exchange (ETDEWEB)

    Arceo, Elena; Ellman, Jonathan; Bergman, Robert

    2010-05-03

    An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.

  3. Molecular interaction of pinic acid with sulfuric acid

    DEFF Research Database (Denmark)

    Elm, Jonas; Kurtén, Theo; Bilde, Merete

    2014-01-01

    We investigate the molecular interactions between the semivolatile α-pinene oxidation product pinic acid and sulfuric acid using computational methods. The stepwise Gibbs free energies of formation have been calculated utilizing the M06-2X functional, and the stability of the clusters is evaluated...... cluster. The involvement of more than one pinic acid molecule in a single cluster is observed to lead to the formation of favorable (pinic acid)2(H2SO4) and (pinic acid)2(H2SO4)2 clusters. The identified most favorable growth paths starting from a single pinic acid molecule lead to closed structures...

  4. Alkyl phosphonic acids and sulfonic acids in the Murchison meteorite

    Science.gov (United States)

    Cooper, George W.; Onwo, Wilfred M.; Cronin, John R.

    1992-01-01

    Homologous series of alkyl phosphonic acids and alkyl sulfonic acids, along with inorganic orthophosphate and sulfate, are identified in water extracts of the Murchison meteorite after conversion to their t-butyl dimethylsilyl derivatives. The methyl, ethyl, propyl, and butyl compounds are observed in both series. Five of the eight possible alkyl phosphonic acids and seven of the eight possible alkyl sulfonic acids through C4 are identified. Abundances decrease with increasing carbon number as observed of other homologous series indigenous to Murchison. Concentrations range downward from approximately 380 nmol/gram in the alkyl sulfonic acid series, and from 9 nmol/gram in the alkyl phosphonic acid series.

  5. Koetjapic acid chloroform hemisolvate

    Directory of Open Access Journals (Sweden)

    Z. D. Nassar

    2010-06-01

    Full Text Available The asymmetric unit of the title compound, C30H46O4·0.5CHCl3, consists of one koetjapic acid [systematic name: (3R,4aR,4bS,7S,8S,10bS,12aS-7-(2-carboxyethyl-3,4b,7,10b,12a-pentamethyl-8-(prop-1-en-2-yl-1,2,3,4,4a,4b,5,6,7,8,9,10,10b,11,12,12a-hexadecahydrochrysene-3-carboxylic acid] molecule and one half-molecule of chloroform solvent, which is disordered about a twofold rotation axis. The symmetry-independent component is further disordered over two sites, with occupancies of 0.30 and 0.20. The koetjapic acid contains a fused four-ring system, A/B/C/D. The A/B, B/C and C/D junctions adopt E/trans/cis configurations, respectively. The conformation of ring A is intermediate between envelope and half-chair and ring B adopts an envelope conformation whereas rings C and D adopt chair conformations. A weak intramolecular C—H...O hydrogen bond is observed. The koetjapic acid molecules are linked into dimers by two pairs of intermolecular O—H...O hydrogen bonds. The dimers are stacked along the c axis.

  6. Microbial Propionic Acid Production

    Directory of Open Access Journals (Sweden)

    R. Axayacatl Gonzalez-Garcia

    2017-05-01

    Full Text Available Propionic acid (propionate is a commercially valuable carboxylic acid produced through microbial fermentation. Propionic acid is mainly used in the food industry but has recently found applications in the cosmetic, plastics and pharmaceutical industries. Propionate can be produced via various metabolic pathways, which can be classified into three major groups: fermentative pathways, biosynthetic pathways, and amino acid catabolic pathways. The current review provides an in-depth description of the major metabolic routes for propionate production from an energy optimization perspective. Biological propionate production is limited by high downstream purification costs which can be addressed if the target yield, productivity and titre can be achieved. Genome shuffling combined with high throughput omics and metabolic engineering is providing new opportunities, and biological propionate production is likely to enter the market in the not so distant future. In order to realise the full potential of metabolic engineering and heterologous expression, however, a greater understanding of metabolic capabilities of the native producers, the fittest producers, is required.

  7. Acid dip for dosemeter

    International Nuclear Information System (INIS)

    Stewart, J.C.; McWhan, A.F.

    1982-01-01

    Background signal in a PTFE based dosemeter caused by impurities in the PTFE and in the active component such as lithium fluoride is substantially reduced by treating the dosemeter with acid. The optimum treatment involves use of hydrofluoric acid at room temperature for approximately one minute, followed by thorough washing with methanol, and finally drying. This treatment is best applied after the original manufacture of the dosemeters. It may also be applied to existing dosemeters after they have been in use for some time. The treatment produces a permanent effect in reducing both the light induced signal and the non-light induced signal. The process may be applied to all types of dosemeter manufactured from PTFE or other plastics or resins which are able to resist brief exposure to acid. The treatment works particularly well with dosemeters based on PTFE and lithium fluoride. It is also applicable to dosemeters based on calcium sulphate, lithium borate and magnesium borate. Acids which may be used include hydrofluoric, hydrochloric, nitric, phosphoric and sulphuric. (author)

  8. Acid Ceramidase in Melanoma

    DEFF Research Database (Denmark)

    Realini, Natalia; Palese, Francesca; Pizzirani, Daniela

    2016-01-01

    Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphing...

  9. Nucleic acids in circulation

    Indian Academy of Sciences (India)

    Elevated blood levels of extracellular nucleic acids have been reported in various disease conditions; such as ageing and age-related degenerative disorders, cancer; acute and chronic inflammatory conditions, severe trauma and autoimmune disorders. In addition to genomic DNA and nucleosomes, mitochondrial DNA is ...

  10. Salicylic Acid Topical

    Science.gov (United States)

    ... the package label for more information.Apply a small amount of the salicylic acid product to one or two small areas you want to treat for 3 days ... know that children and teenagers who have chicken pox or the flu should not use topical salicylic ...

  11. Acid Rain: Science Projects.

    Science.gov (United States)

    Stubbs, Harriett S.

    1989-01-01

    Presented is a science activity designed to help students monitor the pH of rainfall. Materials, procedures and follow-up activities are listed. A list of domestic and foreign sources of information is provided. Topics which relate to acid precipitation are outlined. (CW)

  12. Hyaluronic Acid Assays

    DEFF Research Database (Denmark)

    Itenov, Theis S; Kirkby, Nikolai S; Bestle, Morten H

    2015-01-01

    BACKGROUD: Hyaluronic acid (HA) is proposed as a marker of functional liver capacity. The aim of the present study was to compare a new turbidimetric assay for measuring HA with the current standard method. METHODS: HA was measured by a particle-enhanced turbidimetric immunoassay (PETIA) and enzyme...

  13. Multifunctional Cinnamic Acid Derivatives

    Directory of Open Access Journals (Sweden)

    Aikaterini Peperidou

    2017-07-01

    Full Text Available Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX inhibition (IC50 = 6 μΜ and antiproteolytic activity (IC50 = 0.425 μΜ. The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC50 = 0.315 μΜ and good LOX inhibitory activity (IC50 = 66 μΜ. Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.

  14. Accidents with sulfuric acid

    Directory of Open Access Journals (Sweden)

    Rajković Miloš B.

    2006-01-01

    Full Text Available Sulfuric acid is an important industrial and strategic raw material, the production of which is developing on all continents, in many factories in the world and with an annual production of over 160 million tons. On the other hand, the production, transport and usage are very dangerous and demand measures of precaution because the consequences could be catastrophic, and not only at the local level where the accident would happen. Accidents that have been publicly recorded during the last eighteen years (from 1988 till the beginning of 2006 are analyzed in this paper. It is very alarming data that, according to all the recorded accidents, over 1.6 million tons of sulfuric acid were exuded. Although water transport is the safest (only 16.38% of the total amount of accidents in that way 98.88% of the total amount of sulfuric acid was exuded into the environment. Human factor was the common factor in all the accidents, whether there was enough control of the production process, of reservoirs or transportation tanks or the transport was done by inadequate (old tanks, or the accidents arose from human factor (inadequate speed, lock of caution etc. The fact is that huge energy, sacrifice and courage were involved in the recovery from accidents where rescue teams and fire brigades showed great courage to prevent real environmental catastrophes and very often they lost their lives during the events. So, the phrase that sulfuric acid is a real "environmental bomb" has become clearer.

  15. Pantothenic acid and biotin

    Science.gov (United States)

    Pantothenic acid and biotin are types of B vitamins. They are water-soluble, which means that the body can't store them. If the body can't use all of the vitamin, the extra vitamins leave the body through the ...

  16. and amino acids

    Indian Academy of Sciences (India)

    Unknown

    P RABINDRA REDDY* and A MOHAN REDDY. Department of ... The mixed ligand complexes of Cu(II), Ni(II) and Co(II) with uridine and amino acids ..... Sabat M, Satyashur K A and Sundaralingam M 1983 J. Am. Chem. Soc. ... Uemura T, Shimura T, Nakamishi H, Tomahiro T, Nagawa Y and Okuno (Yohmei) H 1991. Inorg.

  17. Lactic acid and lactates

    NARCIS (Netherlands)

    Schreurs, V.V.A.M.

    2010-01-01

    This review aims to integrate the present state of knowledge on lactate metabolism in human and mammalian physiology as far as it could be subject to nutritional interventions. An integrated view on the nutritional, metabolic and physiological aspects of lactic acid and lactates might open a

  18. Origin of fatty acids

    International Nuclear Information System (INIS)

    Prieur, B.E.

    1995-01-01

    The appearance of fatty acids and membranes is one of the most important events of the prebiotic world because genesis of life required the compartmentalization of molecules. Membranes allowed cells to become enriched with molecules relevant for their evolution and gave rise to gradients convertible into energy. By virtue of their hydrophobic/hydrophilic interface, membranes developed certain enzymatic activities impossible in the aqueous phase. A prebiotic cell is an energy unit but it is also an information unit. It has a past, a present and a future. The biochemistry of fatty acids involves acetylCoA, malonylCoA and an enzyme, acyl synthetase, which joins both molecules. After substitution of the acetyl group in place of the carboxyl group of malonyl derivatives, the chain is reduced and dehydrated to crotonyl derivatives. These molecules can again react with malonylCoA to form unsaturated chain; they can also undergo a new reduction step to form butyryl derivatives which can react with malonylCoA to form a longer aliphatic chain. The formation of malonylCoA consumes ATP. The reduction step needs NADPH and proton. Dehydration requires structural information because the reduction product is chiral (D configuration). It is unlikely that these steps were possible in a prebiotic environment. Thus we have to understand how fatty acids could appear in the prebiotic era. This hypothesis about the origin of fatty acids is based on the chemistry of sulfonium ylides and sulfonium salts. The most well-known among these molecules are S-melthyl-methionine and S-adenosyl methionine. The simplest sulfonium cation is the trimethylsulfonium cation. Chemists have evidence that these products can produce olefin when they are heated or flashed with UV light in some conditions. I suggest that these volatile products can allow the formation of fatty acids chains in atmospheric phase with UV and temperature using methanol as starting material. Different synthetic pathways will be

  19. Fatty acid-producing hosts

    Science.gov (United States)

    Pfleger, Brian F; Lennen, Rebecca M

    2013-12-31

    Described are hosts for overproducing a fatty acid product such as a fatty acid. The hosts include an exogenous nucleic acid encoding a thioesterase and, optionally, an exogenous nucleic acid encoding an acetyl-CoA carboxylase, wherein an acyl-CoA synthetase in the hosts are functionally delected. The hosts prefereably include the nucleic acid encoding the thioesterase at an intermediate copy number. The hosts are preferably recominantly stable and growth-competent at 37.degree. C. Methods of producing a fatty acid product comprising culturing such hosts at 37.degree. C. are also described.

  20. Acetic acid extraction from aqueous solutions using fatty acids

    NARCIS (Netherlands)

    IJmker, H.M.; Gramblicka, M.; Kersten, Sascha R.A.; van der Ham, Aloysius G.J.; Schuur, Boelo

    2014-01-01

    A major challenge for production of acetic acid via bio-based routes is cost-effective concentration and purification of the acetic acid from the aqueous solutions, for which liquid–liquid extraction is a possible method. A main challenge in extraction of acetic acid from dilute aqueous solutions is

  1. College Chemistry Students' Mental Models of Acids and Acid Strength

    Science.gov (United States)

    McClary, LaKeisha; Talanquer, Vicente

    2011-01-01

    The central goal of this study was to characterize the mental models of acids and acid strength expressed by advanced college chemistry students when engaged in prediction, explanation, and justification tasks that asked them to rank chemical compounds based on their relative acid strength. For that purpose we completed a qualitative research…

  2. Cytotoxic effect of betulinic acid and betulinic acid acetate isolated ...

    African Journals Online (AJOL)

    Cytotoxic effect of betulinic acid and betulinic acid acetate isolated from Melaleuca cajuput on human myeloid leukemia (HL-60) cell line. ... The cytotoxic effect of betulinic acid (BA), isolated from Melaleuca cajuput a Malaysian plant and its four synthetic derivatives were tested for their cytotoxicity in various cell line or ...

  3. Industrial ecotoxicology "acid rain".

    Science.gov (United States)

    Astolfi, E; Gotelli, C; Higa, J

    1986-01-01

    The acid rain phenomenon was studied in the province of Cordoba, Argentina. This study, based on a previously outlined framework, determined the anthropogenic origin of the low pH due to the presence of industrial hydrochloric acid wastage. This industrial ecotoxicological phenomenon seriously affected the forest wealth, causing a great defoliation of trees and shrubs, with a lower effect on crops. A survey on its effects on human beings has not been carried out, but considering the corrosion caused to different metals and its denouncing biocide effect on plants and animals, we should expect to find some kind of harm to the health of the workers involved or others engaged in farming, and even to those who are far away from the polluting agent.

  4. Radioimmunoassay for jasmonic acid

    Energy Technology Data Exchange (ETDEWEB)

    Knoefel, H.D.; Brueckner, C.; Kramell, R.; Sembdner, G.; Schreiber, K. (Akademie der Wissenschaften der DDR, Halle/Saale. Inst. fuer Biochemie der Pflanzen)

    1984-01-01

    A radioimmunoassay (RIA) for the natural plant growth regulator jasmonic acid (JA) was developed. The antiserum was raised in rabbits against (+-)-JA linked to bovine serum albumin. As tracer tritium labelled (+-)-JA (spec. act. 7.4 x 10/sup 9/ Bq x mmol/sup -1/) was used. Cross-reactivity studies with compounds structurally related to JA demonstrated the antiserum to be specific for JA, abscisic acid normally present in the same extract does not interfer. The RIA has a detection limit of 2 ng (-)-JA methylester, a measuring range 2-200 ng, and no extensive purification is required prior to estimation. Therefore, in JA analysis the RIA described is superior to GC, HPLC, and bioassay. This new method has been employed for studies on the distribution of JA in different plant organs of the broad bean, Vicia faba L.

  5. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  6. N-(3-Methylphenylsuccinamic acid

    Directory of Open Access Journals (Sweden)

    B. Thimme Gowda

    2010-02-01

    Full Text Available In the crystal structure of the title compound, C11H13NO3, the conformations of the N—H and C=O bonds in the amide segment are anti to each other, and that of the amide H atom is anti to the meta-methyl group in the benzene ring. Furthermore, the conformations of the amide oxygen and the carbonyl O atom of the acid segment are also anti to the adjacent –CH2 groups. The C=O and O—H bonds of the acid group are syn to each other. In the crystal, the molecules are packed into infinite chains through intermolecular N—H...O and O—H...O hydrogen bonds.

  7. N-(3-Chlorophenylmaleamic acid

    Directory of Open Access Journals (Sweden)

    B. Thimme Gowda

    2010-07-01

    Full Text Available In the title compound, C10H8ClNO3, the molecular conformation is stabilized by two intramolecular hydrogen bonds. The first is a short O—H...O hydrogen bond within the maleamic acid unit and the second is a C—H...O hydrogen bond which connects the amide group with the phenyl ring. The maleamic acid unit is essentially planar, with an r.m.s. deviation of 0.044 Å, and makes a dihedral angle of 15.2 (1° with the phenyl ring. In the crystal, intermolecular N—H...O hydrogen bonds link the molecules into C(7 chains running [010].

  8. Mortar fights acid corrosion

    Energy Technology Data Exchange (ETDEWEB)

    1982-05-14

    The burning of coal or oil to produce heat required to operate a power boiler also generates a severe corrosion problem within the interior of the duct and stacks used to emit the flue gas into the atmosphere. How can concrete and steel be protected from the effects of acid attack, when the acids are carried in a gas form, or come into direct contact with the steel or concrete from spillage or immersion conditions. Industry in North America has found that the solution to this problem is to build an outside concrete column, in this case of Portland cement, and inside that column, build a totally independent brick liner bonded with Sauereisen mortar.

  9. (Radioiodinated free fatty acids)

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, Jr., F. F.

    1987-12-11

    The traveler participated in the Second International Workshop on Radioiodinated Free Fatty Acids in Amsterdam, The Netherlands where he presented an invited paper describing the pioneering work at the Oak Ridge National Laboratory (ORNL) involving the design, development and testing of new radioiodinated methyl-branched fatty acids for evaluation of heart disease. He also chaired a technical session on the testing of new agents in various in vitro and in vivo systems. He also visited the Institute for Clinical and Experimental Nuclear Medicine in Bonn, West Germany, to review, discuss, plan and coordinate collaborative investigations with that institution. In addition, he visited the Cyclotron Research Center in Liege, Belgium, to discuss continuing collaborative studies with the Osmium-191/Iridium-191m radionuclide generator system, and to complete manuscripts and plan future studies.

  10. Acidity of Scandinavian precipitation

    Energy Technology Data Exchange (ETDEWEB)

    Barrett, E; Bordin, G

    1955-01-01

    Data on the pH of the total monthly precipitation at stations of a Swedish network for sampling and chemical analysis of precipitation and atmospheric aerosols during the year July 1953 to June 1954 are presented and discussed, together with the pH data from the first two months of operation of a large pan-Scandinavian net. It is found that well-defined regions of acidity and alkalinity relative to the pH of water in equilibrium with atmospheric carbon dioxide exist, and that these regions persist to such an extent that the monthly deviations from the pattern of the annual mean pH at stations unaffected by local pollution show persistently high acidity, while inland northern stations show equally persistent alkalinity. Some possible reasons for the observed distributions are considered.

  11. Omega-3 fatty acids (image)

    Science.gov (United States)

    Omega-3 fatty acids are a form of polyunsaturated fat that the body derives from food. Omega-3s (and omega-6s) are known as essential fatty acids (EFAs) because they are important for good health. ...

  12. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2007-01-01

    Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness.......Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness....

  13. Halogenated fatty acids

    DEFF Research Database (Denmark)

    Mu, Huiling; Sundin, Peter; Wesén, Clas

    1997-01-01

    Halogenated fatty acids are the major contributors to organohalogen compounds in lipids of marine mammals, fish, and bivalves. For the initial characterization of these recently noticed compounds, a determination of the halogen concentration has usually been combined with some lipid isolation......), atomic emission spectrometry, and mass spectrometry. For most environmental samples, chlorinated FAMEs must be enriched prior to GC. ELCD is a useful detection method for indicating halogenated FAMEs in the chromatograms, and tentative identification of the halogenated species can be obtained...

  14. Accidents with sulfuric acid

    OpenAIRE

    Rajković Miloš B.

    2006-01-01

    Sulfuric acid is an important industrial and strategic raw material, the production of which is developing on all continents, in many factories in the world and with an annual production of over 160 million tons. On the other hand, the production, transport and usage are very dangerous and demand measures of precaution because the consequences could be catastrophic, and not only at the local level where the accident would happen. Accidents that have been publicly recorded during the last eigh...

  15. Sources of atmospheric acidity

    International Nuclear Information System (INIS)

    Clarke, A.G.

    1992-01-01

    The emissions of acid gases from anthropogenic sources and their impact on the environment are the main concern of this book. However, that impact can only be assessed if all the naturally occurring sources of these gases are also known and can be quantified. Given the widely dispersed nature of the natural sources and the problems of measurement of trace species at low concentrations, often in remote regions, the quantification is a very difficult task. Nevertheless, considerable progress has been made over the last decade. In this chapter both man-made and natural sources of atmospheric acidity will be reviewed, but the emphasis will be placed not so much on the global balances as on the scale of the natural sources in relation to the man-made sources. This requires that the very uneven geographical distribution of emissions and the lifetime of individual chemical species be taken into account. The emissions considered are sulphur compounds, nitrogen compounds, chlorine compounds and organic acids. The anthropogenic sources discussed are the combustion of fossil fuels and certain industrial processes. Emissions data for anthropogenic sources are given for the United Kingdom, Europe, USA and globally. A list of 95 references is given. (Author)

  16. Whence the acid raindrop

    International Nuclear Information System (INIS)

    Heaton, T.H.E.

    1987-01-01

    Absorption of NO 2 can cause damage in animals and plants and, if present trends for NO x emissions continue, their by-product nitric acid may soon overtake sulphuric acid as the main acidifying agent of 'acid' rain. In response to this problem the feasibility of reducing NO x emissions from power stations is being studied. Although there can be no doubt that these expensive controls are desirable, their benefits are difficult to predict for two reasons: NO x is not only emitted by fuel combustion and the degree to which an industrialised country benefits from the implementation of NO x emission controls depends on how much its pollutant 'fall out' is immediately returned from the atmosphere, and how much is exported to neighbouring countries. The above factors involve questions regarding the source and reaction mechanisms for nitrogen compounds in the atmosphere. Because stable isotope ratio analysis has proved to be of value in providing answers to such questions in other environments, an investigation of the 15 N/ 14 N ratios of atmospheric gases (NO x , NH 3 ) and their solution products in rain (NO 3 , NH + 4 ) seemed to be justified

  17. Hepatic Toxicity of Perfluorocarboxylic Acids.

    Science.gov (United States)

    1996-07-01

    1995). 3. N. V. Reo, C. M. Goecke, L. Narayanan, and B. M. Jarnot. "Effects of Perfluoro-n-octanoic Acid , Perfluoro-n-decanoic Acid , and Clofibrate ...Artz, and B. M. Jarnot: "ILiver Phosphorous Metabolic Response to Perfluorocarboxylic Acids and Clofibrate in Rats and Guinea Pigs: A 31 P NMR Study...Peroxisome Induction by Perfluoro-n-decanoic Acid and Clofibrate in the Rat: Proliferation Versus Activity." International Society for the Study of

  18. Acids and bases solvent effects on acid-base strenght

    CERN Document Server

    Cox, Brian G

    2013-01-01

    Acids and bases are ubiquitous in chemistry. Our understanding of them, however, is dominated by their behaviour in water. Transfer to non-aqueous solvents leads to profound changes in acid-base strengths and to the rates and equilibria of many processes: for example, synthetic reactions involving acids, bases and nucleophiles; isolation of pharmaceutical actives through salt formation; formation of zwitter- ions in amino acids; and chromatographic separation of substrates. This book seeks to enhance our understanding of acids and bases by reviewing and analysing their behaviour in non-aqueous solvents. The behaviour is related where possible to that in water, but correlations and contrasts between solvents are also presented.

  19. Sequential injection redox or acid-base titration for determination of ascorbic acid or acetic acid.

    Science.gov (United States)

    Lenghor, Narong; Jakmunee, Jaroon; Vilen, Michael; Sara, Rolf; Christian, Gary D; Grudpan, Kate

    2002-12-06

    Two sequential injection titration systems with spectrophotometric detection have been developed. The first system for determination of ascorbic acid was based on redox reaction between ascorbic acid and permanganate in an acidic medium and lead to a decrease in color intensity of permanganate, monitored at 525 nm. A linear dependence of peak area obtained with ascorbic acid concentration up to 1200 mg l(-1) was achieved. The relative standard deviation for 11 replicate determinations of 400 mg l(-1) ascorbic acid was 2.9%. The second system, for acetic acid determination, was based on acid-base titration of acetic acid with sodium hydroxide using phenolphthalein as an indicator. The decrease in color intensity of the indicator was proportional to the acid content. A linear calibration graph in the range of 2-8% w v(-1) of acetic acid with a relative standard deviation of 4.8% (5.0% w v(-1) acetic acid, n=11) was obtained. Sample throughputs of 60 h(-1) were achieved for both systems. The systems were successfully applied for the assays of ascorbic acid in vitamin C tablets and acetic acid content in vinegars, respectively.

  20. Molecular Structure of Nucleic Acids

    Indian Academy of Sciences (India)

    Molecular Structure of Nucleic Acids. A Structure for Deoxyribose Nucleic Acid. J. D. Watson and F. H. C. Crick. Medical Research Council Unit for the Study of the Molecular Structure of Biological. Systems, Cavendish Laboratory, Cambridge. April 2. We wish to suggest a structure for the salt of deoxyribose nucleic acid ...

  1. Fumaric acid production by fermentation

    NARCIS (Netherlands)

    Roa Engel, C.A.; Straathof, A.J.J.; Zijlmans, T.W.; Van Gulik, W.M.; Van der Wielen, L.A.M.

    2008-01-01

    Abstract The potential of fumaric acid as a raw material in the polymer industry and the increment of cost of petroleum-based fumaric acid raises interest in fermentation processes for production of this compound from renewable resources. Although the chemical process yields 112% w/w fumaric acid

  2. Pantothenic acid biosynthesis in zymomonas

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Luan; Tomb, Jean-Francois; Viitanen, Paul V.

    2014-07-01

    Zymomonas is unable to synthesize pantothenic acid and requires this essential vitamin in growth medium. Zymomonas strains transformed with an operon for expression of 2-dehydropantoate reductase and aspartate 1-decarboxylase were able to grow in medium lacking pantothenic acid. These strains may be used for ethanol production without pantothenic acid supplementation in seed culture and fermentation media.

  3. Danburite decomposition by hydrochloric acid

    International Nuclear Information System (INIS)

    Mamatov, E.D.; Ashurov, N.A.; Mirsaidov, U.

    2011-01-01

    Present article is devoted to decomposition of danburite of Ak-Arkhar Deposit of Tajikistan by hydrochloric acid. The interaction of boron containing ores of Ak-Arkhar Deposit of Tajikistan with mineral acids, including hydrochloric acid was studied. The optimal conditions of extraction of valuable components from danburite composition were determined. The chemical composition of danburite of Ak-Arkhar Deposit was determined as well. The kinetics of decomposition of calcined danburite by hydrochloric acid was studied. The apparent activation energy of the process of danburite decomposition by hydrochloric acid was calculated.

  4. Waste acid detoxification and reclamation

    International Nuclear Information System (INIS)

    Brouns, T.M.; Stewart, T.L.

    1988-01-01

    Economically feasible processes that reduce the volume, quantity, and toxicity of metal-bearing waste acids by reclaiming, reusing, and recycling spent acids and metal salts are being developed and demonstrated. The acids used in the demonstrations are generated during metal-finishing operations used in nuclear fuel fabrication; HF-HNO 3 , HNO 3 , and HNO 3 -H 2 SO 4 wastes result from Zr etching, Cu stripping, and chemical milling of U. At discharge, wastes contain high concentrations of acid and one major metal impurity. The waste minimization process used to reclaim acid from these three streams incorporates three processes for acid regeneration and reclamation. Normally, HNO 3 remains in the bottoms when an aqueous acid solution is distilled; however, in the presence of H 2 SO 4 , HNO 3 will distill to the overhead stream. In this process, nitrates and fluorides present as free acid and metal salts can be reclaimed as acid for recycle to the metal-finishing processes. Uranium present in the chemical milling solution can be economically recovered from distillation bottoms and refined. Using acid distillation, the volume of chemical milling solution discharged as waste can be reduced by as much as 60% depending on the H 2 SO 4 concentration. A payback period of 2.2 years has been estimated for this process. The development and demonstration of precipitation and distillation processes for detoxification and reclamation of waste acid is supported by the US Department of Energy's Hazardous Waste Remedial Actions Program (HAZWRAP)

  5. New Acid Combination for a Successful Sandstone Acidizing

    Science.gov (United States)

    Shafiq, M. U.; Mahmud, H. K. B.; Rezaee, R.

    2017-05-01

    With the development of new enhanced oil recovery techniques, sandstone acidizing has been introduced and played a pivotal role in the petroleum industry. Different acid combinations have been applied, which react with the formation, dissolve the soluble particles; thus increase the production of hydrocarbons. To solve the problems which occurred using current preflush sandstone acidizing technology (hydrochloric acid); a new acid combination has been developed. Core flooding experiments on sandstone core samples with dimensions 1.5 in. × 3 in. were conducted at a flow rate of 2 cm3/min. A series of hydrochloric-acetic acid mixtures with different ratios were tested under 150°F temperature. The core flooding experiments performed are aimed to dissolve carbonate, sodium, potassium and calcium particles from the core samples. These experiments are followed by few important tests which include, porosity-permeability, pH value, Inductively Coupled Plasma (ICP) analysis and Nuclear Magnetic Resonance (NMR measurements). All the results are compared with the results of conventional hydrochloric acid technology. NMR and porosity analysis concluded that the new acid combination is more effective in creating fresh pore spaces and thus increasing the reservoir permeability. It can be seen from the pore distribution before and after the acidizing. Prior applying acid; the large size of pores appears most frequently in the pore distribution while with the applied acid, it was found that the small pore size is most the predominant of the pore distribution. These results are validated using ICP analysis which shows the effective removal of calcium and other positive ions from the core sample. This study concludes that the combination of acetic-hydrochloric acid can be a potential candidate for the preflush stage of sandstone acidizing at high temperature reservoirs.

  6. Urban acid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Conlan, D.E.; Longhurst, J.W.S.; Gee, D.R.; Hare, S.E.

    1991-07-01

    In this document results from the Greater Manchester Acid Deposition Survey (GMADS), an urban precipitation chemistry network, for 1990 are presented. Full analytical methods are described along with the precision and accuracy of the methods used. The spatial variability of precipitation chemistry and deposition over this urban region was investigated using a network of twenty collectors. Concentrations of non marine sulphate, ammonium, calcium and hydrogen, and nitrogen dioxide gas concentrations all show significant spatial variability. The spatial variability of the deposition rates of non marine sulphate, nitrate, ammonium, hydrogen and calcium were significant. (Author).

  7. Synthesis of aminoaldonic acids

    DEFF Research Database (Denmark)

    Jørgensen, Christel Thea

    With the aim of synthesising aminoaldonic acids, two 2-acetamido-2-deoxyaldonolactones with D-galacto (6) and D-arabino (11) configuration were prepared from acetylated sugar formazans in analogy with a known procedure. Empolying the same procedure to acetylated sugar phenylhydrazones gave mixtures...... and 82, respectively. The aminolactone 84 was converted into the corresponding amino sugar 89.With the aim of synthesising substrates for the Pictet-Spengler reaction three 4-aldehydo acetamidodideoxytetronolactones 92, 97 and 103 were prepared by periodate cleavage of the corresponding hexonolactones...

  8. Folic Acid: MedlinePlus Health Topic

    Science.gov (United States)

    ... acid in diet (Medical Encyclopedia) Also in Spanish Topic Image MedlinePlus Email Updates Get Folic Acid updates ... acid - test Folic acid in diet Related Health Topics Vitamins National Institutes of Health The primary NIH ...

  9. Solid acid catalysis from fundamentals to applications

    CERN Document Server

    Hattori, Hideshi

    2014-01-01

    IntroductionTypes of solid acid catalystsAdvantages of solid acid catalysts Historical overviews of solid acid catalystsFuture outlookSolid Acids CatalysisDefinition of acid and base -Brnsted acid and Lewis acid-Acid sites on surfacesAcid strengthRole of acid sites in catalysisBifunctional catalysisPore size effect on catalysis -shape selectivity-Characterization of Solid Acid Catalysts Indicator methodTemperature programmed desorption (TPD) of ammoniaCalorimetry of adsorption of basic moleculesInfrare

  10. Uracil in formic acid hydrolysates of deoxyribonucleic acid

    Science.gov (United States)

    Schein, Arnold H.

    1966-01-01

    1. When DNA is hydrolysed with formic acid for 30min. at 175° and the hydrolysate is chromatographed on paper with propan-2-ol–2n-hydrochloric acid, in addition to expected ultraviolet-absorbing spots corresponding to guanine, adenine, cytosine and thymine, an ultraviolet-absorbing region with RF similar to that of uracil can be detected. Uracil was separated from this region and identified by its spectra in acid and alkali, and by its RF in several solvent systems. 2. Cytosine, deoxyribocytidine and deoxyribocytidylic acid similarly treated with formic acid all yielded uracil, as did a mixture of deoxyribonucleotides. 3. Approx. 4% of deoxyribonucleotide cytosine was converted into uracil by the formic acid treatment. ImagesFig. 1. PMID:5949371

  11. Uric acid nephrolithiasis: An update.

    Science.gov (United States)

    Cicerello, Elisa

    2018-04-01

    Uric acid nephrolithiasis appears to increase in prevalence. While a relationship between uric acid stones and low urinary pH has been for long known, additional association with various metabolic conditions and pathophysiological basis has recently been elucidated. Some conditions such as diabetes and metabolic syndrome disease, excessive dietary intake, and increased endogenous uric acid production and/or defect in ammoniagenesis are associated with low urinary pH. In addition, the phenomenon of global warming could result in an increase in areas with greater climate risk for uric acid stone formation. There are three therapeutic steps to be taken for management of uric acid stones: identification of urinary pH profiles, assessment of urinary volume status, and identification of disorders leading to excessive uric acid production. However, the most important factor for uric acid stone formation is acid urinary pH, which is a prerequisite for uric acid precipitation. This article reviews recent insights into the pathophysiology of uric acid stones and their management.

  12. Bile Acid Metabolism and Signaling

    Science.gov (United States)

    Chiang, John Y. L.

    2015-01-01

    Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans. PMID:23897684

  13. Electrolytic nature of aqueous sulfuric acid. 2. Acidity.

    Science.gov (United States)

    Fraenkel, Dan

    2012-09-27

    In part 1 of this study, I reported that the Debye-Hückel limiting law and the smaller-ion shell (SiS) model of strong electrolyte solutions fit nicely with the experimental mean ionic activity coefficient (γ(±)) of aqueous sulfuric acid as a function of concentration and of temperature when the acid is assumed to be a strong 1-3 electrolyte. Here, I report that the SiS-derived activity coefficient of H(+), γ(H(+)), of the 1-3 acid is comparable to that of aqueous HCl. This agrees with titration curves showing, as well-known, that sulfuric acid in water is parallel in strength to aqueous HCl. The calculated pH is in good accord with the Hammett acidity function, H(0), of aqueous sulfuric acid at low concentration, and differences between the two functions at high concentration are discussed and explained. This pH-H(0) relation is consistent with the literature showing that the H(0) of sulfuric acid (in the 1-9 M range) is similar to those of HCl and the other strong mineral monoprotic acids. The titration of aqueous sulfuric acid with NaOH does not agree with the known second dissociation constant of 0.010 23; rather, the constant is found to be ~0.32 and the acid behaves upon neutralization as a strong diprotic acid practically dissociating in one step. A plausible reaction pathway is offered to explain how the acid may transform, upon base neutralization, from a dissociated H(4)SO(5) (as 3H(+) and HSO(5)(3-)) to a dissociated H(2)SO(4) even though the equilibrium constant of the reaction H(+) + HSO(5)(3-) ↔ SO(4)(2-) + H(2)O, at 25 °C, is 10(-37) (part 1).

  14. Counter current extraction of phosphoric acid: Food grade acid production

    International Nuclear Information System (INIS)

    Shlewit, H.; AlIbrahim, M.

    2009-01-01

    Extraction, scrubbing and stripping of phosphoric acid from the Syrian wet-phosphoric acid was carried out using Micro-pilot plant of mixer settler type of 8 l/h capacity. Tributyl phosphate (TBP)/di-isopropyl ether (DIPE) in kerosene was used as extractant. Extraction and stripping equilibrium curves were evaluated. The number of extraction and stripping stages to achieve the convenient and feasible yield was determined. Detailed flow sheet was suggested for the proposed continuous process. Data obtained include useful information for the design of phosphoric acid extraction plant. The produced phosphoric acid was characterized using different analytical techniques. (author)

  15. Acidizing reservoirs while chelating iron with sulfosalicylic acid

    Energy Technology Data Exchange (ETDEWEB)

    McLaughlin, W A; Berkshire, D C

    1980-09-30

    A well treating process is described in which an aqueous solution of a strong acid capable of dissolving solids in a manner increasing the permeability of a subterranean earth formation is injected into a subterranean reservoir that contains an asphaltenic oil. At least the first injected portion of the aqueous acid and a solution or homogeneous dispersion of at least enough 5-sulfosalicylic acid to chelate with and prevent the formation of iron-asphaltene solids are included with substantially all of the ferric ions that become dissolved within the strong acid solution that enters the earth formation. 10 claims.

  16. Danburite decomposition by sulfuric acid

    International Nuclear Information System (INIS)

    Mirsaidov, U.; Mamatov, E.D.; Ashurov, N.A.

    2011-01-01

    Present article is devoted to decomposition of danburite of Ak-Arkhar Deposit of Tajikistan by sulfuric acid. The process of decomposition of danburite concentrate by sulfuric acid was studied. The chemical nature of decomposition process of boron containing ore was determined. The influence of temperature on the rate of extraction of boron and iron oxides was defined. The dependence of decomposition of boron and iron oxides on process duration, dosage of H 2 SO 4 , acid concentration and size of danburite particles was determined. The kinetics of danburite decomposition by sulfuric acid was studied as well. The apparent activation energy of the process of danburite decomposition by sulfuric acid was calculated. The flowsheet of danburite processing by sulfuric acid was elaborated.

  17. Recovering uranium from phosphoric acid

    International Nuclear Information System (INIS)

    Anon.

    1979-01-01

    Wet-process phosphoric acid contains a significant amount of uranium. This uranium totals more than 1,500 tons/yr in current U.S. acid output--and projections put the uranium level at 8,000 tons/yr in the year 2000. Since the phosphoric acid is a major raw material for fertilizers, uranium finds its way into those products and is effectively lost as a resource, while adding to the amount of radioactive material that can contaminate the food chain. So, resource-conservation and environmental considerations both make recovery of the uranium from phosphoric acid desirable. This paper describes the newly developed process for recovering uranium from phosphoric acid by using solvent-extraction technique. After many extractants had been tested, the researchers eventually selected the combination of di (2-ethylhexyl) phosphoric acid (DEPA) and trioctylphosphine oxide (TOPO) as the most suitable. The flowscheme of the process is included

  18. Acid mine drainage

    Science.gov (United States)

    Bigham, Jerry M.; Cravotta, Charles A.

    2016-01-01

    Acid mine drainage (AMD) consists of metal-laden solutions produced by the oxidative dissolution of iron sulfide minerals exposed to air, moisture, and acidophilic microbes during the mining of coal and metal deposits. The pH of AMD is usually in the range of 2–6, but mine-impacted waters at circumneutral pH (5–8) are also common. Mine drainage usually contains elevated concentrations of sulfate, iron, aluminum, and other potentially toxic metals leached from rock that hydrolyze and coprecipitate to form rust-colored encrustations or sediments. When AMD is discharged into surface waters or groundwaters, degradation of water quality, injury to aquatic life, and corrosion or encrustation of engineered structures can occur for substantial distances. Prevention and remediation strategies should consider the biogeochemical complexity of the system, the longevity of AMD pollution, the predictive power of geochemical modeling, and the full range of available field technologies for problem mitigation.

  19. Dicarboxylic acids from electric discharge

    Science.gov (United States)

    Zeitman, B.; Chang, S.; Lawless, J. G.

    1974-01-01

    An investigation was conducted concerning the possible synthesis of a suite of dicarboxylic acids similar to that found in the Murchison meteorite. The investigation included the conduction of a chemical evolution experiment which simulated electric discharge through the primitive atmosphere of the earth. The suite of dicarboxylic acids obtained in the electric discharge experiment is similar to that of the Murchison meteorite, except for the fact that 2-chlorosuccinic acid is present in the spark discharge.

  20. Uranium extraction from phosphoric acid

    International Nuclear Information System (INIS)

    Araujo Figueiredo, C. de

    1984-01-01

    The recovery of uranium from phosphoric liquor by two extraction process is studied. First, uranium is reduced to tetravalent condition and is extracted by dioctypyrophosphoric acid. The re-extraction is made by concentrated phosphoric acid with an oxidizing agent. The re-extract is submitted to the second process and uranium is extracted by di-ethylhexilphosphoric acid and trioctylphosphine oxide. (M.A.C.) [pt

  1. Acid precipitation literature review

    Energy Technology Data Exchange (ETDEWEB)

    Seip, H M; Andersen, B; Andersson, G; Hov, Oe; Kucera, V; Moseholm, L

    1986-01-01

    There is an increasing number of publications on acid deposition and related phenomena. Interest in these topics has also been reflected in a considerable number of meetings and conferences in this field. The largest of these in 1985 was the ''International Symposium on Acidic Precipitation'' (Muskoka, Ontario). Most work so far has been carried out in North America and Europe. There is, however, an increasing interest in obtaining a better picture of sensitive areas and possible acidification in other parts of the world. Anthropogenic SO/sub 2/ emissions have been estimated to be (in TgSyr/sup -1/): 2.4 (Africa), 4.1 (South America), 0.7 (Ocenia), and 18.3 (Asia). The largest increase during the last decade has been in Asia. Based on Studies of precipitation in remote areas it has been suggested that the natural background concentration for sulphate in many areas should be about 6 ..mu..eq 1/sup -1/. A new study of sulphate and nitrate in Greenland snow showed that both ions increased by a factor of about 2 from 1895 to 1978. The concentrations of SO/sub 2/ at Norwegian rural sites show a decreasing trend since late 1970s, while concentrations of sulphate in air show no clear trend. More reliable models for transformation, transport and deposition of chemicals are being developed, including three-dimensional grid models to describe episodes of elevated pollution levels lasting for a few days. Model calculations indicate that control of hydrocarbon (HC) emissions is much more efficient in reducing the ozone level in southern Scandinavia in episodes influenced by long-range transported pollutants than NO/sub x/ control of combined NO/sub x/ and HC control. 36 refs. (EG).

  2. A radioimmunoassay for abscisic acid

    International Nuclear Information System (INIS)

    Walton, D.; Dashek, W.; Galson, E.

    1979-01-01

    We have developed a radioimmunoassay (RIA) for abscisic acid (ABA) in the 0.1 ng to 2.5 ng range. Antibodies were obtained from rabbits immunized with ABA bound via its carboxyl group to bovine serum albumin. Cross-reactivity studies indicate that ABA esters are completely cross-reactive with ABA, while trans, trans abscisic acid (t-ABA) phaseic acid (PA) and dihydrophaseic acid (DPA) have much lower but significant cross-reactivities. Purification methods which reduce the levels of cross-reacting substances are described. (orig.) 891 AJ/orig. 892 MKO [de

  3. Acid digestion of organic materials

    International Nuclear Information System (INIS)

    Capp, P.D.

    1988-01-01

    To overcome the high temperatures involved in straight incineration of organic waste and the difficulty of extracting actinides from the ash various research establishments throughout the world, including Winfrith and Harwell in the UK, have carried out studies on an alternative chemical combustion method known as acid digestion. The basis of the technique is to digest the waste in concentrated sulphuric acid containing a few percent of nitric acid at a temperature of about 250 0 C. Acid digestion residues consist mainly of non-refractory inorganic sulphates and oxides from which any actinide materials can easily be extracted. (author)

  4. [Fatty acids in confectionery products].

    Science.gov (United States)

    Daniewski, M; Mielniczuk, E; Jacórzyński, B; Pawlicka, M; Balas, J; Filipek, A; Górnicka, M

    2000-01-01

    The content of fat and fatty acids in 144 different confectionery products purchased on the market in Warsaw region during 1997-1999 have been investigated. In examined confectionery products considerable variability of both fat and fatty acids content have been found. The content of fat varied from 6.6% (coconut cookies) up to 40% (chocolate wafers). Saturated fatty acids were present in both cis and trans form. Especially trans fatty acids reach (above 50%) were fats extracted from nut wafers, coconuts wafers.

  5. Preparation and characterization Al3+-bentonite Turen Malang for esterification fatty acid (palmitic acid, oleic acid and linoleic acid)

    Science.gov (United States)

    Abdulloh, Abdulloh; Aminah, Nanik Siti; Triyono, Mudasir, Trisunaryanti, Wega

    2016-03-01

    Catalyst preparation and characterization of Al3+-bentonite for esterification of palmitic acid, oleic acid and linoleic acid has been done. Al3+-bentonite catalyst was prepared from natural bentonite of Turen Malang through cation exchange reaction using AlCl3 solution. The catalysts obtained were characterized by XRD, XRF, pyridine-FTIR and surface area analyser using the BET method. Catalyst activity test of Al3+-bentonite for esterification reaction was done at 65°C using molar ratio of metanol-fatty acid of 30:1 and 0.25 g of Al3+-bentonite catalyst for the period of ½, 1, 2, 3, 4 and 5 hours. Based on the characterization results, the Al3+-bentonite Turen Malang catalyst has a d-spacing of 15.63 Ǻ, acid sites of Brönsted and Lewis respectively of 230.79 µmol/g and 99.39 µmol/g, surface area of 507.3 m2/g and the average of radius pore of 20.09 Å. GC-MS analysis results of the oil phase after esterification reaction showed the formation of biodiesel (FAME: Fatty acid methyl ester), namely methyl palmitate, methyl oleate and methyl linoleate. The number of conversions resulted in esterification reaction using Al3+-bentonite Turen Malang catalyst was 74.61%, 37.75%, and 20, 93% for the esterification of palmitic acid, oleic acid and linoleic acid respectively.

  6. Zirconium for nitric acid solutions

    International Nuclear Information System (INIS)

    Yau, T.L.

    1984-01-01

    The excellent corrosion resistance of zirconium in nitric acid has been known for over 30 years. Recently, there is an increasing interest in using zirconium for nitric acid services. Therefore, an extensive research effort has been carried out to achieve a better understanding of the corrosion properties of zirconium in nitric acid. Particular attention is paid to the effect of concentration, temperature, structure, solution impurities, and stress. Immersion, autoclave, U-bend, and constant strain-rate tests were used in this study. Results of this study indicate that the corrosion resistance of zirconium in nitric acid is little affected by changes in temperature and concentration, and the presence of common impurities such as seawater, sodium chloride, ferric chloride, iron, and stainless steel. Moreover, the presence of seawater, sodium chloride, ferric chloride, and stainless steel has little effect on the stress corrosion craking (SCC) susceptibility of zirconium in 70% nitric acid at room temperatures. However, zirconium could be attacked by fluoride-containing nitric acid and the vapors of chloride-containing nitric acid. Also, high sustained tensile stresses should be avoided when zirconium is used to handle 70% nitric acid at elevated temperatures or > 70% nitric acid

  7. ACETIC ACID AND A BUFFER

    DEFF Research Database (Denmark)

    2009-01-01

    The present invention relates to a composition comprising : a) 0.01-20% wt/wt acetic acid and b) a physiologically tolerable buffer capable of maintaining acetic acid at a pH in the range of 2-7; and use of such a composition as an antimicrobial agent.......The present invention relates to a composition comprising : a) 0.01-20% wt/wt acetic acid and b) a physiologically tolerable buffer capable of maintaining acetic acid at a pH in the range of 2-7; and use of such a composition as an antimicrobial agent....

  8. How salicylic acid takes transcriptional control over jasmonic acid signaling

    NARCIS (Netherlands)

    Caarls, Lotte|info:eu-repo/dai/nl/371746213; Pieterse, Corné M J|info:eu-repo/dai/nl/113115113; van Wees, Saskia C M|info:eu-repo/dai/nl/185445373

    2015-01-01

    Transcriptional regulation is a central process in plant immunity. The induction or repression of defense genes is orchestrated by signaling networks that are directed by plant hormones of which salicylic acid (SA) and jasmonic acid (JA) are the major players. Extensive cross-communication between

  9. C-11 Acid and the Stereochemistry of Abietic Acid

    Indian Academy of Sciences (India)

    IAS Admin

    While many features, like the phenanthrene-type of fusion of the three ... thought to contain the original ring A of abietic acid, retaining the. 'nuclear methyl .... Thinking that the anhydride he had obtained by the action of heat on the C-11 acid ...

  10. Composition of amino acids, fatty acids and dietary fibre monomers ...

    African Journals Online (AJOL)

    There is increasing demand for sources of energy and non-meat protein with balanced amino acid profiles worldwide. Nuts are rich in protein and essential amino acids, and have a high energy value due to their high fat content. Kernels from two wild fruits in Mozambique, Adansonia digitata and Sclerocarya birrea, were ...

  11. Application of citric acid in acid stimulation treatments

    Energy Technology Data Exchange (ETDEWEB)

    Alkhaldi, M.H.; Sarma, H.K. [Adelaide Univ., Adelaide (Australia); Nasr-el-Din, H.A. [Texas A and M Univ., College Station, TX (United States)

    2009-07-01

    A rotating disk apparatus was used to investigate mass transfer during the reaction of citric acid with calcite. The study evaluated the effects of initial acid concentrations, temperature, and disk rotational speed on the effective diffusion coefficient of citric acid. The diffusion coefficient was calculated at 25, 40, and 50 degrees C using various citric acid concentrations. The study indicated that the coefficient was a function of the interactions between calcium citrate precipitation and counter calcium ions. At high acid concentrations, the effects of calcium citrate precipitation and counter calcium ions were significant. The calculated citric acid diffusion coefficients were not comparable with measured effective diffusion coefficients using the rotating disk. At lower initial citric acid concentrations, the effects of both calcium citrate precipitation and counter calcium ions on citric acid diffusivity were minimal. It was concluded that temperature effects on the diffusion coefficient followed Arrhenius law. Activation energy was equal to 37.9 kJ/mol. 34 refs., 4 tabs., 13 figs.

  12. Bile acid analysis in human disorders of bile acid biosynthesis

    NARCIS (Netherlands)

    Vaz, Frédéric M.; Ferdinandusse, Sacha

    2017-01-01

    Bile acids facilitate the absorption of lipids in the gut, but are also needed to maintain cholesterol homeostasis, induce bile flow, excrete toxic substances and regulate energy metabolism by acting as signaling molecules. Bile acid biosynthesis is a complex process distributed across many cellular

  13. Peptide Nucleic Acids Having Amino Acid Side Chains

    DEFF Research Database (Denmark)

    1998-01-01

    A novel class of compounds, known as peptide nucleic acids, bind complementary DNA and RNA strands more strongly than the corresponding DNA or RNA strands, and exhibit increased sequence specificity and solubility. The peptide nucleic acids comprise ligands selected from a group consisting...

  14. Biopropionic acid production via molybdenumcatalyzed deoxygenation of lactic acid

    NARCIS (Netherlands)

    Korstanje, T.J.; Kleijn, H.; Jastrzebski, J.T.B.H.; Klein Gebbink, R.J.M.

    2013-01-01

    As the search for non-fossil based building blocks for the chemical industry increases, new methods for the deoxygenation of biomass-derived substrates are required. Here we present the deoxygenation of lactic acid to propionic acid, using a catalyst based on the non-noble and abundant metal

  15. Cytotoxic effect of betulinic acid and betulinic acid acetate isolated ...

    African Journals Online (AJOL)

    GREGORY

    2010-09-20

    Sep 20, 2010 ... Betulinic acid acetate (BAAC) was most effective than other betulinic acid derivatives. It had most ... blastoma (Schmidt et al., 1997), malignant brain tumor .... 96 well plate and incubated in 37oC, 5% CO2 and 90% humidity.

  16. Classifying Your Food as Acid, Low-Acid, or Acidified

    OpenAIRE

    Bacon, Karleigh

    2012-01-01

    As a food entrepreneur, you should be aware of how ingredients in your product make the food look, feel, and taste; as well as how the ingredients create environments for microorganisms like bacteria, yeast, and molds to survive and grow. This guide will help you classifying your food as acid, low-acid, or acidified.

  17. Origin of nucleic acids

    International Nuclear Information System (INIS)

    Prieur, B.E.

    1995-01-01

    The appearance of nucleic acids is the first event after the birth of membranes which made it possible to assure the perenniality of information. The complexity of these molecules has led some scientists to propose that they were not prebiotic but rather derived a more simple and achiral primitive ancestor. This hypothesis suggests that ribose possesses properties that allowed the formation of certain polysaccharides which evolved to RNA. The first step of the hypothesis is the selection and concentration of ribofuranose. This sugar has chelating properties and its alpha-ribofuranose is favoured in the chelating position. The density of the sugar with a heavy cation is greater than water and thus the complex can escape the UV radiation at the surface of the ocean. The particularity of ribose is to be able to form a homochiral regular array of these basic chelating structures with pyrophosphite. These arrays evolve towards the formation of polysaccharides (poly ribose phosphate) which have a very organized structure. These polysaccharides in turn evolve to RNA by binding of adenine and deoxyguanine which are HCN derivatives that can react with the polysaccharides. The primitive RNA is methylated and oxidized to form prebiotic RNA with adenosine, cytidine, 7methyl-guanosine and ribothymidine as nucleic bases. The pathway of biosynthesis of DNA form RNA will be studied. I suggest that the appearance of DNA results form the interaction between prebiotic double stranded RNA and proteins. DNA could be a product of RNA degradation by proteins. The catabolism of RNA to DNA requires a source of free radicals, protons and hydrides. RNA cannot produce free radicals, which are provided by the phenol group of the amino acid tyrosien. Protons are provided by the medium and hydrides are provided by 7-methyl-guanosine which can fix hydrides coming from hydrogen gas and donate them for the transformation of a riboside to a deoxyriboside. This pathway suggests that DNA appeared at

  18. Preparation of fulvic acid and low-molecular organic acids by oxidation of weathered coal humic acid

    Energy Technology Data Exchange (ETDEWEB)

    Shinozuka, T.; Ito, A.; Sasaki, O.; Yazawa, Y.; Yamaguchi, T. [Chiba Institute of Technolgy, Chiba (Japan). Dept. of Industrial Chemistry

    2002-07-01

    Weathered coal contains much humic acid and a little fulvic acid. Therefore, the production of fulvic acid, the most valuable humic substance because of its water-solubility, was examined by ozone and hydrogen peroxide oxidation of humic acid extracted form Xinjiang (China) weathered coal. The resulting products of the oxidation were water soluble fulvic acid and organic acids, mainly formic acid and oxalic acid. The product yield of fulvic acid was 20 (C%) and that of organic acids were 39 (C%) for formic and acid 13 (C%) for oxalic acid. The formed fulvic acid showed a higher content of oxygen and carboxyl groups, than those of the extracted one from the original weathered coal.

  19. Ascorbic acid in bronchial asthma

    African Journals Online (AJOL)

    1983-04-23

    Apr 23, 1983 ... by comparing the pre-ascorbic acid results with those obtained 21/2 hours after the intravenous ... (ASO), C-reactive protein and antibodies to certain respiratory viruses. These investigations were ..... vitamin.6 However, other investigators were unable to detect any protective effects of ascorbic acid on the ...

  20. Chloroacetic acids in environmental processes

    Czech Academy of Sciences Publication Activity Database

    Matucha, Miroslav; Gryndler, Milan; Forczek, Sándor; Uhlířová, H.; Fuksová, Květoslava; Schröder, P.

    2003-01-01

    Roč. 1, - (2003), s. 127-130 ISSN 1610-3653 R&D Projects: GA ČR GA522/02/0874 Institutional research plan: CEZ:AV0Z5038910 Keywords : Dichloroacetic acid * Trichloroacetic acid * Microbial degradation Subject RIV: GK - Forestry

  1. Acid Rain: An Educational Opportunity?

    Science.gov (United States)

    Marion, James I.

    1984-01-01

    Deals with how educators can handle the subject of acid rain; illustrates suggestions with experiences of grade nine students visiting Frost Valley Environmental Education Center (Oliverea, New York) to learn scientific concepts through observation of outdoor phenomena, including a stream; and discusses acid rain, pH levels, and pollution control…

  2. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2003-01-01

    The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness.......The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness....

  3. Getting Back to Basics (& Acidics)

    Science.gov (United States)

    Rhodes, Sam

    2006-01-01

    This article describes a few novel acid-base experiments intended to introduce students to the basic concepts of acid-base chemistry and provide practical examples that apply directly to the study of biology and the human body. Important concepts such as the reaction between carbon dioxide and water, buffers and protein denaturation, are covered.…

  4. Reactive extraction and recovery of levulinic acid, formic acid and furfural from aqueous solutions containing sulphuric acid

    NARCIS (Netherlands)

    Brouwer, Thomas; Blahusiak, Marek; Babic, Katarina; Schuur, Boelo

    2017-01-01

    Levulinic acid (LA) can be produced from lignocellulosic materials via hydroxylation followed by an acid-catalyzed conversion of hexoses. Inorganic homogeneous catalysts are mostly used, in particular sulphuric acid, yielding a mixture of LA with sulphuric acid, formic acid (FA) and furfural.

  5. Studies on radiolysis of amino acids, (4)

    International Nuclear Information System (INIS)

    Oku, Tadatake

    1978-01-01

    In order to elucidate the effect of adding methionine on the loss of amino acid by γ-irradiation in amino acid mixture, because methionine is one of the most radio-sensitive in amino acids, the remaining amino acids in γ-irradiated aqueous solution of amino acid mixture were studied by determining the total amount of each remaining amino acid. The mixture of 18 amino acids which contains methionine and that of 17 amino acids without methionine were used. Amino acids and the irradiation products were determined with an automatic amino acid analyzer. The total amount of remaining amino acids in the irradiated solution of 18 amino acid mixture was more than that of 17 amino acid mixture. The order of the total amount of each remaining amino acid by low-dose irradiation was Gly>Ala>Asp>Glu>Val>Ser, Pro>Ile, Leu>Thr>Lys>Tyr>Arg>His>Phe>Try>Cys>Met. In case of the comparison of amino acids of same kinds, the total remaining amount of each amino acid in amino acid mixture was more than that of individually irradiated amino acid. The total remaining amounts of glycine, alanine and aspartic acid in irradiated 17 amino acid mixture resulted in slight increase. Ninhydrin positive products formed from 18 amino acid mixture irradiated with 2.640 x 10 3 rad were ammonia, methionine sulfoxide and DOPA of 1.34, 0.001 and 0.25 μmoles/ml of the irradiated solution, respectively. (Kobake, H.)

  6. N-(3-Nitrophenylmaleamic acid

    Directory of Open Access Journals (Sweden)

    B. Thimme Gowda

    2010-07-01

    Full Text Available In the title compound, C10H8N2O5, the molecule is slightly distorted from planarity. The molecular structure is stabilized by two intramolecular hydrogen bonds. The first is a short O—H...O hydrogen bond (H...O distance = 1.57 Å within the maleamic acid unit and the second is a C—H...O hydrogen bond (H...O distance = 2.24 Å which connects the amide group with the benzene ring. The nitro group is twisted by 6.2 (2° out of the plane of the benzene ring. The crystal structure manifests a variety of hydrogen bonding. The packing is dominated by a strong intermolecular N—H...O interaction which links the molecules into chains running along the b axis. The chains within a plane are further assembled by three additional types of intermolecular C—H...O hydrogen bonds to form a sheet parallel to the (overline{1}01 plane.

  7. Bioactive phenolic acids from Scorzonera radiata Fisch.

    Directory of Open Access Journals (Sweden)

    N Tsevegsuren

    2014-09-01

    Full Text Available Chromatographic separation of the crude extract obtained from the aerial parts of the Mongolian medicinal plant Scorzonera radiata yielded five new dihydrostilbenes [4], two new flavonoids, one new quinic acid derivative, as well as twenty known compounds including eight quinic acid derivatives, four flavonoids, two coumarins, five simple benzoic acids, and one monoterpene glycoside. We present here results on isolation and structural identification some active phenolic compounds from the Scorzonera radiata - eight quinic acid derivatives (quinic acid, 4,5-dicaffeoylquinic acid, 4,5-dicaffeoyl-epi-quinic acid, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoyl-epi-quinic acid, chlorogenic acid, 5-p-coumaroylquinic acid (trans, 5-p-coumaroylquinic acid (cis. Quinic acid derivatives exhibited antioxidative activity.DOI: http://dx.doi.org/10.5564/mjc.v12i0.177 Mongolian Journal of Chemistry Vol.12 2011: 78-84

  8. Biophysical properties of phenyl succinic acid derivatised hyaluronic acid

    DEFF Research Database (Denmark)

    Neves-Petersen, Maria Teresa; Klitgaard, Søren; Skovsen, Esben

    2010-01-01

    Modification of hyaluronic acid (HA) with aryl succinic anhydrides results in new biomedical properties of HA as compared to non-modified HA, such as more efficient skin penetration, stronger binding to the skin, and the ability to blend with hydrophobic materials. In the present study, hyaluronic...... acid has been derivatised with the anhydride form of phenyl succinic acid (PheSA). The fluorescence of PheSA was efficiently quenched by the HA matrix. HA also acted as a singlet oxygen scavenger. Fluorescence lifetime(s) of PheSA in solution and when attached to the HA matrix has been monitored...

  9. Analytical application of aminohydroxamic acids

    International Nuclear Information System (INIS)

    Fadl Elmoula, Abd ELfatah Abdella

    2000-11-01

    Anthranilic hydroxamic acid was prepared by coupling of methylanthranilate (prepared by esterification of anthranilic acid with methyl alcohol using the fisher-speir method) with freshly prepared hydroxylamine. The lignad was characterized by the usual reaction of hydroxamic acid with acidic V(V) and Fe(III) solutions that gives blood-red colour in amyl alcohol and deep-violet colour in aqueous solution, respectively. The absorbance of Fe(III)-hydroxamic acids complexes increases with increase of pH. In this study, the effect of pH on the absorbance of Fe(III)-anthranilic hydroxamic acid was in accordance with this trend. The maximum absorbance was obtained at pH 5.0 at maximum wavelength of 482 nm. For Cu(II)-anthranilic hydroxamic acid complex, the use of acidic basic pH lead to precipitation of Cu(II)-ligand complex. But when using buffer pH (acetic acid/sodium acetate) a clear green colour of Cu(II)-ligand complex was obtained. The maximum wavelength of 390 nm. V(V)-anthranilic hydroxamic acid complex was extracted in acidic medium in amyl alcohol at pH 2.0 because in aqueous solution V(V)-anthranilic hydroxamic acid complex has not clear colour. It was observed the the maximum extraction in acidic medium decrease sharply with the increasing of pH value. The maximum wavelength for maximum absorbance was recorded at 472 nm. V(V) interfered with determination of Fe(III)) above concentration of 2 ppm, whereas Cu(II) interferes slightly with the determination of Fe(III) ions even at a high concentration of the Cu(II) ions. Both Cu(II) and Ni(II) do not interfere with the determination of V(V) ions even at high concentrations, Fe(III) ion produced slight interference, while Mo(VI) ions have a pronounced interference. Both V(V) and Fe(III) ions interfered markedly with the determination of Cu(II) ions, and made impractical under conditions. However, the calibration curves for the three metal ions produced a practical linear dynamic range.(Author)

  10. Placement of acid spoil materials

    Energy Technology Data Exchange (ETDEWEB)

    Pionke, H B; Rogowski, A S

    1982-06-01

    Potentially there are several chemical and hydrologic problems associated with placement of acid spoil materials. The rationale for a deep placement well below the soil surface, and preferably below a water table, is to prevent or minimize oxidation of pyrite to sulfuric acid and associated salts by reducing the supply of oxygen. If, however, substantial sulfuric acid or associated salts are already contained within the spoil because of present or previous mining, handling and reclamation operations (or if large supplies of indigenous salts exist, placement below a water table) may actually increase the rate of acid and salt leaching. Specific placement of acid- and salt-containing spoil should be aimed at preventing contact with percolating water or rising water tables. We recommend placement based on chemical and physical spoil properties that may affect water percolation O/sub 2/ diffusion rates in the profile. Both the deeper placement of acid spoil and coarser particle size can substantially reduce the amount of acid drainage. Placement above the water table with emphasis on percolate control may be better for high sulfate spoils, while placement below the non-fluctuating water table may be better for pyritic spoils.

  11. Aquatic chemistry of acid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Stumm, W; Sigg, L; Schnoor, J L

    1987-01-01

    The occurrence of acid precipitation in many regions of the Northern hemisphere is a consequnece of human interference in the cycles that unite land, water and atmosphere. The oxidation of carbon, sulfur and nitrogen, resulting mostly from fossil fuel burning, rivals oxidation processes induced by photosynthesis and respiration and disturbs redox conditions in the atmosphere. The paper discusses oxidation-reduction reactions, particularly those involving atmospheric pollutants that are important in the formation of acid precipitation. Topics covered are: a stoichiometric model of acid rain formation; sulfur dioxide and ammonia adsorption; acid neutralizing capacity. The paper concludes that explanations of simple chemical equilibria between gases and water aid our understanding of how acidifying gases become dissolved in cloud water, in droplets of falling rain, or in fog. Rigorous definitions of base- or acid-neutralizing capacities are prerequisites to measuring and interpreting residual acidity in dry and wet deposition and for assessing the disturbance caused by the transfer of acid to terrestrial and aquatic ecosystems. 20 references.

  12. catalyzed oxidation of some amino acids by acid bromate

    African Journals Online (AJOL)

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    ABSTRACT: Kinetic investigations on Pd(II) catalyzed oxidation of dl-serine and dl- ... A suitable mechanism in agreement with observed kinetics has been ..... In acidic solution of potassium bromate quick .... Annual Review of Biochemistry.

  13. Cytotoxic effect of betulinic acid and betulinic acid acetate isolated ...

    African Journals Online (AJOL)

    GREGORY

    2010-09-20

    Sep 20, 2010 ... Betulinic acid exerts a selective anti-tumor activity on cultured human melanoma .... percentage of proliferation was calculated by the following formula: Proliferation ..... artificially imposing the cell cycle checkpoint. Among.

  14. Influence of fluorozirconic acid on sulfuric acid anodizing of aluminum

    OpenAIRE

    Elaish, R.; Curioni, M.; Gowers, K.; Kasuga, A.; Habazaki, H.; Hashimoto, T.; Skeldon, P.

    2017-01-01

    The effects of additions of fluorozirconic acid to sulfuric acid on the anodizing behavior of aluminum have been investigated under a constant voltage at temperatures of 0 and 20◦C. The fluoroacid increased the rate of film growth, with a dependence on the fluoroacid concentration, the electrolyte temperature and the anodizing time. Compositional analyses showed that fluorine species were present in the films. However, zirconium species were absent. The fluoroacid generally enhanced film diss...

  15. Docosahexaenoic acid affects arachidonic acid uptake in megakaryocytes

    International Nuclear Information System (INIS)

    Schick, P.K.; Webster, P.

    1987-01-01

    Dietary omega 3 fatty acids are thought to prevent atherosclerosis, possibly by modifying platelet (PT) function and arachidonic acid (20:4) metabolism. The study was designed to determine whether omega 3 fatty acids primarily affect 20:4 metabolism in megakaryocytes (MK), bone marrow precursors of PT, rather than in circulating PT. MK and PT were isolated from guinea pigs and incubated with [ 14 C]-20:4 (0.13uM). Docosahexaenoic acid (22:6) is a major omega 3 fatty acid in marine oils. The incubation of MK with 22:6 (0.1, 1.0 uM) resulted in the decrease of incorporation of [ 14 C]-20:4 into total MK phospholipids, 16% and 41% respectively. Alpha-linolenic acid (18:3), a major omega 3 fatty acid present in American diets, had no effect on 20:4 uptake in MK. 22:6 primarily affected the uptake of [ 14 C]-20:4 into phosphatidylethanolamine (PE) and phosphatidylserine (PS) in MK. In MK, 22:6 (0.1, 1.0 uM) caused a decrease of incorporation of [ 14 C]-20:4 into PE, 21% and 55% respectively; a decrease into PS, 16% and 48% respectively; but only a decrease of 4% and 18%, respectively, into phosphatidylcholine; and a decrease of 3% and 21% into phosphatidylinositol 22:6 (3.0 uM) had no effect on the uptake of AA into PT phospholipids. The study shows that 22:6 has a selective effect on AA uptake in MK and that the acylation or transacylation of PE and PS are primarily affected. 22:6 and other marine omega 3 fatty acids appear to primarily affect megakaryocytes which may result in the production of platelets with abnormal content and compartmentalization of AA

  16. Treatment of acid mine wastewaters

    International Nuclear Information System (INIS)

    Hayward, D.; Barnard, R.

    1993-01-01

    Acid mine drainage often results from the oxidation sulfide minerals to form sulfuric acid. As a consequence, high concentrations of metals in the both the suspended and dissolved state result from the low pH water. This paper discusses several of the more common treatment methods for acid mine drainage including the use of chemical precipitation agents, pH correction agents, filtration methods, and biodegradation methods. Advanced treatment technologies are also briefly described and include microfiltration, reverse osmosis, ion exchange, and electrodialysis

  17. Amino Acids from a Comet

    Science.gov (United States)

    Cook, Jamie Elisla

    2009-01-01

    NASA's Stardust spacecraft returned samples from comet 81P/Wild 2 to Earth in January 2006. Examinations of the organic compounds in cometary samples can reveal information about the prebiotic organic inventory present on the early Earth and within the early Solar System, which may have contributed to the origin of life. Preliminary studies of Stardust material revealed the presence of a suite of organic compounds including several amines and amino acids, but the origin of these compounds (cometary- vs. terrestrial contamination) could not be identified. We have recently measured the carbon isotopic ratios of these amino acids to determine their origin, leading to the first detection of a coetary amino acid.

  18. PRODUCTION OF TRIFLUOROACETIC ACID COMPOUNDS

    Science.gov (United States)

    Haworth, W.N.; Stacey, M.

    1949-08-30

    A process is described for the preparation of trifluoroacetic acid. Acetone vapor diluted wlth nitrogen and fluorine also diluted with nltrogen are fed separately at a temperature of about 210 deg C into a reaction vessel containing a catalyst mass selected from-the group consisting of silver and gold. The temperature in the reaction vessel is maintained in the range of 200 deg to 250 deg C. The reaction product, trifluoroacetyl fluoride, is absorbed in aqueous alkali solution. Trifluoroacetic acid is recovered from the solution by acidification wlth an acid such as sulfuric followed by steam distillation.

  19. Arsanilic acid blindness in pigs

    Energy Technology Data Exchange (ETDEWEB)

    Menges, R.W.; Kintner, L.D.; Selby, L.A.; Stewart, R.W.; Marlenfeld, C.J.

    1970-06-01

    Blindness in pigs that were given an overdosage of arsanilic acid is reported. A 0.0375% level of arsanilic acid was fed to 640 pigs for 90 days beginning when the animals were 3 months old. Approximately one month after the start of feeding, partial or complete blindness was observed in 50 of the pigs. Clinical signs, pathologic findings and the chemical analysis of hair are discussed. The level of arsanilic acid used was that recommended for the control of swine dysentery, to be fed for only five or six days. The overdosage resulted from a misunderstanding between the farmer and the feed mill.

  20. Molar extinction coefficients of some fatty acids

    DEFF Research Database (Denmark)

    Sandhu, G.K.; Singh, K.; Lark, B.S.

    2002-01-01

    ) and stearic acid (C18H36O2), has been measured at the photon energies 81, 356, 511, 662, 1173 and 1332 keV. Experimental values for the molar extinction coefficient, the effective atomic number and the electron density have been derived and compared with theoretical calculations. There is good agreement......The attenuation of gamma rays in some fatty acids, viz. formic acid (CH2O2), acetic acid (C2H4O2), propionic acid (C3H6O2), butyric acid (C4H8O2), n-hexanoic acid (C6H12O2), n-caprylic acid (C8H16O2), lauric acid (C12H24O2), myristic acid (C14H28O2), palmitic acid (C16H32O2), oleic acid (C18H34O2...

  1. Studies on radiolysis of amino acids, 1

    International Nuclear Information System (INIS)

    Oku, Tadatake

    1977-01-01

    In order to elucidate the radiolysis of amino acid, peptide, protein and enzyme, the radiolytic mechanisms of neutral amino acids (glycine, L-alanine, L-valine, L-leucine, L-isoleucine, L-serine, and L-threonine) and acidic amino acids (L-aspartic acid, L-glutamic acid and DL-amino-n-adipic acid) were studied in the presence of air or in the atmosphere nitrogen. An aqueous solution of 1 mM. of each amino acid was sealed in a glass ampoule under air or nitrogen. Irradiation of amino acid solutions was carried out with γ-rays of 60 Co at doses of 4.4-2,640x10 3 rads. The amino acids and the radiolytic products formed were determined by ion-exchange chromatography. From the results of determining amino acids and the radiolytic products formed and their G-values, the radiolytic mechanisms of the amino acids were discussed. (auth.)

  2. Ectopic expression of Crambe abyssinica lysophosphatidic acid ...

    African Journals Online (AJOL)

    USER

    2010-06-21

    Jun 21, 2010 ... lysophosphatidic acid acyltransferase in transgenic rapeseed increases its oil .... pathway [fatty acid desaturase-2 (BnFAD2, AY577313), fatty acid desaturase-3 ..... Acyltransferases from basic science to modified seed oils.

  3. Treatment of Fatty Acid Oxidation Disorders

    Science.gov (United States)

    ... Treatment of fatty acid oxidation disorders Treatment of fatty acid oxidation disorders E-mail to a friend Please ... this page It's been added to your dashboard . Fatty acid oxidation disorders are rare health conditions that affect ...

  4. Transport of ascorbic acid and dehydroascorbic acid by pancreatic islet cells from neonatal rats

    DEFF Research Database (Denmark)

    Zhou, A; Farver, O; Thorn, N A

    1991-01-01

    . Dehydroascorbic acid was converted to ascorbic acid by an unknown mechanism after uptake. The uptake of both ascorbic acid and dehydroascorbic acid was inhibited by tri-iodothyronine, and uptake of ascorbic acid, but not of dehydroascorbic acid, was inhibited by glucocorticoids. Isolated secretory granules...

  5. Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity

    OpenAIRE

    Haeusler, Rebecca A.; Camastra, Stefania; Nannipieri, Monica; Astiarraga, Brenno; Castro-Perez, Jose; Xie, Dan; Wang, Liangsu; Chakravarthy, Manu; Ferrannini, Ele

    2015-01-01

    We measured plasma bile acids, markers of bile acid synthesis, and expression of bile acid transporters in obese and nonobese subjects. We found that obesity was associated with increased bile acid synthesis and 12-hydroxylation, blunted response of plasma bile acids to insulin infusion or a mixed meal, and decreased expression of liver bile acid transporters.

  6. Simultaneous analysis of small organic acids and humic acids using high performance size exclusion chromatography

    NARCIS (Netherlands)

    Qin, X.P.; Liu, F.; Wang, G.C.; Weng, L.P.

    2012-01-01

    An accurate and fast method for simultaneous determination of small organic acids and much larger humic acids was developed using high performance size exclusion chromatography. Two small organic acids, i.e. salicylic acid and 2,3-dihydroxybenzoic acid, and one purified humic acid material were used

  7. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Oleic acid derived from tall oil fatty acids. 172... FOOD FOR HUMAN CONSUMPTION Multipurpose Additives § 172.862 Oleic acid derived from tall oil fatty acids. The food additive oleic acid derived from tall oil fatty acids may be safely used in food and as...

  8. Thermometric titration of acids in pyridine.

    Science.gov (United States)

    Vidal, R; Mukherjee, L M

    1974-04-01

    Thermometric titration of HClO(4), HI, HNO(3), HBr, picric acid o-nitrobenzoic acid, 2,4- and 2,5-dinitrophenol, acetic acid and benzoic acid have been attempted in pyridine as solvent, using 1,3-diphenylguanidine as the base. Except in the case of 2,5-dinitrophenol, acetic acid and benzoic acid, the results are, in general, reasonably satisfactory. The approximate molar heats of neutralization have been calculated.

  9. 21 CFR 184.1091 - Succinic acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Succinic acid. 184.1091 Section 184.1091 Food and... Substances Affirmed as GRAS § 184.1091 Succinic acid. (a) Succinic acid (C4H6O4, CAS Reg. No. 110-15-6), also referred to as amber acid and ethylenesuccinic acid, is the chemical 1,4-butanedioic acid. It is...

  10. Mannuronic Acids : Reactivity and Selectivity

    NARCIS (Netherlands)

    Codee, Jeroen D. C.; Walvoort, Marthe T. C.; de Jong, Ana-Rae; Lodder, Gerrit; Overkleeft, Herman S.; van der Marel, Gijsbert A.

    2011-01-01

    This review describes our recent studies toward the reactivity and selectivity of mannopyranosyl uronic acid donors, which have been found to be very powerful donors for the construction of beta-mannosidic linkages.

  11. Vanadocene reactions with hydroxy acids

    International Nuclear Information System (INIS)

    Latyaeva, V.N.; Lineva, A.N.; Zimina, S.V.; Ehllert, O.G.; Arsen'eva, T.I.

    1984-01-01

    To prepare a series of vanadium cyclopentadienylcarboxylates soluble in water, the vanadocene reactions with lactic, γ-oxybutyric-, salicylic,- gallic-, orotic-, and acetylsalicylic acids have been studied. To determine the influence of cyclopentadienyl groups, bound with a vanadium atom, on the physiological activity of the complexes formed, vanadium halides are made to react with lactic acid. Only the vanadocene reaction with orotic acid was conducted in an aqueous medium, other interactions were realized in the diethyl ether, toluene, T, H, P medium. The interaction of vanadocene and vanadium halides with lactic-, salicylic-, acetylsalicylic- and gallic acids was found to lead to the formation of water-soluble vanadium complexes of Cp 2 , VOCOR or CpV (OCOR) 2 type. The data on the produced compounds yield, their IR spectra, decomposition temperatures, solubility, effective magnetic moments are presented

  12. Uranium extraction from phosphoric acid

    International Nuclear Information System (INIS)

    Lounis, A.

    1983-05-01

    A study has been carried out for the extraction of uranium from phosphoric acid produced in Algeria. First of all, the Algerian phosphoric acid produced in Algeria by SONATRACH has been characterised. This study helped us to synthesize a phosphoric acid that enabled us to pass from laboratory tests to pilot scale tests. We have then examined extraction and stripping parameters: diluent, DZEPHA/TOPO ratio and oxidising agent. The laboratory experiments enabled us to set the optimum condition for the choice of diluent, extractant concentration, ratio of the synergic mixture, oxidant concentration, redox potential. The equilibrium isotherms lead to the determination of the number of theoretical stages for the uranium extraction and stripping of uranium, then the extraction from phosphoric acid has been verified on a pilot scale (using a mixer-settler)

  13. Uronic acids in oligosaccharide synthesis

    NARCIS (Netherlands)

    Bos, Leendert Johannes van den

    2007-01-01

    This Thesis reports on research aimed at the assembly of acidic and zwitterionic polysaccharides of bacterial origin, using suitably protected 1-thioglycoside residues. Thioglycosides are attractive monosaccharide building blocks because of their high stability towards the diverse reaction

  14. Bile acid sequestrants for cholesterol

    Science.gov (United States)

    ... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

  15. N-substituted iminodiacetic acids

    International Nuclear Information System (INIS)

    Nunn, A.; Loberg, M.

    1982-01-01

    The chemical preparation of several new N-substituted iminodiacetic acid derivatives are described. These compounds when complexed with sup(99m)Tc provide useful radiopharmaceuticals for the external imaging of the hepatobiliary system. (U.K.)

  16. Compact oleic acid in HAMLET.

    Science.gov (United States)

    Fast, Jonas; Mossberg, Ann-Kristin; Nilsson, Hanna; Svanborg, Catharina; Akke, Mikael; Linse, Sara

    2005-11-07

    HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a complex between alpha-lactalbumin and oleic acid that induces apoptosis in tumor cells, but not in healthy cells. Heteronuclear nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of 13C-oleic acid in HAMLET, and to study the 15N-labeled protein. Nuclear Overhauser enhancement spectroscopy shows that the two ends of the fatty acid are in close proximity and close to the double bond, indicating that the oleic acid is bound to HAMLET in a compact conformation. The data further show that HAMLET is a partly unfolded/molten globule-like complex under physiological conditions.

  17. Nucleic Acid-Based Nanoconstructs

    Science.gov (United States)

    Focuses on the design, synthesis, characterization, and development of spherical nucleic acid constructs as effective nanotherapeutic, single-entity agents for the treatment of glioblastoma multiforme and prostate cancers.

  18. PHYSIOLOGY OF ACID BASE BALANCE

    Directory of Open Access Journals (Sweden)

    Awati

    2014-12-01

    Full Text Available Acid-base, electrolyte, and metabolic disturbances are common in the intensive care unit. Almost all critically ill patients often suffer from compound acid-base and electrolyte disorders. Successful evaluation and management of such patients requires recognition of common patterns (e.g., metabolic acidosis and the ability to dissect one disorder from another. The intensivists needs to identify and correct these condition with the easiest available tools as they are the associated with multiorgan failure. Understanding the elements of normal physiology in these areas is very important so as to diagnose the pathological condition and take adequate measures as early as possible. Arterial blood gas analysis is one such tool for early detection of acid base disorder. Physiology of acid base is complex and here is the attempt to simplify it in our day to day application for the benefit of critically ill patients.

  19. Structural features of lignohumic acids

    Czech Academy of Sciences Publication Activity Database

    Novák, František; Šestauberová, Martina; Hrabal, R.

    2015-01-01

    Roč. 1093, August (2015), s. 179-185 ISSN 0022-2860 Institutional support: RVO:60077344 Keywords : C-13 NMR * FTIR * humic acids * lignohumate * lignosulfonate * structure Subject RIV: DF - Soil Science Impact factor: 1.780, year: 2015

  20. Biomaterials made of bile acids

    Institute of Scientific and Technical Information of China (English)

    ZHANG JiaWei; ZHU XiaoXia

    2009-01-01

    The use of natural compounds in the preparation of new materials can improve the biocompatibility of the materials and avoid any potential toxicity of the degradation products when used for biomedical applications.Bile acids are amphiphilic molecules biosynthesized in the liver.They are used to prepare various polymers and oligomers.These polymers made of bile acids are promising materials in both biomedical and pharmaceutical fields.

  1. Biomaterials made of bile acids

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The use of natural compounds in the preparation of new materials can improve the biocompatibility of the materials and avoid any potential toxicity of the degradation products when used for biomedical applications. Bile acids are amphiphilic molecules biosynthesized in the liver. They are used to prepare various polymers and oligomers. These polymers made of bile acids are promising materials in both biomedical and pharmaceutical fields.

  2. Alternative to Nitric Acid Passivation

    Science.gov (United States)

    Kessel, Kurt R.

    2016-01-01

    Corrosion is an extensive problem that affects the National Aeronautics and Space Administration (NASA) and European Space Agency (ESA). The deleterious effects of corrosion result in steep costs, asset downtime affecting mission readiness, and safety risks to personnel. It is vital to reduce corrosion costs and risks in a sustainable manner. The primary objective of this effort is to qualify citric acid as an environmentally-preferable alternative to nitric acid for passivation of stainless steel alloys.

  3. Performance of Different Acids on Sandstone Formations

    Directory of Open Access Journals (Sweden)

    M. A. Zaman

    2013-12-01

    Full Text Available Stimulation of sandstone formations is a challenging task, which involves several chemicals and physical interactions of the acid with the formation. Some of these reactions may result in formation damage. Mud acid has been successfully used to stimulate sandstone reservoirs for a number of years. It is a mixture of hydrofluoric (HF and hydrochloric (HCl acids designed to dissolve clays and siliceous fines accumulated in the near-wellbore region. Matrix acidizing may also be used to increase formation permeability in undamaged wells. The change may be up to 50% to 100% with the mud acid. For any acidizing process, the selection of acid (Formulation and Concentration and the design (Pre-flush, Main Acid, After-flush is very important. Different researchers are using different combinations of acids with different concentrations to get the best results for acidization. Mainly the common practice is combination of Hydrochloric Acid – Hydrofluoric with Concentration (3% HF – 12% HCl. This paper presents the results of a laboratory investigation of Orthophosphoric acid instead of hydrochloric acid in one combination and the second combination is Fluoboric and formic acid and the third one is formic and hydrofluoric acid. The results are compared with the mud acid and the results calculated are porosity, permeability, and FESEM Analysis and Strength tests. All of these new combinations shows that these have the potential to be used as acidizing acids on sandstone formations.

  4. Ursodeoxycholic acid for nonalcoholic steatohepatitis.

    Science.gov (United States)

    Wu, Sheng-di; Li, Lei; Wang, Ji-yao

    2012-11-01

    The aim of this study was to evaluate the effects of ursodeoxycholic acid on patients with nonalcoholic steatohepatitis using meta-analysis. PubMed, EMBASE, Web of Science, Cochrane Library, Chinese Biomedical Databases, and article references were searched. We included randomized controlled trials using liver biopsy as a reference standard. We identified three eligible studies. Among histological responses, only lobular inflammation improved in the high-dose ursodeoxycholic acid subgroup compared with the control group [mean deviation (MD): -0.23 (-0.40, -0.06), P=0.008]. However, fibrosis may tend to increase [MD: 0.08 (-0.04, 0.20), P=0.17]. Among biochemical responses, γ-glutamyl transpeptidase reduction was significantly greater in the ursodeoxycholic acid group than in the placebo group, and the reduction tendency was only shown in the high-dose subgroup [MD: -35.58 (-52.60, -18.56), Pursodeoxycholic acid subgroup compared with the control group [MD: 0.43 (0.14, 0.72), P=0.004]. Ursodeoxycholic acid-treated patients did not differ significantly from control patients with regard to alanine transaminase, aspartate aminotransferase, and alkaline phosphatase activities. Adverse events were nonspecific and considered of no major clinical relevance. Ursodeoxycholic acid in monotherapy has no substantial positive effect on nonalcoholic steatohepatitis.

  5. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  6. Effects of dietary conjugated linoleic acid and linoleic:linolenic acid ratio on polyunsaturated fatty acid status in laying hens.

    Science.gov (United States)

    Du, M; Ahn, D U; Sell, J L

    2000-12-01

    A study was conducted to determine the effects of dietary conjugated linoleic acid (CLA) and the ratio of linoleic:linolenic acid on long-chain polyunsaturated fatty acid status. Thirty-two 31-wk-old White Leghorn hens were randomly assigned to four diets containing 8.2% soy oil, 4.1% soy oil + 2.5% CLA (4.1% CLA source), 4.1% flax oil + 2.5% CLA, or 4.1% soy oil + 4.1% flax oil. Hens were fed the diets for 3 wk before eggs and tissues were collected for the study. Lipids were extracted from egg yolk and tissues, classes of egg yolk lipids were separated, and fatty acid concentrations of total lipids, triglyceride, phosphatidylethanolamine, and phosphatidylcholine were analyzed by gas chromatography. The concentrations of monounsaturated fatty acids and non-CLA polyunsaturated fatty acids were reduced after CLA feeding. The amount of arachidonic acid was decreased after CLA feeding in linoleic acid- and linolenic acid-rich diets, but amounts of eicosapentaenoic acid and docosahexaenoic acid were increased in the linolenic-rich diet, indicating that the synthesis or deposition of long-chain n-3 fatty acids was accelerated after CLA feeding. The increased docosahexaenoic acid and eicosapentaenoic acid contents in lipid may be compensation for the decreased arachidonic acid content. Dietary supplementation of linoleic acid increased n-6 fatty acid levels in lipids, whereas linolenic acid increased n-3 fatty acid levels. Results also suggest that CLA might not be elongated to synthesize long-chain fatty acids in significant amounts. The effect of CLA in reducing the level of n-6 fatty acids and promoting the level of n-3 fatty acids could be related to the biological effects of CLA.

  7. Specific bile acid radioimmunoassays for separate determinations of unconjugated cholic acid, conjugated cholic acid and conjugated deoxycholic acid in serum and their clinical application

    International Nuclear Information System (INIS)

    Matern, S.; Gerok, W.

    1977-01-01

    Specific radioimmunoassays for separate determinations of serum unconjugated cholic, conjugated cholic and conjugated deoxycholic acids have been developed. Prior to the radioimmunoassay, extraction of serum bile acids was performed with Amberlite XAD-2. Unconjugated cholic acid was separated from glyco- and taurocholic acids by thin-layer chromatography. At 50% displacement of bound labeled glyco[ 3 H]cholic acid using antiserum obtained after immunization with cholic acid-bovine serum albumin-conjugate the cross-reactivity of taurocholic acid was 100%, cholic acid 80%, glycochenodeoxycholic acid 10%, chenodeoxycholic acid 7%, conjugated deoxycholic acid 3%, and conjugated lithocholic acid 3 H]cholic acid was linear on a logit-log plot from 5 to 80 pmol of unlabeled glycocholic acid. Fasting serum conjugated cholic acid in healthy subjects was 0.68 +- 0.34 μmol/l. Unconjugated cholic acid was determined by a solid phase radioimmunoassay using the cholic acid antibody chemically bound to Sepharose. The displacement curve of [ 3 H]cholic acid in the solid phase radioimmunoassay was linear on a logit-log plot from 5 to 200 pmol of unlabeled cholic acid. The coefficient of variation between samples was 5%. Fasting serum conjugated deoxycholic acid concentrations in 10 healthy subjects ranged from 0.18 to 0.92 μmol/l determined by a radioimmunoassay using antiserum obtained after immunization with deoxycholic acid-bovine serum albumin-conjugate. The clinical application of these bile acid radioimmunoassays is shown by an 'oral cholate tolerance test' as a sensitive indicator of liver function and by an 'oral cholyglycine tolerance test' as a useful test for bile acid absorption. (orig.) [de

  8. Bile acids: regulation of apoptosis by ursodeoxycholic acid.

    Science.gov (United States)

    Amaral, Joana D; Viana, Ricardo J S; Ramalho, Rita M; Steer, Clifford J; Rodrigues, Cecília M P

    2009-09-01

    Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been related to membrane damage, but also to nondetergent effects, such as oxidative stress and apoptosis. Strikingly, hydrophilic ursodeoxycholic acid (UDCA), and its taurine-conjugated form (TUDCA), show profound cytoprotective properties. Indeed, these molecules have been described as potent inhibitors of classic pathways of apoptosis, although their precise mode of action remains to be clarified. UDCA, originally used for cholesterol gallstone dissolution, is currently considered the first choice therapy for several forms of cholestatic syndromes. However, the beneficial effects of both UDCA and TUDCA have been tested in other experimental pathological conditions with deregulated levels of apoptosis, including neurological disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Here, we review the role of bile acids in modulating the apoptosis process, emphasizing the anti-apoptotic effects of UDCA and TUDCA, as well as their potential use as novel and alternate therapeutic agents for the treatment of apoptosis-related diseases.

  9. [Regulating acid stress resistance of lactic acid bacteria--a review].

    Science.gov (United States)

    Wu, Chongde; Huang, Jun; Zhou, Rongqing

    2014-07-04

    As cell factories, lactic acid bacteria are widely used in food, agriculture, pharmaceutical and other industries. Acid stress is one the important survival challenges encountered by lactic acid bacteria both in fermentation process and in the gastrointestinal tract. Recently, the development of systems biology and metabolic engineering brings unprecedented opportunity for further elucidating the acid tolerance mechanisms and improving the acid stress resistance of lactic acid bacteria. This review addresses physiological mechanisms of lactic acid bacteria during acid stress. Moreover, strategies to improve the acid stress resistance of lactic acid were proposed.

  10. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  11. Determination of dissociation constants or propionic acid and lactic acid (2-hydroxypropionic acid) by potentiometry and conductometry

    International Nuclear Information System (INIS)

    Saeeduddin; Khanzada, A.W.K.

    2004-01-01

    Dissociation constants of propionic acid and 2-hydroxypropionic acid (lactic acid) have been studied at different temperatures between 25 to 50 deg. C interval. Propionic acid is analyzed by conductometry while 2-hydroxypropionic acid is analyzed by potentiometry. Both investigated compounds are symmetrical carboxylic acids having same length of carbon chain but are markedly different in ionic behavior. We were interested to see how the hydroxyl group (-OH) induction in propionic acid affects on pKa values of 2-hydroxypropionic acid. We observed that as temperature increases pKa values increase. The increase is observed for both the investigated compounds. PKa values of 2-hydroxypropionic acid are lower as compared to propionic acid because of electron withdrawing (-OH). (author)

  12. 17,21-Secohopanoic acids, 25-norhopanoic acids, and 28-norhopanoic acids in source rocks and crude oils

    Energy Technology Data Exchange (ETDEWEB)

    Xueming Pan; Philp, R.P. [University of Oklahoma, Norman, OK (United States). School of Geology and Geophysics

    2006-09-15

    The presence of three families of hopanoic acids, 17,21-secohopanoic acids, 25-norhopanoic acids, and 28-norhopanoic acids, is discussed. Oils from West Siberia and tar balls from the Seychelles Islands were found to contain relatively high proportions of 17,21-secohopanoic acids. These acids have not been previously reported in any oils or source rocks. A heavily biodegraded West Siberian oil, was found to contain an homologous series of 25-norhopanoic acids co-occurring with the 25-norhopanes as previously reported in only a small number of oils from Campos Basin, Brazil. 28-Norhopanoic acids have been reported in various sediments and extracts of the Monterey Shale, but in this study their occurrence has been extended to oils, degraded oils, and tar balls sourced from the Monterey Shale. The primary purpose herein is to report the occurrence of these acids and possible relationships between the acids and corresponding hydrocarbons. (Author)

  13. Gallic Acid, Ellagic Acid and Pyrogallol Reaction with Metallic Iron

    International Nuclear Information System (INIS)

    Jaen, J. A.; Gonzalez, L.; Vargas, A.; Olave, G.

    2003-01-01

    The reaction between gallic acid, ellagic acid and pyrogallol with metallic iron was studied using infrared and Moessbauer spectroscopy. Most hydrolysable tannins with interesting anticorrosive or inhibition properties are structurally related to these compounds, thus they may be used as models for the study of hydrolysable tannins and related polyphenols. The interaction was followed up to 3 months. Results indicated two different behaviors. At polyphenol concentrations higher than 1% iron converts to sparingly soluble and amorphous ferric (and ferrous) polyphenolate complexes. At lower concentrations (0.1%), the hydrolysis reactions are dominant, resulting in the formation of oxyhydroxides, which can be further reduced to compounds like magnetite by the polyphenols.

  14. Gallic Acid, Ellagic Acid and Pyrogallol Reaction with Metallic Iron

    Energy Technology Data Exchange (ETDEWEB)

    Jaen, J. A., E-mail: jjaen@ancon.up.ac.p [Universidad de Panama, Departamento de Quimica Fisica, Facultad de Ciencias Naturales, Exactas y Tecnologia (Panama); Gonzalez, L.; Vargas, A.; Olave, G. [Universidad de Panama, Escuela de Quimica, Facultad de Ciencias Naturales, Exactas y Tecnologia (Panama)

    2003-06-15

    The reaction between gallic acid, ellagic acid and pyrogallol with metallic iron was studied using infrared and Moessbauer spectroscopy. Most hydrolysable tannins with interesting anticorrosive or inhibition properties are structurally related to these compounds, thus they may be used as models for the study of hydrolysable tannins and related polyphenols. The interaction was followed up to 3 months. Results indicated two different behaviors. At polyphenol concentrations higher than 1% iron converts to sparingly soluble and amorphous ferric (and ferrous) polyphenolate complexes. At lower concentrations (0.1%), the hydrolysis reactions are dominant, resulting in the formation of oxyhydroxides, which can be further reduced to compounds like magnetite by the polyphenols.

  15. The bile acids, deoxycholic acid and ursodeoxycholic acid, regulate colonic epithelial wound healing.

    Science.gov (United States)

    Mroz, Magdalena S; Lajczak, Natalia K; Goggins, Bridie J; Keely, Simon; Keely, Stephen J

    2018-03-01

    The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T 84 cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl - channels, whereas inhibition of CFTR activity with either CFTR- inh -172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes

  16. 15N NMR spectroscopic investigation of nitrous and nitric acids in sulfuric acid solutions of varying acidities

    International Nuclear Information System (INIS)

    Prakash, G.K.S.; Heiliger, L.; Olah, G.A.

    1990-01-01

    Both nitrous and nitric acids were studied in sulfuric acid solutions of varying acid strengths by 15 N NMR spectroscopy. The study gives new insights into the nature of intermediates present at different acid strengths. Furthermore, we have also discovered a novel redox reaction between NO 2 + and NO + ions involving the intermediacy of their respective acids. A mechanism is proposed to explain the observed results. 13 refs., 2 figs., 1 tab

  17. Distillation Separation of Hydrofluoric Acid and Nitric Acid from Acid Waste Using the Salt Effect on Vapor-Liquid Equilibrium

    Science.gov (United States)

    Yamamoto, Hideki; Sumoge, Iwao

    2011-03-01

    This study presents the distillation separation of hydrofluoric acid with use of the salt effect on the vapor-liquid equilibrium for acid aqueous solutions and acid mixtures. The vapor-liquid equilibrium of hydrofluoric acid + salt systems (fluorite, potassium nitrate, cesium nitrate) was measured using an apparatus made of perfluoro alkylvinylether. Cesium nitrate showed a salting-out effect on the vapor-liquid equilibrium of the hydrofluoric acid-water system. Fluorite and potassium nitrate showed a salting-in effect on the hydrofluoric acid-water system. Separation of hydrofluoric acid from an acid mixture containing nitric acid and hydrofluoric acid was tested by the simple distillation treatment using the salt effect of cesium nitrate (45 mass%). An acid mixture of nitric acid (5.0 mol · dm-3) and hydrofluoric acid (5.0 mol · dm-3) was prepared as a sample solution for distillation tests. The concentration of nitric acid in the first distillate decreased from 5.0 mol · dm-3 to 1.13 mol · dm-3, and the concentration of hydrofluoric acid increased to 5.41 mol · dm-3. This first distillate was further distilled without the addition of salt. The concentrations of hydrofluoric acid and nitric acid in the second distillate were 7.21 mol · dm-3 and 0.46 mol · dm-3, respectively. It was thus found that the salt effect on vapor-liquid equilibrium of acid mixtures was effective for the recycling of acids from acid mixture wastes.

  18. Branched-Chain Amino Acids

    Directory of Open Access Journals (Sweden)

    Matteo Ghiringhelli

    2015-07-01

    Full Text Available Our study is focused on evaluation and use of the most effective and correct nutrients. In particular, our attention is directed to the role of certain amino acids in cachectic patients. During parenteral nutrition in humans, physician already associates in the PN-bags different formulations including amino acids, lipids and glucose solutions or essential amino acids solution alone or exclusively branched-chain amino acids (BCAA. Studies investigated the effects of dietary BCAA ingestion on different diseases and conditions such as obesity and metabolic disorders, liver disease, muscle atrophy, cancer, impaired immunity or injuries (surgery, trauma, burns, and sepsis. BCAAs have been shown to affect gene expression, protein metabolism, apoptosis and regeneration of hepatocytes, and insulin resistance. They have also been shown to inhibit the proliferation of liver cancer cells in vitro, and are essential for lymphocyte proliferation and dendritic cell maturation. Oral or parenteral administration of these three amino acids will allow us to evaluate the real efficacy of these compounds during a therapy to treat malnutrition in subjects unable to feed themselves.

  19. 21 CFR 172.860 - Fatty acids.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Fatty acids. 172.860 Section 172.860 Food and Drugs... Multipurpose Additives § 172.860 Fatty acids. The food additive fatty acids may be safely used in food and in... and their associated fatty acids manufactured from fats and oils derived from edible sources: Capric...

  20. SHORT COMMUNICATION DETERMINATION OF AMINO ACIDS ...

    African Journals Online (AJOL)

    B. S. Chandravanshi

    The purpose of this study was to assess the levels of free and total amino acid ... Gas chromatographic method with flame ionization detector (GC-FID) was ... Total amino acid analysis was done on acid hydrolysates of RJ samples by the ion-exchange ... The data of amino acids and protein content for all analyzed fresh and.

  1. 21 CFR 582.5013 - Ascorbic acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ascorbic acid. 582.5013 Section 582.5013 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS... 1 § 582.5013 Ascorbic acid. (a) Product. Ascorbic acid. 1 Amino acids listed in this subpart may be...

  2. Effect of propionic acid on citric acid fermentation in an integrated citric acid-methane fermentation process.

    Science.gov (United States)

    Xu, Jian; Bao, Jia-Wei; Su, Xian-Feng; Zhang, Hong-Jian; Zeng, Xin; Tang, Lei; Wang, Ke; Zhang, Jian-Hua; Chen, Xu-Sheng; Mao, Zhong-Gui

    2016-03-01

    In this study, an integrated citric acid-methane fermentation process was established to solve the problem of wastewater treatment in citric acid production. Citric acid wastewater was treated through anaerobic digestion and then the anaerobic digestion effluent (ADE) was further treated and recycled for the next batch citric acid fermentation. This process could eliminate wastewater discharge and reduce water resource consumption. Propionic acid was found in the ADE and its concentration continually increased in recycling. Effect of propionic acid on citric acid fermentation was investigated, and results indicated that influence of propionic acid on citric acid fermentation was contributed to the undissociated form. Citric acid fermentation was inhibited when the concentration of propionic acid was above 2, 4, and 6 mM in initial pH 4.0, 4.5 and, 5.0, respectively. However, low concentration of propionic acid could promote isomaltase activity which converted more isomaltose to available sugar, thereby increasing citric acid production. High concentration of propionic acid could influence the vitality of cell and prolong the lag phase, causing large amount of glucose still remaining in medium at the end of fermentation and decreasing citric acid production.

  3. Influence of acidified acidity to uranium bioleaching

    International Nuclear Information System (INIS)

    Li Jiang; Liu Yajie; Zheng Zhihong; Yuan Baohua; Shen Chuan; Shi Weijun

    2012-01-01

    The relationship between the acidified acidity and the acid consumption and uranium leaching rate in the process of uranium bioleaching is investigated. Results indicate that higher uranium leaching rate is obtained when the relatively high acidity was applied at beginning. For different minerals, although the original acidity should be different, lower original acidity was not better for shortening leaching period and improving uranium leaching rate. It confirms 30-40 g/L sulfuric acid as the original acidity was more suitable and more than 30 g/ L should be applied if the mineral particle sizes were larger. (authors)

  4. Queensland Mines plant trials with Caro's acid

    International Nuclear Information System (INIS)

    Lucas, G.C.; Fulton, E.J.; Vautier, F.E.; Waters, D.J.; Ring, R.J.

    1983-01-01

    Laboratory leach tests have been carried out to compare the effectiveness of Caro's acid (permonosulphuric acid) as an alternative oxidant to pyrolusite in the leaching of uranium ores. Results demonstrated that Caro's acid reduced acid consumption in leaching and the time required for neutralisation of tailings liquor. The uranium extraction was unaffected by choice of oxidant. A plant trial confirmed that significant savings in acid and lime usage can be achieved under plant conditions. Plant operations also demonstrated that Caro's acid has a number of significant operating advantages over pyrolusite. Queensland Mines Ltd. have recently decided to convert their leaching process from pyrolusite to Caro's acid

  5. Tumor Acidity as Evolutionary Spite

    International Nuclear Information System (INIS)

    Alfarouk, Khalid O.; Muddathir, Abdel Khalig; Shayoub, Mohammed E. A.

    2011-01-01

    Most cancer cells shift their metabolic pathway from a metabolism reflecting the Pasteur-effect into one reflecting the Warburg-effect. This shift creates an acidic microenvironment around the tumor and becomes the driving force for a positive carcinogenesis feedback loop. As a consequence of tumor acidity, the tumor microenvironment encourages a selection of certain cell phenotypes that are able to survive in this caustic environment to the detriment of other cell types. This selection can be described by a process which can be modeled upon spite: the tumor cells reduce their own fitness by making an acidic environment, but this reduces the fitness of their competitors to an even greater extent. Moreover, the environment is an important dimension that further drives this spite process. Thus, diminishing the selective environment most probably interferes with the spite process. Such interference has been recently utilized in cancer treatment

  6. Mine waters: Acidic to circumneutral

    Science.gov (United States)

    Nordstrom, D. Kirk

    2011-01-01

    Acid mine waters, often containing toxic concentrations of Fe, Al, Cu, Zn, Cd, Pb, Ni, Co, and Cr, can be produced from the mining of coal and metallic deposits. Values of pH for acid mine waters can range from –3.5 to 5, but even circumneutral (pH ≈ 7) mine waters can have high concentrations of As, Sb, Mo, U, and F. When mine waters are discharged into streams, lakes, and the oceans, serious degradation of water quality and injury to aquatic life can ensue, especially when tailings impoundments break suddenly. The main acid-producing process is the exposure of pyrite to air and water, which promotes oxidative dissolution, a reaction catalyzed by microbes. Current and future mining should plan for the prevention and remediation of these contaminant discharges by the application of hydrogeochemical principles and available technologies, which might include remining and recycling of waste materials.

  7. Preparation of deuterated succinic acids

    Energy Technology Data Exchange (ETDEWEB)

    Tashiro, Masashi; Tsuzuki, Hirohisa; Goto, Hideyuki; Ogasahara, Shoji; Mataka, Shuntaro (Kyushu Univ., Fukuoka (Japan)); Isobe, Shin-ichiro; Yonemitsu, Tadashi (Kyushu Sangyo Univ., Fukuoka (Japan). Dept. of Industrial Chemistry)

    1991-04-01

    Succinic (2,3-{sup 2}H{sub 2})- and (2,2,3,3-{sup 2}H{sub 4})-acids were prepared from maleic anhydride and dimethyl fumarate, and acetylene dicarboxylic acid and its dimethyl ester by treatment with Cu-Al and Ni-Al alloys in 10% NaOD-D{sub 2}0 in 95% to 100% isotopic purity. The succinic {sup 2}H{sub 4} acid having high isotopic purity was also obtained on the hydrolysis of 1,2-ethanedinitrile with alkaline deuterium oxide. Based on the {sup 1}H({sup 2}H) spectra analysis of N-(o-biphenyl)(2,3-{sup 2}H{sub 2})succinimide, it was elucidated that the Raney alloy reduction with alkaline deuterium oxide proceeds stepwise. (author).

  8. Nitric Acid Poisoning: Case Report

    International Nuclear Information System (INIS)

    Quintero Giraldo, Maria Paulina; Quiceno Calderon, William de Jesus; Melo Arango Catalina

    2011-01-01

    Nitric acid (HNO 3 ) is a corrosive fluid that, when in contact with reducing agents, generates nitrogen oxides that are responsible for inhalation poisoning. We present two cases of poisoning from nitric acid gas inhalation resulting from occupational exposure. Imaging findings were similar in both cases, consistent with adult respiratory distress syndrome (ARDS): bilaterally diffuse alveolar opacities on the chest X-ray and a cobblestone pattern on computed tomography (CT).one of the patients died while the other evolved satisfactorily after treatment with n-acetyl cysteine and mechanical ventilation. The diagnosis of nitric acid poisoning was made on the basis of the history of exposure and the way in which the radiological findings evolved.

  9. Uranium extraction in phosphoric acid

    International Nuclear Information System (INIS)

    Araujo Figueiredo, C. de

    1984-01-01

    Uranium is recovered from the phosphoric liquor produced from the concentrate obtained from phosphorus-uraniferous mineral from Itataia mines (CE, Brazil). The proposed process consists of two extraction cycles. In the first one, uranium is reduced to its tetravalent state and then extracted by dioctylpyrophosphoric acid, diluted in Kerosene. Re-extraction is carried out with concentrated phosphoric acid containing an oxidising agent to convert uranium to its hexavalent state. This extract (from the first cycle) is submitted to the second cycle where uranium is extracted with DEPA-TOPO (di-2-hexylphosphoric acid/tri-n-octyl phosphine oxide) in Kerosene. The extract is then washed and uranium is backextracted and precipitated as commercial concentrate. The organic phase is recovered. Results from discontinuous tests were satisfactory, enabling to establish operational conditions for the performance of a continuous test in a micro-pilot plant. (Author) [pt

  10. Geological aspects of acid deposition

    International Nuclear Information System (INIS)

    Bricker, O.P.

    1984-01-01

    The general pattern of rain falling on the earth and reacting with the materials of the lithosphere (the weathering reactions so familiar to every beginning geology student) began soon after the earth was formed and has continued to the present. Anthropogenic additions to the natural acidic components of the atmosphere have increased since the time of the industrial revolution until they now rival or exceed those of the natural system. The severity of the environmental perturbations caused by these anthropogenic additions to the atmosphere has become a hotly debated topic in scientific forums and in the political arena. The six chapters in this book address various aspects of the acid deposition phenomenon from a geological perspective. It is hoped that the geological approach will be useful in bringing the problem more clearly into focus and may shed light on the geochemical processes that modify the chemical composition of acid deposition after it encounters and reacts with the materials of the lithosphere

  11. Identifying a base in a nucleic acid

    Science.gov (United States)

    Fodor, Stephen P. A.; Lipshutz, Robert J.; Huang, Xiaohua

    2005-02-08

    Devices and techniques for hybridization of nucleic acids and for determining the sequence of nucleic acids. Arrays of nucleic acids are formed by techniques, preferably high resolution, light-directed techniques. Positions of hybridization of a target nucleic acid are determined by, e.g., epifluorescence microscopy. Devices and techniques are proposed to determine the sequence of a target nucleic acid more efficiently and more quickly through such synthesis and detection techniques.

  12. Salicylic acid-independent plant defence pathways

    OpenAIRE

    Pieterse, C.M.J.; Loon, L.C. van

    1999-01-01

    Salicylic acid is an important signalling molecule involved in both locally and systemically induced disease resistance responses. Recent advances in our understanding of plant defence signalling have revealed that plants employ a network of signal transduction pathways, some of which are independent of salicylic acid. Evidence is emerging that jasmonic acid and ethylene play key roles in these salicylic acid-independent pathways. Cross-talk between the salicylic acid-dependent and the salicy...

  13. Glutamic acid as anticancer agent: An overview

    OpenAIRE

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K.

    2013-01-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. I...

  14. 21 CFR 186.1316 - Formic acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Formic acid. 186.1316 Section 186.1316 Food and... Substances Affirmed as GRAS § 186.1316 Formic acid. (a) Formic acid (CH2O2, CAS Reg. No. 64-18-6) is also referred to as methanoic acid or hydrogen carboxylic acid. It occurs naturally in some insects and is...

  15. 21 CFR 184.1021 - Benzoic acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Benzoic acid. 184.1021 Section 184.1021 Food and... Substances Affirmed as GRAS § 184.1021 Benzoic acid. (a) Benzoic acid is the chemical benzenecarboxylic acid (C7H6O2), occurring in nature in free and combined forms. Among the foods in which benzoic acid occurs...

  16. 21 CFR 184.1065 - Linoleic acid.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Linoleic acid. 184.1065 Section 184.1065 Food and... Substances Affirmed as GRAS § 184.1065 Linoleic acid. (a) Linoleic acid ((Z, Z)-9, 12-octadecadienoic acid (C17H31COOH) (CAS Reg. No. 60-33-3)), a straight chain unsaturated fatty acid with a molecular weight of 280.5...

  17. Fatty acid composition and amino acid profile of two freshwater ...

    African Journals Online (AJOL)

    The proximate, fatty and amino acids composition of two commercially important freshwater fish species Clarias gariepinus and Tilapia zillii. purchased from local fishermen in two landing sites in Lagos State, Nigeria were determined. Live specimens of C. gariepinus were purchased while samples of T. zillii were stored in ...

  18. Nitrous Acid as an Oxidant in Acidic Media

    Science.gov (United States)

    1979-09-25

    current work is the account of Ogsts and Sawski3 who studied the oxidation of benzyl ethers at 90C in acidic, aqueous dioxane. They found an increase in...and G. Tobin, Chem. Com., 180 (1978); (b) J. Hoggett , R. Moodie, and K. Schofield, Chem. Comm., 605 (1969). 15. (a) B. Challis and A. Lawson. J. Chem

  19. Kinetics of oxidation of acidic amino acids by sodium N ...

    Indian Academy of Sciences (India)

    Unknown

    BAB) has been carried out in aqueous HClO4 medium at 30°C. The rate shows first- ... amino acids by chloramines 7,8 while, little attention has been focused on ... in glass-stoppered pyrex boiling tubes whose outer surface was coated ... BAB in a measured aliquot (5 ml each) of the reaction mixture at different intervals of.

  20. Amino acids analysis during lactic acid fermentation by single strain ...

    African Journals Online (AJOL)

    L. salivarius alone showed relatively good assimilation of various amino acids that existed at only a little amounts in MRS media (Asn, Asp, Cit, Cys, Glu, His, Lys, Orn, Phe, Pro, Tyr, Arg, Ile, Leu, Met, Ser, Thr, Trp and Val), whereas Ala and Gly accumulated in L. salivarius cultures. P. acidilactici, in contrast, hydrolyzed the ...