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Sample records for inhibitor sodium butyrate

  1. HDAC inhibitor sodium butyrate augments the MEF2C enhancement of Nampt expression under hypoxia.

    PubMed

    Yan, Shao-Fei; You, Hong-Jie; Xing, Tian-Yu; Zhang, Chen-Guang; Ding, Wei

    2014-01-01

    Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme for the salvage biosynthesis of nicotinamide adenine dinucleotide (NAD). Although elevated level of Nampt expression has been observed in various cancers, the involvement of Nampt promoter regulation was not well understood. We have identified a cluster of MEF2 recognition sites upstream of the functional hypoxia response elements (HREs) within the human Nampt promoter, and demonstrated that the two MEF2 sites at -1272 and -1200 were functional to upregulate the promoter activity by luciferase reporter assays. The Nampt promoter was able to be activated cooperatively following hypoxic stimulation by CoCl₂ treatment with associated MEF2C overexpression. During the investigation on MEF2C regulation of endogenous Nampt expression in HeLa cells, the most significant enhancement of Nampt expression observed was by overexpression of MEF2C in combination with sodium butyrate exposure. By chromatin immunoprecipitation with a MEF2C anti-body, we found that MEF2C indeed interacted with endogenous Nampt promoter. The requirement of HDAC inhibition for the MEF2C enhancement of Nampt transcription was verified by RNAi of HDAC. Our results were in support of reports indicating that MEF2 family transcription factors interacted with HDACs and regulated downstream gene expression at the epigenetic levels. Our study provided important evidence to demonstrate the sophisticated mechanism of endogenous Nampt promoter regulation, and therefore, will help to better understand the Nampt overexpression in cancer progression, especially in the context of MEF2C upregulation which frequently occurred in cancer development and drug resistance. PMID:23888946

  2. Reciprocal modulation of histone deacetylase inhibitors sodium butyrate and trichostatin A on the energy metabolism of breast cancer cells.

    PubMed

    Rodrigues, Mariana Figueiredo; Carvalho, Érika; Pezzuto, Paula; Rumjanek, Franklin David; Amoêdo, Nivea Dias

    2015-05-01

    Tumor cells display different bioenergetic profiles when compared to normal cells. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin A in breast cancer cells representing different stages of aggressiveness and metabolic profile. When testing the effect of NaB and TSA on viability of cells, it was shown that non-tumorigenic MCF-10A cells were less affected by increasing doses of the drugs than the tumorigenic, hormone dependent, tightly cohesive MCF-7, T-47D and the highly metastatic triple-negative MDA-MB 231 cells. T-47D cells were the most sensitive to treatment with both, NaB and TSA. Experiments measuring anchorage- independent growth of tumor cells showed that MCF-7, T-47D, and MDA-MB-231 cells were equally sensitive to the treatment with NaB. The NaB induced an attenuation of glycolysis, reflected by a decrease in lactate release in MCF-7 and T47D lines. Pyruvate kinase activity was significantly enhanced by NaB in MDA-MB-231 cells only. In contrast, the inhibitor enhanced lactate dehydrogenase activity specifically in T-47 D cells. Glucose-6-phosphate dehydrogenase activity was shown to be differentially modulated by NaB in the cell lines investigated: the enzyme was inhibited in MCF-7 cells, whereas in T-47D and MDA-MB-231 cells, G6PDH was activated. NaB and TSA were able to significantly increase the oxygen consumption by MDA-MB-231 and T-47D cells. Collectively the results show that epigenetic changes associated to acetylation of proteins in general affect the energy metabolism in all cancer cell lines and that mitochondria may occupy a central role in metastasis. PMID:25510910

  3. Histone deacetylase inhibitors sodium butyrate and valproic acid delay spontaneous cell death in purified rat retinal ganglion cells

    PubMed Central

    Boyle, Jennifer; Pielen, Amelie; Lagrèze, Wolf Alexander

    2011-01-01

    Purpose Histone deacetylase inhibitors (HDACi) have neuroprotective effects under various neurodegenerative conditions, e.g., after optic nerve crush (ONC). HDACi-mediated protection of central neurons by increased histone acetylation has not previously been demonstrated in rat retinal ganglion cells (RGCs), although epigenetic changes were shown to be associated with cell death after ONC. We investigated whether HDACi can delay spontaneous cell death in purified rat RGCs and analyzed concomitant histone acetylation levels. Methods RGCs were purified from newborn (postnatal day [P] 0–P2) rat retinas by immunopanning with antibodies against Thy-1.1 and culturing in serum-free medium for 2 days. RGCs were treated with HDACi, each at several different concentrations: 0.1–10 mM sodium butyrate (SB), 0.1–2 mM valproic acid (VPA), or 0.5–10 nM trichostatin A (TSA). Negative controls were incubated in media alone, while positive controls were incubated in 0.05–0.4 IU/µl erythropoietin. Survival was quantified by counting viable cells using phase-contrast microscopy. The expression of acetylated histone proteins (AcH) 3 and 4 was analyzed in RGCs by immunohistochemistry. Results SB and VPA enhanced RGC survival in culture, with both showing a maximum effect at 0.1 mM (increase in survival to 188% and 163%, respectively). Their neuroprotective effect was comparable to that of erythropoietin at 0.05 IU/µl. TSA 0.5–1.0 nM showed no effect on RGC survival, and concentrations ≥5 nM increased RGC death. AcH3 and AcH4 levels were only significantly increased in RGCs treated with 0.1 mM SB. VPA 0.1 mM produced only a slight effect on histone acetylation. Conclusions Millimolar concentrations of SB and VPA delayed spontaneous cell death in purified RGCs; however, significantly increased histone acetylation levels were only detectable in RGCs after SB treatment. As the potent HDACi TSA was not neuroprotective, mechanisms other than histone acetylation may be the

  4. Colonic mucin synthesis is increased by sodium butyrate.

    PubMed

    Finnie, I A; Dwarakanath, A D; Taylor, B A; Rhodes, J M

    1995-01-01

    The effects of sodium butyrate and sodium bromo-octanoate (an inhibitor of beta oxidation) on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. Epithelial biopsy specimens were incubated for 16 hours in RPMI 1640 with glutamine, supplemented with 10% fetal calf serum and N-acetyl-[3H]-glucosamine ([3H]-Glc NAc), and differing concentrations of sodium butyrate. Incorporation of [3H] Glc NAc into mucin by normal epithelium at least 10 cm distant from colonic cancer was increased in the presence of sodium butyrate in a dose dependent manner, with maximum effect (476%) at a concentration of 0.1 mM (number of specimens = 24 from six patients, p < 0.001). The increase in response to butyrate was not seen when specimens were incubated in the presence of the beta oxidation inhibitor sodium bromo-octanoate 0.05 M. The striking increase in mucin synthesis that results when butyrate is added to standard nutrient medium suggests that this may be an important mechanism affecting the rate of mucin synthesis in vivo and may also explain the therapeutic effect of butyrate in colitis. PMID:7890244

  5. Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.

    PubMed

    Valvassori, Samira S; Resende, Wilson R; Budni, Josiane; Dal-Pont, Gustavo C; Bavaresco, Daniela V; Réus, Gislaine Z; Carvalho, André F; Gonçalves, Cinara L; Furlanetto, Camila B; Streck, Emilio L; Quevedo, João

    2015-01-01

    The aim of the present study was to evaluate the effects of sodium butyrate on depressive-like behavior and mitochondrial alteration parameters in animal models of depression induced by maternal deprivation or chronic mild stress in Wistar rats. maternal deprivation was established by separating pups from their mothers for 3 h daily from postnatal day 1 to day 10. Chronic mild stress was established by water deprivation, food deprivation, restraint stress, isolation and flashing lights. Sodium butyrate or saline was administered twice a day for 7 days before the behavioral tests. Depressive behavior was evaluated using the forced swim test. The activity of tricarboxylic acid cycle enzymes (succinate dehydrogenase and malate dehydrogenase) and of mitochondrial chain complexes (I, II, II-III and IV) was measured in the striatum of rats. From these analyses it can be observed that sodium butyrate reversed the depressive-like behavior observed in both animal models of depression. Additionally, maternal deprivation and chronic mild stress inhibited mitochondrial respiratory chain complexes and increased the activity of tricarboxylic acid cycle enzymes. Sodium butyrate treatment reversed -maternal deprivation and chronic mild stress- induced dysfunction in the striatum of rats. In conclusion, sodium butyrate showed antidepressant effects in maternal deprivation and chronic mild stress-treated rats, and this effect can be attributed to its action on the neurochemical pathways related to depression. PMID:26216027

  6. The effects of sodium butyrate, an inhibitor of histone deacetylase, on the cocaine- and sucrose-maintained self-administration in rats.

    PubMed

    Sun, Jie; Wang, Lei; Jiang, Baohong; Hui, Bin; Lv, Zhigang; Ma, Lan

    2008-08-15

    In order to substantiate the concept that cocaine behavioral effects may be influenced by histone modification, rats were trained to self-administer cocaine intravenously (0.75 mg/(kginjection)), and were systemically pretreated with sodium butyrate (NaBu), a potent histone deacetylase inhibitor, before the test session during the maintenance phase. The effect of NaBu on a control reinforcer (sucrose)-induced self-administration was also assessed. NaBu (100-200 mg/kg) was inactive in altering the cocaine (0.75 mg/(kg injection))-maintained responding and at the highest dose (400 mg/kg) it did increase cocaine-induced lever presses during the maintenance phase. On the other hand, sucrose-reinforcing potential was not altered when NaBu was given at the highest dose (400 mg/kg). These findings extend previous observations that changes in histone acetylation are relevant to cocaine-induced behavioral effects. Given that histone acetylase inhibitor enhances cocaine-induced behavioral plasticity, the therapeutic benefits of histone acetyltransferase inhibitors warrant further investigation in the experimental models of cocaine abuse. PMID:18599214

  7. Histone deacetylase inhibitor sodium butyrate suppresses proliferation and promotes apoptosis in osteosarcoma cells by regulation of the MDM2–p53 signaling

    PubMed Central

    Xie, Chuhai; Wu, Boyi; Chen, Binwei; Shi, Qunwei; Guo, Jianhong; Fan, Ziwen; Huang, Yan

    2016-01-01

    Histone deacetylase inhibitors have been reported to induce tumor cell growth arrest, differentiation, and apoptosis. This study aimed to investigate the effects of one histone deacetylase inhibitorsodium butyrate (SB) – on osteosarcoma (OS) cell proliferation and apoptosis and also the molecular mechanisms by which SB exerts regulatory effects on OS cells. U2OS and MG63 cells were treated with SB at various concentrations. Then, cell proliferation and apoptosis were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry assays, respectively; the expression of Ki67, Bax, Bcl-2, MDM2, and p53 proteins was determined by using Western blot assay. The results showed that SB suppressed proliferation in a concentration-dependent manner and promoted apoptosis of OS cells. In addition, SB enhanced p53 expression and decreased MDM2 expression, indicating that SB can regulate MDM2–p53 feedback loop. p53 inhibited proliferation and promoted apoptosis, whereas MDM2 promoted proliferation and suppressed apoptosis, which indicated that functional effect of SB on OS cell lines at least in part depended on the MDM2–p53 signaling. We also explored the effect of SB on OS cells in vivo and found that SB suppressed the growth of OS cells with no noticeable effect on activity and body weight of mice in vivo. These findings will offer new clues for OS development and progression and offer SB as a potent targeted agent for OS treatment. PMID:27445491

  8. Histone deacetylase inhibitor sodium butyrate suppresses proliferation and promotes apoptosis in osteosarcoma cells by regulation of the MDM2-p53 signaling.

    PubMed

    Xie, Chuhai; Wu, Boyi; Chen, Binwei; Shi, Qunwei; Guo, Jianhong; Fan, Ziwen; Huang, Yan

    2016-01-01

    Histone deacetylase inhibitors have been reported to induce tumor cell growth arrest, differentiation, and apoptosis. This study aimed to investigate the effects of one histone deacetylase inhibitor - sodium butyrate (SB) - on osteosarcoma (OS) cell proliferation and apoptosis and also the molecular mechanisms by which SB exerts regulatory effects on OS cells. U2OS and MG63 cells were treated with SB at various concentrations. Then, cell proliferation and apoptosis were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry assays, respectively; the expression of Ki67, Bax, Bcl-2, MDM2, and p53 proteins was determined by using Western blot assay. The results showed that SB suppressed proliferation in a concentration-dependent manner and promoted apoptosis of OS cells. In addition, SB enhanced p53 expression and decreased MDM2 expression, indicating that SB can regulate MDM2-p53 feedback loop. p53 inhibited proliferation and promoted apoptosis, whereas MDM2 promoted proliferation and suppressed apoptosis, which indicated that functional effect of SB on OS cell lines at least in part depended on the MDM2-p53 signaling. We also explored the effect of SB on OS cells in vivo and found that SB suppressed the growth of OS cells with no noticeable effect on activity and body weight of mice in vivo. These findings will offer new clues for OS development and progression and offer SB as a potent targeted agent for OS treatment. PMID:27445491

  9. Sodium Butyrate Induces Endoplasmic Reticulum Stress and Autophagy in Colorectal Cells: Implications for Apoptosis

    PubMed Central

    Zhang, Jintao; Yi, Man; Zha, Longying; Chen, Siqiang; Li, Zhijia; Li, Cheng; Gong, Mingxing; Deng, Hong; Chu, Xinwei; Chen, Jiehua; Zhang, Zheqing; Mao, Limei; Sun, Suxia

    2016-01-01

    Purpose Butyrate, a short-chain fatty acid derived from dietary fiber, inhibits proliferation and induces cell death in colorectal cancer cells. However, clinical trials have shown mixed results regarding the anti-tumor activities of butyrate. We have previously shown that sodium butyrate increases endoplasmic reticulum stress by altering intracellular calcium levels, a well-known autophagy trigger. Here, we investigated whether sodium butyrate-induced endoplasmic reticulum stress mediated autophagy, and whether there was crosstalk between autophagy and the sodium butyrate-induced apoptotic response in human colorectal cancer cells. Methods Human colorectal cancer cell lines (HCT-116 and HT-29) were treated with sodium butyrate at concentrations ranging from 0.5–5mM. Cell proliferation was assessed using MTT tetrazolium salt formation. Autophagy induction was confirmed through a combination of Western blotting for associated proteins, acridine orange staining for acidic vesicles, detection of autolysosomes (MDC staining), and electron microscopy. Apoptosis was quantified by flow cytometry using standard annexinV/propidium iodide staining and by assessing PARP-1 cleavage by Western blot. Results Sodium butyrate suppressed colorectal cancer cell proliferation, induced autophagy, and resulted in apoptotic cell death. The induction of autophagy was supported by the accumulation of acidic vesicular organelles and autolysosomes, and the expression of autophagy-associated proteins, including microtubule-associated protein II light chain 3 (LC3-II), beclin-1, and autophagocytosis-associated protein (Atg)3. The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine inhibited sodium butyrate induced autophagy. Furthermore, sodium butyrate treatment markedly enhanced the expression of endoplasmic reticulum stress-associated proteins, including BIP, CHOP, PDI, and IRE-1a. When endoplasmic reticulum stress was inhibited by pharmacological (cycloheximide and mithramycin

  10. Anti-inflammatory effect of sodium butyrate preconditioning during myocardial ischemia/reperfusion

    PubMed Central

    HU, XIAORONG; ZHANG, KAI; XU, CHANGWU; CHEN, ZHIQAING; JIANG, HONG

    2014-01-01

    High mobility group box 1 protein (HMGB1) has an important role in myocardial ischemia/reperfusion (I/R) injury. Sodium butyrate, an inhibitor of histone deacetylase, has been shown to inhibit HMGB1 expression. In the present study, the effect of sodium butyrate on myocardial I/R injury in rats was investigated. Anesthetized male rats were intraperitoneally administered sodium butyrate (100 or 300 mg/kg) 30 min prior to the induction of ischemia. The rats were then subjected to ischemia for 30 min followed by reperfusion for 4 h. Infarct size, lactate dehydrogenase (LDH), creatine kinase (CK) and superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels were then measured. The expression of HMGB1 was assessed using western blot analysis. The results demonstrated that pretreatment with sodium butyrate (300 mg/kg) significantly reduced the infarct size, as well as the levels of LDH and CK (P<0.05). In addition, sodium butyrate (300 mg/kg) was shown to significantly inhibit the I/R-induced increase in the level of MDA and reduction in the level of SOD (P<0.05). Furthermore, treatment with sodium butyrate (300 mg/kg) was found to significantly inhibit the expression of TNF-α, IL-6 and HMGB1 induced by I/R injury (P<0.05). In conclusion, the results from the present study suggest that preconditioning with sodium butyrate may attenuate myocardial I/R injury by inhibition of the expression of inflammatory mediators during myocardial I/R. PMID:24944626

  11. Protective role of sodium butyrate, a HDAC inhibitor on beta-cell proliferation, function and glucose homeostasis through modulation of p38/ERK MAPK and apoptotic pathways: study in juvenile diabetic rat.

    PubMed

    Khan, S; Jena, G B

    2014-04-25

    Type 1 diabetes (T1D) also known as juvenile diabetes is a chronic autoimmune disorder that precipitates in genetically susceptible individuals by environmental factors particularly during early age. Both genetic and epigenetic factors are implicated in the beta-cell development, proliferation, differentiation and function. Recent evidences suggested that there is a link between diabetes and histone deacetylases (HDACs), because HDAC inhibitors promote beta-cell development, proliferation and function as well as improve glucose homeostasis. Sodium butyrate (NaB) is a short chain fatty acid having HDAC inhibition activity. The present study was aimed to investigate the protective role of NaB treatment on the beta-cell proliferation, function and glucose homeostasis as well as apoptosis in juvenile diabetic rat. Diabetes was induced by single injection of STZ (60 mg/kg, i.p.) in chilled citrate buffer, while NaB (500 mg/kg/day) was administrated by i.p. route for 21 days as pre- and post-treatment schedule. Plasma glucose and insulin levels, HbA1c, glucose tolerance, apoptosis, and expression of proliferating cell nuclear antigen (PCNA), p38, p53, caspase-3, extracellular signal-regulated kinase-1/2 (ERK-1/2), forkhead box protein O1 (FOXO1) and insulin receptor substrate-1 (IRS-1) as well as histone acetylation were evaluated. NaB treatment decreased plasma glucose, HbA1c, beta-cell apoptosis and improved plasma insulin level and glucose homeostasis through HDAC inhibition and histone acetylation in diabetic animal as compared to control. NaB treatment improved the beta-cell proliferation, function and glucose homeostasis as well as reduced beta-cell apoptosis in juvenile diabetic rat by the modulation of p38/ERK MAPK and apoptotic pathway. PMID:24530320

  12. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev; Singh, Sumel

    2015-09-15

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD. PMID:26048426

  13. FLOW CYTOMETRIC EVALUATION OF THE EFFECTS OF SODIUM BUTYRATE ON APOPTOSIS OF BOVINE NEUTROPHILS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine blood neutrophils(PMN) from four clinically healthy cows were suspended in Dulbecco's minimal essential medium and incubated at 37C for 0, 2 or 6 hours in medium alone, with 100ng/ml bacterial endotoxin, 160nM sodium butyrate, 16uM actinomycin D, mixture of sodium butyrate and bacterial endot...

  14. Effect of Sodium Butyrate on Growth Performance and Response to Lipopolysaccharide in Weanling Pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two experiments were conducted to determine the effects of dietary sodium butyrate on growth performance and response to E. coli. lipopolysaccharide (LPS) in weanling pigs. In the first 28 d experiment, 180 pigs (initial BW 6.3 kg) were fed 0, 0.05, 0.1, 0.2, and 0.4% sodium butyrate, or 110 mg/kg d...

  15. Sodium butyrate mitigates in vitro ammonia generation in cecal content of laying hens.

    PubMed

    Wang, Anping; Wang, Yan; Di Liao, Xin; Wu, Yinbao; Liang, Juan Boo; Laudadio, Vito; Tufarelli, Vincenzo

    2016-08-01

    One of the environmental challenges that modern poultry industry faced is odor pollution caused by ammonia emission. The objectives of the study were to determine the effect of sodium butyrate on the production of ammonia in the cecal contents of laying hens using in vitro gas production study and to elucidate the mechanism behind it. The study consisted of a control (without sodium butyrate), and three experimental groups added with 10, 15, and 20 mg of sodium butyrate, respectively. Results showed that ammonia production in headspace of the syringe decreased by 8.2, 23, and 23 %, respectively, while ammonium production from the fermentation broth decreased by 6.3, 14.4, and 13.7 %, respectively. Sodium butyrate had no significant effect on the contents of uric acid and urea, nitrate-N, or total N in all treatments. However, sodium butyrate decreased the urease and uricase activities (P < 0.05) in the fermentation broth. Sodium butyrate also altered volatile fatty acids profile of the fermentation broth by decreasing the production of isovalerate (P < 0.05) and increasing those of acetate, butyrate, and isobutyrate (P < 0.05). The MiSeq System Sequencing results showed that sodium butyrate increased the relative abundance of Bacteroides and Faecalibacterium (P < 0.05) and decreased the relative abundance of Desulfovibrio, Helicobacter, and Campylobacter (P < 0.05).Our results concluded that sodium butyrate changes the diversity and relative abundance of the microbes which altered the fermentation characteristics leading to reduction in ammonia production. PMID:27154844

  16. Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA.

    PubMed

    Ying, Mingyao; Xu, Rener; Wu, Xiaohui; Zhu, Huaxing; Zhuang, Yuan; Han, Min; Xu, Tian

    2006-05-01

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease caused by polyglutamine expansion within the Atrophin-1 protein. To study the mechanism of this disease and to test potential therapeutic methods, we established Atro-118Q transgenic mice, which express in neurons a mutant human Atrophin-1 protein that contains an expanded stretch of 118 glutamines. Consistent with the results from previous studies on transgenic mice that expressed mutant Atrophin-1 with 65 glutamines, Atro-118Q mice exhibited several neurodegenerative phenotypes that are commonly seen in DRPLA patients, including ataxia, tremors, and other motor defects. Overexpression of wild-type human Atrophin-1 could not rescue the motor and survival defects in Atro-118Q mice, indicating that the mutant protein with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggested that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. We further show that intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases and suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms. PMID:16407196

  17. Sodium butyrate protects the intestinal barrier function in peritonitic mice

    PubMed Central

    Han, Xiaofeng; Song, Huimin; Wang, Yunlei; Sheng, Yingmo; Chen, Jie

    2015-01-01

    Objective: Peritonitis is a commonly seen disease with high morbidity and mortality. It is prevalently considered that the impaired intestinal barrier during peritonitis is the access point of gut microbes into the blood system, and acts as the engine of the following systemic infection. In our previous study, we found that Sodium Butyrate (NaB) was protective on intestinal barrier function. In this study, we aim to evaluate the effects of NaB on overwhelming infection animal models of peritonitis. Methods: Mouse cecal ligation and puncture (CLP) model was used to study the effects of NaB on the intestinal barrier. Experimental animals were fed of NaB by gavage. Post-CLP mortality, gut permeability and intestinal histological alterations were studied. Results: Gastrointestinal NaB pharmacodynamics profiles after medication were studied. Measurements of NaB concentration in chyme showed significantly higher intestinal concentration of NaB in the NaB treated group than that of the control group. CLP-induced mortality was significantly decreased by oral NaB treatments. Gut permeability was largely increased after CLP, which was partially prevented by NaB feeding. Histological study showed that intestinal, especially ileal injury following peritonitis was substantially alleviated by NaB treatments. Moreover, tissue regeneration was also prompted by NaB. Conclusion: NaB has a potential protective effect on intestinal barrier function in peritonitis. PMID:26064302

  18. Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway.

    PubMed

    Wang, Xukai; He, Gang; Peng, Yan; Zhong, Weitian; Wang, Yan; Zhang, Bo

    2015-01-01

    Insulin resistance (IR) is a common feature of Type II diabetes, metabolic disorders, hypertension and other vascular diseases. Recent studies showed that obesity-induced inflammation may be critical for IR. To investigate the anti-inflammatory effect of sodium butyrate (NaB) on obesity-induced inflammation, the db/db mice were intraperitoneally injected with NaB for 6 weeks. Glucose control was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT). Adipose tissue was harvested for gene expression analysis. 3T3-L1 adipocytes were treated with Tnf-α to mimic the inflammatory state and gene expression was detected by realtime PCR and Western blotting. Our results showed that NaB treatment improved glucose control in db/db mice as determined by GTT and ITT tests. Gene expression analysis showed that NaB inhibited cytokines and immunological markers including CD68, Interferon-γ and Mcp in adipose tissues in db/db mice. Moreover, NaB inhibited cytokine releasing in 3T3-L1 adipocytes treated with TNF-α. Further analysis of inflammation pathway showed that NLRP3 was activated in db/db mice, which was efficiently inhibited by NaB treatment. Our data suggest that inhibition of obesity-induced inflammation alleviates IR, and NaB might be a potential anti-inflammatory agent for obesity. PMID:26234821

  19. Sodium butyrate alleviates adipocyte inflammation by inhibiting NLRP3 pathway

    PubMed Central

    Wang, Xukai; He, Gang; Peng, Yan; Zhong, Weitian; Wang, Yan; Zhang, Bo

    2015-01-01

    Insulin resistance (IR) is a common feature of Type II diabetes, metabolic disorders, hypertension and other vascular diseases. Recent studies showed that obesity-induced inflammation may be critical for IR. To investigate the anti-inflammatory effect of sodium butyrate (NaB) on obesity-induced inflammation, the db/db mice were intraperitoneally injected with NaB for 6 weeks. Glucose control was evaluated by glucose tolerance test (GTT) and insulin tolerance test (ITT). Adipose tissue was harvested for gene expression analysis. 3T3-L1 adipocytes were treated with Tnf-α to mimic the inflammatory state and gene expression was detected by realtime PCR and Western blotting. Our results showed that NaB treatment improved glucose control in db/db mice as determined by GTT and ITT tests. Gene expression analysis showed that NaB inhibited cytokines and immunological markers including CD68, Interferon-γ and Mcp in adipose tissues in db/db mice. Moreover, NaB inhibited cytokine releasing in 3T3-L1 adipocytes treated with TNF-α. Further analysis of inflammation pathway showed that NLRP3 was activated in db/db mice, which was efficiently inhibited by NaB treatment. Our data suggest that inhibition of obesity-induced inflammation alleviates IR, and NaB might be a potential anti-inflammatory agent for obesity. PMID:26234821

  20. Effects of Sodium Butyrate on Methamphetamine-Sensitized Locomotor Activity

    PubMed Central

    Harkness, John H.; Hitzemann, Robert J.; Edmunds, Stephanie; Phillips, Tamara J.

    2012-01-01

    Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, vehicle or NaB (630 mg/kg, intraperitoneally) was administered 30 min prior to MA challenge in mice treated repeatedly with MA (10 days of 2 mg/kg MA) or saline (10 days), and then locomotor response to MA challenge was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30 min prior to each MA exposure (10 days of 1 or 2 mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, appeared to increase striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior. PMID:23137698

  1. The proteomic study of sodium butyrate antiproliferative/cytodifferentiation effects on K562 cells.

    PubMed

    Grebenová, Dana; Kuzelová, Katerina; Pluskalová, Michaela; Peslová, Gabriela; Halada, Petr; Hrkal, Zbynek

    2006-01-01

    Employing methods of cell biology and proteome analysis tools, we examined effects of an inhibitor of histone deacetylases, sodium butyrate (SB), on the proliferation/differentiation characteristics of chronic myelogenous leukemia (CML)-derived cells K562. SB suppressed proliferation of K562 cells by inducing cell cycle arrest in G1 phase, which was followed by their transition to G0 phase (decrease of Ki-67 antigen-positive cells) and erythroid differentiation (increased glycophorin A expression and synthesis of hemoglobins). Neither terminal apoptosis (low counts of TUNEL-positive cells) nor necrosis (moderate counts of propidium iodide-positive cells) occurred. Importantly, SB attenuated protein expression of CML-related chimeric kinase BCR-ABL that is responsible for the deregulated proliferation of CML cells. The proteomic analysis (2-D electrophoresis combined with MALDI-TOF mass spectrometry and/or Western blotting) revealed several proteins that were differentially expressed or their mobility was altered due to butyrate treatment, namely, HSP90, HSP70, p23, cyclophilin A (CYPA), prefoldin2 (PFD2) and alpha-, gamma-, epsilon-human globin chains. Perturbation of HSP90 multichaperone complex of which BCR-ABL is the client protein is presumably a cause of BCR-ABL suppression. Changes in other proteins with chaperonic functions, CYPA and PFD2, may reflect SB antiproliferative and cytodifferentiation effects. PMID:16978890

  2. Regulation of T-type calcium channel expression by sodium butyrate in prostate cancer cells.

    PubMed

    Weaver, Erika M; Zamora, Francis J; Puplampu-Dove, Yvonne A; Kiessu, Ezechielle; Hearne, Jennifer L; Martin-Caraballo, Miguel

    2015-02-15

    Several cellular mechanisms contribute to the neuroendocrine differentiation of prostate cancer cells, including exposure to sodium butyrate (NaBu), a naturally occurring salt of the short chain fatty acid n-butyric acid. NaBu belongs to a class of histone deacetylase inhibitors with potential anticancer function. T-type calcium channel expression constitutes an important route for calcium influx in tumor cells that may trigger changes in cell proliferation and differentiation. In this work we investigated the role NaBu on the differentiation of lymph node carcinoma of the prostate (LNCaP) cells and its effect on T-type Ca(2+) channel expression. NaBu stimulates the morphological and molecular differentiation of LNCaP cells. Stimulation of LNCaP cells with NaBu evokes a significant increase in the expression of the Cav3.2 T-type channel subunits. Furthermore, the increased Cav3.2 expression promotes membrane insertion of T-type Ca(2+) channels capable of generating fast inactivating Ca(2+) currents, sensitive to 100μM Ni(2+) ions. Inhibition of T-type Ca(2+) channel function reduces the outgrowth of neurite-like processes in LNCaP cells. NaBu-evoked expression of T-type Ca(2+) channels is also involved in the regulation of cell viability. Inhibition of T-type Ca(2+) channels causes a significant reduction in the viability of LNCaP cells treated with 1mM NaBu, suggesting that Ca(2+) influx via T-type channels can promote cell proliferation. However, increased expression of T-type Ca(2+) channels enhanced the cytotoxic effect of thapsigargin and paclitaxel on cell proliferation. These findings demonstrate that NaBu stimulates T-type Ca(2+) channel expression, thereby regulating both the morphological differentiation and growth of prostate cancer cells. PMID:25557765

  3. Performance of cellulose acetate butyrate membranes in hyperfiltration of sodium chloride and urea feed solution

    NASA Technical Reports Server (NTRS)

    Wydeven, T.; Leban, M.

    1973-01-01

    Cellulose acetate butyrate (CAB) membranes are shown to give high salt and urea rejection with water flux of about 3 gallons/sq ft per day at 600 psig. Membranes prepared from a formulation containing glyoxal show a significant increase in flux and decrease in salt and urea rejection with drying time. Zero drying time gives maximum urea and salt rejection and is therefore most suitable for hyperfiltration of sodium chloride and urea feed solution.

  4. Melatonin and its precursors in Y79 human retinoblastoma cells: Effect of sodium butyrate

    NASA Technical Reports Server (NTRS)

    Deng, Mei Hua; Coviella, Ignacio Lopez G.; Lynch, Harry J.; Wurtman, Richard J.

    1991-01-01

    The release of melatonin and the production of its precursors, S-hydroxytryptophan and serotonin, in cultured Y79 human retinoblastoma cells were studied. This biosynthetic capability was found to be dependent on cell differentiation, which was initiated by culturing Y79 cells for 7 days in dishes coated with poly-D-lysine to promote cell adhesion to the surface of the culture dishes. Differentiation was further induced by exposing the cell monolayer to sodium butyrate (3 mM) for 3 days. This protocol dramatically increased the release of melatonin, and the syntheses of 5-hydroxytryptophan and serotonin in response to forskolin stimulation. Exposure to dopamine (10 micro-M) or L-DOPA (100 micro-M) markedly diminished the forskolin-stimulated release of melatonin, as well as the production of 5-hydroxytryptophan and serotonin. These observations indicate that Y79 cells represent a primitive cell line which, following appropriate differentiation (e.g. treatment with sodium butyrate) can display biochemical characteristics similar to those of the human retina. Moreover, serotonin synthesis and melatonin release appear to be coupled in Y79 cells. The inhibition of melatonin release by dopamine supports the hypothesis that in these cells, melatonin and dopamine are components of a retinal feedback loop.

  5. Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial

    PubMed Central

    2012-01-01

    Background Treatment of shigellosis in rabbits with butyrate reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. Here, we aimed to evaluate whether butyrate can be used as an adjunct to antibiotics in the treatment of shigellosis in patients. Methods A randomized, double-blind, placebo-controlled, parallel-group designed clinical trial was conducted. Eighty adult patients with shigellosis were randomized to either the Intervention group (butyrate, n = 40) or the Placebo group (normal saline, n = 40). The Intervention group was given an enema containing sodium butyrate (80 mM), twice daily for 3 days, while the Placebo group received the same dose of normal saline. The primary endpoint of the trial was to assess the efficacy of butyrate in improving clinical, endoscopic and histological features of shigellosis. The secondary endpoint was to study the effect of butyrate on the induction of antimicrobial peptides in the rectum. Clinical outcomes were assessed and concentrations of antimicrobial peptides (LL-37, human beta defensin1 [HBD-1] and human beta defensin 3 [HBD-3]) and pro-inflammatory cytokines (interleukin-1β [IL-1β] and interleukin-8 [IL-8]) were measured in the stool. Sigmoidoscopic and histopathological analyses, and immunostaining of LL-37 in the rectal mucosa were performed in a subgroup of patients. Results Compared with placebo, butyrate therapy led to the early reduction of macrophages, pus cells, IL-8 and IL-1β in the stool and improvement in rectal histopathology. Butyrate treatment induced LL-37 expression in the rectal epithelia. Stool concentration of LL-37 remained significantly higher in the Intervention group on days 4 and 7. Conclusion Adjunct therapy with butyrate during shigellosis led to early reduction of inflammation and enhanced LL-37 expression in the rectal epithelia with prolonged release of LL-37 in the stool. Trial Registration Clinical

  6. Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells.

    PubMed

    Roy, Jeremy; Denovan-Wright, Eileen M; Linsdell, Paul; Cowley, Elizabeth A

    2006-11-01

    Cystic fibrosis (CF) is caused by genetic mutations that lead to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The most common mutation, DeltaF508, causes inefficient trafficking of mutant CFTR protein from the endoplasmic reticulum to the cell membrane. Therapeutic efforts have been aimed at increasing the level of DeltaF508-CFTR protein in the membrane using agents such as sodium butyrate. In this study, we investigated the effects of culturing a human airway epithelial cell line, Calu-3, in the presence of 5 mM sodium butyrate. Within 24 h, butyrate exposure caused a significant decrease in the basal, as well as Ca(2+)-activated, anion secretion by Calu-3 cell monolayers, determined by the change in transepithelial short-circuit current in response to the Ca(2+)-elevating agent thapsigargin. The secretory response to 1-ethyl-2-benzimidazolinone, an activator of the basolateral Ca(2+)-activated K(+) channel KCNN4, was similarly reduced by butyrate treatment. Quantitative PCR revealed that these functional effects were associated with dramatic decreases in mRNA for both KCNN4 and CFTR. Furthermore, the KCNQ1 K(+) channel was upregulated after butyrate treatment. We suggest that prolonged exposure to sodium butyrate downregulates the expression of both KCNN4 and CFTR, leading to a functional loss of Ca(2+)-activated anion secretion. Thus, butyrate may inhibit, rather than stimulate, the anion secretory capacity of human epithelial cells that express wild-type CFTR, particularly in tissues that normally exhibit robust Ca(2+)-activated secretion. PMID:17047984

  7. Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH).

    PubMed

    Jin, Cheng Jun; Sellmann, Cathrin; Engstler, Anna Janina; Ziegenhardt, Doreen; Bergheim, Ina

    2015-12-14

    Overnutrition, insulin resistance and an impaired intestinal barrier function are discussed as critical factors in the development of non-alcoholic fatty liver disease. Not only butyrate-producing probiotics as well as supplementation of sodium butyrate (SoB) have been suggested to bear protective effects on liver damage of various aetiologies. However, whether an oral consumption of SoB has a protective effect on Western-style diet (WSD)-induced non-alcoholic steatohepatitis (NASH) and if so molecular mechanism involved has not yet been determined. Eight-week-old C57BL/6J mice were pair-fed either a liquid control or WSD±0·6 g/kg body weight SoB. After 6 weeks, markers of liver damage, inflammation, toll-like receptor (TLR)-4 signalling, lipid peroxidation and glucose as well as lipid metabolism were determined in the liver tissue. Tight junction protein levels were determined in the duodenal tissue. SoB supplementation had no effects on the body weight gain or liver weight of WSD-fed mice, whereas liver steatosis and hepatic inflammation were significantly decreased (e.g. less inflammatory foci and neutrophils) when compared with mice fed only a WSD. Tight junction protein levels in duodenum, hepatic mRNA expression of TLR-4 and sterol regulatory element-binding protein 1c were altered similarly in both WSD groups when compared with controls, whereas protein levels of myeloid differentiation primary response gene 88, inducible nitric oxide synthase, 4-hydroxynonenal protein adducts and F4/80 macrophages were only significantly induced in livers of mice fed only the WSD. In summary, these data suggest that an oral supplementation of SoB protects mice from inflammation in the liver and thus from the development of WSD-induced NASH. PMID:26450277

  8. Control of placental alkaline phosphatase gene expression in HeLa cells: induction of synthesis by prednisolone and sodium butyrate

    SciTech Connect

    Chou, J.Y.; Takahashi, S.

    1987-06-16

    HeLa S/sub 3/ cells produce an alkaline phosphatase indistinguishable from the enzyme from human term placenta. The phosphatase activity in these cells was induced by both prednisolone and sodium butyrate. Both agents stimulated de novo synthesis of the enzyme. The increase in phosphatase activity paralleled the increase in immunoactivity and biosynthesis of placental alkaline phosphatase. The fully processed phosphatase monomer in control, prednisolone-treated or butyrate-treated cells was a 64.5 K polypeptide, measured by both incorporation of L-(/sup 35/S)methionine into enzyme protein and active-site labeling. The 64.5K polypeptide was formed by the incorporation of additional N-acetylneuraminic acid moieties to a precursor polypeptide of 61.5K. However, this biosynthetic pathway was identified only in butyrate-treated cells. In prednisolone-treated cells, the processing of 61.5K to 64.5K monomer was accelerated, and the presence of the 61.5 precursor could only be detected by either neuraminidase or monensin treatment. Phosphatase mRNA which comigrated with the term placental alkaline phosphatase mRNA of 2.7 kilobases was induced in the presence of either prednisolone or butyrate. Alkaline phosphatase mRNA is untreated HeLa S/sub 3/ cells migrated slightly faster than the term placental alkaline phosphatase mRNA. Butyrate also induced a second still faster migrating alkaline phosphatase mRNA. Both prednisolone and butyrate increased the steady-state levels of placental alkaline phosphatase mRNA. The data indicate that the increase in phosphatase mRNA by prednisolone and butyrate resulted in the induction of alkaline phosphatase activity and biosynthesis in HeLa S/sub 3/ cells. Furthermore, both agents induced the expression of different alkaline phosphatase gene transcripts without altering its protein product.

  9. Effects of Early Intervention with Sodium Butyrate on Gut Microbiota and the Expression of Inflammatory Cytokines in Neonatal Piglets.

    PubMed

    Xu, Jumei; Chen, Xue; Yu, Shuiqing; Su, Yong; Zhu, Weiyun

    2016-01-01

    Butyrate in the gut of animals has potential properties including regulating the innate immune, modulating the lipid metabolism, and protecting gut healthy. So far, only limited information on the impact of butyrate on the neonatal is available. This study aimed to investigate effects of oral administration of sodium butyrate (SB) on gut microbiota and the expression of inflammatory cytokine in neonatal piglets. Ten litters of crossbred newborn piglets were randomly allocated to the SB and control (CO) groups, each group consisted of five litters (replicates). Piglets in the SB group were orally administrated with 7 to 13 ml sodium butyrate solution (150 mmol/l) per day from the age of 1 to 7 days, respectively; piglets in the CO group were treated with the same dose of physiological saline. On days 8 and 21 (of age), gut digesta and tissues were collected for the analysis of microbiota, butyrate concentration and gene expression of inflammatory cytokine. Results showed that there was no difference in the butyrate concentration in the gut of piglets on days 8 and 21 between two groups. Real-time PCR assay showed that SB had no effect on the numbers of total bacteria in the stomach, ileum, and colon. MiSeq sequencing of the V3-V4 region of the 16S rRNA gene revealed that SB increased the richness in the stomach and colon, and the diversity of colonic microbiota on day 8 (P < 0.05). Genera Acinetobacter, Actinobacillus, Facklamia, Globicatella, Kocuria, Rothia, unclassified Leptotrichiaceae, unclassified Neisseriaceae, and unclassified Prevotellaceae in the stomach were increased in relative abundance by SB treatment, whereas the abundances of Lactobacillus decreased on day 8 (P < 0.05). At the genus and operational taxonomic unit (OTU) levels, SB had low impact on bacterial community in the ileum and colon on days 8 and 21. SB treatment decreased the expression of IL-6, IL-8, IFN-γ, IL-10, TGF-β, and histone deacetylase 1 (HDAC1) in the ileum of piglets on day 8

  10. Melatonin and its precursors in Y79 human retinoblastoma cells - Effect of sodium butyrate

    NASA Technical Reports Server (NTRS)

    Deng, Mei H.; Lopez G.-Coviella, Ignacio; Lynch, Harry J.; Wurtman, Richard J.

    1991-01-01

    We studied the release of melatonin and the production of its precursors, 5-hydroxytryptophan and serotonin, in cultured Y79 human retinoblastoma cells. This biosynthetic capability was found to be dependent on cell differentiation, which was initiated by culturing Y79 cells for 7 days in dishes coated with poly-D-lysine to promote cell adhesion to the surface of the culture dishes. Differentiation was further induced by exposing the cell monolayer to sodium butyrate (3 mM) for three days. This protocol dramatically increased the release of melatonin, and the syntheses of 5-hydroxytryptophan and serotonin in response to forskolin stimulation. Exposure to dopamine or L-DOPA markedly diminished the forskolin-stimulated release of melatonin, as well as the production of 5-hydroxytryptophan and serotonin. These observations indicate that Y79 cells represent a primitive cell line which, following appropriate differentiation can display biochemical characteristics similar to those of the human retina. Moreover, serotonin synthesis and melatonin release appear to be coupled in Y79 ceils.

  11. Effect of feeding sodium butyrate in the late finishing period on Salmonella carriage, seroprevalence, and growth of finishing pigs.

    PubMed

    Walia, Kavita; Argüello, Hector; Lynch, Helen; Leonard, Finola C; Grant, Jim; Yearsley, Dermot; Kelly, Sinead; Duffy, Geraldine; Gardiner, Gillian E; Lawlor, Peadar G

    2016-09-01

    Pork is an important source of human salmonellosis and low-cost on-farm control measures may provide a useful element in reducing the prevalence of this pathogen in food. This study investigated the effectiveness of dietary supplementation with sodium butyrate administered to finisher pigs for ∼4-weeks prior to slaughter to control Salmonella shedding on highly contaminated farms. Two trials (A and B) were conducted on two commercial pig farms, which had a history of high Salmonella seroprevalence. In both trials, pens (14 pens of 12 pigs/pen in Trial A and 12 pens of 12-17 pigs/pen in Trial B) were randomly assigned to a control (finisher feed without additive) or a treatment group (the same feed with 3kg sodium butyrate/t) for 24-28days, depending on the trial. Faeces were collected from each pig on days 0, 12 and 24/28, and blood, caecal digesta and ileocaecal/mesenteric lymph nodes were collected from the slaughterhouse. Pigs were weighed at the start and end of the trials, feed intake was recorded, and carcass quality parameters were recorded at slaughter. In Trial A, Salmonella shedding was reduced in the treatment compared to the control group at the end of the trial (30% versus 57% probability of detecting Salmonella in faeces, respectively; p<0.001). This reflected the serology results, with detection of a lower seroprevalence in the treatment compared to the control group using the 20% optical density cut-off (69.5% versus 89%; p=0.001). However, no effect on faecal shedding or seroprevalance was observed in Trial B, which may be explained by the detection of a concomitant infection with Lawsonia intracellularis. No significant differences in Salmonella recovery rates were observed in the caecal digesta or lymph nodes in either trial. Furthermore, feed intake, weight gain, and feed conversion efficiency (FCE) did not differ between groups (p>0.05) in either trial. Numerical improvements in weight gain and FCE were found with sodium butyrate treatment

  12. Effect of sodium butyrate supplementation in milk replacer and starter diet on rumen development in calves.

    PubMed

    Gorka, P; Kowalski, Z M; Pietrzak, P; Kotunia, A; Kiljanczyk, R; Flaga, J; Holst, J J; Guilloteau, P; Zabielski, R

    2009-10-01

    Rumen development is an important factor determining early solid feed intake and performance in cattle. A popular trend towards early weaning of newborn dairy calves necessitated looking for ways of accelerating the gastrointestinal tract (GIT) development. The present study aimed to determine the effect of sodium butyrate (NaB) supplementation in milk replacer and starter diet on rumen development in rearing calves. Fourteen bull calves (5-day-old) were randomly allocated to two groups: Control (C) and NaB. The later received 0.3 % NaB in milk replacer and starter diet. Animals were in experiment up to age of 26 days. Addition of NaB to milk replacer and starter diet had no effect on daily growth rate, but reduced the weight loss observed in C calves in first 11 days of age. Additionally, the NaB calves weighed more at the end of the study and tended to have higher growth rate in the whole trial period (P<0.15). The NaB calves showed a tendency toward higher reticulorumen weight (P=0.13) and higher reticulorumen weight expressed as a percent of whole stomach weight (P=0.02) as compared to control. Histometry analysis indicated larger rumen papillae length and width (P<0.01) in NaB group, and no change in muscle layer thickness, as compared to control. Plasma glucagon-like peptide-2 relative increase was higher in NaB group than in C group, and may be involved in rumen development. In conclusion, supplementation of the diet (milk replacer and starter diet) with NaB may enhance rumen development in neonatal calves. PMID:19996481

  13. Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice

    PubMed Central

    Sun, Jing; Wang, Fangyan; Li, Haixiao; Zhang, Huiqing; Jin, Jiangtao; Chen, Wenqian; Pang, Mengqi; Yu, Junjie; He, Yiwen; Liu, Jiaming; Liu, Chunfeng

    2015-01-01

    Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect. PMID:26064905

  14. Management of traveller's diarrhoea with a combination of sodium butyrate, organic acids, and A-300 silicon dioxide

    PubMed Central

    Mackiewicz, Jacek; Wejman-Matela, Anna; Krokowicz, Piotr; Drews, Michal; Banasiewicz, Tomasz

    2014-01-01

    Introduction Traveller's diarrhoea (TD), defined by UNICEF/WHO as three or more unformed stools with or without other symptoms, imposes a considerable burden on travellers from developed countries. Various efforts have focused on decreasing the prevalence and severity of this condition. Aim To assess the efficacy of a combination of sodium butyrate, organic acids, and A-300 silicon dioxide in treatment providing symptomatic relief of TD. Material and methods The study was conducted in accordance with a protocol presented to the Bioethical committee of Poznan University of Medical Sciences. A total of 278 patients travelling to countries with higher risk of diarrhoea for at least 10 days were divided into a study arm being administered, in case of TD, a combination of sodium butyrate, organic acids, and A-300 silicon dioxide (n = 139) and a placebo arm (n = 139) with placebo administration. Results Forty-seven patients completed the study (22 in the study arm and 25 in the placebo arm). The diarrhoea occurrence after initiation of treatment at first symptoms was significantly lower in the study arm as compared to the placebo arm (9% vs. 36%, p = 0.041). Also, subjects from the study arm more frequently reported that the regimen administered had been efficient for their symptoms in comparison to the placebo arm (72.7% vs. 32%, p = 0.008). No adverse effects of the administered medication were noted during the study. Conclusions Sodium butyrate, organic acids, and A-300 silicon dioxide can be successful in decreasing symptoms of TD. Because of its efficacy and lack of observed side effects it has a strong potential in the treatment of patients with TD. PMID:25396003

  15. All-Trans Retinoic Acid and Sodium Butyrate Enhance Natriuretic Peptide Receptor A Gene Transcription: Role of Histone Modification

    PubMed Central

    Kumar, Prerna; Periyasamy, Ramu; Das, Subhankar; Neerukonda, Smitha; Mani, Indra

    2014-01-01

    The objective of the present study was to delineate the mechanisms of GC-A/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) expression in vivo. We used all-trans retinoic acid (ATRA) and histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) to examine the expression and function of Npr1 using gene-disrupted heterozygous (1-copy; +/−), wild-type (2-copy; +/+), and gene-duplicated heterozygous (3-copy; ++/+) mice. Npr1+/− mice exhibited increased renal HDAC and reduced histone acetyltransferase (HAT) activity; on the contrary, Npr1++/+ mice showed decreased HDAC and enhanced HAT activity compared with Npr1+/+ mice. ATRA and NaBu promoted global acetylation of histones H3-K9/14 and H4-K12, reduced methylation of H3-K9 and H3-K27, and enriched accumulation of active chromatin marks at the Npr1 promoter. A combination of ATRA-NaBu promoted recruitment of activator-complex containing E26 transformation–specific 1, retinoic acid receptor α, and HATs (p300 and p300/cAMP response element–binding protein-binding protein–associated factor) at the Npr1 promoter, and significantly increased renal NPRA expression, GC activity, and cGMP levels. Untreated 1-copy mice showed significantly increased systolic blood pressure and renal expression of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) compared with 2- and 3-copy mice. Treatment with ATRA and NaBu synergistically attenuated the expression of α-SMA and PCNA and reduced systolic blood pressure in Npr1+/− mice. Our findings demonstrate that epigenetic upregulation of Npr1 gene transcription by ATRA and NaBu leads to attenuation of renal fibrotic markers and systolic blood pressure in mice with reduced Npr1 gene copy number, which will have important implications in prevention and treatment of hypertension-related renal pathophysiological conditions. PMID:24714214

  16. Comparative effects of sodium butyrate and flavors on feed intake of lactating sows and growth performance of piglets.

    PubMed

    Wang, Jun; Yang, Mei; Xu, Shengyu; Lin, Yan; Che, Lianqiang; Fang, Zhengfeng; Wu, De

    2014-06-01

    We examined the effects of sodium butyrate and flavors on feed intake of lactating sows and growth performance of piglets. A total of 52 primiparous sows (Large White) were randomly divided into four treatments (n = 13) and received 6 g/kg sodium butyrate (SB), fruit-milk (FM) flavor and fruit-milk-anise (FMA) flavor with pair feeding to the mothers receiving the control diet. The feeding trial lasted for 29 days, including 21 days of nursing and 8 days of post-weaning period, respectively. The nursing and weaning piglets received creep diets with the same flavor or SB supplement as their mother. The results showed that FMA flavor increased average daily feed intake (ADFI) of lactating sows (P < 0.01), as well as improved litter weight gain (P = 0.05) and ADFI (P < 0.01) of nursing pigs among treatments. Indeed, greater ADFI and average daily gain of weaning piglets for the initial 8 days after weaning was observed in the FMA group compared with those in the control group (P < 0.01). These findings indicated that adding FMA flavor was superior to SB for increasing feed intake of lactating sows and improving growth performance of piglets. PMID:24773759

  17. Thermotropic ionic liquid crystals. II. 1H and 23Na NMR study of the smectic mesophase of molten sodium n-butyrate and sodium isovalerate

    NASA Astrophysics Data System (ADS)

    Bonekamp, J. E.; Eguchi, T.; Plesko, S.; Jonas, J.

    1983-08-01

    The 1H and 23Na NMR studies of smectic ionic mesophases of molten sodium n-butyrate and sodium isovalerate are reported over the temperature range of the stability of the liquid crystalline phases. The 1H spin-lattice relaxation times T1 at ν0=9.2, 24.3, and 60 MHz for the anions of both the systems are interpreted in terms of diffusion intermolecular relaxation mechanism. The predicted anion diffusion coefficients are in agreement with those measured directly by spin-echo technique and indicate that the anion diffuses rapidly. In contrast to the T1 relaxation mechanism the results obtained for the proton relaxation times in the rotating coordinate frame T1ρ indicate that the order-fluctuation relaxation mechanism determines the frequency dispersion of T1ρ. The analysis of the T1ρ data provides an approximate measure of the order parameter S as a function of temperature. Fourier transform spectra of the 23Na transitions show that the electric field gradient (EFG) at the Na+ ion is nonaveraged and of such a strength as to produce a second order quadrupole effect in the spectra of the central transition. From the first-order splitting, the quadrupole coupling constant (QCC) is obtained as a function of temperature. The gradual temperature change of QCC demonstrates that only a single liquid crystalline phase exists over the temperature interval of the stability of the smectic mesophase. Using approximate analysis the correlation time τc for the EFG fluctuation is obtained from the 23Na T1 data for the melts of both sodium n-butyrate and sodium isovalerate.

  18. Study of liquid-solid catalytic reaction of epichlorohydrin with sodium butyrate in the presence of tetrabutylammonium bromide

    NASA Astrophysics Data System (ADS)

    Huang, Qiang; Meng, Qingyi; Ban, Chunlan; Zhang, Rui; Gao, Yingyu

    2016-08-01

    The liquid-solid catalytic reaction of epichlorohydrin and sodium butyrate with tetrabutylammonium bromide as a phase transfer catalyst was studied in this paper. The shrinking core model was applied. The analysis of the reaction based on the kinetic model showed a reaction-controlled regime at temperatures varying from 90 to 100°C. The exterior diffusivity was removed between 300 and 400 rpm. The internal diffusivity was removed when the particle size was 2 × 10-4 m. Reaction rate constants were calculated at different temperatures. The correlation was obtained when the proposed kinetic model was applied to all the experimental data for predictive evaluations and the activation energy was 37.01 kJ mol-1.

  19. Thalidomide is more efficient than sodium butyrate in enhancing GATA-1 and EKLF gene expression in erythroid progenitors derived from HSCs with β-globin gene mutation

    PubMed Central

    Jalali Far, Mohammad Ali; Dehghani Fard, Ali; Hajizamani, Saiedeh; Mossahebi-Mohammadi, Majid; Yaghooti, Hamid; Saki, Najmaldin

    2016-01-01

    Background: Efficient induction of fetal hemoglobin (HbF) is considered as an effective therapeutic approach in beta thalassemia. HbF inducer agents can induce the expression of γ-globin gene and produce high levels of HbF via different epigenetic and molecular mechanisms. Thalidomide and sodium butyrate are known as HbF inducer drugs. Material and methods: CD133+ stem cells were isolated from umbilical cord blood of a newborn with minor β-thalassemia in order to evaluate the effects of these two drugs on the in vitro expression of GATA-1 and EKLF genes as erythroid transcription factors. CD133+ stem cells were expanded and differentiated into erythroid lineage and then treated with thalidomide and sodium butyrate and finally analyzed by quantitative real-time PCR. Statistical analysis was performed using student’s t-test by SPSS software. Results: Thalidomide and sodium butyrate increased GATA-1 and EKLF gene expression, compared to the non-treated control (P<0.05). Conclusion: Thalidomide was more efficient than sodium butyrate in augmenting expression of GATA-1 and EKLF genes. It seems that GATA-1 and EKLF have crucial roles in the efficient induction of HbF by thalidomide. PMID:27047649

  20. Glucocorticoid receptor-dependent disruption of a specific nucleosome on the mouse mammary tumor virus promoter is prevented by sodium butyrate.

    PubMed Central

    Bresnick, E H; John, S; Berard, D S; LeFebvre, P; Hager, G L

    1990-01-01

    Our laboratory has previously developed cell lines derived from mouse NIH 3T3 fibroblasts and C127 mammary tumor cells that stably express mouse mammary tumor virus (MMTV) long terminal repeat fusion genes in bovine papillomavirus-based episomes. Glucocorticoid hormone strongly activates transcription from episomes and induces the disruption of a single nucleosome in an array of phased nucleosomes on the MMTV promoter. Sodium butyrate inhibits the glucocorticoid hormone-dependent development of a nuclease-hypersensitive site that is due to the displacement of this nucleosome, and inhibits induction of RNA transcripts from episomes. Saturation binding studies show that butyrate treatment does not significantly affect the amount or the hormone-binding affinity of the glucocorticoid receptor. In a transient transfection assay, glucocorticoid hormone can activate transcription from a MMTV long terminal repeat-driven luciferase gene construct equivalently in untreated and butyrate-treated cells, indicating that the soluble factors necessary for transactivation of the MMTV promoter are unaffected by butyrate. The differential effect of butyrate on the induction of stable chromatin templates and transiently expressed plasmids suggests that butyrate prevents nucleosome displacement and represses transcription by inducing a modification of chromatin. Images PMID:2160080

  1. Effects of Sodium Butyrate and Its Synthetic Amide Derivative on Liver Inflammation and Glucose Tolerance in an Animal Model of Steatosis Induced by High Fat Diet

    PubMed Central

    Mattace Raso, Giuseppina; Simeoli, Raffaele; Russo, Roberto; Iacono, Anna; Santoro, Anna; Paciello, Orlando; Ferrante, Maria Carmela; Canani, Roberto Berni; Calignano, Antonio; Meli, Rosaria

    2013-01-01

    Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. Insulin resistance (IR) appears to be critical in its pathogenesis. We evaluated the effects of sodium butyrate (butyrate) and its synthetic derivative N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA) in a rat model of insulin resistance and steatosis induced by high-fat diet (HFD). Methods After weaning, young male Sprague-Dawley rats were divided into 4 groups receiving different diets for 6 weeks: 1. control group (standard diet); 2. HFD; 3. HFD plus butyrate (20 mg/kg/die) and 4. HFD plus FBA (42.5 mg/Kg/die, the equimolecular dose of butyrate). Liver tissues of the rats were analyzed by Western blot and real-time PCR. Insulin resistance, liver inflammation and Toll-like pattern modifications were determined. Results Evaluation of these two preparations of butyrate showed a reduction of liver steatosis and inflammation in HFD fed animals. The compounds showed a similar potency in the normalisation of several variables, such as transaminases, homeostasis model assessment for insulin resistance index, and glucose tolerance. Both treatments significantly reduced hepatic TNF-α expression and restored GLUTs and PPARs, either in liver or adipose tissue. Finally, FBA showed a higher potency in reducing pro-inflammatory parameters in the liver, via suppression of Toll-like receptors and NF-κB activation. Conclusions Our results demonstrated a protective effect of butyrate in limiting molecular events underlying the onset of IR and NAFLD, suggesting a potential clinical relevance for this substance. In particular, its derivative, FBA, could represent an alternative therapeutic option to sodium butyrate, sharing a comparable efficacy, but a better palatability and compliance. PMID:23861927

  2. Butyrate: A dietary inhibitor of histone deacetylases and an epigenetic regulator

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The short-chain fatty acids (SCFAs) acetate, propionate and butyrate, also known as volatile fatty acids (VFA), are produced in the gastrointestinal tract by microbial fermentation. Consumption of dietary fibers has been shown to have positive metabolic health effects, such as increasing satiety, an...

  3. Effects of Sodium Butyrate Treatment on Histone Modifications and the Expression of Genes Related to Epigenetic Regulatory Mechanisms and Immune Response in European Sea Bass (Dicentrarchus Labrax) Fed a Plant-Based Diet

    PubMed Central

    Díaz, Noelia; Rimoldi, Simona; Ceccotti, Chiara; Gliozheni, Emi; Piferrer, Francesc

    2016-01-01

    Bacteria that inhabit the epithelium of the animals’ digestive tract provide the essential biochemical pathways for fermenting otherwise indigestible dietary fibers, leading to the production of short-chain fatty acids (SCFAs). Of the major SCFAs, butyrate has received particular attention due to its numerous positive effects on the health of the intestinal tract and peripheral tissues. The mechanisms of action of this four-carbon chain organic acid are different; many of these are related to its potent regulatory effect on gene expression since butyrate is a histone deacetylase inhibitor that play a predominant role in the epigenetic regulation of gene expression and cell function. In the present work, we investigated in the European sea bass (Dicentrarchus labrax) the effects of butyrate used as a feed additive on fish epigenetics as well as its regulatory role in mucosal protection and immune homeostasis through impact on gene expression. Seven target genes related to inflammatory response and reinforcement of the epithelial defense barrier [tnfα (tumor necrosis factor alpha) il1β, (interleukin 1beta), il-6, il-8, il-10, and muc2 (mucin 2)] and five target genes related to epigenetic modifications [dicer1(double-stranded RNA-specific endoribonuclease), ehmt2 (euchromatic histone-lysine-N-methyltransferase 2), pcgf2 (polycomb group ring finger 2), hdac11 (histone deacetylase-11), and jarid2a (jumonji)] were analyzed in fish intestine and liver. We also investigated the effect of dietary butyrate supplementation on histone acetylation, by performing an immunoblotting analysis on liver core histone extracts. Results of the eight-week-long feeding trial showed no significant differences in weight gain or SGR (specific growth rate) of sea bass that received 0.2% sodium butyrate supplementation in the diet in comparison to control fish that received a diet without Na-butyrate. Dietary butyrate led to a twofold increase in the acetylation level of histone H4 at

  4. Effects of Sodium Butyrate Treatment on Histone Modifications and the Expression of Genes Related to Epigenetic Regulatory Mechanisms and Immune Response in European Sea Bass (Dicentrarchus Labrax) Fed a Plant-Based Diet.

    PubMed

    Terova, Genciana; Díaz, Noelia; Rimoldi, Simona; Ceccotti, Chiara; Gliozheni, Emi; Piferrer, Francesc

    2016-01-01

    Bacteria that inhabit the epithelium of the animals' digestive tract provide the essential biochemical pathways for fermenting otherwise indigestible dietary fibers, leading to the production of short-chain fatty acids (SCFAs). Of the major SCFAs, butyrate has received particular attention due to its numerous positive effects on the health of the intestinal tract and peripheral tissues. The mechanisms of action of this four-carbon chain organic acid are different; many of these are related to its potent regulatory effect on gene expression since butyrate is a histone deacetylase inhibitor that play a predominant role in the epigenetic regulation of gene expression and cell function. In the present work, we investigated in the European sea bass (Dicentrarchus labrax) the effects of butyrate used as a feed additive on fish epigenetics as well as its regulatory role in mucosal protection and immune homeostasis through impact on gene expression. Seven target genes related to inflammatory response and reinforcement of the epithelial defense barrier [tnfα (tumor necrosis factor alpha) il1β, (interleukin 1beta), il-6, il-8, il-10, and muc2 (mucin 2)] and five target genes related to epigenetic modifications [dicer1(double-stranded RNA-specific endoribonuclease), ehmt2 (euchromatic histone-lysine-N-methyltransferase 2), pcgf2 (polycomb group ring finger 2), hdac11 (histone deacetylase-11), and jarid2a (jumonji)] were analyzed in fish intestine and liver. We also investigated the effect of dietary butyrate supplementation on histone acetylation, by performing an immunoblotting analysis on liver core histone extracts. Results of the eight-week-long feeding trial showed no significant differences in weight gain or SGR (specific growth rate) of sea bass that received 0.2% sodium butyrate supplementation in the diet in comparison to control fish that received a diet without Na-butyrate. Dietary butyrate led to a twofold increase in the acetylation level of histone H4 at

  5. Efficacy of the dietary histone deacetylase inhibitor butyrate alone or in combination with vitamin A against proliferation of MCF-7 human breast cancer cells.

    PubMed

    Andrade, F O; Nagamine, M K; Conti, A De; Chaible, L M; Fontelles, C C; Jordão Junior, A A; Vannucchi, H; Dagli, M L Z; Bassoli, B K; Moreno, F S; Ong, T P

    2012-09-01

    The combined treatment with histone deacetylase inhibitors (HDACi) and retinoids has been suggested as a potential epigenetic strategy for the control of cancer. In the present study, we investigated the effects of treatment with butyrate, a dietary HDACi, combined with vitamin A on MCF-7 human breast cancer cells. Cell proliferation was evaluated by the crystal violet staining method. MCF-7 cells were plated at 5 x 10(4) cells/mL and treated with butyrate (1 mM) alone or combined with vitamin A (10 µM) for 24 to 120 h. Cell proliferation inhibition was 34, 10 and 46% following treatment with butyrate, vitamin A and their combination, respectively, suggesting that vitamin A potentiated the inhibitory activities of butyrate. Furthermore, exposure to this short-chain fatty acid increased the level of histone H3K9 acetylation by 9.5-fold (Western blot), but not of H4K16, and increased the expression levels of p21WAF1 by 2.7-fold (Western blot) and of RARβ by 2.0-fold (quantitative real-time PCR). Our data show that RARβ may represent a molecular target for butyrate in breast cancer cells. Due to its effectiveness as a dietary HDACi, butyrate should be considered for use in combinatorial strategies with more active retinoids, especially in breast cancers in which RARβ is epigenetically altered. PMID:22714808

  6. Sodium Butyrate Ameliorates L-Arginine-Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress.

    PubMed

    Kanika, Gayathri; Khan, Sabbir; Jena, Gopabandhu

    2015-08-01

    Several reports indicated that histone deacetylases (HDACs) play a crucial role in inflammation and fibrogenesis. Sodium butyrate (SB) is a short-chain fatty acid having HDAC inhibition potential. The present study aimed to evaluate the protective effect of SB against L-arginine (L-Arg)-induced pancreatic fibrosis in Wistar rats. Pancreatic fibrosis was induced by twice intraperitoneal (i.p.) injections of 20% L-Arg (250 mg/100 g) at 2-h interval on day 1, 4, 7, and 10, whereas SB (800 mg/kg/day) was administrated for 10 days. At the end of the study, biochemical estimations, histological alterations, DNA damage, and the expression of various proteins were evaluated. Posttreatment of SB decreased L-Arg-induced oxidative and nitrosative stress, DNA damage, histological alterations, and fibrosis. Interestingly, posttreatment of SB significantly decreased the expression of α-smooth muscle actin, interleukin-1β, inducible nitric oxide synthase, and 3-nitrotyrosine. The present study demonstrated that posttreatment of SB alleviates L-Arg-induced pancreatic damage and fibrosis in rat. PMID:25774002

  7. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice.

    PubMed

    Li, Haixiao; Sun, Jing; Wang, Fangyan; Ding, Guoqiang; Chen, Wenqian; Fang, Renchi; Yao, Ye; Pang, Mengqi; Lu, Zhong-Qiu; Liu, Jiaming

    2016-07-01

    Sodium butyrate (SB) has been widely used to treat cerebral diseases. The aim of the present study is to examine the neuroprotective effects of SB on early TBI in mice and to explore the underlying mechanisms of these effects. TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS), brain oedema was measured by brain water content, and blood-brain barrier (BBB) permeability was evaluated by Evans blue (EB) dye extravasation. Neuronal injury was assessed by hematoxylin and eosin (H&E) staining and Fluoro-Jade C staining. The expression of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1), was analysed by western blotting and immunofluorescence. Our results showed that mice subjected to TBI exhibited worsened NSS, brain oedema, neuronal damage and BBB permeability. However, these were all attenuated by SB. Moreover, SB reversed the decrease in occludin and ZO-1 expression induced by TBI. These findings suggest that SB might attenuate neurological deficits, brain oedema, neuronal change and BBB damage, as well as increase occludin and ZO-1 expression in the brain to protect against TBI. The protective effect of SB may be correlated with restoring the BBB following its impairment. PMID:27017959

  8. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice.

    PubMed

    Subramanian, Umadevi; Kumar, Prerna; Mani, Indra; Chen, David; Kessler, Isaac; Periyasamy, Ramu; Raghavaraju, Giri; Pandey, Kailash N

    2016-07-01

    The objective of the present study was to examine the genetically determined differences in the natriuretic peptide receptor-A (NPRA) gene (Npr1) copies affecting the expression of cardiac hypertrophic markers, proinflammatory mediators, and matrix metalloproteinases (MMPs) in a gene-dose-dependent manner. We determined whether stimulation of Npr1 by all-trans retinoic acid (RA) and histone deacetylase (HDAC) inhibitor sodium butyric acid (SB) suppress the expression of cardiac disease markers. In the present study, we utilized Npr1 gene-disrupted heterozygous (Npr1(+/-), 1-copy), wild-type (Npr1(+/+), 2-copy), gene-duplicated (Npr1(++/+), 3-copy) mice, which were treated intraperitoneally with RA, SB, and a combination of RA/SB, a hybrid drug (HB) for 2 wk. Untreated 1-copy mice showed significantly increased heart weight-body weight (HW/BW) ratio, blood pressure, hypertrophic markers, including beta-myosin heavy chain (β-MHC) and proto-oncogenes (c-fos and c-jun), proinflammatory mediator nuclear factor kappa B (NF-κB), and MMPs (MMP-2, MMP-9) compared with 2-copy and 3-copy mice. The heterozygous (haplotype) 1-copy mice treated with RA, SB, or HB, exhibited significant reduction in the expression of β-MHC, c-fos, c-jun, NF-κB, MMP-2, and MMP-9. In drug-treated animals, the activity and expression levels of HDAC were significantly reduced and histone acetyltransferase activity and expression levels were increased. The drug treatments significantly increased the fractional shortening and reduced the systolic and diastolic parameters of the Npr1(+/-) mice hearts. Together, the present results demonstrate that a decreased Npr1 copy number enhanced the expression of hypertrophic markers, proinflammatory mediators, and MMPs, whereas an increased Npr1 repressed the cardiac disease markers in a gene-dose-dependent manner. PMID:27199456

  9. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

    PubMed Central

    Saldanha, Sabita N.; Kala, Rishabh; Tollefsbol, Trygve O.

    2014-01-01

    Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in colorectal cancer cells. PMID:24518414

  10. Sodium butyrate reduces insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat: A comparative study with metformin.

    PubMed

    Khan, Sabbir; Jena, Gopabandhu

    2016-07-25

    Recent evidences highlighted that histone deacetylases (HDACs) can deacetylate the histone, various transcription factors and regulatory proteins, which directly or indirectly affect glucose metabolism. The present study aimed to evaluate the comparative effects of sodium butyrate (NaB) and metformin on the glucose homeostasis, insulin-resistance, fat accumulation and dyslipidemia in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet (HFD) and low dose streptozotocin (STZ, 35 mg/kg). NaB at the doses of 200 and 400 mg/kg twice daily as well as metformin (as a positive control) 150 mg/kg twice daily for 10 consecutive weeks were administered by i.p. and oral route, respectively. NaB treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, dyslipidemia and gluconeogenesis, which are comparable to metformin treatment. Further, NaB treatment ameliorated the micro- and macro-vesicular steatosis in liver and fat deposition in brown adipose tissue, white adipose tissue (adipocytes hypertrophy) as well as pancreatic beta-cell damage. In the present study, both NaB and metformin inhibited the diabetes-associated increased HDACs activity, thereby increased the acetylation of histone H3 in liver. The present findings demonstrated that NaB and metformin reduced insulin-resistance, dyslipidemia, fat accumulation and gluconeogenesis thereby improved the glucose homeostasis in rat. Thus, NaB might be a promising molecule for the prevention and treatment of type-2 diabetes and dyslipidemia. PMID:27270450

  11. HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2.

    PubMed

    Wächtershäuser, A; Akoglu, B; Stein, J

    2001-07-01

    Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Butyrate, a short-chain fatty acid, reduces proliferation and induces differentiation of human colon cancer cells. The aim of our study was to determine the effect of mevastatin, alone or in combination with butyrate, on proliferation, the cell cycle and apoptosis in the human colorectal carcinoma cell line Caco-2. In this report we show that mevastatin combined with butyrate synergistically suppressed growth of Caco-2 cells in a dose- and time-dependent manner. In addition, incubation with mevastatin arrested cells in the G1 phase of the cell cycle after 24 h with a switch to the G2/M phase after 72 h. This was accompanied by a down-regulation of cyclin-dependent kinases (cdk) 4 and cdk 6 as well as cyclin D1, while cdk 2 and cyclin E protein levels remained unchanged during mevastatin treatment. Cell cycle inhibitors p21 and p27 were significantly upregulated by mevastatin. The proapoptotic properties of mevastatin were further enhanced by co-incubation with butyrate. Lastly, the effects of mevastatin could be reversed by addition of mevalonate, but not farnesyl- or geranylgeranylpyrophosphate, intermediate products of cholesterol synthesis, to the medium. These results suggest that HMG-CoA reductase inhibitors like mevastatin may enhance the antiproliferative effect of butyrate in colon cancer cells via induction of apoptosis together with a G0/G1 cell cycle arrest. PMID:11408350

  12. Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB.

    PubMed

    Joseph, Jeena; Mudduluru, Giridhar; Antony, Sini; Vashistha, Surabhi; Ajitkumar, Parthasarathi; Somasundaram, Kumaravel

    2004-08-19

    Histone deacetylase (HDAC) inhibitors induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (NaB), a short chain fatty acid, is a HDAC inhibitor and is produced in the colonic lumen as a consequence of microbial degradation of dietary fibers. In order to dissect out the mechanism of NaB-induced growth inhibition of cancer cells, we carried out expression profiling of a human lung carcinoma cell line (H460) treated with NaB using a cDNA microarray. Of the total 1728 genes analysed, there were 32 genes with a mean expression value of 2.0-fold and higher and 66 genes with a mean expression value 3.0-fold and lower in NaB-treated cells. For a few selected genes, we demonstrate that their expression pattern by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis is matching with the results obtained by microarray analysis. Closer view at the expression profile of NaB-treated cells revealed the downregulation of a total of 16 genes associated with cytokine signaling, in particular, interferon gamma (IFNgamma) pathway. In good correlation, NaB-pretreated cells failed to induce interferon regulatory factor 1, an INFgamma target gene, efficiently upon IFNgamma addition. These results suggest that NaB inhibits proinflammatory cytokine signaling pathway, thus providing proof of mechanism for its anti-inflammatory activity. We also found that NaB induced three genes, which are known metastatic suppressors, and downregulated 11 genes, which have been shown to promote metastasis. Upregulation of metastatic suppressor Kangai 1 (KAI1) by NaB in a time-dependent manner was confirmed by RT-PCR analysis. The differential regulation of metastasis-associated genes by NaB provides explanation for the anti-invasive properties of NaB. Therefore, our study presents new evidence for pathways regulated by NaB, thus providing evidence for the mechanism behind anti-inflammatory and antimetastatic activities of NaB. PMID:15318170

  13. Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

    SciTech Connect

    Saldanha, Sabita N.; Kala, Rishabh; Tollefsbol, Trygve O.

    2014-05-15

    Bioactive compounds are considered safe and have been shown to alter genetic and epigenetic profiles of tumor cells. However, many of these changes have been reported at molecular concentrations higher than physiologically achievable levels. We investigated the role of the combinatorial effects of epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, and sodium butyrate (NaB), a dietary microbial fermentation product of fiber, in the regulation of survivin, which is an overexpressed anti-apoptotic protein in colon cancer cells. For the first time, our study showed that the combination treatment induced apoptosis and cell cycle arrest in RKO, HCT-116 and HT-29 colorectal cancer cells. This was found to be regulated by the decrease in HDAC1, DNMT1, survivin and HDAC activity in all three cell lines. A G2/M arrest was observed for RKO and HCT-116 cells, and G1 arrest for HT-29 colorectal cancer cells for combinatorial treatment. Further experimentation of the molecular mechanisms in RKO colorectal cancer (CRC) cells revealed a p53-dependent induction of p21 and an increase in nuclear factor kappa B (NF-κB)-p65. An increase in double strand breaks as determined by gamma-H2A histone family member X (γ-H2AX) protein levels and induction of histone H3 hyperacetylation was also observed with the combination treatment. Further, we observed a decrease in global CpG methylation. Taken together, these findings suggest that at low and physiologically achievable concentrations, combinatorial EGCG and NaB are effective in promoting apoptosis, inducing cell cycle arrest and DNA-damage in CRC cells. - Highlights: • EGCG and NaB as a combination inhibits colorectal cancer cell proliferation. • The combination treatment induces DNA damage, G2/M and G1 arrest and apoptosis. • Survivin is effectively down-regulated by the combination treatment. • p21 and p53 expressions are induced by the combination treatment. • Epigenetic proteins DNMT1 and HDAC1 are

  14. Effect of method of delivery of sodium butyrate on maturation of the small intestine in newborn calves.

    PubMed

    Górka, P; Pietrzak, P; Kotunia, A; Zabielski, R; Kowalski, Z M

    2014-02-01

    The effect of sodium butyrate (SB) supplementation in milk replacer (MR), starter mixture (SM), or both on small intestine maturation in newborn calves was investigated. Twenty-eight male calves with a mean age of 5 (± 1) d were randomly allocated into 1 of 4 groups (7 animals per group) and fed (1) MR and SM, without SB (MR(-) and SM(-), respectively; MR(-)/SM(-)); (2) MR(-) and SM supplemented with SB encapsulated within triglyceride matrix (SM(+), 0.6% as fed; MR(-)/SM(+)); (3) MR supplemented with crystalline SB (MR(+), 0.3% as fed) and SM(-) (MR(+)/SM(-)); or (4) MR(+) and SM(+) (MR(+)/SM(+)). The MR was offered in amounts equal to 10% of initial body weight of the calf. The SM was blended with whole corn grain (50/50; wt/wt) and offered ad libitum as a starter diet. Calves were slaughtered at 26 d (± 1) of age and small intestine development was investigated. Treatment with MR(+) decreased villus height in the proximal jejunum and decreased villus height, crypt depth, and tunica mucosa thickness in the middle jejunum, whereas treatment with SM(+) tended to increase small intestine weight and crypt depth in the proximal jejunum, and increased villus height in the distal jejunum. In the duodenum, crypt depth and tunica mucosa thickness were greater for the MR(-)/SM(+) group compared with MR(-)/SM(-), MR(+)/SM(-), and MR(+)/SM(+) groups. In the ileum, crypt depth was less for MR(-)/SM(+) compared with MR(-)/SM(-). Supplementation with SB in both MR and SM enhanced cell proliferation and decreased apoptosis in the middle jejunum mucosa. Regarding brush border enzyme activities, addition of SB to MR increased lactase activity in the middle jejunum and maltase activity in the distal jejunum, and tended to increase lactase activity in the distal jejunum, aminopeptidase A activity in the middle jejunum and ileum, and aminopeptidase N activity in the ileum. In contrast, SM(+) increased dipeptidylpeptidase IV activity in the distal jejunum and tended to increase

  15. The impact of a specific blend of essential oil components and sodium butyrate in feed on growth performance and Salmonella counts in experimentally challenged broilers.

    PubMed

    Cerisuelo, A; Marín, C; Sánchez-Vizcaíno, F; Gómez, E A; de la Fuente, J M; Durán, R; Fernández, C

    2014-03-01

    Essential oils (EO) and short-chain fatty acids have potential antimicrobial activity in broilers. This study aimed to investigate the effect of a specific blend of EO and a combination of this blend of EO with sodium-butyrate on growth performance and Salmonella colonization in broilers. A total of 480 one-day-old male broilers were distributed into 5 treatments (8 pens per treatment and 12 birds per pen) and reared during 42 d in experimental conditions. Dietary treatments consisted of the addition of different doses of EO (0 mg/kg, control; 50 mg/kg, EO50 and 100 mg/kg, EO100) or a combination of EO with 1 g/kg of sodium-butyrate (B; EO50 + B, EOB50 and EO100 + B, EOB100) to a basal diet. All birds were orally infected with 10(8) cfu of Salmonella Enteritidis on d 7 of study. Individual BW and feed intake per pen were measured at arrival and on a weekly basis. The prevalence and enumeration of Salmonella in feces was determined per treatment at 72 h postinfection and on d 23 and 37 of study. At slaughter, cecal content and liver samples from 16 birds per treatment were cultured for Salmonella and cecal pH was measured. No differences were observed on growth performance among treatments. All fecal samples analyzed were positive for Salmonella from d 10 to the end of the rearing period. At slaughter, Salmonella contamination (positive samples) in cecum was lower in birds fed EOB50 compared with the other treatments (P < 0.05), whereas birds fed the control diet showed the highest colonization rates. The pH of the cecal content was not different among treatments. Thus, EO or its combination with sodium-butyrate did not affect growth performance. However, a clear effectiveness of these products was observed in Salmonella control, especially when low doses of EO were combined with sodium-butyrate (EOB50). PMID:24604853

  16. Use of Sodium Butyrate as an Alternative to Dietary Fiber: Effects on the Embryonic Development and Anti-Oxidative Capacity of Rats

    PubMed Central

    Lin, Yan; Fang, Zheng-feng; Che, Lian-qiang; Xu, Sheng-yu; Wu, De; Wu, Cai-mei; Wu, Xiu-qun

    2014-01-01

    In this study, we evaluated the effect of replacing dietary fiber with sodium butyrate on reproductive performance and antioxidant defense in a high fat diet during pregnancy by using a rat model. Eighty virgin female Sprague Dawley rats were fed one of four diets—(1) control diet (C group), (2) high fat + high fiber diet (HF group), (3) high-fat +5% sodium butyrate diet (SB group), and (4) HF diet + α-cyano-4-hydroxy cinnamic acid (CHC group)—intraperitoneally on days 8, 10, 12, 14, and 16 of gestation. SB and dietary fiber had similar effects on improving fetal number and reducing the abortion rate; however, the anti-oxidant capacity of maternal serum, placenta, and fetus was superior in the HF group than in the SB group. In comparison, CHC injection decreased reproductive performance and antioxidant defense. Both dietary fiber (DF) and SB supplementation had a major but different effect on the expression of anti-oxidant related genes and nutrient transporters genes. In summary, our data indicate that SB and DF showed similar effect on reproductive performance, but SB cannot completely replace the DF towards with respect to redox regulation in high-fat diet; and SB might influence offspring metabolism and health differently to DF. PMID:24852604

  17. Diabetic ketoacidosis, sodium glucose transporter-2 inhibitors and the kidney.

    PubMed

    Palmer, Biff F; Clegg, Deborah J; Taylor, Simeon I; Weir, Matthew R

    2016-08-01

    Diabetic ketoacidosis is a serious metabolic condition that may occur in patients with either Type 1 or Type 2 diabetes. The accumulation of ketoacids in the serum is a consequence of insulin deficiency and glucagon excess. Sodium Glucose Transporter 2 (SGLT2) inhibitors are novel therapeutic treatments for improving glucose homeostasis in patients with diabetes. Through reductions in glucose reabsorption by the kidney, they lower serum glucose in patients with Type 2 diabetes and they improve glucose control whether used alone or in combination with other therapies. Mechanistically, these drugs increase serum ketoacids and increase glucagon production, which in some individuals, can lead to formation of diabetic ketoacidosis. This review will first focus in how the kidney normally handles ketoacids, and second will discuss how the SGLT2 inhibitors affect the kidney in such a way so as to enhance the risk for development of ketoacidosis in susceptible individuals. PMID:27240541

  18. Comparison of the butyrate effects on neurotransmitter receptors in neurohybrids NG108-15 and NCB-20 cells

    SciTech Connect

    Zhu, X.Z.; Chuang, D.M.

    1987-08-31

    The authors previous study demonstrated that long term treatment of NCB-20 cells with sodium butyrate resulted in a marked increase in the density of delta-opioid receptors with a much lesser effect on muscarinic cholinergic and no effect on alpha/sub 2/-adrenergic receptors. In the present study the authors investigated the effect of sodium butyrate on these three types of receptors in NG108-15 cells whose neuroblastoma parent is the same as that of NCB-20 cells. Long term treatment of NG108-15 cells with sodium butyrate (0.5 mM) induced a 2-fold increase in the density of the specific binding of /sup 3/H-clonidine. A comparable increase in the number of binding sites was detected when /sup 3/H-yohimbine was used as the receptor ligand. The butyrate-induced increase in the alpha/sub 2/-adrenergic receptor binding could be totally abolished by treatment with a protein synthesis inhibitor, cycloheximide, suggesting that synthesis of receptor protein is involved. The same butyrate treatment had no significant effect on opioid and muscarinic cholinergic receptor bindings. Thus, butyrate effects on the expression of these three types of receptors in NG108-15 and NCB-20 cells are dramatically different. These data suggest that induction by butyrate of neurotransmitter receptors requires concerted action of genetic factors of both parents of the neurohybrids. 22 references, 2 figures, 2 tables.

  19. Sensitization of human colon cancer cells to sodium butyrate-induced apoptosis by modulation of sphingosine kinase 2 and protein kinase D

    SciTech Connect

    Xiao, Min; Liu, Yungang; Zou, Fei

    2012-01-01

    Sphingosine kinases (SphKs) have been recognized as important proteins regulating cell proliferation and apoptosis. Of the two isoforms of SphK (SphK1 and SphK2), little is known about the functions of SphK2. Sodium butyrate (NaBT) has been established as a promising chemotherapeutic agent, but the precise mechanism for its effects is unknown. In this study, we investigated the role of SphK2 in NaBT-induced apoptosis of HCT116 colon cancer cells. The results indicated that following NaBT treatment SphK2 was translocated from the nucleus to the cytoplasm, leading to its accumulation in the cytoplasm; in the meantime, only mild apoptosis occurred. However, downregulation of SphK2 resulted in sensitized apoptosis, and overexpression of SphK2 led to even lighter apoptosis; these strongly indicate an inhibitory role of SphK2 in cell apoptosis induced by NaBT. After knocking down protein kinase D (PKD), another protein reported to be critical in cell proliferation/apoptosis process, by using siRNA, blockage of cytoplasmic accumulation of SphK2 and sensitized apoptosis following NaBT treatment were observed. The present study suggests that PKD and SphK2 may form a mechanism for the resistance of cancer cells to tumor chemotherapies, such as HCT116 colon cancer cells to NaBT, and these two proteins may become molecular targets for designation of new tumor-therapeutic drugs. -- Highlights: Black-Right-Pointing-Pointer In the present study sodium butyrate (10 mM) induced mild apoptosis of cancer cells. Black-Right-Pointing-Pointer The apoptosis was negatively regulated by cytoplasmic Sphingosine Kinase 2 (SphK2). Black-Right-Pointing-Pointer Translocation of SphK2 from nucleus to cytoplasm was mediated by protein kinase D. Black-Right-Pointing-Pointer Downregulation of SphK2 or protein kinase D leads to sensitized cell apoptosis.

  20. Sodium borohydride removes aldehyde inhibitors for enhancing biohydrogen fermentation.

    PubMed

    Lin, Richen; Cheng, Jun; Ding, Lingkan; Song, Wenlu; Zhou, Junhu; Cen, Kefa

    2015-12-01

    To enhance biohydrogen production from glucose and xylose in the presence of aldehyde inhibitors, reducing agent (i.e., sodium borohydride) was in situ added for effective detoxification. The detoxification efficiencies of furfural (96.7%) and 5-hydroxymethylfurfural (5-HMF, 91.7%) with 30mM NaBH4 were much higher than those of vanillin (77.3%) and syringaldehyde (69.3%). Biohydrogen fermentation was completely inhibited without detoxification, probably because of the consumption of nicotinamide adenine dinucleotide (NADH) by inhibitors reduction (R-CHO+2NADH→R-CH2OH+2NAD(+)). Addition of 30mM NaBH4 provided the reducing power necessary for inhibitors reduction (4R-CHO+NaBH4+2H2O→4R-CH2OH+NaBO2). The recovered reducing power in fermentation resulted in 99.3% recovery of the hydrogen yield and 64.6% recovery of peak production rate. Metabolite production and carbon conversion after detoxification significantly increased to 63.7mM and 81.9%, respectively. PMID:26342346

  1. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress.

    PubMed

    Sun, Jing; Wang, Fangyan; Hong, Guangliang; Pang, Mengqi; Xu, Hailing; Li, Haixiao; Tian, Feng; Fang, Renchi; Yao, Ye; Liu, Jiaming

    2016-04-01

    Sodium butyrate (NaB) has exhibited neuroprotective activity. This study aimed to explore that NaB exerts beneficial effects on chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and its possible mechanisms. The behavioral tests including sucrose preference test (SPT), open field test (OFT), tail suspension test (TST) and forced swimming test (FST) were to evaluate the antidepressant effects of NaB. Then changes of Nissl's body in the hippocampus, brain serotonin (5-HT) concentration, brain-derived neurotrophic factor (BDNF) and tight junctions (TJs) proteins level were assessed to explore the antidepressant mechanisms. Our results showed that CUMS caused significant depression-like behaviors, neuropathological changes, and decreased brain 5-HT concentration, TJs protein levels and BDNF expression in the hippocampus. However, NaB treatment significantly ameliorated behavioral deficits of the CUMS-induced mice, increased 5-HT concentration, increased BDNF expression, and up-regulated Occludin and zonula occludens-1(ZO-1) protein levels in the hippocampus, which demonstrated that NaB could partially restore CUMS-induced blood-brain barrier (BBB) impairments. Besides, the pathologic changes were alleviated. In conclusion, these results demonstrated that NaB significantly improved depression-like behaviors in CUMS-induced mice and its antidepressant actions might be related with, at least in part, the increasing brain 5-HT concentration and BDNF expression and restoring BBB impairments. PMID:26957230

  2. Digital mRNA profiling of N-glycosylation gene expression in recombinant Chinese hamster ovary cells treated with sodium butyrate.

    PubMed

    Lee, Sang Min; Kim, Yeon-Gu; Lee, Eun Gyo; Lee, Gyun Min

    2014-02-10

    To understand the effects of sodium butyrate (NaBu) on protein glycosylation, recombinant Chinese hamster ovary (rCHO) cells producing Fc-fusion glycoprotein were subjected to 3mM NaBu. The addition of NaBu to the cultures reduced the relative proportion of acidic isoforms and sialic acid content of the glycoprotein. Fifty-two N-glycosylation-related gene expressions were also assessed by the NanoString nCounter system, which can provide a direct digital readout using custom-designed color-coded probes. Among them, ten genes (ugp, slc35a2, ganc, man1a, man1c, mgat5a, st3gal5, glb1, neu1, and neu3) were up-regulated and three genes (b4galt2, st3gal3, and neu2) were down-regulated significantly. Altered expression patterns in st3gal3, neu1, and neu3, which have roles in the sialic acid biosynthesis pathway, correlated with reduced sialic acid content of the glycoprotein by NaBu. Taken together, the results obtained in this study provide a better understanding of the detrimental effect of NaBu on N-glycosylation in rCHO cells. PMID:24333461

  3. Regulation of the beta-adrenergic receptor-adenylate cyclase complex of 3T3-L1 fibroblasts by sodium butyrate

    SciTech Connect

    Stadel, J.M.; Poksay, K.S.; Nakada, M.T.; Crooke, S.T.

    1986-05-01

    Mouse 3T3-L1 fibroblasts contain beta-adrenergic receptors (BAR), predominantly of the B/sub 1/ subtype. Incubation of these cells with 2-10 mM sodium butyrate (SB) for 24-48 hr results in a switch in the BAR subtype from B/sub 1/ to B/sub 2/ and promotes a 1.5 to 2.5 fold increase in total BAR number. Other short chain acids were not as effective as SB in promoting changes in BAR. BAR were assayed in membranes prepared from the 3T3-L1 cells using the radiolabeled antagonist (/sup 125/I)-cyanopindolol and the B/sub 2/ selective antagonist ICI 118.551. BAR subtype switch was confirmed functionally by measuring cellular cAMP accumulation in response to agonists. The structure and amount of the alpha subunits of the guanine nucleotide regulatory proteins N/sub s/ and N/sub i/ were determined by ADP-ribosylation using /sup 32/P-NAD and either cholera toxin or pertussis toxin for labeling of the respective subunits. Preincubation of cells with 5 mM SB for 48 hr resulted in a 2-3 fold increase in the labeling of the alpha subunits of both N/sub s/ and N/sub i/. A protein of M/sub r/ = 44,000 showed enhanced labeling by cholera toxin following SB treatment of the cells. These data indicate SB concomitantly regulates expression of BAR subtype and components of the adenylate cyclase in 3T3-L1 cells.

  4. Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning

    PubMed Central

    Henagan, Tara M; Stefanska, Barbara; Fang, Zhide; Navard, Alexandra M; Ye, Jianping; Lenard, Natalie R; Devarshi, Prasad P

    2015-01-01

    Background and Purpose Sodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood. Experimental Approach The anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB. Key Results NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the −1 nucleosome in association with altered gene expression. Conclusions and Implications NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing −1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete β-oxidation and a lean, insulin sensitive phenotype. PMID:25559882

  5. Synthesis, molecular modeling and biological evaluation of novel 2-allyl amino 4-methyl sulfanyl butyric acid as α-amylase and α-glucosidase inhibitor

    NASA Astrophysics Data System (ADS)

    Balan, Kannan; Perumal, Perumal; Sundarabaalaji, Narayanan; Palvannan, Thayumanavan

    2015-02-01

    In the present study 2-allyl amino 4-methyl sulfanyl butyric acid (AMSB) was synthesized in good yield. AMSB was characterized by Fourier transforms infrared spectroscopy (FTIR), Nuclear magnetic resonance (NMR) (1H and 13C) and Liquid chromatography mass spectrometry (LCMS). The radical scavenging activity and reducing power assay of AMSB was assessed using 1-1-diphenyl 2-picryl hydrazyl (DPPH), 2,2‧-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) (ABTS) and ferric ion reducing antioxidant power assay (FRAP) and was found to be 44.1, 34.71 and 41.7 μg/ml respectively. The compound showed effective inhibition against α-amylase and α-glucosidase. AMSB was identified to be a reversible mixed noncompetitive inhibitor of α-amylase and α-glucosidase. The molecular docking study was carried out to evaluate the specific groove binding properties and affords valuable information of AMSB binding mode in the active site of α-glucosidase the study may lead to the which leads to the rational design of new class of antidiabetic drugs targeting α-glucosidase based on AMSB in near future.

  6. The activation of the TLR2/p38 pathway by sodium butyrate in bovine mammary epithelial cells is involved in the reduction of Staphylococcus aureus internalization.

    PubMed

    Alva-Murillo, Nayeli; Medina-Estrada, Ivan; Báez-Magaña, Marisol; Ochoa-Zarzosa, Alejandra; López-Meza, Joel E

    2015-12-01

    Staphylococcus aureus is an etiological agent of human and animal diseases, and it is able to internalize into non-professional phagocytic cells (i.e. bovine mammary epithelial cells, bMECs), which is an event that is related to chronic and recurrent infections. bMECs contribute to host innate immune responses (IIR) through TLR pathogen recognition, whereby TLR2 is the most relevant for S. aureus. In a previous report, we showed that sodium butyrate (NaB, 0.5mM), which is a short chain fatty acid (SCFA), reduced S. aureus internalization into bMECs by modulating their IIR. However, the molecular mechanism of this process has not been described, which was the aim of this study. The results showed that the TLR2 membrane abundance (MA) and mRNA expression were induced by 0.5mM NaB ∼1.6-fold and ∼1.7-fold, respectively. Additionally, 0.5mM NaB induced p38 phosphorylation, but not JNK1/2 or ERK1/2 phosphorylation in bMECs, which reached the baseline when the bMECs were S. aureus-challenged. Additionally, bMECs that were treated with 0.5mM NaB (24h) showed activation of 8 transcriptional factors (AP-1, E2F-1, FAST-1, MEF-1, EGR, PPAR, ER and CBF), which were partially reverted when the bMECs were S. aureus-challenged. Additionally, 0.5mM NaB (24h) up-regulated mRNA expression of the antimicrobial peptides, TAP (∼4.8-fold), BNBD5 (∼3.2-fold) and BNBD10 (∼2.6-fold). Notably, NaB-treated and S. aureus-challenged bMECs increased the mRNA expression of all of the antimicrobial peptides that were evaluated, and this was evident for LAP and BNBD5. In the NaB-treated bMECs, we did not detect significant expression changes for IL-1β and IL-6 and only TNF-α, IL-10 and IL-8 were induced. Interestingly, the NaB-treated and S. aureus-challenged bMECs maintained the anti-inflammatory response that was induced by this SCFA. In conclusion, our results suggest that 0.5mM NaB activates bMECs via TLR2/p38, which leads to improved antimicrobial defense before/after pathogen

  7. The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T

    SciTech Connect

    Hatayama, Hajime; Iwashita, Jun; Kuwajima, Akiko; Abe, Tatsuya . E-mail: abetats@akita-pu.ac.jp

    2007-05-11

    The short fatty acid, butyrate, which is produced by intestinal anaerobic bacteria in the colon, has inhibitory activity on histone deacetylases (HDACs). Treatment of the human colon cancer cell line, LS174T, with 1-2 mM sodium butyrate stimulated MUC2 mucin production, as determined by histological PAS staining of carbohydrate chains of mucin, and confirmed at the protein and mRNA levels by immunoblotting with anti-MUC2 antibody and real-time RT-PCR, respectively. Increases in acetylated histone H3 in the LS174T cells treated with butyrate suggest inhibition of HDACs in these cells. Butyrate-stimulated MUC2 production in the LS174T cells was inhibited by the MEK inhibitor, U0126, implicating the involvement of extracellular signal-regulated kinase (ERK) cascades in this process. Proliferation of the LS174T cells was inhibited by butyrate treatment. Although apoptotic nuclear DNA fragmentation could not be detected, cell-cycle arrest at the G0/G1 phase in the butyrate-treated cells was demonstrated by flow cytometry. Thus butyrate, an HDAC inhibitor, inhibits proliferation of LS174T cells but stimulates MUC2 production in individual cells.

  8. Daily Sodium Butyrate Enema for the Prevention of Radiation Proctitis in Prostate Cancer Patients Undergoing Radical Radiation Therapy: Results of a Multicenter Randomized Placebo-Controlled Dose-Finding Phase 2 Study

    SciTech Connect

    Maggio, Angelo; Magli, Alessandro; Rancati, Tiziana; Fiorino, Claudio; Valvo, Francesca; Fellin, Giovanni; Ricardi, Umberto; Munoz, Fernando; Cosentino, Dorian; Cazzaniga, Luigi Franco; Valdagni, Riccardo; Vavassori, Vittorio

    2014-07-01

    Purpose: To evaluate the efficacy of sodium butyrate enemas (NABUREN) in prostate cancer radiation therapy (RT) in reducing the incidence, severity, and duration of acute RT-induced proctitis. Methods and Materials: 166 patients, randomly allocated to 1 of 4 groups (rectal sodium butyrate 1 g, 2 g, or 4 g daily or placebo), were treated with NABUREN during and 2 weeks after RT. The grade of proctitis was registered in a daily diary. The correlation between NABUREN and proctitis was investigated through χ{sup 2} statistics. The toxicity endpoints considered were as follows: total number of days with grade ≥1 proctitis (≥G1); total number of days with grade ≥2 proctitis (≥G2); ≥G1 and ≥G2 proctitis lasting at least 3 and 5 consecutive days starting from week 4 (≥G1+3d, ≥G2+3d); damaging effects of RT on rectal mucosa as measured by endoscopy. The relationship between endpoints and pretreatment morbidities, hormonal therapy, presence of diabetes or hypertension, abdominal surgery, or hemorrhoids was investigated by univariate analysis. Results: The patients were randomly allocated to the 4 arms. No difference in the distribution of comorbidities among the arms was observed (P>.09). The mean ≥G1 and ≥G2 proctitis were 7.8 and 4.9 for placebo and 8.9 and 4.7 for the NABUREN group, respectively. No favorable trend in reduction of incidence, severity, and duration of ≥G1 and ≥G2 proctitis was observed with NABUREN use. In univariate analysis, ≥G1+3d toxicity was found to be related to hemorrhoids (P=.008), and a slight correlation was found between ≥G2 proctitis and hormonal therapy (P=.06). The RT effects on rectal mucosa as based on endoscopic assessment were mainly related to diabetes (P<.01). Endoscopy data at 6 week showed no significant difference between the placebo and butyrate arms. The other investigated endpoints were not correlated with any of the clinical risk factors analyzed. Conclusion: There was no evidence of efficacy

  9. Sodium-Glucose Cotransporter 2 Inhibitors: Possible Anti-Atherosclerotic Effects Beyond Glucose Lowering.

    PubMed

    Yanai, Hidekatsu; Katsuyama, Hisayuki; Hamasaki, Hidetaka; Adachi, Hiroki; Moriyama, Sumie; Yoshikawa, Reo; Sako, Akahito

    2016-01-01

    The new drug for type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT-2) inhibitor, is reversible inhibitor of SGLT-2, leading to reduction of renal glucose reabsorption and decrease of plasma glucose, in an insulin-independent manner. In addition to glucose control, the management of coronary risk factors is very important for patients with diabetes. Here we reviewed published articles about the possible anti-atherosclerotic effects beyond glucose lowering of the SGLT-2 inhibitors. We searched by using Pubmed, and found 770 published articles about SGLT-2 inhibitors. Among 10 kinds of SGLT-2 inhibitors, the number of published articles about dapagliflozin was the greatest among SGLT-2 inhibitors. Since SGLT-2 inhibitors have similar chemical structures, we concentrated on the published articles about dapagliflozin. SGLT-2 inhibitors are proved to be significantly associated with weight loss and reduction of blood pressure by a relatively large number of studies. The studies investigating effects of dapagliflozin on visceral fat, insulin sensitivity, serum lipids, inflammation and adipocytokines are very limited. An influence of increase in glucagon secretion by SGLT-2 inhibitors on metabolic risk factors remains unknown. PMID:26668677

  10. Modulation of the epithelial sodium channel (ENaC) by bacterial metalloproteases and protease inhibitors.

    PubMed

    Butterworth, Michael B; Zhang, Liang; Liu, Xiaoning; Shanks, Robert M; Thibodeau, Patrick H

    2014-01-01

    The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP) from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC), leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions. PMID:24963801

  11. Sodium Channel Inhibitors Reduce DMPK mRNA and Protein.

    PubMed

    Witherspoon, Luke; O'Reilly, Sean; Hadwen, Jeremiah; Tasnim, Nafisa; MacKenzie, Alex; Farooq, Faraz

    2015-08-01

    Myotonic dystrophy type 1 (DM1) is caused by an expanded trinucleotide (CTG)n tract in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. This results in the aggregation of an expanded mRNA forming toxic intranuclear foci which sequester splicing factors. We believe down-regulation of DMPK mRNA represents a potential, and as yet unexplored, DM1 therapeutic avenue. Consequently, a computational screen for agents which down-regulate DMPK mRNA was undertaken, unexpectedly identifying the sodium channel blockers mexiletine, prilocaine, procainamide, and sparteine as effective suppressors of DMPK mRNA. Analysis of DMPK mRNA in C2C12 myoblasts following treatment with these agents revealed a reduction in the mRNA levels. In vivo analysis of CD1 mice also showed DMPK mRNA and protein down-regulation. The role of DMPK mRNA suppression in the documented efficacy of this class of compounds in DM1 is worthy of further investigation. PMID:26011798

  12. Flavonolignans As a Novel Class of Sodium Pump Inhibitors

    PubMed Central

    Kubala, Martin; Čechová, Petra; Geletičová, Jaroslava; Biler, Michal; Štenclová, Tereza; Trouillas, Patrick; Biedermann, David

    2016-01-01

    We examined the inhibitory effects of three flavonolignans and their dehydro- derivatives, taxifolin and quercetin on the activity of the Na+/K+-ATPase (NKA). The flavonolignans silychristin, dehydrosilychristin and dehydrosilydianin inhibited NKA with IC50 of 110 ± 40 μM, 38 ± 8 μM, and 36 ± 14 μM, respectively. Using the methods of molecular modeling, we identified several possible binding sites for these species on NKA and proposed the possible mechanisms of inhibition. The binding to the extracellular- or cytoplasmic C-terminal sites can block the transport of cations through the plasma membrane, while the binding on the interface of cytoplasmic domains can inhibit the enzyme allosterically. Fluorescence spectroscopy experiments confirmed the interaction of these three species with the large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45). The flavonolignans are distinct from the cardiac glycosides that are currently used in NKA treatment. Because their binding sites are different, the mechanism of inhibition is different as well as the range of active concentrations, one can expect that these new NKA inhibitors would exhibit also a different biomedical actions than cardiac glycosides. PMID:27065883

  13. Suppression of caspase-11 expression by histone deacetylase inhibitors

    SciTech Connect

    Heo, Hyejung; Yoo, Lang; Shin, Ki Soon; Kang, Shin Jung

    2009-01-02

    It has been well documented that histone deacetylase inhibitors suppress inflammatory gene expression. Therefore, we investigated whether histone deacetylase inhibitors modulate the expression of caspase-11 that is known as an inducible caspase regulating both inflammation and apoptosis. In the present study, we show that sodium butyrate and trichostatin A, two structurally unrelated inhibitors of histone deacetylase (HDAC), effectively suppressed the induction of caspase-11 in mouse embryonic fibroblasts stimulated with lipopolysaccharides. Sodium butyrate inhibited the activation of upstream signaling events for the caspase-11 induction such as activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, degradation of inhibitor of {kappa}B, and activation of nuclear factor-{kappa}B. These results suggest that the HDAC inhibitor suppressed cytosolic signaling events for the induction of caspase-11 by inhibiting the deacetylation of non-histone proteins.

  14. Electrochemical research on corrosion behavior of A3 steel in compound sodium molybadate and organic inhibitor solution

    NASA Astrophysics Data System (ADS)

    Sun, C. X.; Chen, Y. M.; Xu, H. W.; Zhang, M.; Chen, M.; Xue, M.; Wu, J. Y.; Huang, C. S.

    2015-07-01

    The electrochemical corrosion behavior of A3 in compound sodium molybdate and organic inhibitor solution was tested by the electrochemical workstation method. The concentration of the compound inhibitor set to range 250 mg/L to 3000 mg/L. The polarization curve results of A3 in different concentration inhibitor solutions show that the inhibitor markedly represses the anodic processes. The EIS has two time constant. The extreme concentration is 1500 mg/L.

  15. A selectivity study of sodium-dependent glucose cotransporter 2/sodium-dependent glucose cotransporter 1 inhibitors by molecular modeling.

    PubMed

    Xu, Jinxing; Yuan, Haoliang; Ran, Ting; Zhang, Yanmin; Liu, Haichun; Lu, Shuai; Xiong, Xiao; Xu, Anyang; Jiang, Yulei; Lu, Tao; Chen, Yadong

    2015-08-01

    Sodium-dependent glucose cotransporters (SGLTs) play an important role in glucose reabsorption in the kidney and have been identified as promising targets to treat diabetes. Because of the side effects like glucose and galactose malabsorption by targeting SGLT1, highly selective SGLT2 inhibitors are more promising in the treatment of diabetes. To understand the mechanism of selectivity, we conducted selectivity-based three-dimensional quantitative structure-activity relationship studies to highlight the structure requirements for highly selective SGLT2 inhibitors. The best comparative molecular field analysis and comparative molecular similarity indices analysis models showed the noncross-validated coefficient (r(2) ) of 0.967 and 0.943, respectively. The predicted correlation coefficients (r(2) pred ) of 0.974 and 0.938 validated the reliability and predictability of these models. Besides, homology models of SGLT2 and SGLT1 were also constructed to investigate the selective mechanism from structure-based perspective. Molecular dynamics simulation and binding free energy calculation were performed on the systems of a potent and selective compound interacting with SGLT2 and SGLT1 to compare the different binding modes. The simulation results showed that the stretch of the methylthio group on Met241 had an essential effect on the different binding modes between SGLT1 and SGLT2, which was consistent with the three-dimensional quantitative structure-activity relationship analysis. Hydrogen bond analysis and binding free energy calculation revealed that SGLT2 binding complex was more stable and favorable than SGLT1 complex, which was highly correlated with the experimental results. Our obtained results give useful information for the investigation of the inhibitors' selectivity between SGLT2 and SGLT1 and will help for further development of highly selective SGLT2 inhibitors. PMID:25753971

  16. Inhibitor of Clostridium perfringens Formed by Heating Sodium Nitrite in a Chemically Defined Medium

    PubMed Central

    Moran, Dennis M.; Tannenbaum, Steven R.; Archer, Michael C.

    1975-01-01

    An inhibitor of Clostridium perfringens formed when low levels of nitrite were autoclaved with a defined chemical medium. A systematic study of the medium revealed that only amino acids and mineral salts were involved in the production of this inhibitor, which was proven to be a toxic compound formed from cysteine, ferrous sulfate, and sodium nitrite. The inhibitor was compared to several known compounds. S-nitrosocysteine inhibited the test organism, but would not form in the test system in amounts large enough to explain the observed inhibition. Roussin red salt was unstable in the test system and therefore was not the inhibitor. Roussin black salt, which was also inhibitory, could form in sufficient amounts to explain the inhibition. A complex of cysteine, iron, and nitrie oxide was detected in the autoclaved solution of cysteine, ferrous sulfate, and sodium nitrite; this cysteine complex did not appear to be inhibitory, however, at levels which could form in the autoclaved medium. The observed inhibition may have been due to the combined effects of sublethal concentrations of each compound. PMID:173239

  17. Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives.

    PubMed

    John, Mathew; Gopinath, Deepa; Jagesh, Rejitha

    2016-01-01

    The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin leads to weight gain and increased risk of hypoglycemia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antihyperglycemic agents which act by blocking the SGLT2 in the proximal tubule of the kidney. They have potential benefits in terms of weight loss and reduction of blood pressure in addition to improvements in glycemic control. Further, one of the SGLT2 inhibitors, empagliflozin has proven benefits in reducing adverse cardiovascular (CV) outcomes in a CV outcome trial. Adding SGLT2 inhibitors to insulin in subjects with type 2 diabetes produced favorable effects on glycemic control without the weight gain and hypoglycemic risks associated with insulin therapy. The general risks of increased genital mycotic infections, urinary tract infections, volume, and osmosis-related adverse effects in these subjects were similar to the pooled data of individual SGLT2 inhibitors. There are subsets of subjects with type 2 diabetes who may have insulin deficiency, beta cell autoimmunity, or is prone to diabetic ketoacidosis. In these subjects, SGLT2 inhibitors should be used with caution to prevent the rare risks of ketoacidosis. PMID:26904465

  18. Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives

    PubMed Central

    John, Mathew; Gopinath, Deepa; Jagesh, Rejitha

    2016-01-01

    The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin leads to weight gain and increased risk of hypoglycemia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antihyperglycemic agents which act by blocking the SGLT2 in the proximal tubule of the kidney. They have potential benefits in terms of weight loss and reduction of blood pressure in addition to improvements in glycemic control. Further, one of the SGLT2 inhibitors, empagliflozin has proven benefits in reducing adverse cardiovascular (CV) outcomes in a CV outcome trial. Adding SGLT2 inhibitors to insulin in subjects with type 2 diabetes produced favorable effects on glycemic control without the weight gain and hypoglycemic risks associated with insulin therapy. The general risks of increased genital mycotic infections, urinary tract infections, volume, and osmosis-related adverse effects in these subjects were similar to the pooled data of individual SGLT2 inhibitors. There are subsets of subjects with type 2 diabetes who may have insulin deficiency, beta cell autoimmunity, or is prone to diabetic ketoacidosis. In these subjects, SGLT2 inhibitors should be used with caution to prevent the rare risks of ketoacidosis. PMID:26904465

  19. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.

    PubMed

    Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

    2016-03-01

    The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes. PMID:26970780

  20. Reductive Carboxylation of Propionate to Butyrate in Methanogenic Ecosystems

    PubMed Central

    Tholozan, J. L.; Samain, E.; Grivet, J. P.; Moletta, R.; Dubourguier, H. C.; Albagnac, G.

    1988-01-01

    During the batch degradation of sodium propionate by the anaerobic sludge from an industrial digestor, we observed a significant amount of butyrate formation. Varying the initial propionate concentrations did not alter the ratio of maximal butyrate accumulation to initial propionate concentration within a large range. By measuring the decrease in the radioactivity of [1-14C]butyrate during propionate degradation, we estimated that about 20% of the propionate was converted to butyrate. Labeled butyrate was formed from [1-14C]propionate with the same specific radioactivity, suggesting a possible direct pathway from propionate to butyrate. We confirmed this hypothesis by nuclear magnetic resonance studies with [13C]propionate. The results showed that [1-13C]-, [2-13C]-, and [3-13C]propionate were converted to [2-13C]-, [3-13C]-, and [4-13C]butyrate, respectively, demonstrating the direct carboxylation on the carboxyl group of propionate without randomization of the other two carbons. In addition, we observed an exchange reaction between C-2 and C-3 of the propionate, indicating that acetogensis may proceed through a randomizing pathway. The physiological significance and importance of various metabolic pathways involved in propionate degradation are discussed, and an unusual pathway of butyrate synthesis is proposed. PMID:16347557

  1. Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes.

    PubMed

    Arakaki, Richard F

    2016-05-01

    Coincident with the high and increasing worldwide prevalence of type 2 diabetes (T2D), a growing armamentarium of antidiabetes medications has been introduced to target different organ systems that play a role in the pathophysiology of T2D. Among these, the sodium-glucose cotransporter-2 (SGLT-2) inhibitors were introduced in the United States in 2013 as a new treatment option to address the hyperglycemia associated with T2D. SGLT-2 inhibitors decrease renal glucose reabsorption, resulting in glucosuria, alleviation of hyperglycemia, and modest weight loss and are associated with a low risk of hypoglycemia. The SGLT-2 inhibitors have been linked to an increased incidence of genital mycotic infections and, to a lesser extent, urinary tract infections, which may limit their utility in some patients. This review examines the prevalence, recurrence rates, treatment options, and responses to treatment of genital and urinary tract infections in patients with T2D receiving SGLT-2 inhibitors, with the aim of guiding clinicians in the most effective use of these agents for the treatment of hyperglycemia. PMID:26982554

  2. Sodium-glucose co-transporter 2 (SGLT2) inhibitors: a growing class of antidiabetic agents

    PubMed Central

    Vivian, Eva M

    2014-01-01

    Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM) achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM). The renal sodium-glucose co-transporter 2 (SGLT2) is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM. PMID:25598831

  3. Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

    PubMed

    Opie, L H

    2014-08-01

    Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

  4. Sodium glucose transporter protein 2 inhibitors: focusing on the kidney to treat type 2 diabetes

    PubMed Central

    Peene, Bernard

    2014-01-01

    Type 2 diabetes mellitus (T2DM) is increasing worldwide. Treatment of T2DM continues to present challenges, with a significant proportion of patients failing to achieve and maintain glycemic targets. Despite the availability of many oral antidiabetic agents, therapeutic efficacy is also offset by side effects such as weight gain and hypoglycemia. Therefore, the search for novel therapeutic agents with an improved benefit–risk profile continues. In the following review we focus on a novel class of oral antidiabetic drugs, the sodium glucose transporter protein 2 (SGLT2) inhibitors, which have unique characteristics. SGLT2 inhibitors focus on the kidney as a therapeutic target, where they inhibit the reabsorption of glucose in the proximal tubule, causing an increase in urinary glucose excretion. Doing this, they reduce plasma glucose independently of the β-cell function of the pancreas. SGLT2 inhibitors are effective at lowering hemoglobin A1c, but also induce weight loss and reduce blood pressure, with a low risk of hypoglycemia. In general, the SGLT2 inhibitors are well tolerated, with the most frequent adverse events being mild urinal and genital infections. Since their primary site of effect is the kidney, these drugs are less effective in patients with impaired kidney function but evidence is emerging that these drugs may also have a protective effect against diabetic nephropathy. This review focuses on the most extensively studied SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin. Dapagliflozin and canagliflozin have already been approved for marketing by the US Food and Drug Administration. The European Medicines Agency has accepted all three drugs for marketing. PMID:25419452

  5. Sodium glucose transporter protein 2 inhibitors: focusing on the kidney to treat type 2 diabetes.

    PubMed

    Peene, Bernard; Benhalima, Katrien

    2014-10-01

    Type 2 diabetes mellitus (T2DM) is increasing worldwide. Treatment of T2DM continues to present challenges, with a significant proportion of patients failing to achieve and maintain glycemic targets. Despite the availability of many oral antidiabetic agents, therapeutic efficacy is also offset by side effects such as weight gain and hypoglycemia. Therefore, the search for novel therapeutic agents with an improved benefit-risk profile continues. In the following review we focus on a novel class of oral antidiabetic drugs, the sodium glucose transporter protein 2 (SGLT2) inhibitors, which have unique characteristics. SGLT2 inhibitors focus on the kidney as a therapeutic target, where they inhibit the reabsorption of glucose in the proximal tubule, causing an increase in urinary glucose excretion. Doing this, they reduce plasma glucose independently of the β-cell function of the pancreas. SGLT2 inhibitors are effective at lowering hemoglobin A1c, but also induce weight loss and reduce blood pressure, with a low risk of hypoglycemia. In general, the SGLT2 inhibitors are well tolerated, with the most frequent adverse events being mild urinal and genital infections. Since their primary site of effect is the kidney, these drugs are less effective in patients with impaired kidney function but evidence is emerging that these drugs may also have a protective effect against diabetic nephropathy. This review focuses on the most extensively studied SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin. Dapagliflozin and canagliflozin have already been approved for marketing by the US Food and Drug Administration. The European Medicines Agency has accepted all three drugs for marketing. PMID:25419452

  6. Retinoid- and sodium-butyrate-induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology.

    PubMed

    Gehrmann, Mathias; Schönberger, Johann; Zilch, Tanja; Rossbacher, Lydia; Thonigs, Gerald; Eilles, Christoph; Multhoff, Gabriele

    2005-01-01

    Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX-) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 microM, 1 microM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX- tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology. PMID:16038410

  7. STUDIES OF POTENTIAL INHIBITORS OF SODIUM ALUMINOSILICATE SCALES IN HIGH-LEVEL WASTE EVAPORATION

    SciTech Connect

    Wilmarth, B; Lawrence Oji, L; Terri Fellinger, T; David Hobbs, D; Nilesh Badheka, N

    2008-02-27

    The Savannah River Site (SRS) has 49 underground storage tanks used to store High Level Waste (HLW). The tank space in these tanks must be managed to support the continued operation of key facilities. The reduction of the tank volumes in these tanks are accomplished through the use of three atmospheric pressure HLW evaporators. For a decade, evaporation of highly alkaline HLW containing aluminum and silicates has produced sodium aluminosilicate scales causing both operation and criticality hazards in the 2H Evaporator System. Segregation of aluminum-rich wastes from silicate-rich wastes minimizes the amount of scale produced and reduces cleaning expenses, but does not eliminate the scaling nor increases operation flexibility in waste process. Similar issues have affected the aluminum refining industry for many decades. Over the past several years, successful commercial products have been identified to eliminate aluminosilicate fouling in the aluminum industry, but have not been utilized in a nuclear environment. Laboratory quantities of three proprietary aluminosilicate scale inhibitors have been produced and been shown to prevent formation of scales. SRNL has been actively testing these potential inhibitors to examine their radiation stability, radiolytic degradation behaviors, and downstream impacts to determine their viability within the HLW system. One of the tested polymers successfully meets the established criteria for application in the nuclear environment. This paper will describe a summary of the methodology used to prioritize laboratory testing protocols based on potential impacts/risks identified for inhibitor deployment at SRS.

  8. Studies of Potential Inhibitors of Sodium Aluminosilicate Scales in High-Level Waste Evaporation

    SciTech Connect

    Oji, L.N.; Fellinger, T.L.; Hobbs, D.T.; Badheka, N.P.; Wilmarth, W.R.

    2008-07-01

    The Savannah River Site (SRS) has 49 underground storage tanks used to store High Level Waste (HLW). The tank space in these tanks must be managed to support the continued operation of key facilities. The reduction of the tank volumes in these tanks are accomplished through the use of three atmospheric pressure HLW evaporators. For a decade, evaporation of highly alkaline HLW containing dissolved aluminate and silicate has produced sodium aluminosilicate scales causing both operation and criticality hazards in the 2H Evaporator System. Segregation of aluminum-rich wastes from silicate-rich wastes minimizes the amount of scale produced and reduces cleaning expenses, but does not eliminate the scaling nor increases operation flexibility in waste process. Similar issues have affected the aluminum refining industry for many decades. Over the past several years, successful commercial products have been identified to eliminate aluminosilicate fouling in the aluminum industry, but have not been utilized in a nuclear environment. Laboratory quantities of three proprietary aluminosilicate scale inhibitors have been produced and been shown to prevent formation of scales. SRNL has been actively testing these potential inhibitors to examine their radiation stability, radiolytic degradation behaviors, and downstream impacts to determine their viability within the HLW system. One of the tested polymers successfully meets the established criteria for application in the nuclear environment. This paper will describe a summary of the methodology used to prioritize laboratory testing protocols based on potential impacts/risks identified for inhibitor deployment at SRS. (authors)

  9. Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight.

    PubMed

    Singh, Awadhesh Kumar

    2015-01-01

    Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from -0.5 to -0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism. PMID:26693421

  10. Sodium glucose co-transporter inhibitors - A new class of old drugs.

    PubMed

    Malhotra, Aneeta; Kudyar, Surbhi; Gupta, Anil K; Kudyar, Rattan P; Malhotra, Pavan

    2015-01-01

    Sodium glucose co-transporter (SGLT) inhibitors are a new class of drugs which are used in the pharmacotherapy of Type-II diabetes, which happens to be a major risk factor for developing both micro as well as macro-vascular complications. These drugs inhibit the glucose reabsorption by inhibiting SGLT, which exhibits a novel and promising mechanism of action by promoting the urinary glucose excretion hence providing a basis of therapeutic intervention. Results of SGLT-II inhibitors are very encouraging as there is a significant elevation of GLP-1 level, which forms the basis of relevance in treatment of diabetes. It targets the HbA1C and keeps a check on its levels. It also exerts other positive benefits such as weight loss, reduction in blood glucose levels, reduction in blood pressure and improvement in insulin resistance and β-cell dysfunction: All contributing to effective glycemic control. SGLT inhibition will develop as effective modality as it has the capability of inhibiting reabsorption of greater percentage of filtered glucose load. PMID:26539362

  11. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside.

    PubMed

    Mudaliar, Sunder; Polidori, David; Zambrowicz, Brian; Henry, Robert R

    2015-12-01

    Type 2 diabetes is a chronic disease with disabling micro- and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors. PMID:26604280

  12. Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight

    PubMed Central

    Singh, Awadhesh Kumar

    2015-01-01

    Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from −0.5 to −0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism. PMID:26693421

  13. Sodium glucose co-transporter inhibitors – A new class of old drugs

    PubMed Central

    Malhotra, Aneeta; Kudyar, Surbhi; Gupta, Anil K.; Kudyar, Rattan P.; Malhotra, Pavan

    2015-01-01

    Sodium glucose co-transporter (SGLT) inhibitors are a new class of drugs which are used in the pharmacotherapy of Type-II diabetes, which happens to be a major risk factor for developing both micro as well as macro-vascular complications. These drugs inhibit the glucose reabsorption by inhibiting SGLT, which exhibits a novel and promising mechanism of action by promoting the urinary glucose excretion hence providing a basis of therapeutic intervention. Results of SGLT-II inhibitors are very encouraging as there is a significant elevation of GLP-1 level, which forms the basis of relevance in treatment of diabetes. It targets the HbA1C and keeps a check on its levels. It also exerts other positive benefits such as weight loss, reduction in blood glucose levels, reduction in blood pressure and improvement in insulin resistance and β-cell dysfunction: All contributing to effective glycemic control. SGLT inhibition will develop as effective modality as it has the capability of inhibiting reabsorption of greater percentage of filtered glucose load. PMID:26539362

  14. Efficacy and safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in diabetes mellitus.

    PubMed

    Fioretto, Paola; Giaccari, Andrea; Sesti, Giorgio

    2015-01-01

    Although antidiabetic agents have been developed to target one or more of the core defects of type 2 diabetes mellitus (T2DM), many patients do not achieve glycemic goals. Inhibition of the sodium-glucose cotransporter 2 (SGLT2) induces glycosuria, reduces glucose toxicity and improves insulin sensitivity and β-cell function. As the mechanism of action of SGLT2 inhibitors is different from other agents and completely insulin-independent, the use of these drugs might potentially be efficacious alone or in combination with any other antidiabetic drug, including insulin. Dapagliflozin is a highly selective and reversible SGLT2 inhibitor approved for use in adult patients with T2DM as monotherapy in patients intolerant of metformin or as adjunctive therapy in patients inadequately controlled on existing antidiabetic medications, including insulin. A literature search conducted using PubMed identified key publications related to the use of dapagliflozin in the treatment of patients with diabetes mellitus. No date limits were applied. This review focuses on the safety and efficacy of this SGLT2 inhibitor. Dapagliflozin produces dose-related reductions in glycosylated hemoglobin (HbA1c) as monotherapy and as add-on to other antidiabetic agents, with significant reductions in body weight. Hypoglycemia is uncommon. Preliminary data from a phase 2 pharmacokinetic/pharmacodynamic study suggest that dapagliflozin may also improve glycemic control in patients with type 1 diabetes mellitus. Clinical trials published to date show that dapagliflozin is safe and effective as monotherapy or as an add-on to insulin or oral antidiabetic agents in patients with T2DM. PMID:26474563

  15. Improved Amplification of Microbial DNA from Blood Cultures by Removal of the PCR Inhibitor Sodium Polyanetholesulfonate

    PubMed Central

    Fredricks, David N.; Relman, David A.

    1998-01-01

    Molecular methods are increasingly used to identify microbes in clinical samples. A common technical problem with PCR is failed amplification due to the presence of PCR inhibitors. Initial attempts at amplification of the bacterial 16S rRNA gene from inoculated blood culture media failed for this reason. The inhibitor persisted, despite numerous attempts to purify the DNA, and was identified as sodium polyanetholesulfonate (SPS), a common additive to blood culture media. Like DNA, SPS is a high-molecular-weight polyanion that is soluble in water but insoluble in alcohol. Accordingly, SPS tends to copurify with DNA. An extraction method was designed for purification of DNA from blood culture media and removal of SPS. Blood culture media containing human blood and spiked with Escherichia coli was subjected to an organic extraction procedure with benzyl alcohol, and removal of SPS was documented spectrophotometrically. Successful amplification of the extracted E. coli 16S rRNA gene was achieved by adding 5 μl of undiluted processed sample DNA to a 50-μl PCR mixture. When using other purification methods, the inhibitory effect of SPS could be overcome only by dilution of these samples. By our extraction technique, even uninoculated blood culture media were found to contain bacterial DNA when they were subjected to broad-range 16S rRNA gene consensus PCR. We conclude that the blood culture additive SPS is a potent inhibitor of PCR, is resistant to removal by traditional DNA purification methods, but can be removed by a benzyl alcohol extraction protocol that results in improved PCR performance. PMID:9738025

  16. Microbial metabolite butyrate facilitates M2 macrophage polarization and function

    PubMed Central

    Ji, Jian; Shu, Dingming; Zheng, Mingzhu; Wang, Jie; Luo, Chenglong; Wang, Yan; Guo, Fuyou; Zou, Xian; Lv, Xiaohui; Li, Ying; Liu, Tianfei; Qu, Hao

    2016-01-01

    Metabolites from intestinal microbes modulate the mucosal immune system by regulating the polarization and expansion of T cells. Whether the microbial metabolites influence macrophage polarization, however, is poorly understood. Here, we show that the large bowel microbial fermentation product, butyrate, facilitates M2 macrophage polarization, in vitro and in vivo. The supernatant from butyrate-treated M2 macrophage increased the migration and enhanced the wound closure rate of MLE-12 cells. Butyrate attenuated intestinal inflammation in mice with dextran sulfate sodium (DSS)-induced colitis, with a significant increase in colonic expression of the M2 macrophage-associated protein, Arg1. M2 macrophage treated with butyrate, had increased activation of the H3K9/STAT6 signaling pathway, suggesting a mechanism for butyrate facilitated M2 macrophage polarization. Collectively, our study indicated that commensal microbe-derived butyrate is a novel activator of STAT6-mediated transcription through H3K9 acetylation driving M2 macrophage polarization, and delineated new insights into the immune interplay underlying inflammatory bowel disease. PMID:27094081

  17. Microbial metabolite butyrate facilitates M2 macrophage polarization and function.

    PubMed

    Ji, Jian; Shu, Dingming; Zheng, Mingzhu; Wang, Jie; Luo, Chenglong; Wang, Yan; Guo, Fuyou; Zou, Xian; Lv, Xiaohui; Li, Ying; Liu, Tianfei; Qu, Hao

    2016-01-01

    Metabolites from intestinal microbes modulate the mucosal immune system by regulating the polarization and expansion of T cells. Whether the microbial metabolites influence macrophage polarization, however, is poorly understood. Here, we show that the large bowel microbial fermentation product, butyrate, facilitates M2 macrophage polarization, in vitro and in vivo. The supernatant from butyrate-treated M2 macrophage increased the migration and enhanced the wound closure rate of MLE-12 cells. Butyrate attenuated intestinal inflammation in mice with dextran sulfate sodium (DSS)-induced colitis, with a significant increase in colonic expression of the M2 macrophage-associated protein, Arg1. M2 macrophage treated with butyrate, had increased activation of the H3K9/STAT6 signaling pathway, suggesting a mechanism for butyrate facilitated M2 macrophage polarization. Collectively, our study indicated that commensal microbe-derived butyrate is a novel activator of STAT6-mediated transcription through H3K9 acetylation driving M2 macrophage polarization, and delineated new insights into the immune interplay underlying inflammatory bowel disease. PMID:27094081

  18. Preparation and application of crosslinked poly(sodium acrylate)--coated magnetite nanoparticles as corrosion inhibitors for carbon steel alloy.

    PubMed

    Atta, Ayman M; El-Mahdy, Gamal A; Al-Lohedan, Hamad A; El-Saeed, Ashraf M

    2015-01-01

    This work presents a new method to prepare poly(sodium acrylate) magnetite composite nanoparticles. Core/shell type magnetite nanocomposites were synthesized using sodium acrylate as monomer and N,N-methylenebisacrylamide (MBA) as crosslinker. Microemulsion polymerization was used for constructing core/shell structures with magnetite nanoparticles as core and poly(sodium acrylate) as shell. Fourier transform infrared spectroscopy (FTIR) was employed to characterize the nanocomposite chemical structure. Transmittance electron microscopy (TEM) was used to examine the morphology of the modified poly(sodium acrylate) magnetite composite nanoparticles. These particle will be evaluated for effective anticorrosion behavior as a hydrophobic surface on stainless steel. The composite nanoparticles has been designed by dispersing nanocomposites which act as a corrosion inhibitor. The inhibition effect of AA-Na/magnetite composites on steel corrosion in 1 M HCl solution was investigated using potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS). Polarization measurements indicated that the studied inhibitor acts as mixed type corrosion inhibitor. EIS spectra exhibit one capacitive loop. The different techniques confirmed that the inhibition efficiency reaches 99% at 50 ppm concentration. This study has led to a better understanding of active anticorrosive magnetite nanoparticles with embedded nanocomposites and the factors influencing their anticorrosion performance. PMID:25594340

  19. Transcriptomic sequencing reveals a set of unique genes activated by butyrate-induced histone modification

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate is a nutritional element with strong epigenetic regulatory activity as an inhibitor of histone deacetylases (HDACs). Based on the analysis of differentially expressed genes induced by butyrate in the bovine epithelial cell using deep RNA-sequencing technology (RNA-seq), a set of unique gen...

  20. Sodium-glucose co-transporter 2 inhibitors: from apple tree to 'Sweet Pee'.

    PubMed

    Hardman, Timothy C; Rutherford, Peter; Dubrey, Simon W; Wierzbicki, Anthony S

    2010-01-01

    The sodium-glucose co-transporter 2 (SGLT2), located in the plasma membrane of cells lining the proximal tubule, facilitates the reabsorbtion of glucose in the kidney. Inhibition of SGLT2 has the potential to reduce blood glucose and represents an opportune target for managing blood glucose. By promoting the excretion of glucose, SGLT2 inhibitors are the first anti-diabetic treatment to target the removal rather than the metabolic redirection of glucose. Their mechanism of action is independent of that of endogenous insulin status and thus provides a means of managing plasma glucose irrespective of a patient's glycaemic status or treatments being used in combination. Several candidate SGLT2 inhibitors based on the core glucoside structure of phlorizin are currently being developed, of which, the metabolically more stable aromatic and heteroaromatic C-glucosides have demonstrated the most promising preclinical and clinical data. The inhibition of SGLT2 by messenger antisense technology is also being investigated. Current indications suggest that short-term benefits, in terms of HbA1(c) reductions, are modest and it remains to be seen whether encouraging exogenous glucose disposal will result in long term patient benefits in terms of returning metabolic balance or even weight loss. Indications are that clinical efficacy will be greater with molecules based on an O-glucoside structure. Concerns have been raised over the safety of these agents, particularly a possible predisposition to urinary tract infections, but these concerns have yet to be confirmed in clinical studies. Clinical development programs will need to establish those patients most likely to benefit from inhibition of SGLT2. PMID:21128897

  1. Transcriptomic Sequencing Reveals a Set of Unique Genes Activated by Butyrate-Induced Histone Modification.

    PubMed

    Li, Cong-Jun; Li, Robert W; Baldwin, Ransom L; Blomberg, Le Ann; Wu, Sitao; Li, Weizhong

    2016-01-01

    Butyrate is a nutritional element with strong epigenetic regulatory activity as a histone deacetylase inhibitor. Based on the analysis of differentially expressed genes in the bovine epithelial cells using RNA sequencing technology, a set of unique genes that are activated only after butyrate treatment were revealed. A complementary bioinformatics analysis of the functional category, pathway, and integrated network, using Ingenuity Pathways Analysis, indicated that these genes activated by butyrate treatment are related to major cellular functions, including cell morphological changes, cell cycle arrest, and apoptosis. Our results offered insight into the butyrate-induced transcriptomic changes and will accelerate our discerning of the molecular fundamentals of epigenomic regulation. PMID:26819550

  2. Transcriptomic Sequencing Reveals a Set of Unique Genes Activated by Butyrate-Induced Histone Modification

    PubMed Central

    Li, Cong-Jun; Li, Robert W.; Baldwin, Ransom L.; Blomberg, Le Ann; Wu, Sitao; Li, Weizhong

    2016-01-01

    Butyrate is a nutritional element with strong epigenetic regulatory activity as a histone deacetylase inhibitor. Based on the analysis of differentially expressed genes in the bovine epithelial cells using RNA sequencing technology, a set of unique genes that are activated only after butyrate treatment were revealed. A complementary bioinformatics analysis of the functional category, pathway, and integrated network, using Ingenuity Pathways Analysis, indicated that these genes activated by butyrate treatment are related to major cellular functions, including cell morphological changes, cell cycle arrest, and apoptosis. Our results offered insight into the butyrate-induced transcriptomic changes and will accelerate our discerning of the molecular fundamentals of epigenomic regulation. PMID:26819550

  3. Evans Blue is not a suitable inhibitor of the epithelial sodium channel δ-subunit.

    PubMed

    Perniss, Alexander; Wolf, Annemarie; Wichmann, Lukas; Schönberger, Matthias; Althaus, Mike

    2015-10-23

    The Epithelial Sodium Channel (ENaC) is a heterotrimeric ion channel which can be either formed by assembly of its α-, β- and γ-subunits or, alternatively, its δ-, β- and γ-subunits. The physiological function of αβγ-ENaC is well established, but the function of δβγ-ENaC remains elusive. The azo-dye Evans Blue (EvB) has been routinely used to discriminate between the two channel isoforms by decreasing transmembrane currents and amiloride-sensitive current fractions of δβγ-ENaC expressing Xenopus oocytes. Even though these results could be reproduced, it was found by precipitation experiments and spectroscopic methods that the cationic amiloride and the anionic EvB directly interact in solution, forming a strong complex. Thereby a large amount of pharmacologically available amiloride is removed from physiological buffer solutions and the effective amiloride concentration is reduced. This interaction did not occur in the presence of albumin. In microelectrode recordings, EvB was able to abrogate the block of δβγ-ENaC by amiloride or its derivative benzamil. In sum, EvB reduces amiloride-sensitive ion current fractions in electrophysiological experiments. This is not a result of a specific inhibition of δβγ-ENaC but rather represents a pharmacological artefact. EvB should therefore not be used as an inhibitor of δ-ENaC. PMID:26365349

  4. Liquid chromatographic determination of clobetasone-17-butyrate in ointments.

    PubMed

    Patel, A G; Patel, R B; Patel, M R

    1990-01-01

    A liquid chromatographic (LC) method has been developed for determination of clobetasone-17-butyrate in ointment using clobetasone propionate as an internal standard. Separation was carried out on a C18 reverse-phase column using water-methanol as a mobile phase. Methylparaben and propylparaben (both sodium salt) used as preservatives did not interfere with separation. Compounds are detected photometrically at 235 nm. Mean assay results for 0.05% commercial ointments were 100.36% (n = 5). Mean recovery of clobetasone-17-butyrate added to commercial ointment was 99.89%. PMID:2289922

  5. Alternate splicing regulated by butyrate in the bovine epithelial cell

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As a signaling molecule and a potent inhibitor of histone deacetylases (HADCs), butyrate exerts its impacts on a broad range of biological processes, such as apoptosis and cell proliferation, in addition to its critical role in energy metabolism in ruminants. In this study, we examined the effect of...

  6. Suppression of asymmetric acid efflux and gravitropism in maize roots treated with auxin transport inhibitors of sodium orthovanadate

    NASA Technical Reports Server (NTRS)

    Mulkey, T. J.; Evans, M. L.

    1982-01-01

    In gravitropically stimulated roots of maize (Zea mays L., hybrid WF9 x 38MS), there is more acid efflux on the rapidly growing upper side than on the slowly growing lower side. In light of the Cholodny/Went hypothesis of gravitropism which states that gravitropic curvature results from lateral redistribution of auxin, the effects of auxin transport inhibitors on the development of acid efflux asymmetry and curvature in gravistimulated roots were examined. All the transport inhibitors tested prevented both gravitropism and the development of asymmetric acid efflux in gravistimulated roots. The results indicate that auxin redistribution may cause the asymmetry of acid efflux, a finding consistent with the Cholodny/Went hypothesis of gravitropism. As further evidence that auxin-induced acid efflux asymmetry may mediate gravitropic curvature, sodium orthovanadate, an inhibitor of auxin-induced H+ efflux was found to prevent both gravitropism and the development of asymmetric acid efflux in gravistimulated roots.

  7. Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin.

    PubMed

    Bogdanffy, Matthew S; Stachlewitz, Robert F; van Tongeren, Susan; Knight, Brian; Sharp, Dale E; Ku, Warren; Hart, Susan Emeigh; Blanchard, Kerry

    2014-01-01

    Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose cotransporter 2, was developed for treatment of type 2 diabetes mellitus. Nonclinical safety of empagliflozin was studied in a battery of tests to support global market authorization. Safety pharmacology studies indicated no effect of empagliflozin on measures of respiratory or central nervous system function in rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively, empagliflozin exhibited a toxicity profile consistent with secondary supratherapeutic pharmacology related to glucose loss and included decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and urinary changes such as polyuria and glucosuria. Microscopic changes were consistently observed in kidney and included tubular nephropathy and interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy (mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in female mice or female rats. Renal adenoma and carcinoma were induced in male mice only at exposures 45 times the maximum clinical dose. These tumors were associated with a spectrum of nonneoplastic changes suggestive of a nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male rats, testicular interstitial cell tumors and hemangiomas of the mesenteric lymph node were observed; both tumors are common in rats and are unlikely to be relevant to humans. These studies demonstrate the nonclinical safety of empagliflozin. PMID:25260362

  8. Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

    PubMed

    Han, Anna; Bennett, Natalie; MacDonald, Amber; Johnstone, Megan; Whelan, Jay; Donohoe, Dallas R

    2016-08-01

    Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc. PMID:26661480

  9. Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice.

    PubMed

    Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

    2016-07-01

    Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin) or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin). In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day. PMID:27430987

  10. A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

    PubMed Central

    Greene, D A; Lattimer, S A; Carroll, P B; Fernstrom, J D; Finegold, D N

    1990-01-01

    A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake. PMID:2185278

  11. Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes

    PubMed Central

    Sharma, M D

    2015-01-01

    In individuals with advanced type 2 diabetes (T2DM), combination therapy is often unavoidable to maintain glycaemic control. Currently metformin is considered the first line of defence, but many patients experience gastrointestinal adverse events, necessitating an alternative treatment approach. Established therapeutic classes, such as sulphonylureas and thiazolidinediones, have some properties undesirable in individuals with T2DM, such as hypoglycaemia risk, weight gain and fluid retention, highlighting the need for newer agents with more favourable safety profiles that can be combined and used at all stages of T2DM. New treatment strategies have focused on both dipeptidyl peptidase (DPP)-4 inhibitors, which improve hyperglycaemia by stimulating insulin secretion in a glucose-dependent fashion and suppressing glucagon secretion, and sodium-glucose co-transporter-2 (SGLT2) inhibitors, which reduce renal glucose reabsorption and induce urinary glucose excretion, thereby lowering plasma glucose. The potential complimentary mechanism of action and good tolerance profile of these two classes of agents make them attractive treatment options for combination therapy with any of the existing glucose-lowering agents, including insulin. Together, the DPP-4 and SGLT2 inhibitors fulfill a need for treatments with mechanisms of action that can be used in combination with a low risk of adverse events, such as hypoglycaemia or weight gain. PMID:25690671

  12. Intraperitoneal administration of butyrate prevents the severity of acetic acid colitis in rats

    PubMed Central

    Malago, Joshua J.; Sangu, Catherine L.

    2015-01-01

    Intrarectal infusion of butyrate improves colorectal disorders including ulcerative colitis (UC). However, it is not established whether systemically administered butyrate benefits such patients. The current study aimed at exploring and comparing the potential of intraperitoneally, intrarectally, and orally administered butyrate against acetic acid (AA)-induced UC in rats. Intrarectal administration of 2 ml of 50% AA was done after or without prior treatment of rats for 7 consecutive days with 100 mg/kg sodium butyrate (SB) intraperitoneally, intrarectally, or orally. Rats were sacrificed after 48 h of AA-treatment. Subsequently, colon sections were processed routinely for histopathological examination. We clinically observed diarrhea, loose stools, and hemoccult-positive stools, and histologically, epithelial loss and ulceration, crypt damage, goblet cell depletion, hemorrhage, and mucosal infiltration of inflammatory cells. The changes were significantly reduced by intraperitoneal, intrarectal, or oral butyrate, with intraperitoneal butyrate exhibiting the highest potency. It is concluded that intraperitoneal administration of butyrate abrogates the lesions of AA-induced UC and its potency surpasses that of intrarectal or oral butyrate. PMID:25743124

  13. Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class?

    PubMed

    Imprialos, Konstantinos P; Sarafidis, Pantelis A; Karagiannis, Asterios I

    2015-11-01

    Diabetes mellitus is a major issue of public health, affecting more than 300 million people worldwide. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) in the renal proximal tubule are a novel class of agents for the treatment of type 2 diabetes mellitus. Inhibition of the SGLT-2 results in reduced glucose reabsorption and improvement in glycemic control. Alongside glucose excretion, SGLT-2 inhibitors also have mild natriuretic and diuretic effects, combining actions of a proximal tubule diuretic and an osmotic diuretic; these properties are expected to lead to small blood pressure (BP) reductions. Clinical studies with dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin used either as monotherapy or add-on therapy and compared with placebo or active treatment have also examined the effect of these agents on BP as a secondary endpoint. Although with some differences between individual agents, all of the approved SGLT-2 inhibitors provided a mild but meaningful reduction in office SBP and DBP. Recent studies with the use of ambulatory blood pressure monitoring suggest that the magnitude of this BP reduction can be even greater. The aim of this review is to systematically summarize and present the studies reporting the effect of approved SGLT-2 inhibitors on BP. PMID:26372321

  14. Butyrate-rich colonic microenvironment is a relevant selection factor for metabolically adapted tumor cells.

    PubMed

    Serpa, Jacinta; Caiado, Francisco; Carvalho, Tânia; Torre, Cheila; Gonçalves, Luís G; Casalou, Cristina; Lamosa, Pedro; Rodrigues, Margarida; Zhu, Zhenping; Lam, Eric W F; Dias, Sérgio

    2010-12-10

    The short chain fatty acid (SCFA) butyrate is a product of colonic fermentation of dietary fibers. It is the main source of energy for normal colonocytes, but cannot be metabolized by most tumor cells. Butyrate also functions as a histone deacetylase (HDAC) inhibitor to control cell proliferation and apoptosis. In consequence, butyrate and its derived drugs are used in cancer therapy. Here we show that aggressive tumor cells that retain the capacity of metabolizing butyrate are positively selected in their microenvironment. In the mouse xenograft model, butyrate-preselected human colon cancer cells gave rise to subcutaneous tumors that grew faster and were more angiogenic than those derived from untreated cells. Similarly, butyrate-preselected cells demonstrated a significant increase in rates of homing to the lung after intravenous injection. Our data showed that butyrate regulates the expression of VEGF and its receptor KDR at the transcriptional level potentially through FoxM1, resulting in the generation of a functional VEGF:KDR autocrine growth loop. Cells selected by chronic exposure to butyrate express higher levels of MMP2, MMP9, α2 and α3 integrins, and lower levels of E-cadherin, a marker for epithelial to mesenchymal transition. The orthotopic model of colon cancer showed that cells preselected by butyrate are able to colonize the animals locally and at distant organs, whereas control cells can only generate a local tumor in the cecum. Together our data shows that a butyrate-rich microenvironment may select for tumor cells that are able to metabolize butyrate, which are also phenotypically more aggressive. PMID:20926374

  15. Microbial electrosynthesis of butyrate from carbon dioxide.

    PubMed

    Ganigué, R; Puig, S; Batlle-Vilanova, P; Balaguer, M D; Colprim, J

    2015-02-21

    This work proves for the first time the bioelectrochemical production of butyrate from CO2 as a sole carbon source. The highest concentration of butyrate achieved was 20.2 mMC, with a maximum butyrate production rate of 1.82 mMC d(-1). The electrochemical characterisation demonstrated that the CO2 reduction to butyrate was hydrogen driven. Production of ethanol and butanol was also observed opening up the potential for biofuel production. PMID:25608945

  16. EUGLYCEMIC DIABETIC KETOACIDOSIS AND SEVERE ACUTE KIDNEY INJURY SECONDARY TO OFF LABEL USE OF SODIUM GLUCOSE COTRANSPORTER-2 INHIBITOR IN A TYPE-1 DIABETIC PATIENT.

    PubMed

    Tahir, Hassan; Wani, Adil; Daruwalla, Vistasp; Daboul, Nour; Sagi, Jahnavi

    2015-01-01

    Sodium glucose Cotransporter-2 (SGLT2) inhibitors are a new class of drug approved for the treatment of type-2 diabetes; however they are also increasingly used off label in type-1 diabetic patients. SGLT2 Inhibitors work by increasing glucose excretion in urine. Euglycemic diabetic ketoacidosis (DKA) is potentially life threatening side effect as patients have normal glucose and minimal symptoms thus delaying diagnosis and treatment. Our case report highlights the risk of using SGLT2 inhibitors in type-1 diabetes and also supports the need for long term studies to define clear efficacy and complications of SGLT 2 inhibitors in both type-1 and type 2 diabetes mellitis. PMID:27004352

  17. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

    PubMed

    Heerspink, Hiddo J L; Perkins, Bruce A; Fitchett, David H; Husain, Mansoor; Cherney, David Z I

    2016-09-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). In contrast, blood pressure lowering, estimated glomerular filtration rate, and albuminuric effects are preserved, and perhaps exaggerated in chronic kidney disease. With regard to long-term clinical outcomes, the EMPA-REG OUTCOME trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) in patients with type 2 diabetes mellitus and established cardiovascular disease randomly assigned to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital

  18. Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease.

    PubMed

    Zanoli, L; Granata, A; Lentini, P; Rastelli, S; Fatuzzo, P; Rapisarda, F; Castellino, P

    2015-01-01

    SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD) the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD. PMID:25785281

  19. Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice.

    PubMed

    Xi, Meiyang; Ge, Jun; Wang, Xiaojian; Sun, Chenbin; Liu, Tianqi; Fang, Liang; Xiao, Qiong; Yin, Dali

    2016-07-15

    Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N'-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human. PMID:27255176

  20. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

    PubMed

    Choi, Chang-Ik

    2016-01-01

    Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine. PMID:27618891

  1. EFFICACY OF SODIUM CHLORITE AS AN INHIBITOR OF ENZYMATIC BROWNING IN APPLE SLICES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sodium chlorite (SC) is an effective sanitizer for inhibiting microbial growth. This investigation was conducted to determine the efficacy of SC as a browning control agent for use on fresh-cut apple slices, applied alone, or in conjunction with organic acids. Additionally, the authors compared the ...

  2. Sodium arsenite down-regulates the expression of X-linked inhibitor of apoptosis protein via translational and post-translational mechanisms in hepatocellular carcinoma

    SciTech Connect

    Chen, Hong; Hao, Yuqing; Wang, Lijing; Jia, Dongwei; Ruan, Yuanyuan; Gu, Jianxin

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Sodium arsenite down-regulates the protein expression level of XIAP in HCC. Black-Right-Pointing-Pointer Sodium arsenite inhibits the de novo XIAP synthesis and its IRES activity. Black-Right-Pointing-Pointer Sodium arsenite decreases XIAP stability and promotes its proteasomal degradation. Black-Right-Pointing-Pointer Overexpression of XIAP attenuates the pro-apoptotic effect of sodium arsenite. -- Abstract: X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitors of apoptosis protein (IAP) family, and has been reported to exhibit elevated expression levels in hepatocellular carcinoma (HCC) and promote cell survival, metastasis and tumor recurrence. Targeting XIAP has proven effective for the inhibition of cancer cell proliferation and restoration of cancer cell chemosensitivity. Arsenic (or sodium arsenite) is a potent anti-tumor agent used to treat patients with acute promyelocytic leukemia (APL). Additionally, arsenic induces cell growth inhibition, cell cycle arrest and apoptosis in human HCC cells. In this study, we identified XIAP as a target for sodium arsenite-induced cytotoxicity in HCC. The exposure of HCC cell lines to sodium arsenite resulted in inhibition of XIAP expression in both a dose- and time-dependent manner. Sodium arsenite blocked the de novo XIAP synthesis and the activity of its internal ribosome entry site (IRES) element. Moreover, treatment with sodium arsenite decreased the protein stability of XIAP and induced its ubiquitin-proteasomal degradation. Overexpression of XIAP attenuated the pro-apoptotic effect of sodium arsenite in HCC. Taken together, our data demonstrate that sodium arsenite suppresses XIAP expression via translational and post-translational mechanisms in HCC.

  3. Vimentin, colon cancer progression and resistance to butyrate and other HDACis.

    PubMed

    Lazarova, Darina L; Bordonaro, Michael

    2016-06-01

    Dietary fibre protects against colorectal cancer (CRC) most likely through the activity of its fermentation product, butyrate. Butyrate functions as a histone deacetylase inhibitor (HDACi) that hyperactivates Wnt signalling and induces apoptosis of CRC cells. However, individuals who consume a high-fibre diet may still develop CRC; therefore, butyrate resistance may develop over time. Furthermore, CRC cells that are resistant to butyrate are cross-resistant to clinically relevant therapeutic HDACis, suggesting that the development of butyrate resistance in vivo can result in HDACi-resistant CRCs. Butyrate/HDACi-resistant CRC cells differ from their butyrate/HDACi-sensitive counterparts in the expression of many genes, including the gene encoding vimentin (VIM) that is usually expressed in normal mesenchymal cells and is involved in cancer metastasis. Interestingly, vimentin is overexpressed in butyrate/HDACi-resistant CRC cells although Wnt signalling is suppressed in such cells and that VIM is a Wnt activity-targeted gene. The expression of vimentin in colonic neoplastic cells could be correlated with the stage of neoplastic progression. For example, comparative analyses of LT97 microadenoma cells and SW620 colon carcinoma cells revealed that although vimentin is not detectable in LT97 cells, it is highly expressed in SW620 cells. Based upon these observations, we propose that the differential expression of vimentin contributes to the phenotypic differences between butyrate-resistant and butyrate-sensitive CRC cells, as well as to the differences between early-stage and metastatic colorectal neoplastic cells. We discuss the hypothesis that vimentin is a key factor integrating epithelial to mesenchymal transition, colonic neoplastic progression and resistance to HDACis. PMID:27072512

  4. Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis.

    PubMed

    Pulliam, Stephanie R; Pellom, Samuel T; Shanker, Anil; Adunyah, Samuel E

    2016-08-01

    Butyrate is a histone deacetylase inhibitor implicated in many studies as a potential therapy for various forms of cancer. High concentrations of butyrate (>1.5mM) have been shown to activate apoptosis in several cancer cell lines including prostate, breast, and leukemia. Butyrate is also known to influence multiple signaling pathways that are mediators of cytokine production. The purpose of this study was to evaluate the impact of high concentrations of butyrate on the cancer microenvironment vis-à-vis apoptosis, cellular migration, and capacity to modulate cytokine expression in cancer cells. The results indicate that high concentrations of butyrate induced a 2-fold activation of caspase-3 and reduced cell viability by 60% in U937 leukemia cells. Within 24h, butyrate significantly decreased the levels of chemokines CCL2 and CCL5 in HL-60 and U937 cells, and decreased CCL5 in THP-1 leukemia cells. Differential effects were observed in treatments with valproic acid for CCL2 and CCL5 indicating butyrate-specificity. Many of the biological effects examined in this study are linked to activation of the AKT and MAPK signaling pathways; therefore, we investigated whether butyrate alters the levels of phosphorylated forms of these signaling proteins and how it correlated with the expression of chemokines. The results show that butyrate may partially regulate CCL5 production via p38 MAPK. The decrease in p-ERK1/2 and p-AKT levels correlated with the decrease in CCL2 production. These data suggest that while promoting apoptosis, butyrate has the potential to influence the cancer microenvironment by inducing differential expression of cytokines. PMID:27253488

  5. Novel Indole-N-glucoside, TA-1887 As a Sodium Glucose Cotransporter 2 Inhibitor for Treatment of Type 2 Diabetes.

    PubMed

    Nomura, Sumihiro; Yamamoto, Yasuo; Matsumura, Yosuke; Ohba, Kiyomi; Sakamaki, Shigeki; Kimata, Hirotaka; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuaki; Ueta, Kiichiro; Tsuda-Tsukimoto, Minoru

    2014-01-01

    Inhibition of the renal sodium glucose cotransporter (SGLT) increases urinary glucose excretion (UGE) and thus reduces blood glucose levels during hyperglycemia. To explore the potential of new antihyperglycemic agents, we synthesized and determined the human SGLT2 (hSGLT2) inhibitory potential of novel substituted 3-benzylindole-N-glucosides 6. Optimization of 6 resulted in the discovery of 3-(4-cyclopropylbenzyl)-4-fluoroindole-N-glucoside 6a-4 (TA-1887), a highly potent and selective hSGLT2 inhibitor, with pronounced antihyperglycemic effects in high-fat diet-fed KK (HF-KK) mice. Our results suggest the potential of indole-N-glucosides as novel antihyperglycemic agents through inhibition of renal SGLT2. PMID:24900773

  6. Histone deacetylase inhibitors reverse manic-like behaviors and protect the rat brain from energetic metabolic alterations induced by ouabain.

    PubMed

    Lopes-Borges, Jéssica; Valvassori, Samira S; Varela, Roger B; Tonin, Paula T; Vieira, Julia S; Gonçalves, Cinara L; Streck, Emilio L; Quevedo, João

    2015-01-01

    Studies have revealed alterations in mitochondrial complexes in the brains of bipolar patients. However, few studies have examined changes in the enzymes of the tricarboxylic acid cycle. Several preclinical studies have suggested that histone deacetylase inhibitors may have antimanic effects. The present study aims to investigate the effects of lithium, valproate and sodium butyrate, a histone deacetylase inhibitor, on the activity of tricarboxylic acid cycle enzymes in the brains of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single intracerebroventricular injection of ouabain or cerebrospinal fluid. Starting on the day following the intracerebroventricular injection, the rats were treated for 7days with intraperitoneal injections of saline, lithium, valproate or sodium butyrate. Risk-taking behavior, locomotor and exploratory activities were measured using the open-field test. Citrate synthase, succinate dehydrogenase, and malate dehydrogenase were examined in the frontal cortex and hippocampus. All treatments reversed ouabain-related risk-taking behavior and hyperactivity in the open-field test. Ouabain inhibited tricarboxylic acid cycle enzymes in the brain, and valproate and sodium butyrate but not lithium reversed this ouabain-induced dysfunction. Thus, protecting the tricarboxylic acid cycle may contribute to the therapeutic effects of histone deacetylase inhibitors. PMID:25433326

  7. The effect of inhibitor sodium nitrate on pitting corrosion of dissimilar material weldment joint of stainless steel AISI 304 and mild steel SS 400

    NASA Astrophysics Data System (ADS)

    Hilca, B. R.; Triyono

    2016-03-01

    This study experimentally evaluated the effect of Sodium Nitrate inhibitor (NaNO3) of 0.1%, 0.3%, and 0.5% on NaCl 3.5% toward pitting corrosion of dissimilar metal welding joint between stainless steel AISI 304 and mild steel SS 400. Electrochemical corrosion was tested using potentiodynamic polarization. Further the Scanning Electron Microscope (SEM) conducted to analyze the specimen. Chemical composition analysis used Energy Dispersive X-ray Spectrometry (EDS). The highest efficiency of sodium nitrate for ER 308 attained 63.8% and 64.89%for ER 309L. The specimen surface which observed through SEM showed decrease of pitting corrosion respectively with the addition of sodium nitrate content as inhibitor.

  8. Mechanism of Butyrate Stimulation of Triglyceride Storage and Adipokine Expression during Adipogenic Differentiation of Porcine Stromovascular Cells.

    PubMed

    Yan, Hui; Ajuwon, Kolapo M

    2015-01-01

    Short chain fatty acids (SCFA), products of microbial fermentation of dietary fiber, exert multiple metabolic effects in cells. Previously, we had demonstrated that soluble fiber influenced fat mass accumulation, gut microbial community structure and SCFA production in pigs. The current study was designed to identify effects of SCFA treatment during adipogenic differentiation of porcine stromovascular cells on lipid metabolism and adipokine expression. Differentiating cells were treated with varying concentrations of butyrate. Results show that butyrate treatment enhanced adipogenesis and lipid accumulation, perhaps through upregulation of glucose uptake and de novo lipogenesis and other mechanisms that include induction of SREBP-1c, C/EBPα/β, GLUT4, LPL, PPARγ, GPAT4, DGAT1 and DGAT2 expression. In addition, butyrate induced adiponectin expression, resulting in activation of downstream target genes, such as AMPK and AKT. Activation of AMPK by butyrate led to phosphorylation of ACC. Although increased ACO gene expression was seen with butyrate treatment, experiments with the peroxisomal fatty acid inhibitor, thioridazine, suggest that butyrate may have an inhibitory effect on peroxisomal fatty acid oxidation. Our studies also provide evidence that butyrate may inhibit lipolysis, perhaps in an FFAR3-dependent manner. Therefore, this study presents a novel paradigm for butyrate action in adipocytes and shows that adipocytes are capable of utilizing butyrate, leading to increased expression of adiponectin for enhanced glucose uptake and improved insulin sensitivity. PMID:26713737

  9. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence

    PubMed Central

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    As type 2 diabetes mellitus (T2DM) is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP) from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I) effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM. PMID:27042423

  10. Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review

    PubMed Central

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3–5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin. PMID:26904466

  11. Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review.

    PubMed

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3-5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin. PMID:26904466

  12. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence.

    PubMed

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    As type 2 diabetes mellitus (T2DM) is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP) from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I) effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM. PMID:27042423

  13. Inter-α-inhibitor blocks epithelial sodium channel activation and decreases nasal potential differences in ΔF508 mice.

    PubMed

    Lazrak, Ahmed; Jurkuvenaite, Asta; Ness, Emily C; Zhang, Shaoyan; Woodworth, Bradford A; Muhlebach, Marianne S; Stober, Vandy P; Lim, Yow-Pin; Garantziotis, Stavros; Matalon, Sadis

    2014-05-01

    Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Inter-α-inhibitor (IαI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IαI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IαI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl(-) currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IαI in ATII cells were accompanied by increased levels of uncleaved (immature) surface α-ENaC. IαI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (∆F508), or CF transmembrane conductance regulator knockout mice with IαI for 3 hours decreased the open probability of their ENaC channels by 50%. ∆F508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IαI in their BALF. A single intranasal instillation of IαI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IαI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of ∆F508 mice. PMID:24303840

  14. Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: A comprehensive review of clinical and preclinical studies.

    PubMed

    Ghosh, Raktim Kumar; Bandyopadhyay, Dhrubajyoti; Hajra, Adrija; Biswas, Monodeep; Gupta, Anjan

    2016-06-01

    Diabetes is a leading cause of morbidity and mortality worldwide. Management of diabetes is changing at a rapid pace. Three new classes of antidiabetic drugs including GLP-1 (Glucagon-like peptide 1), DPP-IV (Dipeptidyl peptidase IV) and SGLT2 (Sodium glucose cotransporter 2) inhibitors have been approved in the last few years. Treating diabetes with the antidiabetic drug does not always reduce the cardiovascular complications of diabetes. On the contrary, there was a huge controversy regarding the effect of rosiglitazone on cardiovascular risk reduction a few years ago. Since then, submission of postmarketing cardiovascular outcome study data has been mandated by US FDA and other drug regulatory agencies for newer antidiabetic medications. This is to avoid further premature claims regarding cardiovascular harm or safety of the newer classes. We already have some cardiovascular safety data available on DPP-IV and GLP-1 groups of medications. Dapagliflozin, canagliflozin, and empagliflozin are currently approved SGLT2 inhibitors. We do not have sufficient cardiovascular outcome data available for this novel class. However, this group of drugs, which act by increasing renal glucose excretion, have also shown some non-glycemic benefits including weight reduction, blood pressure control, diuretic action, renal protection, decrease in arterial stiffness and uric acid reduction. Empagliflozin, a new member of SGLT2 class, showed significant cardiovascular morbidity and mortality benefit in recently published EMPA-REG OUTCOME trial. The authors summarize all the published clinical and preclinical cardiovascular outcome data of SGLT2 inhibitors, including recently completed and ongoing major clinical trials in this comprehensive review. PMID:27017118

  15. Butyric acid in irritable bowel syndrome.

    PubMed

    Załęski, Andrzej; Banaszkiewicz, Aleksandra; Walkowiak, Jarosław

    2013-01-01

    Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS. PMID:24868283

  16. Butyric acid in irritable bowel syndrome

    PubMed Central

    Załęski, Andrzej; Walkowiak, Jarosław

    2013-01-01

    Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS. PMID:24868283

  17. Butyrate and glucose metabolism by colonocytes in experimental colitis in mice

    PubMed Central

    Ahmad, M; Krishnan, S; Ramakrishna, B; Mathan, M; Pulimood, A; Murthy, S

    2000-01-01

    BACKGROUND/AIMS—Impaired colonocyte metabolism of butyrate has been implicated in the aetiopathogenesis of ulcerative colitis. Colonocyte butyrate metabolism was investigated in experimental colitis in mice.
METHODS—Colitis was induced in Swiss outbred white mice by oral administration of 4% dextran sulphate sodium (DSS). Colonocytes isolated from colitic and normal control mice were incubated with [14C]butyrate or glucose, and production of 14CO2, as well as of intermediate metabolites (acetoacetate, β-hydroxybutyrate and lactate), was measured. The effect of different substrate concentrations on oxidation was also examined.
RESULTS—Butyrate oxidation (µmol/h per mg protein; mean (SEM)) was significantly reduced in DSS colitis, values on day 7 of DSS administration being 0.177 (0.007) compared with 0.406 (0.035) for control animals (p<0.001). Glucose oxidation (µmol/h per mg protein; mean (SEM)) on day 7 of DSS administration was significantly higher than in controls (0.06 (0.006) v 0.027 (0.004), p<0.001). Production of β-hydroxybutyrate was decreased and production of lactate increased in DSS colitis compared with controls. Increasing butyrate concentration from 10 to 80 mM enhanced oxidation in DSS colitis (0.036 (0.002) to 0.285 (0.040), p<0.001), although it continued to remain lower than in controls. Surface and crypt epithelial cells showed similar ratios of butyrate to glucose oxidation. When 1 mM DSS was added to normal colonocytes in vitro, it did not alter butyrate oxidation. The initial histological lesion of DSS administration was very patchy and involved crypt cells. Abnormal butyrate oxidation became apparent only after six days of DSS administration, at which time histological abnormalities were more widespread.
CONCLUSIONS—Colonocyte metabolism of butyrate, but not of glucose, is impaired in DSS colitis, and may be important in pathophysiology. Histological abnormalities preceded measurable defects in butyrate

  18. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

    SciTech Connect

    Sharma, Bhupesh Sharma, P.M.

    2013-11-15

    Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in

  19. Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger

    PubMed Central

    Lorrain, Janine; Briand, Véronique; Favennec, Evelyne; Duval, Nicole; Grosset, Alain; Janiak, Philip; Hoornaert, Christian; Cremer, Gérard; Latham, Christopher; O'Connor, Stephen E

    2000-01-01

    The NHE1 isoform of the Na+/H+ exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na+/H+ antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide.Recovery of pHi following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na+/H+ exchanger. pHi recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC50 3.3±1.3 nM) versus NHE2-expressing cells (2.3±1.0 μM). The respective IC50 values for cariporide were 103±28 nM (NHE1) and 73±46 μM (NHE2).In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10–100 μg kg−1 min−1 i.v.) inhibited ischaemia-mediated ventricular tachycardia (71–100%) and reperfusion-induced ventricular fibrillation (75–87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg−1) produced anti-arrhythmic effects when administered either before or during ischaemia.Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2±3.4% (control group) versus 15.3±3.9% (SL 59.1227 0.6 mg kg−1 i.v.).SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na+/H+ exchanger inhibitor. It possesses marked cardioprotective properties. PMID:11082127

  20. Accumulation of heme oxygenase-1 (HSP32) in Xenopus laevis A6 kidney epithelial cells treated with sodium arsenite, cadmium chloride or proteasomal inhibitors.

    PubMed

    Music, Ena; Khan, Saad; Khamis, Imran; Heikkila, John J

    2014-11-01

    The present study examined the effect of sodium arsenite, cadmium chloride, heat shock and the proteasomal inhibitors MG132, withaferin A and celastrol on heme oxygenase-1 (HO-1; also known as HSP32) accumulation in Xenopus laevis A6 kidney epithelial cells. Immunoblot analysis revealed that HO-1 accumulation was not induced by heat shock but was enhanced by sodium arsenite and cadmium chloride in a dose- and time-dependent fashion. Immunocytochemistry revealed that these metals induced HO-1 accumulation in a granular pattern primarily in the cytoplasm. Additionally, in 20% of the cells arsenite induced the formation of large HO-1-containing perinuclear structures. In cells recovering from sodium arsenite or cadmium chloride treatment, HO-1 accumulation initially increased to a maximum at 12h followed by a 50% reduction at 48 h. This initial increase in HO-1 levels was likely the result of new synthesis as it was inhibited by cycloheximide. Interestingly, treatment of cells with a mild heat shock enhanced HO-1 accumulation induced by low concentrations of sodium arsenite and cadmium chloride. Finally, we determined that HO-1 accumulation was induced in A6 cells by the proteasomal inhibitors, MG132, withaferin A and celastrol. An examination of heavy metal and proteasomal inhibitor-induced HO-1 accumulation in amphibians is of importance given the presence of toxic heavy metals in aquatic habitats. PMID:25064141

  1. Sodium-glucose cotransport inhibitors: mechanisms, metabolic effects and implications for the treatment of diabetic patients with chronic kidney disease.

    PubMed

    Vlotides, George; Mertens, Peter R

    2015-08-01

    Remarkable progress has been achieved in the field of diabetes with the development of incretin analogues, dipeptidyl peptidase IV inhibitors and novel insulin analogues; nevertheless, there is an unmet need for additional therapeutic options. Individualization of HbA1c target levels is a recent progress within the field. Approximately 50% of diabetics do not reach a previously aspired treatment goal of glycosylated HbA1 levels below 7% and often face a vicious circle with accelerated weight gain. Current antidiabetic therapeutics mainly target the decline in insulin secretion and ameliorate insulin resistance. In this regard a new generation of drugs, denoted gliflozines, that specifically interfere with sodium-glucose cotransporters (SGLT)-2 and exhibit a favourable impact on glucose metabolism in patients with type 2 diabetes are emerging as hopeful avenues. The resultant negative energy balance caused by glucosuria results in long-term weight losses, significantly reduced HbA1c levels approximating 0.5-1.0% and may in addition exert beneficial effects on blood pressure, reactive oxygen products and inflammatory mediators. Recent studies indicate improvement in β-cell glucose sensitivity and insulin sensitivity in patients treated with gliflozines, a decrease in tissue glucose disposal and interestingly an increase in endogenous glucose production. The list of side effects observed under SGLT2 inhibition includes increased rates of genitourinary infections, balanitis, vulvovaginitis, hypotensive episodes and acute deterioration of kidney function. Main questions towards the safety profile are still unanswered given that long-term clinical outcome data with SGLT2 inhibition are lacking and the cardiovascular safety profile is under scrutiny in large trials. Thus, the successful development of selective SGLT2 inhibitors for therapeutic use in diabetics has a huge potential to meet patients' needs. However, it awaits quick results from clinical trials with

  2. Pharmacophore modeling, virtual screening and 3D-QSAR studies of 5-tetrahydroquinolinylidine aminoguanidine derivatives as sodium hydrogen exchanger inhibitors.

    PubMed

    Bhatt, Hardik G; Patel, Paresh K

    2012-06-01

    Sodium hydrogen exchanger (SHE) inhibitor is one of the most important targets in treatment of myocardial ischemia. In the course of our research into new types of non-acylguanidine, SHE inhibitory activities of 5-tetrahydroquinolinylidine aminoguanidine derivatives were used to build pharmacophore and 3D-QSAR models. Genetic Algorithm Similarity Program (GASP) was used to derive a 3D pharmacophore model which was used in effective alignment of data set. Eight molecules were selected on the basis of structure diversity to build 10 different pharmacophore models. Model 1 was considered as the best model as it has highest fitness score compared to other nine models. The obtained model contained two acceptor sites, two donor atoms and one hydrophobic region. Pharmacophore modeling was followed by substructure searching and virtual screening. The best CoMFA model, representing steric and electrostatic fields, obtained for 30 training set molecules was statistically significant with cross-validated coefficient (q(2)) of 0.673 and conventional coefficient (r(2)) of 0.988. In addition to steric and electrostatic fields observed in CoMFA, CoMSIA also represents hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. CoMSIA model was also significant with cross-validated coefficient (q(2)) and conventional coefficient (r(2)) of 0.636 and 0.986, respectively. Both models were validated by an external test set of eight compounds and gave satisfactory prediction (r(pred)(2)) of 0.772 and 0.701 for CoMFA and CoMSIA models, respectively. This pharmacophore based 3D-QSAR approach provides significant insights that can be used to design novel, potent and selective SHE inhibitors. PMID:22546667

  3. Euglycemic Diabetic Ketoacidosis in a 27 year-old female patient with type-1-Diabetes treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor Canagliflozin.

    PubMed

    Bader, Nimrah; Mirza, Lubna

    2016-01-01

    We are reporting a timely case of atypical euglycemic diabetic ketoacidosis in a type 1 diabetic patient treated with sodium-glucose cotransporter-2 (SGLT-2) inhibitor canagliflozin. The clinical history, physical examination findings and laboratory values are described. Other causes of acidosis such as salicylate toxicity or alcohol intoxication were excluded. Ketoacidosis resolved after increasing dextrose and insulin doses supporting the hypothesis that SGLT-2 inhibitors may lead to hypoinsulinemia. Euglycemic ketoacidosis did not recur in our patient after discontinuing canagliflozin. We recommend reserving SGLT2 inhibitor therapy to type 2 diabetics, discontinuing medication and treating patients presenting with ketoacidosis due to SGLT-2 inhibitors with higher concentrations of dextrose with appropriate doses of insulin to help resolve acidosis. PMID:27375734

  4. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet.

    PubMed

    Hayami, Tomohide; Kato, Yoshiro; Kamiya, Hideki; Kondo, Masaki; Naito, Ena; Sugiura, Yukako; Kojima, Chika; Sato, Sami; Yamada, Yuichiro; Kasagi, Rina; Ando, Toshihito; Noda, Saeko; Nakai, Hiromi; Takada, Eriko; Asano, Emi; Motegi, Mikio; Watarai, Atsuko; Kato, Koichi; Nakamura, Jiro

    2015-09-01

    We present a case of a 32-year-old diabetic woman with Prader-Willi syndrome who developed severe ketoacidosis caused by a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a novel class of antihyperglycemic agents, during a strict low-carbohydrate diet. At admission, a serum glucose level of 191 mg/dL was relatively low, though laboratory evaluations showed severe ketoacidosis. This is the first report of ketoacidosis caused by a SGLT2 inhibitor. It is necessary to not only pay attention when using a SGLT2 inhibitor in patients following a low-carbohydrate diet, but also to start a low-carbohydrate diet in patients treated with a SGLT2 inhibitor because of a high risk for developing ketoacidosis. PMID:26417418

  5. Euglycemic Diabetic Ketoacidosis in a 27 year-old female patient with type-1-Diabetes treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor Canagliflozin

    PubMed Central

    Bader, Nimrah; Mirza, Lubna

    2016-01-01

    We are reporting a timely case of atypical euglycemic diabetic ketoacidosis in a type 1 diabetic patient treated with sodium-glucose cotransporter-2 (SGLT-2) inhibitor canagliflozin. The clinical history, physical examination findings and laboratory values are described. Other causes of acidosis such as salicylate toxicity or alcohol intoxication were excluded. Ketoacidosis resolved after increasing dextrose and insulin doses supporting the hypothesis that SGLT-2 inhibitors may lead to hypoinsulinemia. Euglycemic ketoacidosis did not recur in our patient after discontinuing canagliflozin. We recommend reserving SGLT2 inhibitor therapy to type 2 diabetics, discontinuing medication and treating patients presenting with ketoacidosis due to SGLT-2 inhibitors with higher concentrations of dextrose with appropriate doses of insulin to help resolve acidosis. PMID:27375734

  6. The Future of Butyric Acid in Industry

    PubMed Central

    Dwidar, Mohammed; Park, Jae-Yeon; Mitchell, Robert J.; Sang, Byoung-In

    2012-01-01

    In this paper, the different applications of butyric acid and its current and future production status are highlighted, with a particular emphasis on the biofuels industry. As such, this paper discusses different issues regarding butyric acid fermentations and provides suggestions for future improvements and their approaches. PMID:22593687

  7. Short-chain fatty acids and colon cancer cells: the vitamin D receptor--butyrate connection.

    PubMed

    Gaschott, Tanja; Stein, Jürgen

    2003-01-01

    Butyrate and its prodrug tributyrin, as well as 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), have important physiological effects on proliferation and differentiation in a variety of malignant cells. The aim of this study was to elucidate the role of the vitamin D receptor (VDR) in butyrate-induced cell differentiation and cell cycle arrest in Caco-2 cells, a human colon cancer cell line. Cell differentiation was evaluated by analyzing the activity of alkaline phosphatase (AP). Protein of VDR, cyclins, cyclin-dependent kinases (cdks) and of cdk inhibitors was quantified by Western blot analysis, VDR-mRNA by PCR. Pre- and postconfluent cells were assessed for VDR binding activity. Cell cycle was analyzed by flow cytometry. Tributyrin significantly increased VDR-mRNA level (250% vs. control) and VDR binding activity. Butyrate also enhanced VDR protein content in the nucleus in a time- and dose-dependent manner and more potently than other short-chain fatty acids of a related structure. Both butyrate (640% vs. control) and 1,25-(OH)2D3 (350% vs. control) significantly stimulated differentiation, whereas combined treatment with butyrate and 1,25-(OH)2D3 resulted in a synergistic amplification of AP activity (1400% vs. control). In the presence of the VDR antagonist ZK 191732, butyrate-induced differentiation was completely abolished (150% vs. control). While butyrate alone increased p21Waf1/Cip1 expression and down-regulated cdk 6 and cyclin A, and combined exposure with 1,25-(OH)2D3 resulted in a synergistic enhancement of butyrate-induced changes, expressions did not change from control level after treatment with butyrate and ZK 191732. G1 cell cycle arrest induced by butyrate was also abolished after combined treatment with butyrate and ZK 191732. In conclusion, differentiation and cell cycle arrest of Caco-2 cells induced by butyrate are mediated by up-regulation of VDR, followed by a stimulation of the negative cell cycle regulator p21Waf1/Cip1 and by a down

  8. Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease

    PubMed Central

    Sanchez, Ramiro A; Sanabria, Hugo; de los Santos, Cecilia; Ramirez, Agustin J

    2015-01-01

    Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real

  9. Incretins and selective renal sodium-glucose co-transporter 2 inhibitors in hypertension and coronary heart disease.

    PubMed

    Sanchez, Ramiro A; Sanabria, Hugo; de Los Santos, Cecilia; Ramirez, Agustin J

    2015-09-10

    Hyperglycemia is associated with an increased risk of cardiovascular disease, and the consequences of intensive therapy may depend on the mechanism of the anti-diabetic agent(s) used to achieve a tight control. In animal models, stable analogues of glucagon-like peptide-1 (GLP-1) were able to reduce body weight and blood pressure and also had favorable effects on ischemia following coronary reperfusion. In a similar way, dipeptidyl peptidase IV (DPP-IV) showed to have favorable effects in animal models of ischemia/reperfusion. This could be due to the fact that DPP-IV inhibitors were able to prevent the breakdown of GLP-1 and glucose-dependent insulinotropic polypeptide, but they also decreased the degradation of several vasoactive peptides. Preclinical data for GLP-1, its derivatives and inhibitors of the DPP-IV enzyme degradation suggests that these agents may be able to, besides controlling glycaemia, induce cardio-protective and vasodilator effects. Notwithstanding the many favorable cardiovascular effects of GLP-1/incretins reported in different studies, many questions remain unanswered due the limited number of studies in human beings that aim to examine the effects of GLP-1 on cardiovascular endpoints. For this reason, long-term trials searching for positive cardiovascular effects are now in process, such as the CAROLINA and CARMELINA trials, which are supported by small pilot studies performed in humans (and many more animal studies) with incretin-based therapies. On the other hand, selective renal sodium-glucose co-transporter 2 inhibitors were also evaluated in the prevention of cardiovascular outcomes in type 2 diabetes. However, it is quite early to draw conclusions, since data on cardiovascular outcomes and cardiovascular death are limited and long-term studies are still ongoing. In this review, we will analyze the mechanisms underlying the cardiovascular effects of incretins and, at the same time, we will present a critical position about the real

  10. Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation

    PubMed Central

    Kelkar, Madhura G.; Senthilkumar, Kalimuthu; Jadhav, Smita; Gupta, Sudeep; Ahn, Beyong-Cheol; De, Abhijit

    2016-01-01

    The aberrant expression of human sodium iodide symporter (NIS) in breast cancer (BC) has raised the possibility of using targeted radioiodide therapy. Here we investigate modulation of endogenous, functional NIS expression by histone deacetylase inhibitors (HDACi) in vitro and in vivo. Luciferase reporter based initial screening of six different HDACi shows 2–10 fold enhancement of NIS promoter activity in majority of the cell types tested. As a result of drug treatment, endogenous NIS transcript and protein shows profound induction in BC cells. To get an insight on the mechanism of such transcriptional activation, role of Stat4, CREB and other transcription factors are revealed by transcription factor profiling array. Further, NIS-mediated intracellular iodide uptake also enhances substantially (p < 0.05) signifying functional relevance of the transcriptional modulation strategy. Gamma camera imaging confirms 30% higher uptake in VPA or NaB treated BC tumor xenograft. Corroborating with such functional impact of NIS, significant reduction in cell survival (p < 0.005) is observed in VPA, NaB or CI994 drug and 131I combination treatment in vivo indicating effective radioablation. Thus, for the first time this study reveals the mechanistic basis and demonstrates functional relevance of HDACi pre-treatment strategy in elevating NIS gene therapy approach for BC management in clinic. PMID:26777440

  11. Diabetic Ketoacidosis in a Patient with Type 2 Diabetes After Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Treatment.

    PubMed

    Storgaard, Heidi; Bagger, Jonatan I; Knop, Filip K; Vilsbøll, Tina; Rungby, Jørgen

    2016-02-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were recently introduced for the treatment of type 2 diabetes (T2D). SGLT2i lower plasma glucose by inhibiting the renal reuptake of glucose leading to glucosuria. Generally, these drugs are considered safe to use. However, recently, SGLT2i have been suggested to predispose to ketoacidosis. Here, we present a case of diabetic ketoacidosis (DKA) developed in an obese, poorly controlled male patient with T2D treated with the SGLT2i dapagliflozin. He was admitted with DKA 5 days after the initiation of treatment with the SGLT2i dapagliflozin. On admission, the primary symptoms were nausea and dizziness, and he was hypertensive (170/103) and tachycardic (119 bpm) and had mild hyperglycaemia (15.3 mmol/l), severe ketonuria and severe metabolic acidosis (pH 7.08). He responded well to infusions of insulin, glucose and saline and was discharged after 72 hr with insulin as the only glucose-lowering therapy. After 1 month, dapagliflozin was reintroduced as add-on to insulin with no recurrent signs of ketoacidosis. During acute illness or other conditions with increased insulin demands in diabetes, SGLT2i may predispose to the formation of ketone bodies and ensuing acidosis. PMID:26291182

  12. Sodium-glucose co-transporter-2 inhibitors as add-on therapy to insulin: rationale and evidences.

    PubMed

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are recently approved class of anti-hyperglycaemic agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT-2I inhibits renal glucose reabsorption, thereby ensuing urinary glucose excretion in a dose-dependent manner. This caloric loss and osmotic diuresis, secondary to increased urinary glucose excretion, has a unique potential to counter insulin induced weight gain and fluid retention, with little potential of hypoglycemic exacerbation. Also, as these agents act independently of insulin secretion or action, they are effective even in long-standing diabetes with depleted β-cell reserve. Improvement in insulin sensitivity, as observed with SGLT-2I can also facilitate insulin action. Furthermore, significant reduction in total daily insulin dosage and reduction of body weight as observed during combination therapy renders SGLT-2I, a near-ideal partner to insulin. This review aims to evaluate the safety and efficacy of currently used SGLT-2I as an add-on to insulin therapy in the treatment of T2DM. PMID:26732230

  13. Exposure−response modelling for empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes

    PubMed Central

    Riggs, Matthew M; Seman, Leo J; Staab, Alexander; MacGregor, Thomas R; Gillespie, William; Gastonguay, Marc R; Woerle, Hans J; Macha, Sreeraj

    2014-01-01

    Aims To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure−response (E−R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM). Methods Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E−R. Results The efficacy model predicted maximal decreases in FPG and HbA1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl−1) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation. Conclusions E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy. PMID:24964723

  14. The Novel Role of the Kidney in Diabetes Management: Sodium-Glucose Co-Transporter 2 Inhibitors.

    PubMed

    Swislocki, Arthur L M; Jialal, Ishwarlal

    2015-09-01

    The global epidemic of diabetes continues to progress, despite efforts of public health agencies and health care systems to identify and treat impacted patients. Although lifestyle is the cornerstone of treatment, there is an array of pharmacologic agents now available, many in classes that did not exist a few years ago. In addition to insulin and its secretogogues, such as sulfonylureas, there are agents that improve insulin action, reduce gastric emptying, reduce glucagon concentrations, and sympathetic nervous system activity. A novel class recently entering the fray includes drugs that interfere with renal glucose reabsorption. These drugs, collectively called sodium-glucose co-transporter 2 (SGLT2) inhibitors, are available both as single agents and in various combinations. They work by promoting glycosuria and may have benefits that extend beyond lowering glycemia, such as weight loss and blood pressure reduction. This review focuses on several of these new agents and considers their efficacy and potential side effects. We address drugs approved for use in the United States at the time of this writing (March, 2015), but do not address recently approved combination agents. PMID:25893855

  15. SKW 6.4 cell differentiation induced by interleukin 6 is stimulated by butyrate.

    PubMed

    Kawamoto, T; Gohda, E; Iji, H; Fujiwara, M; Yamamoto, I

    1998-08-01

    We investigated if sodium butyrate (NaBu), an inhibitor of histone deacetylase, and its analogs modulate cytokine-induced differentiation of the human B cell line SKW 6.4 transformed by the Epstein-Barr virus. NaBu markedly enhanced interleukin (IL)-6-induced IgM production with an accompanying increase in the level of histone H4 acetylation and augmented IgM production induced by IL-4 and phorbol 12-myristate 13-acetate. From both the enhancing effect of cell differentiation and the effect of inducing histone hyperacetylation in SKW 6.4 cells, other histone deacetylase inhibitors and NaBu analogs were divided into three groups: those that increased both IL-6-induced antibody production and histone acetylation, those that caused histone hyperacetylation, but failed to induce the differentiation, and those that were ineffective at inducing either activity. No agent that enhanced IgM production without inducing histone hyperacetylation was found among the inhibitors and analogs we tested. These results suggest that the increase in the histone acetylation is necessary, but it is insufficient to augment differentiation of SKW 6.4 cells. Thus another activity of NaBu in addition to the inhibition of histone deacetylase may be involved in promoting IL-6-induced differentiation. Our results also suggest that fatty acids that have a straight chain of four carbon atoms or are branched with four and five carbon atoms, which contain no hydrophilic substituents, or those with similar structures, show this other activity. PMID:9826026

  16. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  17. Activation of PPAR{gamma} is not involved in butyrate-induced epithelial cell differentiation

    SciTech Connect

    Ulrich, S.; Waechtershaeuser, A.; Loitsch, S.; Knethen, A. von; Bruene, B.; Stein, J. . E-mail: j.stein@em.uni-frankfurt.de

    2005-10-15

    Histone deacetylase-inhibitors affect growth and differentiation of intestinal epithelial cells by inducing expression of several transcription factors, e.g. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) or vitamin D receptor (VDR). While activation of VDR by butyrate mainly seems to be responsible for cellular differentiation, the activation of PPAR{gamma} in intestinal cells remains to be elucidated. The aim of this study was to determine the role of PPAR{gamma} in butyrate-induced cell growth inhibition and differentiation induction in Caco-2 cells. Treatment with PPAR{gamma} ligands ciglitazone and BADGE (bisphenol A diglycidyl) enhanced butyrate-induced cell growth inhibition in a dose- and time-dependent manner, whereas cell differentiation was unaffected after treatment with PPAR{gamma} ligands rosiglitazone and MCC-555. Experiments were further performed in dominant-negative PPAR{gamma} mutant cells leading to an increase in cell growth whereas butyrate-induced cell differentiation was again unaffected. The present study clearly demonstrated that PPAR{gamma} is involved in butyrate-induced inhibition of cell growth, but seems not to play an essential role in butyrate-induced cell differentiation.

  18. Involvement of the Antioxidant Effect and Anti-inflammatory Response in Butyrate-Inhibited Vascular Smooth Muscle Cell Proliferation

    PubMed Central

    Mathew, Omana P.; Ranganna, Kasturi; Milton, Shirlette G.

    2014-01-01

    Epigenetic mechanisms by altering the expression and, in turn, functions of target genes have potential to modify cellular processes that are characteristics of atherosclerosis, including inflammation, proliferation, migration and apoptosis/cell death. Butyrate, a natural epigenetic modifier and a histone deacetylase inhibitor (HDACi), is an inhibitor of vascular smooth muscle cell (VSMC) proliferation, a critical event in atherogenesis. Here, we examined whether glutathione peroxidases (GPxs), a family of antioxidant enzymes, are modulated by butyrate, contributing to its antiproliferation action on VSMC through the regulation of the inflammatory response by using western blotting, immunostaining methods and activity assay. Treatment of VSMC with butyrate not only upregulates glutathione peroxidase (GPx) 3 and GPx4, but also increases the overall catalytic activity of GPx supporting involvement of antioxidant effect in butyrate arrested VSMC proliferation. Moreover, analysis of the redox-sensitive NF-κB transcription factor system, the target of GPx, reveals that butyrate causes downregulation of IKKα, IKKβ, IkBα and NF-κBp65 expression and prevents NF-κBp65 phosphorylation at serine536 causing inhibition of the expression NF-κB target inflammatory genes, including inducible nitric oxide synthase, VCAM-1 and cyclooxygenase-2. Overall, these observations suggest a link between the antioxidant effect and anti-inflammatory response in butyrate-arrested VSMC proliferation, accentuating the atheroprotective and therapeutic potential of natural products, like butyrate, in vascular proliferative diseases. PMID:25390157

  19. Restricted Distribution of the Butyrate Kinase Pathway among Butyrate-Producing Bacteria from the Human Colon

    PubMed Central

    Louis, Petra; Duncan, Sylvia H.; McCrae, Sheila I.; Millar, Jacqueline; Jackson, Michelle S.; Flint, Harry J.

    2004-01-01

    The final steps in butyrate synthesis by anaerobic bacteria can occur via butyrate kinase and phosphotransbutyrylase or via butyryl-coenzyme A (CoA):acetate CoA-transferase. Degenerate PCR and enzymatic assays were used to assess the presence of butyrate kinase among 38 anaerobic butyrate-producing bacterial isolates from human feces that represent three different clostridial clusters (IV, XIVa, and XVI). Only four strains were found to possess detectable butyrate kinase activity. These were also the only strains to give PCR products (verifiable by sequencing) with degenerate primer pairs designed within the butyrate kinase gene or between the linked butyrate kinase/phosphotransbutyrylase genes. Further analysis of the butyrate kinase/phosphotransbutyrylase genes of one isolate, L2-50, revealed similar organization to that described previously from different groups of clostridia, along with differences in flanking sequences and phylogenetic relationships. Butyryl-CoA:acetate CoA-transferase activity was detected in all 38 strains examined, suggesting that it, rather than butyrate kinase, provides the dominant route for butyrate formation in the human colonic ecosystem that contains a constantly high concentration of acetate. PMID:15028695

  20. Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor.

    PubMed

    Devineni, Damayanthi; Polidori, David

    2015-10-01

    The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose

  1. Non-occlusive Mesenteric Ischemia with Diabetic Ketoacidosis and Lactic Acidosis Following the Administration of a Sodium Glucose Co-transporter 2 Inhibitor.

    PubMed

    Gocho, Naoki; Aoki, Ema; Okada, Chiho; Omura, Kazuki; Hirashima, Takeshi; Suzuki, Natsuko; Tanaka, Hideki; Omori, Yasue

    2016-01-01

    We herein describe a patient with non-occlusive mesenteric ischemia (NOMI) potentially associated with the administration of a sodium glucose co-transporter 2 (SGLT2) inhibitor. A 60-year-old man with type 1 diabetes was transferred to our hospital due to vomiting and respiratory distress. He was treated with insulin, metformin and a SGLT2 inhibitor, which had recently been added. He was diagnosed with intestinal ischemia complicated by diabetic ketoacidosis and lactic acidosis. Urgent exploratory surgery was performed, and the gangrenous bowel was resected. Histological findings confirmed the diagnosis of NOMI. The administration of SGLT2 inhibitors therefore requires certain exceptions for type 1 diabetes and cautious monitoring for the occurrence of these possible adverse effects. PMID:27374678

  2. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

    PubMed

    Lazar, Alexandra; Lenkey, Nora; Pesti, Krisztina; Fodor, Laszlo; Mike, Arpad

    2015-01-01

    The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively. PMID:26441665

  3. Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2.

    PubMed

    Ohgaki, Ryuichi; Wei, Ling; Yamada, Kazunori; Hara, Taiki; Kuriyama, Chiaki; Okuda, Suguru; Ueta, Kiichiro; Shiotani, Masaharu; Nagamori, Shushi; Kanai, Yoshikatsu

    2016-07-01

    Canagliflozin, a selective sodium/glucose cotransporter (SGLT) 2 inhibitor, suppresses the renal reabsorption of glucose and decreases blood glucose level in patients with type 2 diabetes. A characteristic of canagliflozin is its modest SGLT1 inhibitory action in the intestine at clinical dosage. To reveal its mechanism of action, we investigated the interaction of canagliflozin with SGLT1 and SGLT2. Inhibition kinetics and transporter-mediated uptake were examined in human SGLT1- or SGLT2-expressing cells. Whole-cell patch-clamp recording was conducted to examine the sidedness of drug action. Canagliflozin competitively inhibited SGLT1 and SGLT2, with high potency and selectivity for SGLT2. Inhibition constant (Ki) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively. (14)C-canagliflozin was suggested to be transported by SGLT2; however, the transport rate was less than that of α-methyl-d-glucopyranoside. Canagliflozin inhibited α-methyl-d-glucopyranoside-induced SGLT1- and SGLT2-mediated inward currents preferentially from the extracellular side and not from the intracellular side. Based on the Ki value, canagliflozin is estimated to sufficiently inhibit SGLT2 from the urinary side in renal proximal tubules. The Ki value for SGLT1 suggests that canagliflozin suppresses SGLT1 in the small intestine from the luminal side, whereas it does not affect SGLT1 in the heart and skeletal muscle, considering the maximal concentration of plasma-unbound canagliflozin. Similarly, SGLT1 in the kidney would not be inhibited, thereby aiding in the prevention of hypoglycemia. After binding to SGLT2, canagliflozin may be reabsorbed by SGLT2, which leads to the low urinary excretion and prolonged drug action of canagliflozin. PMID:27189972

  4. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway

    PubMed Central

    Lazar, Alexandra; Lenkey, Nora; Pesti, Krisztina; Fodor, Laszlo; Mike, Arpad

    2015-01-01

    The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One-way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3, and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone, and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa) of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule), which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel). Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively. PMID:26441665

  5. Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor.

    PubMed

    Deng, Meichun; Luo, Xuan; Jiang, Liping; Chen, Hanchun; Wang, Jun; He, Hailun; Liang, Songping

    2013-09-01

    Huwentoxin-IV (HWTX-IV, also named Mu-theraphotoxin-Hh2a) is a typical inhibitor cystine knot peptide isolated from the venom of Chinese tarantula Ornithoctonus huwena and is found to inhibit tetrodotoxin-sensitive (TTX-S) sodium channels from mammalian sensory neurons. This peptide binds to neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II in neuronal sodium channels. However, the molecular surface of HWTX-IV interaction with sodium channels remains unknown. In this study, we synthesized HWTX-IV and three mutants (T28D, R29A and Q34D) and characterized their functions on TTX-S sodium channels from adult rat dorsal root ganglion (DRG) neurons. Analysis of liquid chromatography, mass spectrometry and circular dichroism spectrum indicated that all four synthetic peptides are properly folded. Synthetic HWTX-IV exhibited the same activity as native HWTX-IV, while three mutations reduced toxin binding affinities by 10-200 fold, indicating that the basic or vicinal polar residues Thr²⁸, Arg²⁹, and Gln³⁴ in C-terminus might play critical roles in the interaction of HWTX-IV with TTX-S sodium channels. PMID:23726857

  6. Increased Systolic and Diastolic Blood Pressure Is Associated With Altered Gut Microbiota Composition and Butyrate Production in Early Pregnancy.

    PubMed

    Gomez-Arango, Luisa F; Barrett, Helen L; McIntyre, H David; Callaway, Leonie K; Morrison, Mark; Dekker Nitert, Marloes

    2016-10-01

    The risk of developing pregnancy-induced hypertension and preeclampsia is higher in obese pregnant women. In obesity, the composition of the gut microbiota is altered. Obesity is also associated with low-grade inflammation. Metabolites from the gut microbiota may contribute to both hypertension and inflammation. The aim of this study is to investigate whether the composition of the gut microbiota in overweight and obese pregnant women is associated with blood pressure and levels of plasminogen activator inhibitor-1. The composition of the gut microbiota was determined with 16S ribosomal RNA sequencing in 205 women at 16 weeks gestation from the SPRING study (the Study of Probiotics in Gestational Diabetes). Expression of butyrate-producing genes in the gut microbiota was assessed by real-time polymerase chain reaction. Plasminogen activator inhibitor-1 levels were measured in fasting serum of a subset of 70 women. Blood pressure was slightly but significantly higher in obese compared with overweight women. The abundance of the butyrate-producing genus Odoribacter was inversely correlated with systolic blood pressure. Butyrate production capacity was decreased, but plasminogen activator inhibitor-1 concentrations increased in obese pregnant women. Plasminogen activator inhibitor-1 levels were inversely correlated with expression of butyrate kinase and Odoribacter abundance. This study shows that in overweight and obese pregnant women at 16 weeks gestation, the abundance of butyrate-producing bacteria and butyrate production in the gut microbiota is significantly negatively associated with blood pressure and with plasminogen activator inhibitor-1 levels. Increasing butyrate-producing capacity may contribute to maintenance of normal blood pressure in obese pregnant women. PMID:27528065

  7. The Intestinal Epithelial Cell Differentiation Marker Intestinal Alkaline Phosphatase (ALPi) Is Selectively Induced by Histone Deacetylase Inhibitors (HDACi) in Colon Cancer Cells in a Kruppel-like Factor 5 (KLF5)-dependent Manner*

    PubMed Central

    Shin, Joongho; Carr, Azadeh; Corner, Georgia A.; Tögel, Lars; Dávaos-Salas, Mercedes; Tran, Hoanh; Chueh, Anderly C.; Al-Obaidi, Sheren; Chionh, Fiona; Ahmed, Naseem; Buchanan, Daniel D.; Young, Joanne P.; Malo, Madhu S.; Hodin, Richard A.; Arango, Diego; Sieber, Oliver M.; Augenlicht, Leonard H.; Dhillon, Amardeep S.; Weber, Thomas K.; Mariadason, John M.

    2014-01-01

    The histone deacetylase inhibitor (HDACi) sodium butyrate promotes differentiation of colon cancer cells as evidenced by induced expression and enzyme activity of the differentiation marker intestinal alkaline phosphatase (ALPi). Screening of a panel of 33 colon cancer cell lines identified cell lines sensitive (42%) and resistant (58%) to butyrate induction of ALP activity. This differential sensitivity was similarly evident following treatment with the structurally distinct HDACi, MS-275. Resistant cell lines were significantly enriched for those harboring the CpG island methylator phenotype (p = 0.036, Chi square test), and resistant cell lines harbored methylation of the ALPi promoter, particularly of a CpG site within a critical KLF/Sp regulatory element required for butyrate induction of ALPi promoter activity. However, butyrate induction of an exogenous ALPi promoter-reporter paralleled up-regulation of endogenous ALPi expression across the cell lines, suggesting the presence or absence of a key transcriptional regulator is the major determinant of ALPi induction. Through microarray profiling of sensitive and resistant cell lines, we identified KLF5 to be both basally more highly expressed as well as preferentially induced by butyrate in sensitive cell lines. KLF5 overexpression induced ALPi promoter-reporter activity in resistant cell lines, KLF5 knockdown attenuated butyrate induction of ALPi expression in sensitive lines, and butyrate selectively enhanced KLF5 binding to the ALPi promoter in sensitive cells. These findings demonstrate that butyrate induction of the cell differentiation marker ALPi is mediated through KLF5 and identifies subsets of colon cancer cell lines responsive and refractory to this effect. PMID:25037223

  8. Butyrate production from high-fiber diet protects against lymphoma tumor.

    PubMed

    Wei, Wei; Sun, Wei; Yu, Shanshan; Yang, Yu; Ai, Limei

    2016-10-01

    Gut microbiota and dietary fiber are critical for protecting body from obesity, diabetes and cancer. Butyrate, produced in the gut by bacterial fermentation of dietary fibers, is demonstrated to be protective against the development of colorectal cancer as a histone deacetylase (HDAC) inhibitor. We report that high-fiber diet and butyrate significantly inhibited the growth lymphoma tumors. Butyrate induced apoptosis of lymphoma tumor cells and significantly up-regulated histone 3 acetylation (H3ac) level and target genes such as Fas, P21, P27. Our results unravel an instrumental role of fiber diet and their metabolites on lymphoma tumor and demonstrate an intervention potential on the prevention and therapy of lymphoma. PMID:26885564

  9. Evolution of the corrosion process of AA 2024-T3 in an alkaline NaCl solution with sodium dodecylbenzenesulfonate and lanthanum chloride inhibitors

    NASA Astrophysics Data System (ADS)

    Zhou, Biner; Wang, Yishan; Zuo, Yu

    2015-12-01

    The evolution of the corrosion process of AA 2024-T3 in 0.58 g L-1 NaCl solution (pH 10) with sodium dodecylbenzenesulfonate (SDBS) and lanthanum chloride inhibitors was studied with electrochemical and surface analysis methods. With the addition of the compounded LaCl3 and SDBS inhibitors, in the early stage the polarization behavior of AA 2024-T3 changed from active corrosion to passivation, and both the general corrosion and pitting corrosion were inhibited. However, with the immersion time extended, the passive behavior gradually disappeared and pitting happened at the Cu-rich phases. After 24 h immersion, the compounded inhibitors still showed good inhibition for general corrosion, but the polarization curve again presented the characteristic similar to active polarization. The compounded inhibitors also inhibited the pitting corrosion to some extent. The acting mechanism of the inhibitors SDBS and La3Cl on the corrosion process of AA 2024-T3 in the test solution was discussed.

  10. Characterization of butyrate transport across the luminal membranes of equine large intestine.

    PubMed

    Nedjadi, Taoufik; Moran, Andrew W; Al-Rammahi, Miran A; Shirazi-Beechey, Soraya P

    2014-10-01

    The diet of the horse, pasture forage (grass), is fermented by the equine colonic microbiota to short-chain fatty acids, notably acetate, propionate and butyrate. Short-chain fatty acids provide a major source of energy for the horse and contribute to many vital physiological processes. We aimed to determine both the mechanism of butyrate uptake across the luminal membrane of equine colon and the nature of the protein involved. To this end, we isolated equine colonic luminal membrane vesicles. The abundance and activity of cysteine-sensitive alkaline phosphatase and villin, intestinal luminal membrane markers, were significantly enriched in membrane vesicles compared with the original homogenates. In contrast, the abundance of GLUT2 protein and the activity of Na(+)-K(+)-ATPase, known markers of the intestinal basolateral membrane, were hardly detectable. We demonstrated, by immunohistochemistry, that monocarboxylate transporter 1 (MCT1) protein is expressed on the luminal membrane of equine colonocytes. We showed that butyrate transport into luminal membrane vesicles is energized by a pH gradient (out < in) and is not Na(+) dependent. Moreover, butyrate uptake is time and concentration dependent, with a Michaelis-Menten constant of 5.6 ± 0.45 mm and maximal velocity of 614 ± 55 pmol s(-1) (mg protein)(-1). Butyrate transport is significantly inhibited by p-chloromercuribenzoate, phloretin and α-cyano-4-hydroxycinnamic acid, all potent inhibitors of MCT1. Moreover, acetate and propionate, as well as the monocarboxylates pyruvate and lactate, also inhibit butyrate uptake. Data presented here support the conclusion that transport of butyrate across the equine colonic luminal membrane is predominantly accomplished by MCT1. PMID:25172888

  11. Molecular pathways: gene-environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention.

    PubMed

    Bultman, Scott J

    2014-02-15

    Gene-environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low-moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression. PMID:24270685

  12. The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

    PubMed Central

    2013-01-01

    Background Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. Methods A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing. Results Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Conclusions/interpretation Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. Trial registration ClinicalTrials.gov: NCT01195675 PMID:23617452

  13. The SCFA butyrate stimulates the epithelial production of retinoic acid via inhibition of epithelial HDAC.

    PubMed

    Schilderink, Ronald; Verseijden, Caroline; Seppen, Jurgen; Muncan, Vanesa; van den Brink, Gijs R; Lambers, Tim T; van Tol, Eric A; de Jonge, Wouter J

    2016-06-01

    In the intestinal mucosa, retinoic acid (RA) is a critical signaling molecule. RA is derived from dietary vitamin A (retinol) through conversion by aldehyde dehydrogenases (aldh). Reduced levels of short-chain fatty acids (SCFAs) are associated with pathological microbial dysbiosis, inflammatory disease, and allergy. We hypothesized that SCFAs contribute to mucosal homeostasis by enhancing RA production in intestinal epithelia. With the use of human and mouse epithelial cell lines and primary enteroids, we studied the effect of SCFAs on the production of RA. Functional RA conversion was analyzed by Adlefluor activity assays. Butyrate (0-20 mM), in contrast to other SCFAs, dose dependently induced aldh1a1 or aldh1a3 transcript expression and increased RA conversion in human and mouse epithelial cells. Epithelial cell line data were replicated in intestinal organoids. In these organoids, butyrate (2-5 mM) upregulated aldh1a3 expression (36-fold over control), whereas aldh1a1 was not significantly affected. Butyrate enhanced maturation markers (Mucin-2 and villin) but did not consistently affect stemness markers or other Wnt target genes (lgr5, olfm4, ascl2, cdkn1). In enteroids, the stimulation of RA production by SCFA was mimicked by inhibitors of histone deacetylase 3 (HDAC3) but not by HDAC1/2 inhibitors nor by agonists of butyrate receptors G-protein-coupled receptor (GPR)43 or GPR109A, indicating that butyrate stimulates RA production via HDAC3 inhibition. We conclude that the SCFA butyrate inhibits HDAC3 and thereby supports epithelial RA production. PMID:27151945

  14. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Metabolic Parameters in Patients With Type 2 Diabetes: A Chart-Based Analysis

    PubMed Central

    Katsuyama, Hisayuki; Hamasaki, Hidetaka; Adachi, Hiroki; Moriyama, Sumie; Kawaguchi, Akiko; Sako, Akahito; Mishima, Shuichi; Yanai, Hidekatsu

    2016-01-01

    Background Effects of the new class of anti-diabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, on metabolic parameters in patients with type 2 diabetes remain largely unknown. Methods We retrospectively picked up patients who had been continuously prescribed SGLT2 inhibitors for 1 month or more between April 2014 and November 2015 by a chart-based analysis, and compared the data before the SGLT2 inhibitor treatment with the data at 1, 2, 3 and 6 months after the SGLLT2 inhibitor treatment started. Results Fifty patients were eligible for the analyses in our study. The HbA1c levels as well as body weight significantly decreased at 1, 2, 3 and 6 months after the start of SGLT2 inhibitors. Systolic blood pressure tended to decrease only at 1 and 2 months, but there was no change at 3 and 6 months. No significant change was observed in serum high-density lipoprotein-cholesterol (HDL-C), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and non-HDL-C levels. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels significantly decreased at 3 and 6 months after the prescription. The hematocrit levels significantly increased at 1, 2, 3 and 6 months, and the estimated glomerular filtration rate (eGFR) levels significantly decreased at 1 month after the start of SGLT2 inhibitors. A significant correlation between reductions in HbA1c levels and HbA1c levels at baseline was observed at 1, 3 and 6 months. The decreases in serum ALT levels were also significantly correlated with the baseline ALT levels at 3 and 6 months. Conclusion Present study demonstrated that SGLT2 inhibitors significantly reduced HbA1c and body weight and improved liver functions, whereas no significant change was observed in serum lipid profiles. PMID:26858798

  15. A sodium-glucose co-transporter 2 inhibitor empagliflozin prevents abnormality of circadian rhythm of blood pressure in salt-treated obese rats.

    PubMed

    Takeshige, Yui; Fujisawa, Yoshihide; Rahman, Asadur; Kittikulsuth, Wararat; Nakano, Daisuke; Mori, Hirohito; Masaki, Tsutomu; Ohmori, Koji; Kohno, Masakazu; Ogata, Hiroaki; Nishiyama, Akira

    2016-06-01

    Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states. PMID:26818652

  16. [Sodium-glucose co-transporter-2 inhibitors: from the bark of apple trees and familial renal glycosuria to the treatment of type 2 diabetes mellitus].

    PubMed

    Mauricio, Dídac

    2013-09-01

    The therapeutic armamentarium for the treatment of hyperglycemia in type 2 diabetes mellitus is still inadequate. We are currently witnessing the introduction of a new mode of hypoglycemic treatment through induction of glycosuria to decrease the availability of the metabolic substrate, i.e. glucose. Clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors are as efficacious as other oral hypoglycemic drugs. This article discusses the basic features of this new treatment concept and the efficacy and safety of this new drug group. PMID:24444522

  17. Effects of butyrate on the expression of insulin-like growth factor binding proteins in bovine kidney epithelial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sodium butyrate induces cell cycle arrest and apoptosis in bovine kidney epithelial cells primarily via down-regulating cell cycle-related gene expression and enhancing expression of pro-apoptotic genes. The insulin-like growth factor (IGF) system plays an essential role in these processes as well a...

  18. An overview of the effect of sodium glucose cotransporter 2 inhibitor monotherapy on glycemic and other clinical laboratory parameters in type 2 diabetes patients

    PubMed Central

    Wang, Yaowen; Hu, Xueting; Liu, Xueying; Wang, Zengqi

    2016-01-01

    Objectives We aimed to determine the effect of sodium glucose cotransporter 2 (SGLT2) inhibitor monotherapy on glycemic and other clinical laboratory parameters versus other antidiabetic medications or placebo therapy in patients with type 2 diabetes mellitus. In addition, we aimed to investigate the risk of diabetic ketoacidosis associated with SGLT2 inhibitor therapy and evaluate its weight-sparing ability. Design Meta-analysis. Materials and methods PubMed and MEDLINE were searched to identify eligible studies up to December 2015. Randomized controlled trials that assessed the efficacy and safety of SGLT2 inhibitor monotherapy versus placebo therapy or active control were considered. The Cochrane Collaboration Risk of Bias Tool was used to evaluate quality and bias. The mean difference was used to evaluate the glycemic and other clinical laboratory parameters for SGLT2 inhibitor intervention versus control by drugs or placebo. Similarly, the risk ratio was used to assess adverse events, and the I2 was used to evaluate heterogeneity. Results SGLT2 inhibitors significantly decreased glycated hemoglobin (HbA1c) (P<0.001), weight (P<0.001), and the low-density lipoprotein/high-density lipoprotein ratio (P=0.03) compared with placebo therapy. No statistically significant changes were found in fasting plasma glucose, 2-hour postprandial glucose, or lipid parameters. Significant changes in the uric acid level were found for SGLT2 inhibitors versus placebo therapy (P=0.005) or active control (P<0.001). Although no significant change in levels of ketones occurred (P=0.93), patients receiving SGLT2 inhibitors were at greater risk of increased ketone bodies. Events suggestive of urinary tract infection and pollakiuria presented the greatest risk for patients receiving SGLT2 inhibitors versus active control or placebo therapy. Conclusion SGLT2 inhibitors significantly decreased HbA1c, body weight, and the low-density lipoprotein/high-density lipoprotein ratio and were found

  19. Sodium-glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes.

    PubMed

    Schwartz, Stanley S; Ahmed, Intekhab

    2016-05-01

    Objective The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D. Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D. Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension. Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2

  20. A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds.

    PubMed

    Rong, Mingqiang; Liu, Jiangxin; Zhang, Meilin; Wang, Gan; Zhao, Gang; Wang, Guodong; Zhang, Yaping; Hu, Kaifeng; Lai, Ren

    2016-01-01

    Members of arachnida, such as spiders and scorpions, commonly produce venom with specialized venom glands, paralyzing their prey with neurotoxins that specifically target ion channels. Two well-studied motifs, the disulfide-directed hairpin (DDH) and the inhibitor cystine knot motif (ICK), are both found in scorpion and spider toxins. As arachnids, ticks inject a neurotoxin-containing cocktail from their salivary glands into the host to acquire a blood meal, but peptide toxins acting on ion channels have not been observed in ticks. Here, a new neurotoxin (ISTX-I) that acts on sodium channels was identified from the hard tick Ixodes scapularis and characterized. ISTX-I exhibits a potent inhibitory function with an IC50 of 1.6 μM for sodium channel Nav1.7 but not other sodium channel subtypes. ISTX-I adopts a novel structural fold and is distinct from the canonical ICK motif. Analysis of the ISTX-I, DDH and ICK motifs reveals that the new ISTX-I motif might be an intermediate scaffold between DDH and ICK, and ISTX-I is a clue to the evolutionary link between the DDH and ICK motifs. These results provide a glimpse into the convergent evolution of neurotoxins from predatory and blood-sucking arthropods. PMID:27407029

  1. A sodium channel inhibitor ISTX-I with a novel structure provides a new hint at the evolutionary link between two toxin folds

    PubMed Central

    Rong, Mingqiang; Liu, Jiangxin; Zhang, Meilin; Wang, Gan; Zhao, Gang; Wang, Guodong; Zhang, Yaping; Hu, Kaifeng; Lai, Ren

    2016-01-01

    Members of arachnida, such as spiders and scorpions, commonly produce venom with specialized venom glands, paralyzing their prey with neurotoxins that specifically target ion channels. Two well-studied motifs, the disulfide-directed hairpin (DDH) and the inhibitor cystine knot motif (ICK), are both found in scorpion and spider toxins. As arachnids, ticks inject a neurotoxin-containing cocktail from their salivary glands into the host to acquire a blood meal, but peptide toxins acting on ion channels have not been observed in ticks. Here, a new neurotoxin (ISTX-I) that acts on sodium channels was identified from the hard tick Ixodes scapularis and characterized. ISTX-I exhibits a potent inhibitory function with an IC50 of 1.6 μM for sodium channel Nav1.7 but not other sodium channel subtypes. ISTX-I adopts a novel structural fold and is distinct from the canonical ICK motif. Analysis of the ISTX-I, DDH and ICK motifs reveals that the new ISTX-I motif might be an intermediate scaffold between DDH and ICK, and ISTX-I is a clue to the evolutionary link between the DDH and ICK motifs. These results provide a glimpse into the convergent evolution of neurotoxins from predatory and blood-sucking arthropods. PMID:27407029

  2. Feed-drug interaction of orally applied butyrate and phenobarbital on hepatic cytochrome P450 activity in chickens.

    PubMed

    Mátis, G; Kulcsár, A; Petrilla, J; Hermándy-Berencz, K; Neogrády, Zs

    2016-08-01

    The expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes may be affected by several nutrition-derived compounds, such as by the commonly applied feed additive butyrate, possibly leading to feed-drug interactions. The aim of this study was to provide some evidence if butyrate can alter the activity of hepatic CYPs in chickens exposed to CYP-inducing xenobiotics, monitoring for the first time the possibility of such interaction. Ross 308 chickens in the grower phase were treated with daily intracoelomal phenobarbital (PB) injection (80 mg/kg BW), applied as a non-specific CYP-inducer, simultaneously with two different doses of intra-ingluvial sodium butyrate boluses (0.25 and 1.25 g/kg BW) for 5 days. Activity of CYP2H and CYP3A subfamilies was assessed by specific enzyme assays from isolated liver microsomes. According to our results, the lower dose of orally administered butyrate significantly attenuated the PB-triggered elevation of both hepatic CYP2H and CYP3A activities, which might be in association with the partly common signalling pathways of butyrate and CYP-inducing drugs, such as that of PB. Based on these data, butyrate may take part in pharmacoepigenetic interactions with simultaneously applied drugs or other CYP-inducing xenobiotics, with possible consequences for food safety and pharmacotherapy. Butyrate was found to be capable to maintain physiological CYP activity by attenuating CYP induction, underlining the safety of butyrate application in poultry nutrition. PMID:26614344

  3. Treatment of Elderly Hypertensive Patients with Epithelial Sodium Channel Inhibitors Combined with a Thiazide Diuretic Reduces Coronary Mortality and Sudden Cardiac Death

    PubMed Central

    Hebert, Patricia R.; Coffey, Christopher S.; Byrne, Daniel W.; Scott, Theresa A.; Fagard, Robert H.; Rottman, Jeffrey N.; Murray, Katherine T.; Oates, John A.

    2008-01-01

    Background No reduction in either coronary mortality or sudden cardiac death (SCD) has been demonstrated in overviews of randomized trials of treatment of hypertension with diuretics. Methods An overview was conducted of coronary mortality and SCD in randomized controlled antihypertensive trials in which an epithelial sodium channel (ENaC) inhibitor/ hydrochlorthiazide (HCTZ) combination was used. Secondarily, an analogous overview in which thiazide diuretic was used alone was performed. Randomized trials that used an ENaC inhibitor/ HCTZ combination (or, alternatively, thiazide diuretic alone) were identified from previous meta-analyses, searches of PubMed, search of the Cochrane Clinical Trials database, and review of publications that addressed the consequences of treating hypertension. Trials in which participants were randomized to either an ENaC inhibitor combined with a thiazide diuretic (or to a thiazide diuretic alone) or to control treatment for at least one year and in which coronary mortality was reported were included. Numbers of events in individual trials were abstracted independently by 2 authors. Results Significant reductions in both coronary mortality and SCD were observed in the overview of trials in which elderly patients received an ENaC inhibitor/ HCTZ combination. The odds ratio (OR) for coronary mortality was 0.59 (95% confidence interval [CI] 0.44, 0.78) and for SCD was 0.60 (95% CI 0.38, 0.94). In contrast, an overview of the trials using thiazide diuretics alone showed no significant reductions of either coronary mortality (OR 0.94; 95% CI 0.81, 1.09) or SCD (OR 1.27; 95% CI 0.93, 1.75). Conclusions Use of an ENaC inhibitor combined with HCTZ for treatment of hypertension in the elderly results in favorable effects on coronary mortality and SCD. PMID:19727429

  4. Practical considerations for the use of sodium-glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes.

    PubMed

    Lam, Karen S L; Chow, Chun Chung; Tan, Kathryn C B; Ma, Ronald C W; Kong, Alice P S; Tong, Peter C Y; Tsang, Man Wo; Chan, Tak Mao; Tang, Sydney C W; Lee, Ka Kui; So, Wing Yee; Tomlinson, Brian

    2016-06-01

    Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term. PMID:26933918

  5. Catalytic upgrading of butyric acid towards fine chemicals and biofuels

    PubMed Central

    Sjöblom, Magnus; Matsakas, Leonidas; Christakopoulos, Paul; Rova, Ulrika

    2016-01-01

    Fermentation-based production of butyric acid is robust and efficient. Modern catalytic technologies make it possible to convert butyric acid to important fine chemicals and biofuels. Here, current chemocatalytic and biocatalytic conversion methods are reviewed with a focus on upgrading butyric acid to 1-butanol or butyl-butyrate. Supported Ruthenium- and Platinum-based catalyst and lipase exhibit important activities which can pave the way for more sustainable process concepts for the production of green fuels and chemicals. PMID:26994015

  6. Synthesis and evaluation of poly(Sodium 2-Acrylamido-2-Methylpropane Sulfonate-co-Styrene)/magnetite nanoparticle composites as corrosion inhibitors for steel.

    PubMed

    El-Mahdy, Gamal A; Atta, Ayman M; Al-Lohedan, Hamad A

    2014-01-01

    Self-stabilized magnetic polymeric composite nanoparticles of coated poly-(sodium 2-acrylamido-2-methylpropane sulfonate-co-styrene)/magnetite (PAMPS-Na-co-St/Fe3O4) were prepared by emulsifier-free miniemulsion polymerization using styrene (St) as a monomer, 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na) as an ionic comonomer, N,N-methylenebisacrylamide (MBA) as crosslinker, hexadecane (HD) as a hydrophobic solvent, and 2,2-azodiisobutyronitrile (AIBN) as an initiator in the presence of hydrophobic oleic acid coated magnetite particles. Hydrophobic oleic acid coated magnetite particles with an average size of about 7-10 nm were prepared with the new modified water-based magnetite ferrofluid, synthesized by a chemical modified coprecipitation method. The morphology and the particle size distributions of the crosslinked PAMPS-Na-co-St/Fe3O4 composite were observed and analyzed by transmission electron microscopy (TEM). The average Fe3O4 content of PAMPS-Na-co-St/Fe3O4 was determined by thermogravimetric analysis (TGA). The inhibitory action of PAMPS-Na-co-St/Fe3O4 towards steel corrosion in 1 M HCl solutions has been investigated by polarization and electrochemical impedance spectroscopy (EIS) methods. Polarization measurements indicate that PAMPS-Na-co-St/Fe3O4 acts as a mixed type-inhibitor and the inhibition efficiency increases with inhibitor concentration. The results of potentiodynamic polarization and EIS measurements clearly showed that the inhibition mechanism involves blocking of the steel surface by inhibitor molecules via adsorption. PMID:24487568

  7. Searching for Synbiotics to increase Colonic Butyrate Concentration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate is produced by microbial fermentation of plant fiber in the gut and a preferred substrate for gut epithelial cells. In ruminants, butyrate contributes to 70% of energy metabolism. In monogastric species, butyrate also plays an important role in energy metabolism in the hindgut. Moreover, bu...

  8. Identification of novel inhibitors of the steroid sulfate carrier 'sodium-dependent organic anion transporter' SOAT (SLC10A6) by pharmacophore modelling.

    PubMed

    Grosser, Gary; Baringhaus, Karl-Heinz; Döring, Barbara; Kramer, Werner; Petzinger, Ernst; Geyer, Joachim

    2016-06-15

    The sodium-dependent organic anion transporter SOAT specifically transports sulfated steroid hormones and is supposed to play a role in testicular steroid regulation and male fertility. The present study aimed to identify novel specific SOAT inhibitors for further in vitro and in vivo studies on SOAT function. More than 100 compounds of different molecular structures were screened for inhibition of the SOAT-mediated transport of dehydroepiandrosterone sulfate in stably transfected SOAT-HEK293 cells. Twenty-five of these with IC50 values covering four orders of magnitude were selected as training set for 3D pharmacophore modelling. The SOAT pharmacophore features were calculated by CATALYST and consist of three hydrophobic sites and two hydrogen bond acceptors. By substrate database screening, compound T 0511-1698 was predicted as a novel SOAT inhibitor with an IC50 of 15 μM. This value was confirmed by cell-based transport assays. Therefore, the developed SOAT pharmacophore model demonstrated its suitability in predicting novel SOAT inhibitors. PMID:27033324

  9. [Effects of histone deacetylase inhibitor sodium valproate on the physical and behavioral development of 129SV mice].

    PubMed

    Burenkova, O V; Aleksandrova, E A; Zarayskaya, I Yu

    2015-01-01

    Sodium valproate is a widely used antiepileptic drug at high dosage levels, but it has been shown to produce a variety of toxic side-effects when used during perinatal period. These effects include increased risk of congenital anomalies and autism. For this reason, valproate is commonly employed in animal model of autism. Sodium valproate has multiple molecular targets including histone deacetylases. Therefore valproate can be utilized as a tool for the modulation of epigenetic modifications of the genome via inhibition of histone deacetylases. It is known that administration of sodium valproate at a dose of 50 mg/kg during early postnatal period leads to increase of the histone H3 acetylation level in the brain. The aim of the present study was to evaluate the effects of multiple valproate injections from 3rd to 6th postnatal day (50 mg/kg s.c.) on physical and sensorimotor development of 129Sv mice. The standard battery of tests was used. Our results show that valproate have no negative effect on physical development, sensorimotor function, and social behavior. The obtained results support the applicability of sodium valproate in our dosing schedule for further experimental modulation of histone acetulation level in the developing brain. PMID:26571806

  10. Biogas Production on Demand Regulated by Butyric Acid Addition

    NASA Astrophysics Data System (ADS)

    Kasper, K.; Schiffels, J.; Krafft, S.; Kuperjans, I.; Elbers, G.; Selmer, T.

    2016-03-01

    Investigating effects of volatile fatty acids on the biogas process it was observed that butyric acid can be used for transient stimulation of the methane production in biogas plants operating with low energy substrates like cattle manure. Upon addition of butyrate the methane output of the reactors doubled within 24 h and reached almost 3-times higher methane yields within 3-4 days. Butyrate was quantitatively eliminated and the reactors returned to the original productivity state within 3 days when application of butyrate was stopped. The opportunity to use butyrate feeding for increased biogas production on demand is discussed.

  11. Benefits/risks of sodium-glucose co-transporter 2 inhibitor canagliflozin in women for the treatment of Type 2 diabetes.

    PubMed

    Kushner, Pamela

    2016-06-01

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin, are used in patients with Type 2 diabetes mellitus (T2DM). In clinical studies, canagliflozin significantly reduced A1C, bodyweight and blood pressure, and was generally well tolerated with no increased risk of hypoglycemia. Most common adverse effects observed were genital mycotic infections and urinary tract infections, and increased urination. Approximately 10% of women treated with canagliflozin experienced a genital mycotic infection compared with 3% treated with placebo; those with a prior history were at greater risk. Approximately 9% of women treated with canagliflozin reported a urinary tract infection compared with 7% treated with placebo. Most adverse events were considered mild to moderate in intensity and responded to standard therapy. Treatment with canagliflozin was effective and generally well tolerated in both women (and men) with T2DM. PMID:26928259

  12. Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine.

    PubMed

    Koltun, Dmitry O; Parkhill, Eric Q; Elzein, Elfatih; Kobayashi, Tetsuya; Jiang, Robert H; Li, Xiaofen; Perry, Thao D; Avila, Belem; Wang, Wei-Qun; Hirakawa, Ryoko; Smith-Maxwell, Catherine; Wu, Lin; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Stafford, Brian; Tang, Jennifer; Belardinelli, Luiz; Zablocki, Jeff A

    2016-07-01

    Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333nM) that has a good separation of late versus peak Nav1.5 current, but did not have a favorable CNS safety window due to high brain penetration (3-fold higher partitioning into brain vs plasma) coupled with potent inhibition of brain sodium channel isoforms (Nav1.1, 1.2, 1.3). We increased the polar surface area from 50 to 84Å(2) by adding a carbonyl to the core and an oxadiazole ring resulting in 3 GS-462808 that had lower brain penetration and serendipitously lower activity at the brain isoforms. Compound 3 has an improved CNS window (>20 rat and dog) relative to 2, and improved anti-ischemic potency relative to ranolazine. The development of 3 was not pursued due to liver lesions in 7day rat toxicology studies. PMID:27038498

  13. N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors.

    PubMed

    Chu, Kuang-Feng; Yao, Chun-Hsu; Song, Jen-Shin; Chen, Chiung-Tong; Yeh, Teng-Kuang; Hsieh, Tsung-Chih; Huang, Chung-Yu; Wang, Min-Hsien; Wu, Szu-Huei; Chang, Wei-En; Chao, Yu-Sheng; Lee, Jinq-Chyi

    2016-05-15

    Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats. PMID:27075813

  14. Blood pressure, intraerythrocyte content, and transmembrane fluxes of sodium during normal and high salt intake in subjects with and without a family history of hypertension: evidence against a sodium transport inhibitor.

    PubMed

    Gudmundsson, O; Andersson, O; Herlitz, H; Jonsson, O; Nauclér, J; Wikstrand, J; Berglund, G

    1984-01-01

    Seventeen young normotensive men with a family history of hypertension in two generations (H) and 15 age-matched control subjects (C) were studied with respect to blood pressure (BP), intraerythrocyte sodium content (IeNa), sodium influx, and rate of sodium efflux. The investigations were done during normal salt intake and after 4 weeks of ordinary intake plus 12 g NaCl daily. BP did not increase significantly in either of the two groups during increased salt intake. During normal salt intake H had a significantly (p less than 0.01) higher IeNa (9.5 +/- 1.5 mmol/L) compared with C (8.2 +/- 1.4 mmol/L). During high salt intake IeNa in H decreased significantly to 8.1 +/- 1.2 mmol/L, the difference from C (7.6 +/- 1.2 mmol/L) not being significant. While the Na influx was similar in the two groups, the rate constant for Na efflux was significantly lower during normal salt intake in H (0.23 +/- 0.08 vs 0.29 +/- 0.1 h-1, p less than 0.05). Salt intake increased the efflux rate constant significantly in H (0.28 +/- 0.08 h-1, p less than 0.05), while it did not change significantly in C (0.32 +/- 0.08 h-1) compared with the value for normal salt intake. Our results suggest that young men with a hereditary predisposition to hypertension have a higher IeNa secondary to a lower rate of Na efflux, while a normal Na influx indicates normal cell permeability to Na. The findings in H during high Na intake--a decreased IeNa and an increased efflux rate of Na--do not favor the existence of a sodium transport inhibitor, in subjects predisposed to hypertension, increasing during high salt intake and volume expansion and acting through inhibition of the Na efflux. PMID:6204156

  15. Carboxymethyl Cellulose Acetate Butyrate: A Review of the Preparations, Properties, and Applications

    PubMed Central

    Kamel, Samir; Salama, Ahmed; Sarhan, Hebat-Allah

    2014-01-01

    Carboxymethyl cellulose acetate butyrate (CMCAB) has gained increasing importance in several fields, particularly in coating technologies and pharmaceutical research. CMCAB is synthesized by esterification of CMC sodium salt with acetic and butyric anhydrides. CMCAB mixed esters are relatively high molecular weight (MW) thermoplastic polymers with high glass transition temperatures (Tg). CMCAB ester is dispersible in water and soluble in a wide range of organic solvents, allowing varied opportunity to the solvent choice. It makes application of coatings more consistent and defect-free. Its ability to slow down the release rate of highly water-soluble compounds and to increase the dissolution of poorly soluble compounds makes CMCAB a unique and potentially valuable tool in pharmaceutical and amorphous solid dispersions (ASD) formulations. PMID:25548679

  16. Concentration of clobetasone butyrate in aqueous humour.

    PubMed Central

    Debnath, S C; Richards, A B

    1983-01-01

    The concentrations of clobetasone butyrate and betamethasone were measured in aqueous humour of patients undergoing cataract extraction 12.5 to 18.5 hours after application into the lower conjunctival sac of an ointment containing 0.1% of the steroid. Samples were assayed from 10 patients receiving clobetasone butyrate and 13 patients receiving betamethasone phosphate. There were measurable concentrations in only 2 samples in the former group, and both were 0.1 ng/ml. In the betamethasone group measurable concentrations were found in 11 samples, and the concentrations ranged from 0.5 to 20.3 ng/ml, with the highest concentrations between 12.5 and 13.5 hours after application. The concentration of betamethasone in the aqueous humour decreased by about 90% in the 6 hours from 12.5 to 18.5 hours after application. It is speculative as to whether it is these differences in pharmacokinetic behaviour, or other differences in biological or physicochemical properties, which are responsible for the minimal effect on intraocular pressure induced by clobetasone butyrate compared with betamethasone. PMID:6824626

  17. Synthesis of L-rhamnose derived chiral bicyclic triazoles as novel sodium-glucose transporter (SGLT) inhibitors.

    PubMed

    Putapatri, Siddamal Reddy; Kanwal, Abhinav; Sridhar, Balasubramanian; Banerjee, Sanjay K; Kantevari, Srinivas

    2014-11-14

    Herein we describe the synthesis of a series of novel fused bicyclic 1,2,3-triazoles from commercially available, natural deoxy sugar, L-rhamnose. The key reactions involved are (i) Zn(OTf)2 catalyzed enantioselective alkynylation of L-rhamnose derived azidoaldehyde and (ii) deprotection of the acid sensitive 1,2-isopropylidene group followed by in situ intramolecular click-cycloaddition of azidoalkynols. Some compounds exhibit excellent sodium-glucose transporter (SGLT1 and SGLT2) inhibition activity. PMID:25175761

  18. Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin-metformin.

    PubMed

    Schwartz, Stanley S; Katz, Arie

    2016-01-01

    In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy. PMID:27042132

  19. Forces and Dynamics of Glucose and Inhibitor Binding to Sodium Glucose Co-transporter SGLT1 Studied by Single Molecule Force Spectroscopy*

    PubMed Central

    Neundlinger, Isabel; Puntheeranurak, Theeraporn; Wildling, Linda; Rankl, Christian; Wang, Lai-Xi; Gruber, Hermann J.; Kinne, Rolf K. H.; Hinterdorfer, Peter

    2014-01-01

    Single molecule force spectroscopy was employed to investigate the dynamics of the sodium glucose co-transporter (SGLT1) upon substrate and inhibitor binding on the single molecule level. CHO cells stably expressing rbSGLT1 were probed by using atomic force microscopy tips carrying either thioglucose, 2′-aminoethyl β-d-glucopyranoside, or aminophlorizin. Poly(ethylene glycol) (PEG) chains of different length and varying end groups were used as tether. Experiments were performed at 10, 25 and 37 °C to address different conformational states of SGLT1. Unbinding forces between ligands and SGLT1 were recorded at different loading rates by changing the retraction velocity, yielding binding probability, width of energy barrier of the binding pocket, and the kinetic off rate constant of the binding reaction. With increasing temperature, width of energy barrier and average life time increased for the interaction of SGLT1 with thioglucose (coupled via acrylamide to a long PEG) but decreased for aminophlorizin binding. The former indicates that in the membrane-bound SGLT1 the pathway to sugar translocation involves several steps with different temperature sensitivity. The latter suggests that also the aglucon binding sites for transport inhibitors have specific, temperature-sensitive conformations. PMID:24962566

  20. Effects of 5-azacytidine and butyrate on differentiation and apoptosis of hepatic cancer cell lines.

    PubMed Central

    Wang, X M; Wang, X; Li, J; Evers, B M

    1998-01-01

    OBJECTIVE: To determine the cellular effects of 5-azacytidine (5-azaC) and sodium butyrate on two human liver cancers, HepG2 and Hep3B. SUMMARY BACKGROUND DATA: Primary liver cancer is a significant health problem; treatment options are limited and prognosis is poor. Recent studies have focused on the role that programmed cell death (i.e., apoptosis) plays in both normal and neoplastic growth: certain genes can either suppress (e.g., Bcl-2, Bcl-xL) or promote (e.g., Bik, Bax, Bak) apoptosis. The identification of novel agents targeted to specific molecular pathways may be beneficial in the treatment of this disease. METHODS: Human liver cancer cell lines HepG2 and Hep3B were treated with 5-azaC alone, butyrate alone, or 5-azaC and butyrate. Morphologic and proliferative changes were assessed by light microscopy and 5-bromo-2'-deoxyuridine staining; flow cytometry was used to determine cell cycle characteristics. Apoptosis was assessed by DNA laddering and the in situ apoptosis detection assay using the TdT-mediated dUTP nick end labeling method. In addition, total RNA and protein were analyzed by ribonuclease protection and Western blot, respectively, to assess changes in the expression of apoptosis-related genes. RESULTS: Treatment with either 5-azaC or butyrate inhibited cell growth and induced apoptosis in both HepG2 and Hep3B cells; the combination of 5-azaC and butyrate was not more effective than either agent alone. 5-azaC alone resulted in a more differentiated-appearing morphology and G2 cell cycle arrest in both cell lines. Treatment with 5-azaC or butyrate affected the expression levels of proteins of the Bcl-2 family. CONCLUSIONS: Both 5-azaC and butyrate induced apoptosis in the HepG2 and Hep3B liver cancer cells; 5-azaC treatment alone produced G2 arrest in both cell lines. Proteins of the Bcl-2 family may play a role in the cellular changes that occur with treatment, but further studies are required to define this potential role. Products of the

  1. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium.

    PubMed

    Zhang, Qianpeng; Wu, Yanqiu; Wang, Jing; Wu, Guojun; Long, Wenmin; Xue, Zhengsheng; Wang, Linghua; Zhang, Xiaojun; Pang, Xiaoyan; Zhao, Yufeng; Zhao, Liping; Zhang, Chenhong

    2016-01-01

    Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn't induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates. PMID:27264309

  2. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells

    PubMed Central

    Li, Robert W; Li, CongJun

    2006-01-01

    Background Global gene expression profiles of bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The bovine microarray with 86,191 distinct 60mer oligonucleotides, each with 4 replicates, was designed and produced with Maskless Array Synthesizer technology. These oligonucleotides represent approximately 45,383 unique cattle sequences. Results 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR) = 0 % were identified. The majority of these genes were repressed by butyrate and associated with cell cycle control. The expression levels of 30 selected genes identified by the microarray were confirmed using real-time PCR. The results from real-time PCR positively correlated (R = 0.867) with the results from the microarray. Conclusion This study presented the genes related to multiple signal pathways such as cell cycle control and apoptosis. The profound changes in gene expression elucidate the molecular basis for the pleiotropic effects of butyrate on biological processes. These findings enable better recognition of the full range of beneficial roles butyrate may play during cattle energy metabolism, cell growth and proliferation, and possibly in fighting gastrointestinal pathogens. PMID:16972989

  3. Accelerated dysbiosis of gut microbiota during aggravation of DSS-induced colitis by a butyrate-producing bacterium

    PubMed Central

    Zhang, Qianpeng; Wu, Yanqiu; Wang, Jing; Wu, Guojun; Long, Wenmin; Xue, Zhengsheng; Wang, Linghua; Zhang, Xiaojun; Pang, Xiaoyan; Zhao, Yufeng; Zhao, Liping; Zhang, Chenhong

    2016-01-01

    Butyrate-producing bacteria (BPB) are potential probiotic candidates for inflammatory bowel diseases as they are often depleted in the diseased gut microbiota. However, here we found that augmentation of a human-derived butyrate-producing strain, Anaerostipes hadrus BPB5, significantly aggravated colitis in dextran sulphate sodium (DSS)-treated mice while exerted no detrimental effect in healthy mice. We explored how the interaction between BPB5 and gut microbiota may contribute to this differential impact on the hosts. Butyrate production and severity of colitis were assessed in both healthy and DSS-treated mice, and gut microbiota structural changes were analysed using high-throughput sequencing. BPB5-inoculated healthy mice showed no signs of colitis, but increased butyrate content in the gut. In DSS-treated mice, BPB5 augmentation did not increase butyrate content, but induced significantly more severe disease activity index and much higher mortality. BPB5 didn’t induce significant changes of gut microbiota in healthy hosts, but expedited the structural shifts 3 days earlier toward the disease phase in BPB5-augmented than DSS-treated animals. The differential response of gut microbiota in healthy and DSS-treated mice to the same potentially beneficial bacterium with drastically different health consequences suggest that animals with dysbiotic gut microbiota should also be employed for the safety assessment of probiotic candidates. PMID:27264309

  4. Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1) in Colorectal Cancer Cells

    PubMed Central

    Sobolewski, Cyril; Sanduja, Sandhya; Blanco, Fernando F.; Hu, Liangyan; Dixon, Dan A.

    2015-01-01

    The RNA-binding protein tristetraprolin (TTP) promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE). In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC) inhibitors (Trichostatin A, SAHA and sodium butyrate) promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells) and cervix carcinoma cells (HeLa). We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1). Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer. PMID:26343742

  5. Radiation induces acid tolerance of Clostridium tyrobutyricum and enhances bioproduction of butyric acid through a metabolic switch

    PubMed Central

    2014-01-01

    Background Butyric acid as a renewable resource has become an increasingly attractive alternative to petroleum-based fuels. Clostridium tyrobutyricum ATCC 25755T is well documented as a fermentation strain for the production of acids. However, it has been reported that butyrate inhibits its growth, and the accumulation of acetate also inhibits biomass synthesis, making production of butyric acid from conventional fermentation processes economically challenging. The present study aimed to identify whether irradiation of C. tyrobutyricum cells makes them more tolerant to butyric acid inhibition and increases the production of butyrate compared with wild type. Results In this work, the fermentation kinetics of C. tyrobutyricum cultures after being classically adapted for growth at 3.6, 7.2 and 10.8 g·L-1 equivalents were studied. The results showed that, regardless of the irradiation used, there was a gradual inhibition of cell growth at butyric acid concentrations above 10.8 g·L-1, with no growth observed at butyric acid concentrations above 3.6 g·L-1 for the wild-type strain during the first 54 h of fermentation. The sodium dodecyl sulfate polyacrylamide gel electrophoresis also showed significantly different expression levels of proteins with molecular mass around the wild-type and irradiated strains. The results showed that the proportion of proteins with molecular weights of 85 and 106 kDa was much higher for the irradiated strains. The specific growth rate decreased by 50% (from 0.42 to 0.21 h-1) and the final concentration of butyrate increased by 68% (from 22.7 to 33.4 g·L-1) for the strain irradiated at 114 AMeV and 40 Gy compared with the wild-type strains. Conclusions This study demonstrates that butyric acid production from glucose can be significantly improved and enhanced by using 12C6+ heavy ion-irradiated C. tyrobutyricum. The approach is economical, making it competitive compared with similar fermentation processes. It may prove useful as

  6. Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors

    PubMed Central

    Harrison, Ian F; Crum, William R; Vernon, Anthony C; Dexter, David T

    2015-01-01

    Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however

  7. Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice

    PubMed Central

    Atageldiyeva, Kuralay; Fujita, Yukihiro; Yanagimachi, Tsuyoshi; Mizumoto, Katsutoshi; Takeda, Yasutaka; Honjo, Jun; Takiyama, Yumi; Abiko, Atsuko; Makino, Yuichi; Haneda, Masakazu

    2016-01-01

    A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver. PMID:27327650

  8. Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice.

    PubMed

    Atageldiyeva, Kuralay; Fujita, Yukihiro; Yanagimachi, Tsuyoshi; Mizumoto, Katsutoshi; Takeda, Yasutaka; Honjo, Jun; Takiyama, Yumi; Abiko, Atsuko; Makino, Yuichi; Haneda, Masakazu

    2016-01-01

    A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver. PMID:27327650

  9. The sodium glucose cotransporter type 2 inhibitor empagliflozin preserves β-cell mass and restores glucose homeostasis in the male zucker diabetic fatty rat.

    PubMed

    Hansen, Henrik H; Jelsing, Jacob; Hansen, Carl Frederik; Hansen, Gitte; Vrang, Niels; Mark, Michael; Klein, Thomas; Mayoux, Eric

    2014-09-01

    Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and antidiabetic efficacy. Through an insulin and β cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by less reduction in β-cell mass with empagliflozin or liraglutide at week 4, whereas only empagliflozin showed β-cell sparing effects also at week 8. Although this study cannot be used to dissociate the absolute antidiabetic efficacy among the different mechanisms of drug action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and antidiabetic efficacy. PMID:24993361

  10. Therapeutic Value of Voltage-Gated Sodium Channel Inhibitors in Breast, Colorectal, and Prostate Cancer: A Systematic Review

    PubMed Central

    Martin, Fabiola; Ufodiama, Chiedu; Watt, Ian; Bland, Martin; Brackenbury, William J.

    2015-01-01

    Although survival rates of breast, colon, and prostate cancers are improving, deaths from these tumors frequently occur due to metastasis. Voltage-gated Na+ channels (VGSCs) are membrane proteins, which regulate membrane current and cellular migration during nervous system organogenesis. VGSCs are also expressed in fibroblasts, immune cells, glia, and metastatic cancer cells. VGSCs regulate migration and invasion of breast, bowel, and prostate cancer cells, suggesting that they may be novel anti-metastatic targets. We conducted a systematic review of clinical and preclinical studies testing the effects of VGSC-inhibiting drugs in cancer. Two-hundred and four publications were identified, of which two human, two mouse, and 20 in vitro publications were included. In the clinical studies, the effect of these drugs on survival and metastatic relapse is not clear. The 22 preclinical studies collectively suggest that several VGSC-inhibiting drugs inhibit cancer proliferation, migration, and invasion. None of the human and only six of the preclinical studies directly investigated the effect of the drugs on VGSC activity. Studies were difficult to compare due to lack of standardized methodology and outcome measures. We conclude that the benefits of VGSC inhibitors require further investigation. Standardization of future studies and outcome measures should enable meaningful study comparisons. PMID:26834632

  11. Induction of cellular deoxyribonucleic acid synthesis in butyrate-treated cells by simian virus 40 deoxyribonucleic acid

    SciTech Connect

    Kawasaki, S.; Diamond, L.; Baserga, R.

    1981-11-01

    Sodium butyrate (3mM) inhibited the entry into the S phase of quiescent 3T3 cells stimulated by serum, but had no effect on the accumulation of cellular ribonucleic acid. Simian virus 40 infection or manual microinjection of cloned fragments from the simian virus 40 A gene caused quiescent 3T3 cells to enter the S phase even in the presence of butyrate. NGI cells, a line of 3T3 cells transformed by simian virus 40, grew vigorously in 3 mM butyrate. Homokaryons were formed between G/sub 1/ and S-phase 3T3 cells. Butyrate inhibited the induction of deoxyribonucleic acid synthesis that usually occurs in G/sub 1/ nuclei when G/sub 1/ cells are fused with S-phase cells. However, when G/sub 1/ 3T3 cells were fused with exponentially growing NGI cells, the 3T3 nuclei were induced to enter deoxyribonucleic acid synthesis. In tsAF8 cells, a ribonucleic acid polymerase II mutant that stops in the G/sub 1/ phase of the cell cycle, no temporal sequence was demonstrated between the butyrate block and the temperature-sensitive block. These results confirm previous reports that certain virally coded proteins can induce cell deoxyribonucleic acid synthesis in the absence of cellular functions that are required by serum-stimulated cells. The author's interpretation of these data is that butyrate inhibited cell growth by inhibiting the expression of genes required for the G/sub o/ ..-->.. G/sub 1/ ..-->.. S transition and that the product of the simian virus 40 A gene overrode this inhibition by providing all of the necessary functions for the entry into the S phase.

  12. Aptiom (eslicarbazepine acetate) as a dual inhibitor of β-secretase and voltage-gated sodium channel: advancement in Alzheimer's disease-epilepsy linkage via an enzoinformatics study.

    PubMed

    Shaikh, Sibhghatulla; Rizvi, Syed M D; Hameed, Nida; Biswas, Deboshree; Khan, Mahiuddin; Shakil, Shazi; Kamal, Mohammad A

    2014-01-01

    Neurodegenerative disorders are increasingly identified as one of the major causes of epilepsy. The relationship of epileptic activity to Alzheimer's disease (AD) is of clinical importance. Voltage-gated sodium channel (VSC) is one of the best targets in the treatment of epilepsy while β-secretase (BACE) has long been observed as a curative target for AD. To explore a possible link between the treatment of AD and epilepsy, the molecular interactions of recently Food and Drug Administration approved antiepileptic drug Aptiom (Eslicarbazepine acetate) with BACE and VSC were studied. Docking study was performed using 'Autodock4.2'. Hydrophobic and pi-pi interactions play critical role in the correct positioning of Eslicarbazepine acetate within the catalytic site of VSC and BACE enzyme to permit docking. Free energy of binding (ΔG) of 'Eslicarbazepine acetate-VSC' interaction and 'Eslicarbazepine acetate-CAS domain of BACE' interaction was found to be -5.97 and -7.19 kcal/mol, respectively. Hence, Eslicarbazepine acetate might act as a potent dual inhibitor of BACE and VSC. However, scope still remains in the determination of the three-dimensional structure of BACE-Eslicarbazepine acetate and VSC-Eslicarbazepine acetate complexes by X-ray crystallography to validate the described data. Further, Aptiom (Eslicarbazepine acetate) could be expected to form the basis of future dual therapy against epilepsy associated neurological disorders. PMID:25230222

  13. Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, and assessment of dose proportionality in healthy participants.

    PubMed

    Devineni, Damayanthi; Manitpisitkul, Prasarn; Murphy, Joseph; Stieltjes, Hans; Ariyawansa, Jay; Di Prospero, Nicholas A; Rothenberg, Paul

    2015-07-01

    Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2, is approved for the treatment of type-2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2-way crossover design: canagliflozin 300 mg/day was administered under fasted (Period-1) and fed (Period-2) conditions or vice versa. Study 2 was a 3-way crossover: participants were randomized to receive three single-doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10-14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47-112.93) and Cmax (ratio: 108.09; 90% CI: 103.45-112.95) were entirely within bioequivalence limits (80-125%). Plasma canagliflozin exposures were dose-proportional as the 90% CI of the slope of the regression line for dose-normalized AUC∞ and Cmax fell entirely within the prespecified limits of -0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well-tolerated. PMID:27136908

  14. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    PubMed

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug. PMID:26608671

  15. Specific cell cycle synchronization with butyrate and cell cycle analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Synchronized cells have been invaluable for many kinds of cell cycle and cell proliferation studies. Butyrate induces cell cycle arrest and apoptosis in MDBK cells. To explore the possibility of using butyrate-blocked cells to obtain synchronized cells, we investigated the property of the cell cyc...

  16. Isolation of unique butyrate-producing bacteria from swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate-producing bacteria in humans contribute to a healthy gastrointestinal tract and are known to be species from clostridial clusters IV, IX, XIVa, and XVI - with the community dominated by clusters XIVa and IV. However, the composition of the butyrate-producing bacterial community in swine is...

  17. Improved In Vitro Antileukemic Activity of All-Trans Retinoic Acid Loaded in Cholesteryl Butyrate Solid Lipid Nanoparticles.

    PubMed

    Silva, Elton Luiz; Lima, Flávia Alves; Carneiro, Guilherme; Ramos Jonas Periera; Gomes, Dawidson Assis; de Souza-Fagundes, Elaine Maria; Ferreira, Lucas Antônio Miranda

    2016-02-01

    All-trans retinoic acid, a hydrophobic drug, has become one of the most successful examples of differentiation agents used for treatment of acute promyelocytic leukemia. On the other hand, histone deacetylase inhibitors, such as cholesteryl butyrate, present differentiating activity and.can potentiate action of drugs such as all-trans retinoic acid. Solid lipid nanoparticles represent a promising alternative for administration of hydrophobic drugs such as ATRA. This study aimed to develop, characterize, and evaluate the cytotoxicity of all-trans retinoic acid-loaded solid lipid nanoparticles for leukemia treatment. The influence of in situ formation of an ion pairing between all-trans retinoic acid and lipophilic amines on the characteristics of the particles (size, zeta potential, encapsulation efficiency) was evaluated. Cholesteryl butyrate, a butyric acid donor, was used as a component of the lipid matrix. In vitro activity on cell viability and distribution of cell cycle phases were evaluated for HL-60, Jurkat, and THP-1 cell lines. The encapsulation efficiency of all-trans retinoic acid in cholesteryl butyrate-solid lipid nanoparticles was significantly increased by the presence of the amine. Inhibition of cell viability by all-trans retinoic acid-loaded solid lipid nanoparticles was more pronounced than the free drug. Analysis of the distribution of cell cycle phases also showed increased activity for all-trans retinoic acid-loaded cholesteryl butyrate-solid lipid nanoparticles, with a clear increase in subdiploid DNA content. The ion pair formation in SLN containing cholesteryl butyrate can be explored as a simple and inexpensive strategy to improve the efficacy and bioavail-ability of ATRA in the treatment of the cancer and metabolic diseases in which this retinoid plays an important role. PMID:27433579

  18. Therapeutic Effects of Benzoxazinorifamycin KRM-1648 Administered Alone or in Combination with a Half-Sized Secretory Leukocyte Protease Inhibitor or the Nonsteroidal Anti-Inflammatory Drug Diclofenac Sodium against Mycobacterium avium Complex Infection in Mice

    PubMed Central

    Sano, Chiaki; Shimizu, Toshiaki; Sato, Katsumasa; Kawauchi, Hideyuki; Kawahara, Shin; Tomioka, Haruaki

    1999-01-01

    The effects of half-sized secretory leukocyte protease inhibitor or diclofenac sodium administered alone or in combination with the benzoxazinorifamycin KRM-1648 on the therapeutic efficacy of KRM-1648 against Mycobacterium avium complex (MAC) in mice were studied. Neither of the two anti-inflammatory drugs affected the efficacy of KRM-1648, while they exerted significant modulating effects on tumor necrosis factor alpha production by MAC-infected macrophages. PMID:9925533

  19. Untangling the fiber yarn: butyrate feeds Warburg to suppress colorectal cancer.

    PubMed

    Sebastián, Carlos; Mostoslavsky, Raul

    2014-12-01

    Dietary composition has an important role in shaping the gut microbiota. In turn, changes in the diet directly impinge on bacterial metabolites present in the intestinal lumen. Whether such metabolites play a role in intestinal cancer has been a topic of hot debate. In this issue of Cancer Discovery, Donohoe and colleagues show that dietary fiber protects against colorectal carcinoma in a microbiota-dependent manner. Furthermore, fiber-derived butyrate acts as a histone deacetylase inhibitor, inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells experiencing the Warburg effect. PMID:25477104

  20. Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice

    PubMed Central

    Chiba, Yumiko; Yamada, Tetsuya; Tsukita, Sohei; Takahashi, Kei; Munakata, Yuichiro; Shirai, Yuta; Kodama, Shinjiro; Asai, Yoichiro; Sugisawa, Takashi; Uno, Kenji; Sawada, Shojiro; Imai, Junta; Nakamura, Kazuhiro; Katagiri, Hideki

    2016-01-01

    Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves. PMID:26963613

  1. Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants

    PubMed Central

    Devineni, Damayanthi; Vaccaro, Nicole; Murphy, Joe; Curtin, Christopher; Mamidi, Rao N.V.S.; Weiner, Sveta; Wang, Shean-Sheng; Ariyawansa, Jay; Stieltjes, Hans; Wajs, Ewa; Di Prospero, Nicholas A.; Rothenberg, Paul

    2015-01-01

    Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Methods: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4 – 12); study 2: canagliflozin 300 mg (days 1 – 17), probenecid 500 mg twice daily (days 15 – 17); and study 3: canagliflozin 300 mg (days 1 – 8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at pre-specified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2 – 8 (study 3). Results: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Conclusion: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control. PMID:25407255

  2. Sodium glucose co-transporter 2 inhibitors for glycemic control in type 2 diabetes mellitus: Quality of reporting of randomized controlled trials

    PubMed Central

    Mittal, Niti; Mittal, Rakesh; Kumar, Harish; Medhi, Bikash

    2016-01-01

    Background: Sodium glucose co-transporter 2 inhibitors represent a novel class of antidiabetic drugs. The reporting quality of the trials evaluating the efficacy of these agents for glycemic control in type 2 diabetes mellitus has not been explored. Our aim was to assess the reporting quality of such randomized controlled trials (RCTs) and to identify the predictors of reporting quality. Materials and Methods: A systematic literature search was conducted for RCTs published till 12 June 2014. Two independent investigators carried out the searches and assessed the reporting quality on three parameters: Overall quality score (OQS) using Consolidated Standards of Reporting Trials (CONSORT) 2010 statement, Jadad score and intention to treat analysis. Inter-rater agreements were compared using Cohen's weighted kappa statistic. Multivariable linear regression analysis was used to identify the predictors. Results: Thirty-seven relevant RCTs were included in the present analysis. The median OQS was 17 with a range from 8 to 21. On Jadad scale, the median score was three with a range from 0 to 5. Complete details about allocation concealment and blinding were present in 21 and 10 studies respectively. Most studies lacked an elaborate discussion on trial limitations and generalizability. Among the factors identified as significantly associated with reporting quality were the publishing journal and region of conduct of RCT. Conclusions: The key methodological items remain poorly reported in most studies. Strategies like stricter adherence to CONSORT guidelines by journals, access to full trial protocols to gain valuable information and full collaboration among investigators and methodologists might prove helpful in improving the quality of published RCT reports. PMID:26955572

  3. Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3β by lithium in the rat kidney cortex.

    PubMed

    Uwai, Yuichi; Kawasaki, Tatsuya; Nabekura, Tomohiro

    2016-06-01

    Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney. In the present study, the phosphorylation status of GSK3β in the kidney cortex of rats administered lithium chloride and foscarnet, a typical inhibitor of NaPi-IIa, was examined using Western blotting. Under a 2-h infusion of lithium chloride, the plasma concentration of lithium was 1.06 mEq/l, and its renal clearance was calculated as 1.18 ml/min/kg, which was 29.6% of creatinine clearance. The abundance of p-GSK3β in the kidney cortex was augmented by the administration of lithium. The simultaneous infusion of foscarnet increased the renal clearance of lithium and its ratio to creatinine clearance as well as the urinary excretion of phosphate. Foscarnet also inhibited the lithium-induced phosphorylation of GSK3β. These results suggest that the reabsorption of lithium by NaPi-IIa triggers the phosphorylation of GSK3β in the rat kidney cortex. PMID:27238574

  4. Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice.

    PubMed

    Chiba, Yumiko; Yamada, Tetsuya; Tsukita, Sohei; Takahashi, Kei; Munakata, Yuichiro; Shirai, Yuta; Kodama, Shinjiro; Asai, Yoichiro; Sugisawa, Takashi; Uno, Kenji; Sawada, Shojiro; Imai, Junta; Nakamura, Kazuhiro; Katagiri, Hideki

    2016-01-01

    Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves. PMID:26963613

  5. Species difference in the mechanism of nonlinear pharmacokinetics of E2074, a novel sodium channel inhibitor, in rats, dogs, and monkeys.

    PubMed

    Nagaya, Yoko; Takenaka, Osamu; Kusano, Kazutomi; Yoshimura, Tsutomu

    2013-05-01

    New chemical entities often exhibit nonlinear pharmacokinetics (PK) profiles in experimental animals. However, the number of studies that have focused on species differences in nonlinear PK is very limited; thus, the aim of this study was to clarify the mechanism of the nonlinear PK of E2074 (2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one), a novel sodium channel inhibitor, in rats, dogs, and monkeys. Nonlinear PK profiles with more than dose-proportional increases of Cmax and area under the plasma concentration curve were observed in all species after oral administration. The Michaelis-Menten constant (Km) values of hepatic microsomal metabolism were 7.23 and 0.41 μM in rats and dogs in vitro, respectively, which were lower than the unbound maximum plasma concentrations after oral administration in vivo, indicating that the nonlinear PK in rats and dogs was attributable to the saturation of hepatic metabolism. However, we do not believe that the saturation of hepatic metabolism was the mechanism of nonlinearity in monkeys because of the high Km value (42.44 μM) observed in liver microsomes. Intestinal metabolism was observed in monkey intestinal microsomes but not in rats and dogs, and the nonlinear PK in monkeys was diminished by inhibition of intestinal metabolism with a concomitant oral dose of ketoconazole. These results suggest that saturation of the intestinal metabolism is the potential mechanism of nonlinearity in monkeys. P-glycoprotein was not involved in the nonlinear PK profiles in any species. In conclusion, the mechanism of the nonlinear PK of E2074 is species dependent, with the saturation of hepatic metabolism in rats and dogs and that of intestinal metabolism in monkeys being the primary cause. PMID:23401471

  6. Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells.

    PubMed

    Tong, Min; Ding, Yunfei; Tai, Hsin-Hsiung

    2006-09-14

    Histone deacetylase (HDAC) inhibitors have been actively exploited as potential anticancer agents. To identify gene targets of HDAC inhibitors, we found that HDAC inhibitors such as sodium butyrate, scriptaid, apicidin and oxamflatin induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a potential cyclooxygenase-2 (COX-2) antagonist and tumor suppressor, in a time and concentration dependent manner in A549 and H1435 lung adenocarcinoma cells. Detailed analyses indicated that HDAC inhibitors activated the 15-PGDH promoter-luciferase reporter construct in transfected A549 cells. A representative HDAC inhibitor, scriptaid, and its negative structural analog control, nullscript, were further evaluated at the chromatin level. Scriptaid but not nullscript induced a significant accumulation of acetylated histones H3 and H4 which were associated with the 15-PGDH promoter as determined by chromatin immunoprecipitation assay. Transforming growth factor-beta1 (TGF-beta1) also induced the expression of 15-PGDH in a time and concentration dependent manner in A549 and H1435 cells. Induction of 15-PGDH expression by TGF-beta1 was synergistically stimulated by the addition of Wnt3A which was inactive by itself. However, combination of TGF-beta and an HDAC inhibitor, scriptaid, only resulted in an additive effect. Together, our results indicate that 15-PGDH is one of the target genes that HDAC inhibitors and TGF-beta may induce to exhibit tumor suppressive effects. PMID:16844092

  7. Butyrate alleviates metabolic impairments and protects pancreatic β cell function in pregnant mice with obesity

    PubMed Central

    Li, Hua-Ping; Chen, Xuan; Li, Ming-Qing

    2013-01-01

    The relative or absolute deficiency of pancreatic β-cell mass function underlies the pathogenesis of diabetes. It is necessary to alleviate the metabolic stress and reduce the demand for insulin to decrease the effects of mutations affecting β-cell expansion. Butyrate is a natural nutrient existed in food and can also be produced physiologically through the intestinal fermentation of fiber. Pregnancy and obesity model would be helpful for understanding how β-cell adapt to insulin resistance and how butyrate alleviate the metabolic impairment and protect pancreatic β cell function in pregnant mice with obesity. C57BL/6J female mice were divided into three groups and fed with high fat food (HF group, 40% energy from fat), high fat with sodium butyrate food (HSF group, 95% HF with 5% butyrate), or control food (CF group, 14% energy from fat), respectively. The feeding would last for 14 weeks before mating and throughout the gestation period. A subset of dams were sacrificed at gestational day (GD) 14.5 to evaluate the changes of metabolism and β-cell function, mass, proliferation and apoptosis, inflammatory reaction of islet from different diet. Pancreases were double immuno-labeled to assess the islet morphology, insulin expression, expression of proliferation gene PCNA and anti-apoptosis gene bcl-2. Moreover, we detected the expression of NF-κB, phosphorylated NF-κB (pNF-κB) to evaluate the islet inflammatory response with immunohistochemistry. Mice fed with HSF showed obviously changes including the decreased values of weight gain, glucose, insulin, triglyceride and total cholesterol level of blood compared with high fat diet group, and the reduced circulating maternal pro-inflammation factors at GD14.5. Mice fed with HF displayed β-cell hyperplasia with a greater β-cell size and β-cell area in pancreas. Furthermore, the higher ratio of apoptosis and inflammatory response were found in HF group compared with HSF and CF group, while the proliferation

  8. Influence of Butyrate Loaded Clinoptilolite Dietary Supplementation on Growth Performance, Development of Intestine and Antioxidant Capacity in Broiler Chickens.

    PubMed

    Wu, Yanan; Zhou, Yanmin; Lu, Changhui; Ahmad, Hussain; Zhang, Hao; He, Jintian; Zhang, Lili; Wang, Tian

    2016-01-01

    The study was conducted to evaluate the effects of dietary butyrate loaded clinoptilolite (CLI-B) on growth performance, pancreatic digestive enzymes, intestinal development and histomorphology, as well as antioxidant capacity of serum and intestinal mucosal in chickens. Two hundred forty 1-day-old commercial Arbor Acres broilers were randomly assigned to 4 groups: CON group (fed basal diets), SB group (fed basal diet with 0.05% sodium butyrate), CLI group (fed basal diet with 1% clinoptilolite), and CLI-B group (fed basal diet with 1% CLI-B). The results showed that supplementation of CLI-B significantly decreased (P < 0.05) feed conservation ratio at both 21 and 42 days of age, improved the pancreatic digestive enzymes activities (P < 0.05), increased the villus length and villus/crypt ratio (P < 0.05), and decreased the crypt depth of intestine (P < 0.05) as compared to the other experimental groups. Furthermore, the CLI-B environment improved the antioxidant capacity by increasing the antioxidant enzyme activities (P < 0.05) in intestine mucosal, and decreasing the NO content and iNOS activity (P < 0.05) in serum. In addition, CLI-B supplementation had improved the development of intestine and antioxidant capacity of broilers than supplementation with either clinoptilolite or butyrate sodium alone. In conclusion, 1% CLI-B supplementation improved the health status, intestine development and antioxidant capacity in broiler chickens, thus appearing as an important feed additive for the poultry industry. PMID:27104860

  9. Influence of Butyrate Loaded Clinoptilolite Dietary Supplementation on Growth Performance, Development of Intestine and Antioxidant Capacity in Broiler Chickens

    PubMed Central

    Wu, Yanan; Zhou, Yanmin; Lu, Changhui; Ahmad, Hussain; Zhang, Hao; He, Jintian; Zhang, Lili; Wang, Tian

    2016-01-01

    The study was conducted to evaluate the effects of dietary butyrate loaded clinoptilolite (CLI-B) on growth performance, pancreatic digestive enzymes, intestinal development and histomorphology, as well as antioxidant capacity of serum and intestinal mucosal in chickens. Two hundred forty 1-day-old commercial Arbor Acres broilers were randomly assigned to 4 groups: CON group (fed basal diets), SB group (fed basal diet with 0.05% sodium butyrate), CLI group (fed basal diet with 1% clinoptilolite), and CLI-B group (fed basal diet with 1% CLI-B). The results showed that supplementation of CLI-B significantly decreased (P < 0.05) feed conservation ratio at both 21 and 42 days of age, improved the pancreatic digestive enzymes activities (P < 0.05), increased the villus length and villus/crypt ratio (P < 0.05), and decreased the crypt depth of intestine (P < 0.05) as compared to the other experimental groups. Furthermore, the CLI-B environment improved the antioxidant capacity by increasing the antioxidant enzyme activities (P < 0.05) in intestine mucosal, and decreasing the NO content and iNOS activity (P < 0.05) in serum. In addition, CLI-B supplementation had improved the development of intestine and antioxidant capacity of broilers than supplementation with either clinoptilolite or butyrate sodium alone. In conclusion, 1% CLI-B supplementation improved the health status, intestine development and antioxidant capacity in broiler chickens, thus appearing as an important feed additive for the poultry industry. PMID:27104860

  10. Rationale for the luminal provision of butyrate in intestinal diseases.

    PubMed

    Wächtershäuser, A; Stein, J

    2000-08-01

    Short chain fatty acids (SCFA), especially butyrate, play central metabolic roles in maintaining the mucosal barrier in the gut. A lack of SCFA, leading to endogenous starvation of enterocytes, may be the cause of ulcerative colitis and other inflammatory conditions. The main source of SCFA is dietary fibre, but they can also be derived from structured lipids, e. g. tributyrin. Once absorbed by non-ionic diffusion or carrier-mediated anion exchanges, SCFA are either used locally as fuel for the enterocytes or enter the portal bloodstream. Butyrate has been shown to increase wound healing and to reduce inflammation in the small intestine. In the colon, butyrate is the dominant energy source for epithelial cells and affects cellular proliferation and differentiation by yet unknown mechanisms. Recent data suggest that the luminal provision of butyrate may be an appropriate means to improve wound healing in intestinal surgery and to ameliorate symptoms of inflammatory bowel diseases. PMID:11079736

  11. Impact of butyric acid on butanol formation by Clostridium pasteurianum.

    PubMed

    Regestein, Lars; Doerr, Eric Will; Staaden, Antje; Rehmann, Lars

    2015-11-01

    The butanol yield of the classic fermentative acetone-butanol-ethanol (ABE) process has been enhanced in the past decades through the development of better strains and advanced process design. Nevertheless, by-product formation and the incomplete conversion of intermediates still decrease the butanol yield. This study demonstrates the potential of increasing the butanol yield from glycerol though the addition of small amounts of butyric acid. The impact of butyric acid was investigated in a 7L stirred tank reactor. The results of this study show the positive impact of butyric acid on butanol yield under pH controlled conditions and the metabolic stages were monitored via online measurement of carbon dioxide formation, pH value and redox potential. Butyric acid could significantly increase the butanol yield at low pH values if sufficient quantities of primary carbon source (glycerol) were present. PMID:26233327

  12. Clinical evaluation of clobetasone butyrate eye drops in episcleritis.

    PubMed Central

    Lloyd-Jones, D; Tokarewicz, A; Watson, P G

    1981-01-01

    Thirty-nine patients took part in a double-blind, between-patient clinical trial to compare clobetasone butyrate, betamethasone phosphate, and placebo eye drops in the treatment of episcleritis. Although from the symptom scores the patients given placebo appeared to do as well as the other patients in the first week of treatment, they did significantly less well after this time. Clobetasone butyrate and betamethasone phosphate eye drops seemed to be equally effective in the treatment of this disease. PMID:7028088

  13. Comparison of desoximetasone and hydrocortisone butyrate in psoriasis.

    PubMed

    Zachariae, H

    1976-01-01

    Thirty psoriatics were treated for 2 weeks on a double-blind controlled basis with desoximetasone (0.25%) and with hydrocortisone butyrate (0.1%). It was a randomised left-right comparative trial. Thirteen out of 27 patients preferred desoximetasone, 3 patients preferred hydrocortisone butyrate. There was also a significantly better effect of desoximetasone as judged by the observer after the second week of treatment. PMID:60029

  14. Effects of Na-butyrate supplementation in milk formula on plasma concentrations of GH and insulin, and on rumen papilla development in calves.

    PubMed

    Kato, Shin-Ichi; Sato, Katsuyoshi; Chida, Haruka; Roh, Sang-Gun; Ohwada, Shyuichi; Sato, Shusuke; Guilloteau, Paul; Katoh, Kazuo

    2011-12-01

    Although the growth-promoting action of sodium-butyrate (Na-butyrate) used as a feed additive has been observed in calves and pigs, the precise mechanisms involved remain to be clarified. In this study, pre-weaning calves were given milk formula (MF) supplemented with butyrate for 6 weeks to investigate its effects on postprandial changes in the plasma concentrations of metabolic hormones, and, simultaneously, on growth performance, the weight of the digestive organs and rumen papilla development. Ingestion of MF increased (P<0.05) the plasma concentrations of GH and insulin as well as the glucose level, but decreased the non-esterified fatty acid concentration. Na-butyrate supplementation in MF or in lactose solution (with the same quantity of lactose contained in the MF, 5%) suppressed the increase in plasma insulin and GH concentrations, and the plasma IGF1 level was not changed. The length of the rumen papilla and the weight of the perirenal fat tended to increase in the calves fed with Na-butyrate-supplemented MF, but the weight of the liver, spleen, and stomach were not changed. In addition, there was no difference in the expression of mRNA for sodium-dependent glucose transporter-1 in the small intestinal epithelial tissues. We conclude that the accelerated growth performance related to the intake of Na-butyrate used as a feed additive reported previously in several species is partly due to improved insulin sensitivity and a better digestive functional development. These data could be applicable to animal and human nutrition. PMID:21911440

  15. Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes

    PubMed Central

    Sha, Sue; Devineni, Damayanthi; Ghosh, Atalanta; Polidori, David; Hompesch, Marcus; Arnolds, Sabine; Morrow, Linda; Spitzer, Heike; Demarest, Keith; Rothenberg, Paul

    2014-01-01

    Introduction This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. Methods Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. Results Canagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values. Conclusions

  16. Modulation of Mononuclear Phagocyte Inflammatory Response by Liposome-Encapsulated Voltage Gated Sodium Channel Inhibitor Ameliorates Myocardial Ischemia/Reperfusion Injury in Rats

    PubMed Central

    Ji, Wen-Jie; Zhang, Li; Dong, Yan; Ge, Lan; Lu, Rui-Yi; Sun, Hai-Ying; Guo, Zao-Zeng; Yang, Guo-Hong; Jiang, Tie-Min; Li, Yu-Ming

    2013-01-01

    Background Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs) have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R) injury and improve post-infarction left ventricular remodeling. Methodology/Principal Findings Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor) entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC α subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b) and β subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-α and CCL5 expression) and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-β1 expression). In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dtmax) and diastolic (-dP/dtmin) functions. Conclusions/Significance Our work for the

  17. Addition of sodium bicarbonate to complete pelleted diets fed to dairy calves.

    PubMed

    Wheeler, T B; Wangsness, P J; Muller, L D; Griel, L C

    1980-11-01

    During two trials, 35 and 27 Holstein calves were fed ad libitum complete, pelleted diets containing either 35% alfalfa (Trial 1) or 35% grass (Trial 2) hay from birth to 12 wk of age. Calves in Trial 1 were fed one of the following diets: control, control + 3.5% sodium chloride, or control + 5% sodium bicarbonate. In Trial 2, diets were: control, control + 5% sodium bicarbonate, or control + 5% sodium bicarbonate + loose, chopped grass hay. Intake of dry matter, gain in body weight, ruminal pH, or fecal starch did not differ. Calves fed sodium bicarbonate in Trial 1 but not 2 had a reduced feed efficiency compared with control and supplemented diets. In Trial 1 added sodium bicarbonate did not alter intake or digestible energy. Addition of sodium bicarbonate increased concentration of ruminal acetate and butyrate and decreased propionate in both trials. Fecal pH was elevated in calves fed sodium bicarbonate diets during both trials. Sodium chloride increased water intake in Trial 1, and sodium bicarbonate increased water indigestible energy. Addition of sodium bicarbonate increased concentration of ruminal acetate and butyrate and decreased propionate in both trials. Fecal pH was elevated in calves fed sodium bicarbonate diets during both trials. Sodium chloride increased water intake in Trial 1, and sodium bicarbonate increased water indigestible energy. Addition of sodium bicarbonate increased concentration of ruminal acetate and butyrate and decreased propionate in both trials. Fecal pH was elevated in calves fed sodium bicarbonate diets during both trials. Sodium chloride increased water intake in Trial 1, and sodium bicarbonate increased water intake in Trial 2. Incidence of free-gas bloat was higher in calves fed sodium bicarbonate in both trials. Addition of sodium bicarbonate to complete pelleted diets containing 35% alfalfa or 35% grass hay appeared to have no benefit for young, growing dairy calves in performance and health. PMID:7440817

  18. Preparation of chitin butyrate by using phosphoryl mixed anhydride system.

    PubMed

    Bhatt, Lok Ranjan; Kim, Bo Mi; Hyun, Kim; Kang, Kyung Hee; Lu, Chichong; Chai, Kyu Yun

    2011-04-01

    Acylation of chitin with butyric acid was performed in the presence of trifluoroacetic anhydride/phosphoric acid mediated system. The products were characterized by (1)H NMR and FT-IR spectroscopy and their solubility was tested in different organic solvents. Inclusion of butyric acid moieties into the parent molecule was confirmed from the (1)H NMR and FT-IR spectra. FT-IR analysis revealed that the degree of acid substitution (DS) of the products was in a range of 1.9-2.38, which increased with increasing the amounts of butyric acid added to the reaction system. Degree of N-deacetylation (DD) of the products, as determined by (1)H NMR was between 54.2% and 65.6%. The products with DS >2.0 were soluble in dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methanol, acetone, chloroform, and acetic acid. PMID:21353204

  19. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?

    PubMed

    Bourassa, Megan W; Alim, Ishraq; Bultman, Scott J; Ratan, Rajiv R

    2016-06-20

    As interest in the gut microbiome has grown in recent years, attention has turned to the impact of our diet on our brain. The benefits of a high fiber diet in the colon have been well documented in epidemiological studies, but its potential impact on the brain has largely been understudied. Here, we will review evidence that butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, can improve brain health. Butyrate has been extensively studied as a histone deacetylase (HDAC) inhibitor but also functions as a ligand for a subset of G protein-coupled receptors and as an energy metabolite. These diverse modes of action make it well suited for solving the wide array of imbalances frequently encountered in neurological disorders. In this review, we will integrate evidence from the disparate fields of gastroenterology and neuroscience to hypothesize that the metabolism of a high fiber diet in the gut can alter gene expression in the brain to prevent neurodegeneration and promote regeneration. PMID:26868600

  20. N-Butyrate alters chromatin accessibility to DNA repair enzymes

    SciTech Connect

    Smith, P.J.

    1986-03-01

    Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents must be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells.

  1. Cholesteryl butyrate solid lipid nanoparticles as a butyric acid pro-drug: effects on cell proliferation, cell-cycle distribution and c-myc expression in human leukemic cells.

    PubMed

    Serpe, Loredana; Laurora, Stefano; Pizzimenti, Stefania; Ugazio, Elena; Ponti, Renata; Canaparo, Roberto; Briatore, Federica; Barrera, Giuseppina; Gasco, Maria Rosa; Bernengo, Maria Grazia; Eandi, Mario; Zara, Gian Paolo

    2004-06-01

    Cholesteryl butyrate solid lipid nanoparticles (chol-but SLN) have been proposed as a pro-drug to deliver butyric acid. We compared the effects on cell growth, cell-cycle distribution and c-myc expression of chol-but SLN and sodium butyrate (Na-but) in the human leukemic cell lines Jurkat, U937 and HL-60. In all the cell lines 0.5 and 1.0 mM chol-but SLN provoked a complete block of cell growth. Cell-cycle analysis demonstrated in Jurkat cells that 0.25 mM chol-but SLN caused a pronounced increase of G2/M cells and a decrease of G0/G1 cells, whereas in U937 and HL-60 cells chol-but SLN led to a dose-dependent increase of G0/G1 cells, with a decrease of G2/M cells. In Jurkat and HL-60 cells 0.5 mM chol-but SLN induced a significant increase of sub-G0/G1 apoptotic cells. Cell growth and cell-cycle distribution were unaffected by the same concentrations of Na-but. A concentration of 0.25 mM chol-but SLN was able to cause a rapid and transient down-regulation of c-myc expression in all the cell lines, whereas 1 mM Na-but caused a slight reduction of c-myc expression only in U937 cells. The results show how chol-but SLN affects the proliferation pattern of both myeloid and lymphoid cells to an extent greater than the natural butyrate. PMID:15166628

  2. Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction.

    PubMed

    Lattal, K Matthew; Barrett, Ruth M; Wood, Marcelo A

    2007-10-01

    Several recent studies have shown that chromatin, the DNA-protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of a previously conditioned stimulus, such as a conditioning context, to evoke a conditioned response is diminished. The authors demonstrate that administration of the HDAC inhibitors sodium butyrate (NaB) systemically or trichostatin A (TSA) intrahippocampally prior to a brief (3-min) contextual extinction session causes context-evoked fear to decrease to levels observed with a long (24-min) extinction session. These results suggest that HDAC inhibitors may enhance learning during extinction and are consistent with other studies demonstrating a role for the hippocampus in contextual extinction. Molecular and behavioral mechanisms through which this enhanced extinction effect may occur are discussed. PMID:17907845

  3. The response of gastrointestinal microbiota to avilamycin, butyrate, and plant extracts in early-weaned pigs.

    PubMed

    Castillo, M; Martín-Orúe, S M; Roca, M; Manzanilla, E G; Badiola, I; Perez, J F; Gasa, J

    2006-10-01

    An experiment was designed to evaluate the effects of 3 different additives on the gastrointestinal microbiota of early-weaned pigs. Early-weaned (18 to 22 d; n = 32) pigs (6.0 +/- 0.10 kg of BW) from 8 litters were randomly distributed into 8 pens. Each pen was assigned 1 of 4 dietary treatments: a prestarter or control diet, the control diet with 0.04% avilamycin (AB), with 0.3% sodium butyrate, or with 0.03% plant extract mixture (XT; standardized mixture with 5% (wt/wt) carvacrol extracted from Origanum spp., 3% cinnamaldehyde extracted from Cinnamonum spp., and 2% capsicum oleoresin from Capsicum annum). At the end of the experimental period, 8 pigs per treatment were killed, and samples of their intestinal content were taken. The total bacterial load along the gastrointestinal tract (GIT; stomach, jejunum, cecum, and distal colon) and the lactobacilli and enterobacteria in the jejunum and cecum were measured by quantitative PCR. The total microbial counts along the GIT did not differ among the diets, but there was an increase in the lactobacilli:enterobacteria ratio in the cecum of the piglets on the XT diet (P = 0.003). Restriction fragment length polymorphism of the PCR-amplified V3, V4, and V5 regions of the 16S rDNA gene showed changes in the structure of the microbial community in the jejunum. Dendrograms grouped animals by diets; control with 0.3% sodium butyrate was the treatment that promoted the biggest changes in the microbial ecosystem, followed by AB and then XT. Biodiversity increased when using additives compared with the control diet (P = 0.002). Microbial metabolic activity along the hindgut was studied using the concentration of purine bases and carbohydrase activities. Different patterns for purine bases were observed between diets (diet x intestinal section, P = 0.01). The control diet reached a maximum purine base concentration at the end of the colon, whereas that of the AB diet was reached at the cecum. We could not detect any cellulase

  4. Comparative effectiveness of sodium-glucose co-transporter 2 inhibitors for controlling hyperglycaemia in patients with type 2 diabetes: protocol for a systematic review and network meta-analysis

    PubMed Central

    Chen, Min; Xie, Chun-Guang; Gao, Hong; Zheng, Hui; Chen, Qin; Fang, Jian-Qiao

    2016-01-01

    Introduction As a new class of glucose-lowering drugs, sodium-glucose co-transporter 2 (SGLT2) inhibitors are effective for controlling hyperglycaemia, however, the relative effectiveness and safety of 6 recently available SGLT2 inhibitors have rarely been studied. Therefore, we aim to perform pairwise comparisons of the 6 SGLT2 inhibitors. Methods and analysis A systematic review and network meta-analysis will be conducted. Clinical studies that examine effectiveness and safety of either canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin or luseogliflozin will be included. These studies will be systematically retrieved in MEDLINE, EMBASE and the Cochrane Library, from inception to November 2015. Two reviewers will independently screen for eligible studies and then extract data from the studies as well as assess risk of bias. Discrepancies in screening and data extraction will be arbitrated by a third reviewer. A traditional meta-analysis will be performed to combine the effect sizes calculated from head-to-head comparisons with a random effect model. The effect sizes computed from indirect comparisons will be further combined in a network meta-analysis. Heterogeneity will be tested with the Cochrane's Q statistic, and publication bias will be assessed using a funnel plot and the Egger's test. Ethics and dissemination Relative effectiveness and harms of the 6 SGLT2 inhibitors will be demonstrated through this systematic review and network meta-analysis. The result of the review will be disseminated through a peer-review journal and conference presentations. Patients, clinicians and policymakers will benefit from this review in selecting a SGLT2 inhibitor for glucose control in patients with type 2 diabetes. Trial registration number PROSPERO CRD42015025981. PMID:26826156

  5. Transcriptome characterization by deep-RNA-sequencing underlies the mechanisms of butyrate-induced epigenomic regulation in bovine cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Volatile short-chain fatty acids (SCFAs, acetate, propionate, and butyrate), especially butyrate, alter cell differentiation, proliferation, motility, and in particular, induce cell cycle arrest and apoptosis through its histone deacetylase (HDAC) inhibition activity. Butyrate is a great inducer of ...

  6. Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes

    PubMed Central

    Brandão, Fabiana AS; Derengowski, Lorena S; Albuquerque, Patrícia; Nicola, André M; Silva-Pereira, Ildinete; Poças-Fonseca, Marcio J

    2015-01-01

    Cryptococcus neoformans undergoes phenotypical changes during host infection in order to promote persistence and survival. Studies have demonstrated that such adaptations require alterations in gene transcription networks by distinct mechanisms. Drugs such as the histone deacetylases inhibitors (HDACi) Sodium Butyrate (NaBut) and Trichostatin A (TSA) can alter the chromatin conformation and have been used to modulate epigenetic states in the treatment of diseases such as cancer. In this work, we have studied the effect of NaBut and TSA on the expression of C. neoformans major virulence phenotypes and on the survival rate of an animal model infected with drugs-treated yeasts. Both drugs affected fungal growth at 37°C more intensely than at 30°C; nonetheless, drugs did not affect cell viability at the concentrations we studied. HDACi also provoked the reduction of the fungal capsule expansion. Phospholipases enzyme activity decreased; mating process and melanin synthesis were also affected by both inhibitors. NaBut led to an increase in the population of cells in G2/M. Treated yeast cells, which were washed in order to remove the drugs from the culture medium prior to the inoculation in the Galleria mellonela infection model, did not cause significant difference at the host survival curve when compared to non-treated cells. Overall, NaBut effects on the impairment of C. neoformans main virulence factors were more intense and stable than the TSA effects. PMID:26103530

  7. The effect of short-chain fatty acids butyrate, propionate, and acetate on urothelial cell kinetics in vitro: potential therapy in augmentation cystoplasty.

    PubMed

    Dyer, J P; Featherstone, J M; Solomon, L Z; Crook, T J; Cooper, A J; Malone, P S

    2005-07-01

    The intestinal element of enterocystoplasty is affected by chronic inflammatory changes, which lead to excess mucus production, urinary tract infections, and stone formation. There is also an increased risk of malignancy. These inflammatory changes may be due to diversion colitis, which affects colonic segments excluded from the faecal stream and likewise may respond to intraluminal short-chain fatty acid (SCFA) therapy. The SCFAs have interesting antiproliferative, differentiating, and pro-apoptotic effects, which are protective against colorectal cancer and may influence the risk of malignancy in enterocystoplasty. Before intravesical therapy can be considered, the effect on normal urothelium must be investigated. Primary urothelial cells cultured from biopsy specimens and transformed urothelial (RT112 and MGH-U1) and intestinal cell lines (HT29 and CaCo-2) were incubated with SCFAs. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure the residual viable biomass to assess cell proliferation. Proliferation of primary and transformed urothelial cells in culture was inhibited by all SCFAs in a similar time- and dose-dependent manner. The concentration of SCFA required to inhibit growth of primary cells by 50% (IC50) was 20 mM of butyrate, 120 mM of propionate, and 240 mM of acetate after incubation for 1 h. After 72 h the IC50 was 2 mM of butyrate, 4 mM of propionate, and 20 mM of acetate. Transformed urothelial and colon cancer cell lines demonstrated similar growth inhibition. Butyrate was the most potent inhibitor of cell proliferation, followed by propionate and then acetate. Growth inhibition is not an immediate cytotoxic effect, and urothelial cells show a degree of adaptation to butyrate and growth recovery after incubation with butyrate. In conclusion, butyrate- and propionate-induced growth inhibition is potentially clinically significant and may have therapeutically beneficial implications in vivo. PMID:15864601

  8. Low doses of arginine butyrate derivatives improve dystrophic phenotype and restore membrane integrity in DMD models.

    PubMed

    Vianello, Sara; Consolaro, Francesca; Bich, Claudia; Cancela, José-Manuel; Roulot, Morgane; Lanchec, Erwan; Touboul, David; Brunelle, Alain; Israël, Maurice; Benoit, Evelyne; de la Porte, Sabine

    2014-06-01

    A new approach to treating Duchenne muscular dystrophy was investigated by using the ester or amide covalent association of arginine [nitric oxide (NO) pathway] and butyrate [histone deacetylase (HDAC) inhibition] in mdx mice and patient myotubes. Two prodrugs were synthesized, and the beneficial effects on dystrophic phenotype were studied. Nerve excitability abnormalities detected in saline-treated mice were almost totally rescued in animals treated at low doses (50-100 mg/kg/d). Force and fatigue resistance were improved ≈60% and 3.5-fold, respectively, and the percentage of necrosis in heart sections was reduced ≈90% in the treated mice. A decrease of >50% in serum creatine kinase indicated an overall improvement in the muscles. Restoration of membrane integrity was studied directly by measuring the reduction (≈74%) of Evans blue incorporation in the limb muscles of the treated animals, the increase in utrophin level, and the normalization of lipid composition of the heart. In cultures of human myotubes (primary cells and cell line), both prodrugs and HDAC inhibitors increased by 2- to 4-fold the utrophin level, which was correctly localized at the membrane. β-Dystroglycan and embryonic myosin protein levels were also increased. Finally, a 50% reduction in the number of spontaneous Ca(2+) spikes was observed after treatment with NO synthase substrate and HDAC inhibitors. Overall, the beneficial effects were obtained with doses 10 (in vivo) and 5 (in vitro) times lower than those of the salt formulation. Altogether, these data constitute proof of principle of the beneficial effects of low doses of arginine butyrate derivatives on muscular dystrophy, enhancing the NO pathway and inhibiting HDAC. PMID:24604079

  9. 4-(2-Methyl-4-chlorophenoxy) butyric acid (MCPB)

    Integrated Risk Information System (IRIS)

    4 - ( 2 - Methyl - 4 - chlorophenoxy ) butyric acid ( MCPB ) ; CASRN 94 - 81 - 5 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Hea

  10. Development of a specific radioimmunoassay for cortisol 17-butyrate

    SciTech Connect

    Smith, G.N.; Lee, Y.F.; Bu'Lock, D.E.; August, P.; Anderson, D.C.

    1983-07-01

    We describe the development and validation of an assay for cortisol 17-butyrate in blood in which there is no significant cross reaction with endogenous corticosteroids at levels encountered normally in man. Preliminary data on blood levels of the drug in absorption studies are presented.

  11. EFFECT OF LEAD ON GAMMA AMINO BUTYRIC ACID SYNTHESIS

    EPA Science Inventory

    The project studies the inhibitory effect of lead on the enzymatic activity of brain glutamic amino acid decarboxylase (GADC). The enzyme is responsible for the catalytic formation of gamma amino butyric acid (GABA) inhibitory neurons which is believed to be involved with the tra...

  12. The Bacterial Fermentation Product Butyrate Influences Epithelial Signaling via Reactive Oxygen Species-Mediated Changes in Cullin-1 Neddylation1

    PubMed Central

    Kumar, Amrita; Wu, Huixia; Collier-Hyams, Lauren S.; Kwon, Young-Man; Hanson, Jason M.; Neish, Andrew S.

    2010-01-01

    The human enteric flora plays a significant role in intestinal health and disease. Populations of enteric bacteria can inhibit the NF-κB pathway by blockade of IκB-α ubiquitination, a process catalyzed by the E3-SCFβ-TrCP ubiquitin ligase. The activity of this ubiquitin ligase is regulated via covalent modification of the Cullin-1 subunit by the ubiquitin-like protein NEDD8. We previously reported that interaction of viable commensal bacteria with mammalian intestinal epithelial cells resulted in a rapid and reversible generation of reactive oxygen species (ROS) that modulated neddylation of Cullin-1 and resulted in suppressive effects on the NF-κB pathway. Herein, we demonstrate that butyrate and other short chain fatty acids supplemented to model human intestinal epithelia in vitro and human tissue ex vivo results in loss of neddylated Cul-1 and show that physiological concentrations of butyrate modulate the ubiquitination and degradation of a target of the E3-SCFβ-TrCP ubiquitin ligase, the NF-κB inhibitor IκB-α. Mechanistically, we show that physiological concentrations of butyrate induces reactive oxygen species that transiently alters the intracellular redox balance and results in inactivation of the NEDD8-conjugating enzyme Ubc12 in a manner similar to effects mediated by viable bacteria. Because the normal flora produces significant amounts of butyrate and other short chain fatty acids, these data provide a functional link between a natural product of the intestinal normal flora and important epithelial inflammatory and proliferative signaling pathways. PMID:19109186

  13. Butyrate activates the monocarboxylate transporter MCT4 expression in breast cancer cells and enhances the antitumor activity of 3-bromopyruvate.

    PubMed

    Queirós, Odília; Preto, Ana; Pacheco, António; Pinheiro, Céline; Azevedo-Silva, João; Moreira, Roxana; Pedro, Madalena; Ko, Young H; Pedersen, Peter L; Baltazar, Fátima; Casal, Margarida

    2012-02-01

    Most malignant tumors exhibit the Warburg effect, which consists in increased glycolysis rates with production of lactate, even in the presence of oxygen. Monocarboxylate transporters (MCTs), maintain these glycolytic rates, by mediating the influx and/or efflux of lactate and are overexpressed in several cancer cell types. The lactate and pyruvate analogue 3-bromopyruvate (3-BP) is an inhibitor of the energy metabolism, which has been proposed as a specific antitumor agent. In the present study, we aimed at determining the effect of 3-BP in breast cancer cells and evaluated the putative role of MCTs on this effect. Our results showed that the three breast cancer cell lines used presented different sensitivities to 3-BP: ZR-75-1 ER (+)>MCF-7 ER (+)>SK-BR-3 ER (-). We also demonstrated that 3-BP reduced lactate production, induced cell morphological alterations and increased apoptosis. The effect of 3-BP appears to be cytotoxic rather than cytostatic, as a continued decrease in cell viability was observed after removal of 3-BP. We showed that pre-incubation with butyrate enhanced significantly 3-BP cytotoxicity, especially in the most resistant breast cancer cell line, SK-BR-3. We observed that butyrate treatment induced localization of MCT1 in the plasma membrane as well as overexpression of MCT4 and its chaperone CD147. Our results thus indicate that butyrate pre-treatment potentiates the effect of 3-BP, most probably by increasing the rates of 3-BP transport through MCT1/4. This study supports the potential use of butyrate as adjuvant of 3-BP in the treatment of breast cancer resistant cells, namely ER (-). PMID:22350013

  14. BUTYRATE DIFFERENTIALLY REGULATES CYTOKINES AND PROLIFERATION IN PORCINE PERIPHERAL BLOOD MONONUCLEAR CELLS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although butyrate modulates proliferation and cytokine production by PBMC in some species, the role of butyrate as a regulator of immunocyte function in the pig has not been studied. Therefore, the primary objective of this study was to determine whether butyrate influences peripheral blood mononuc...

  15. Swine Intestinal Tract Harbors a High Diversity of Butyrate-Producing Bacteria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate is a preferred energy source of human colonic epithelial cells, and changes in the communities of butyrate-producing bacteria have been associated with adverse health. We hypothesize that in swine, like in humans, butyrate-producing bacteria contribute to a healthy intestinal ecosystem. T...

  16. Quantification of transcriptome responses of the rumen epithelium to butyrate infusion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Short-chain fatty acids (SCFAs), such as butyrate, produced by gut microorganisms play an important role in energy metabolism and physiology in ruminants as well as in human health. Butyrate is a preferred substrate in the rumen epithelium where approximately 90% of butyrate is metabolized. Additi...

  17. Role of rumen butyrate in regulation of nitrogen utilization and urea nitrogen kinetics in growing sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate, a major rumen VFA, has been indirectly linked to enhancement of urea recycling based on increased expression of urea transporter (UT-B) in the rumen epithelia of steers fed a rumen butyrate-enhancing diet. Two studies were conducted to quantify the effect of elevated rumen butyrate concent...

  18. Effects of supplementary butyrate on butanol production and the metabolic switch in Clostridium beijerinckii NCIMB 8052: genome-wide transcriptional analysis with RNA-Seq

    PubMed Central

    2013-01-01

    Background Butanol (n-butanol) has high values as a promising fuel source and chemical feedstock. Biobutanol is usually produced by the solventogenic clostridia through a typical biphasic (acidogenesis and solventogenesis phases) acetone-butanol-ethanol (ABE) fermentation process. It is well known that the acids produced in the acidogenic phase are significant and play important roles in the switch to solventogenesis. However, the mechanism that triggers the metabolic switch is still not clear. Results Sodium butyrate (40 mM) was supplemented into the medium for the ABE fermentation with Clostridium beijerinckii NCIMB 8052. With butyrate addition (reactor R1), solvent production was triggered early in the mid-exponential phase and completed quickly in < 50 h, while in the control (reactor R2), solventogenesis was initiated during the late exponential phase and took > 90 h to complete. Butyrate supplementation led to 31% improvement in final butanol titer, 58% improvement in sugar-based yield, and 133% improvement in butanol productivity, respectively. The butanol/acetone ratio was 2.4 versus 1.8 in the control, indicating a metabolic shift towards butanol production due to butyrate addition. Genome-wide transcriptional dynamics was investigated with RNA-Seq analysis. In reactor R1, gene expression related to solventogenesis was induced about 10 hours earlier when compared to that in reactor R2. Although the early sporulation genes were induced after the onset of solventogenesis in reactor R1 (mid-exponential phase), the sporulation events were delayed and uncoupled from the solventogenesis. In contrast, in reactor R2, sporulation genes were induced at the onset of solventogenesis, and highly expressed through the solventogenesis phase. The motility genes were generally down-regulated to lower levels prior to stationary phase in both reactors. However, in reactor R2 this took much longer and gene expression was maintained at comparatively higher levels

  19. A kinetic-metabolic model based on cell energetic state: study of CHO cell behavior under Na-butyrate stimulation.

    PubMed

    Ghorbaniaghdam, Atefeh; Henry, Olivier; Jolicoeur, Mario

    2013-04-01

    A kinetic-metabolic model approach describing and simulating Chinese hamster ovary (CHO) cell behavior is presented. The model includes glycolysis, pentose phosphate pathway, TCA cycle, respiratory chain, redox state and energetic metabolism. Growth kinetic is defined as a function of the major precursors for the synthesis of cell building blocks. Michaelis-Menten type kinetic is used for metabolic intermediates as well as for regulatory functions from energy shuttles (ATP/ADP) and cofactors (NAD/H and NADP/H). Model structure and parameters were first calibrated using results from bioreactor cultures of CHO cells expressing recombinant t-PA. It is shown that the model can simulate experimental data for all available experimental data, such as extracellular glucose, glutamine, lactate and ammonium concentration time profiles, as well as cell energetic state. A sensitivity analysis allowed identifying the most sensitive parameters. The model was then shown to be readily adaptable for studying the effect of sodium butyrate on CHO cells metabolism, where it was applied to the cases with sodium butyrate addition either at mid-exponential growth phase (48 h) or at the early plateau phase (74 h). In both cases, a global optimization routine was used for the simultaneous estimation of the most sensitive parameters, while the insensitive parameters were considered as constants. Finally, confidence intervals for the estimated parameters were calculated. Results presented here further substantiate our previous findings that butyrate treatment at mid-exponential phase may cause a shift in cellular metabolism toward a sustained and increased efficiency of glucose utilization channeled through the TCA cycle. PMID:22976819

  20. Induction of peroxisomes by butyrate-producing probiotics.

    PubMed

    Weng, Huachun; Endo, Kosuke; Li, Jiawei; Kito, Naoko; Iwai, Naoharu

    2015-01-01

    We previously found that peroxisomal biogenesis factor 11a (Pex11a) deficiency is associated with a reduction in peroxisome abundance and impaired fatty acid metabolism in hepatocytes, and results in steatosis. In the present study, we investigated whether butyrate induces Pex11a expression and peroxisome proliferation, and studied its effect on lipid metabolism. C57BL/6 mice fed standard chow or a high-fat diet (HFD) were treated with tributyrin, 4-phelybutyrate acid (4-PBA), or the butyrate-producing probiotics (Clostridium butyricum MIYAIRI 588 [CBM]) plus inulin (dietary fiber), and the body weight, white adipose tissue, serum triglycerides, mRNA expression, and peroxisome abundance were evaluated. Tributyrin or 4-PBA treatment significantly decreased body weight and increased hepatic mRNA expression of peroxisome proliferator-activated receptor-α (PPARα) and Pex11a. In addition, 4-PBA treatment increased peroxisome abundance and the expression of genes involved in peroxisomal fatty acid β-oxidation (acyl-coenzyme A oxidase 1 and hydroxysteroid [17-beta] dehydrogenase 4). CBM and inulin administration reduced adipose tissue mass and serum triglycerides, induced Pex11a, acyl-coenzyme A oxidase 1, and hydroxysteroid (17-beta) dehydrogenase 4 genes, and increased peroxisome abundance in mice fed standard chow or an HFD. In conclusion, elevation of butyrate availability (directly through administration of butyrate or indirectly via administration of butyrate-producing probiotics plus fiber) induces PPARα and Pex11a and the genes involved in peroxisomal fatty acid β-oxidation, increases peroxisome abundance, and improves lipid metabolism. These results may provide a new therapeutic strategy against hyperlipidemia and obesity. PMID:25659146

  1. Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5)

    PubMed Central

    Huard, Kim; Brown, Janice; Jones, Jessica C.; Cabral, Shawn; Futatsugi, Kentaro; Gorgoglione, Matthew; Lanba, Adhiraj; Vera, Nicholas B.; Zhu, Yimin; Yan, Qingyun; Zhou, Yingjiang; Vernochet, Cecile; Riccardi, Keith; Wolford, Angela; Pirman, David; Niosi, Mark; Aspnes, Gary; Herr, Michael; Genung, Nathan E.; Magee, Thomas V.; Uccello, Daniel P.; Loria, Paula; Di, Li; Gosset, James R.; Hepworth, David; Rolph, Timothy; Pfefferkorn, Jeffrey A.; Erion, Derek M.

    2015-01-01

    Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints. PMID:26620127

  2. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.

    PubMed

    Koltun, Dmitry O; Parkhill, Eric Q; Elzein, Elfatih; Kobayashi, Tetsuya; Notte, Gregory T; Kalla, Rao; Jiang, Robert H; Li, Xiaofen; Perry, Thao D; Avila, Belem; Wang, Wei-Qun; Smith-Maxwell, Catherine; Dhalla, Arvinder K; Rajamani, Sridharan; Stafford, Brian; Tang, Jennifer; Mollova, Nevena; Belardinelli, Luiz; Zablocki, Jeff A

    2016-07-01

    We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication. PMID:27080178

  3. The Drug of Abuse γ-Hydroxybutyrate Is a Substrate for Sodium-Coupled Monocarboxylate Transporter (SMCT) 1 (SLC5A8): Characterization of SMCT-Mediated Uptake and Inhibition

    PubMed Central

    Cui, Dapeng; Morris, Marilyn E.

    2009-01-01

    γ-Hydroxybutyric acid (GHB), a drug of abuse, is a substrate of monocarboxylate transporters (MCTs). Sodium-coupled monocarboxylate transporter 1 (SMCT1; SLC5A8) is expressed in kidney, thyroid gland, neurons, and intestinal tract and exhibits substrate specificity similar to that of the proton-dependent MCT (SLC16A) family. The role of SMCT1 in GHB disposition has not been determined. In this study we characterized the driving force, transport kinetics, and inhibitors of GHB uptake, as well as expression of SMCT and MCT isoforms, in rat thyroid follicular (FRTL-5) cells. GHB, as well as the monocarboxylates butyrate and d-lactate, exhibited sodium-dependent uptake at pH 7.4, which could be described with a simple Michaelis-Menten equation plus a diffusional component [Km 0.68 ± 0.30 mM, Vmax 3.50 ± 1.58 nmol · mg–1 · min–1, and diffusional clearance (P) 0.25 ± 0.08 μl · mg–1 · min–1]. In the absence of sodium, GHB uptake was significantly increased at lower pH, suggesting proton-gradient dependent transport. Reverse transcriptase-polymerase chain reaction and Western analyses demonstrated the expression of SMCT1, MCT1, and MCT2 in FRTL-5 cells, supporting the activity results. Sodium-dependent GHB uptake in FRTL-5 cells was inhibited by MCT substrates (d-lactate, l-lactate, pyruvate, and butyrate), nonsteroidal anti-inflammatory drugs (ibuprofen, ketoprofen, and naproxen), and probenecid. IC50 values for l-lactate, ibuprofen, ketoprofen, and probenecid were 101, 31.6, 64.4, and 380 μM, respectively. All four inhibitors also significantly inhibited GHB uptake in rat MCT1 gene-transfected MDA/MB231 cells, suggesting they are not specific for SMCT1. Luteolin and α-cyano-4-hydroxycinnimate represent specific proton-dependent MCT inhibitors. Our findings indicate that GHB is a substrate for both sodium- and proton-dependent MCTs and identified specific inhibitors of MCTs. PMID:19389857

  4. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells

    SciTech Connect

    Chiaro, Christopher; Lazarova, Darina L.; Bordonaro, Michael

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer We investigate mechanisms responsible for butyrate resistance in colon cancer cells. Black-Right-Pointing-Pointer Tcf3 modulates butyrate's effects on Wnt activity and cell growth in resistant cells. Black-Right-Pointing-Pointer Tcf3 modulation of butyrate's effects differ by cell context. Black-Right-Pointing-Pointer Cell cycle factors are overexpressed in the resistant cells. Black-Right-Pointing-Pointer Reversal of altered gene expression can enhance the anti-cancer effects of butyrate. -- Abstract: Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cells Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G{sub 1} to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that prevent or

  5. A quantitative LC-MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats.

    PubMed

    Kobuchi, Shinji; Ito, Yukako; Yano, Kyoka; Sakaeda, Toshiyuki

    2015-09-01

    Ipragliflozin is a highly potent and selective sodium-dependent glucose co-transporter-2 (SGLT2) inhibitor, a novel class of hypoglycemic agents. The aim of the present study was to establish a new highly sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitative analysis of ipragliflozin in rat plasma and apply this method to a pharmacokinetic study in rats. Empagliflozin was used as an internal standard (I.S.) and liquid-liquid extraction was conducted using tert-butyl methyl ether. Chromatographic separation was accomplished on a Quicksorb ODS (2.1mm i.d.×150mm, 5μm in size) with acetonitrile/0.1% formic acid (90:10, v/v) at a flow rate of 0.2mL/min. An API 3200 triple quadrupole mass spectrometer operating in the positive electrospray ionization mode with multiple reaction monitoring was used to detect ipragliflozin and I.S. transitions: m/z 422.0 [M+NH4](+)→151.0 for ipragliflozin and m/z 451.2 [M+H](+)→71.0 for I.S. Inter- and intra-day accuracies and precisions were within ±15%. This validated method was successfully applied to a pharmacokinetic study of ipragliflozin in rats. This assay method may contribute to assessment of novel SGLT2 inhibitors using the rat as an animal model. PMID:26209767

  6. Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat.

    PubMed

    Huber, John D; Bentzien, Jörg; Boyer, Stephen J; Burke, Jennifer; De Lombaert, Stéphane; Eickmeier, Christian; Guo, Xin; Haist, James V; Hickey, Eugene R; Kaplita, Paul; Karmazyn, Morris; Kemper, Raymond; Kennedy, Charles A; Kirrane, Thomas; Madwed, Jeffrey B; Mainolfi, Elizabeth; Nagaraja, Nelamangara; Soleymanzadeh, Fariba; Swinamer, Alan; Eldrup, Anne B

    2012-08-23

    Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts. PMID:22803959

  7. Sodium Test

    MedlinePlus

    ... be limited. Home Visit Global Sites Search Help? Sodium Share this page: Was this page helpful? Also known as: Na Formal name: Sodium Related tests: Chloride , Bicarbonate , Potassium , Electrolytes , Osmolality , Basic ...

  8. Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens.

    PubMed

    Cardoso, Fernanda C; Dekan, Zoltan; Rosengren, K Johan; Erickson, Andelain; Vetter, Irina; Deuis, Jennifer R; Herzig, Volker; Alewood, Paul F; King, Glenn F; Lewis, Richard J

    2015-08-01

    Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1.7 > hNaV1.6 > hNaV1.2 > hNaV1.1 > hNaV1.3 channels in fluorescent assays. NaV1.7 inhibition was diminished (IC50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNaV1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μM. Unlike most spider toxins that modulate NaV channels, Tp1a inhibited hNaV1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNaV1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNaV1.7 inhibitors for treatment of chronic pain. PMID:25979003

  9. Long-Term Culture of Porcine Induced Pluripotent Stem-Like Cells Under Feeder-Free Conditions in the Presence of Histone Deacetylase Inhibitors.

    PubMed

    Petkov, Stoyan; Glage, Silke; Nowak-Imialek, Monika; Niemann, Heiner

    2016-03-01

    The reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is a complex process that involves significant epigenetic alterations in the reprogrammed cells. Epigenetic modifiers such as histone deacetylase (HDAC) inhibitors have been shown to increase the efficiency of derivation of iPSCs in humans and mice. In this study, we used three HDAC inhibitors, valproic acid, sodium butyrate, and suberoylanilide hydroxamic acid, together with ascorbic acid, for derivation and long-term feeder-free culture of porcine iPS-like cells. In the absence of exogenous growth factors and/or small molecules, these inhibitors were able to maintain the expression of key pluripotency markers, including genes known to be specific for naive pluripotent state in mouse stem cells, for over 60 passages under feeder-free conditions. Surprisingly, the cells became dependent on HDAC inhibitors for the maintenance of proliferation. Moreover, despite showing successful integration into blastocysts upon injection, the cells were unable to undergo normal differentiation in vitro and in vivo in the form of teratomas. Our results suggest that HDAC inhibitors maintain pluripotency gene expression of porcine iPSC-like cells in long-term culture, but prevent lineage specification, requiring further optimization of culture conditions for porcine iPSC derivation. PMID:26691930

  10. Discovery of (phenoxy-2-hydroxypropyl)piperidines as a novel class of voltage-gated sodium channel 1.7 inhibitors.

    PubMed

    Suzuki, Sayaka; Kuroda, Takeshi; Kimoto, Hiroko; Domon, Yuki; Kubota, Kazufumi; Kitano, Yutaka; Yokoyama, Tomihisa; Shimizugawa, Akiko; Sugita, Ryusuke; Koishi, Ryuta; Asano, Daigo; Tamaki, Kazuhiko; Shinozuka, Tsuyoshi; Kobayashi, Hiroyuki

    2015-11-15

    A novel class of NaV1.7 inhibitors has been identified by high-throughput screening followed by structure activity relationship studies. Among this series of compounds, piperidine 9o showed potent human and mouse NaV1.7 inhibitory activities with fair subtype selectivity over NaV1.5. Compound 9o successfully demonstrated analgesic efficacy in mice comparable to that of the currently used drug, mexiletine, but with an expanded central nervous system safety margin. PMID:26358159

  11. Strategies for production of butanol and butyl-butyrate through lipase-catalyzed esterification.

    PubMed

    Xin, Fengxue; Basu, Anindya; Yang, Kun-Lin; He, Jianzhong

    2016-02-01

    In this study, a fermentation process for production of butanol and butyl-butyrate by using Clostridium sp. strain BOH3 is developed. This strain is able to produce butyric acid and butanol when it ferments 60 g/L xylose. Meanwhile, it also excreted indigenous lipases (induced by olive oil) which naturally convert butyric acid and butanol into 1.2 g/L of butyl-butyrate. When Bio-OSR was used as both an inducer for lipase and extractant for butyl-butyrate, the butyl-butyrate concentration can reach 6.3 g/L. To further increase the yield, additional lipases and butyric acid are added to the fermentation system. Moreover, kerosene was used as an extractant to remove butyl-butyrate in situ. When all strategies are combined, 22.4 g/L butyl-butyrate can be produced in a fed-batch reactor spiked with 70 g/L xylose and 7.9 g/L butyric acid, which is 4.5-fold of that in a similar system (5 g/L) with hexadecane as the extractant. PMID:26710347

  12. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Increases Circulating Zinc-Α2-Glycoprotein Levels in Patients with Type 2 Diabetes

    PubMed Central

    Liao, Xin; Wang, Xuemei; Li, Haopeng; Li, Ling; Zhang, Guohao; Yang, Mengliu; Yuan, Lei; Liu, Hua; Yang, Gangyi; Gao, Lin

    2016-01-01

    ZAG has recently been characterized as a potent metabolic regulator, but the effect of anti-diabetic agents on ZAG in humans remains unknown. Our aim was to study the effects of SGLT2 inhibitor on circulating ZAG and ADI in nT2DM. 162 subjects with nT2DM were treated by a placebo or DAPA. After 3-months of DAPA therapy, HbA1c, FBG, 2h-PBG, FFA, TG, blood pressure, BMI, WHR, body weight, FAT%, FINS, and HOMA-IR in T2DM patients decreased significantly, whereas HDL-C was significantly increased. Importantly, circulating ZAG and ADI levels in these patients were also significantly increased after DAPA therapy. Basal ZAG levels were associated with changes in BMI, FAT%, TC, HbA1c, HDL-C and ADI at post-treatment, whereas basal ADI levels were associated with changes in FAT%, TC, HbA1c, FFA and HDL-c. In vitro, DAPA treatment showed increased ZAG expression and secretion in HepG2 cells. When combined with a PPAR-γinhibitor GW9662, the effect of DAPA on ZAG was abrogated. These findings suggest that circulating ZAG can be regulated by DAPA, and DAPA promotes the expression and secretion of ZAG in the liver via the activation of PPAR-γ. The changes in ZAG induced by DAPA may play a physiologic role in enhancing insulin sensitivity. PMID:27611858

  13. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Increases Circulating Zinc-Α2-Glycoprotein Levels in Patients with Type 2 Diabetes.

    PubMed

    Liao, Xin; Wang, Xuemei; Li, Haopeng; Li, Ling; Zhang, Guohao; Yang, Mengliu; Yuan, Lei; Liu, Hua; Yang, Gangyi; Gao, Lin

    2016-01-01

    ZAG has recently been characterized as a potent metabolic regulator, but the effect of anti-diabetic agents on ZAG in humans remains unknown. Our aim was to study the effects of SGLT2 inhibitor on circulating ZAG and ADI in nT2DM. 162 subjects with nT2DM were treated by a placebo or DAPA. After 3-months of DAPA therapy, HbA1c, FBG, 2h-PBG, FFA, TG, blood pressure, BMI, WHR, body weight, FAT%, FINS, and HOMA-IR in T2DM patients decreased significantly, whereas HDL-C was significantly increased. Importantly, circulating ZAG and ADI levels in these patients were also significantly increased after DAPA therapy. Basal ZAG levels were associated with changes in BMI, FAT%, TC, HbA1c, HDL-C and ADI at post-treatment, whereas basal ADI levels were associated with changes in FAT%, TC, HbA1c, FFA and HDL-c. In vitro, DAPA treatment showed increased ZAG expression and secretion in HepG2 cells. When combined with a PPAR-γinhibitor GW9662, the effect of DAPA on ZAG was abrogated. These findings suggest that circulating ZAG can be regulated by DAPA, and DAPA promotes the expression and secretion of ZAG in the liver via the activation of PPAR-γ. The changes in ZAG induced by DAPA may play a physiologic role in enhancing insulin sensitivity. PMID:27611858

  14. Effects of orally applied butyrate bolus on histone acetylation and cytochrome P450 enzyme activity in the liver of chicken – a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Butyrate is known as histone deacetylase inhibitor, inducing histone hyperacetylation in vitro and playing a predominant role in the epigenetic regulation of gene expression and cell function. We hypothesized that butyrate, endogenously produced by intestinal microbial fermentation or applied as a nutritional supplement, might cause similar in vivo modifications in the chromatin structure of the hepatocytes, influencing the expression of certain genes and therefore modifying the activity of hepatic microsomal drug-metabolizing cytochrome P450 (CYP) enzymes. Methods An animal study was carried out in chicken as a model to investigate the molecular mechanisms of butyrate’s epigenetic actions in the liver. Broiler chicks in the early post-hatch period were treated once daily with orally administered bolus of butyrate following overnight starvation with two different doses (0.25 or 1.25 g/kg body weight per day) for five days. After slaughtering, cell nucleus and microsomal fractions were separated by differential centrifugation from the livers. Histones were isolated from cell nuclei and acetylation of hepatic core histones was screened by western blotting. The activity of CYP2H and CYP3A37, enzymes involved in biotransformation in chicken, was detected by aminopyrine N-demethylation and aniline-hydroxylation assays from the microsomal suspensions. Results Orally added butyrate, applied in bolus, had a remarkable impact on nucleosome structure of hepatocytes: independently of the dose, butyrate caused hyperacetylation of histone H2A, but no changes were monitored in the acetylation state of H2B. Intensive hyperacetylation of H3 was induced by the higher administered dose, while the lower dose tended to increase acetylation ratio of H4. In spite of the observed modification in histone acetylation, no significant changes were observed in the hepatic microsomal CYP2H and CYP3A37 activity. Conclusion Orally added butyrate in bolus could cause in vivo

  15. Less-toxic corrosion inhibitors

    NASA Technical Reports Server (NTRS)

    Humphries, T. S.

    1981-01-01

    Combinations of borates, nitrates, phosphates, silicates, and sodium MBT protect aluminum from corrosion in fresh water. Most effective combinations contained sodium phosphate and were alkaline. These inhibitors replace toxic chromates which are subject to governmental restrictions, but must be used in larger quantities. Experimental exposure times varied from 1 to 14 months depending upon nature of submersion solution.

  16. Curcumin represses the activity of inhibitor-κB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation.

    PubMed

    Kao, Ning-Jo; Hu, Jia-Yuan; Wu, Chien-Sheng; Kong, Zwe-Ling

    2016-09-01

    In this study, we investigated the preventive effects of curcumin using dextran sulfate sodium (DSS)-induced colitis and the potential role of curcumin in regulation of anti-inflammation through S-nitrosylation. After curcumin treatment for 6days, the body weight and disease activity index of DSS-induced mice was alleviated and the colonic length was also rescued. Western blot presented that the protein expression of iNOS can be reduced by curcumin. Consistently, mRNA level of iNOS and pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, was also repressed. Moreover, Curcumin reduced the amount of nitrite in DSS-induced colitis but not affected total S-nitrosylation level on proteins on day 6, indicating that curcumin inhibited NO oxidation. Furthermore, the protection of S-nitrosylation on IKKβ in DSS-induced colitis for 6days by curcumin caused the repression of IκB phosphorylation and NF-κB activation. In conclusion, this study verified that curcumin-mediated S-nitrosylation may be as an important regulator for anti-inflammation in DSS-induced colitis of mice. PMID:27233000

  17. Biosynthesis of heparin. Effects of n-butyrate on cultured mast cells

    SciTech Connect

    Jacobsson, K.G.; Riesenfeld, J.; Lindahl, U.

    1985-10-05

    Murine mastocytoma cells were incubated in vitro with inorganic (TVS)sulfate, in the absence or presence of 2.5 mM n-butyrate, and labeled heparin was isolated. The polysaccharide produced in the presence of butyrate showed a lower charge density on anion exchange chromatography than did the control material and a 3-fold increased proportion of components with high affinity for antithrombin. Structural analysis of heparin labeled with (TH) glucosamine in the presence of butyrate showed that approximately 35% of the glucosamine units were N-acetylated, as compared to approximately 10% in the control material; the nonacetylated glucosamine residues were N-sulfated. The presence of butyrate thus leads to an inhibition of the N-deacetylation/N-sulfation process in heparin biosynthesis, along with an augmented formation of molecules with high affinity for antithrombin. Preincubation of the mastocytoma cells with butyrate was required for manifestation of either effect; when the preincubation period was reduced from 24 to 10 h the effects of butyrate were no longer observed. A polysaccharide formed on incubating mastocytoma microsomal fraction with UDP-(TH)glucuronic acid, UDP-N-acetylglucosamine, and 3'-phosphoadenylylsulfate in the presence of 5 mM butyrate showed the same N-acetyl/N-sulfate ratio as did the corresponding control polysaccharide, produced in the absence of butyrate. These findings suggest that the effect of butyrate on heparin biosynthesis depends on the integrity of the cell.

  18. Butyrate-induced changes in nuclease sensitivity of chromatin cannot be correlated with transcriptional activation

    SciTech Connect

    Birren, B.W.; Taplitz, S.J.; Herschman, H.R.

    1987-11-01

    The authors examined in the H4IIE rat heptoma cell line the relationship between butyrate-induced changes in the nuclease sensitivity of chromatin and changes in transcriptional activity of specific genes. The butyrate-inducible metallothionein I (MT-I) gene underwent a dramatic increase in DNase I sensitivity after 3 h of butyrate treatment. However, genes not transcribed in H4IIE cells underwent the same changes in DNase I sensitivity. Thus, butyrate-induced increases in DNase I sensitivity are not sufficient for the transcriptional activation of a gene. Butyrate treatment has also been reported to alter the sensitivity of sequence to micrococcal nuclease (MNase) in a manner reflecting their tissue-specific expression. Butyrate exposure caused increased digestion of the MT-I gene by MNase. However, butyrate-induced MNase sensitivity also occurred for genes which are neither transcribed in untreated cells nor butyrate inducible. Moreover, cadmium, a potent transcriptional activator of the MT-I gene, does not alter the sensitivity of the MT-I gene to MNase. Thus, the butyrate-induced alterations in MNase sensitivity are neither sufficient for, necessary for, nor indicative of transcriptional activation.

  19. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    PubMed

    Whittle, Nigel; Singewald, Nicolas

    2014-04-01

    A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy

  20. Role of incretin-based therapies and sodium-glucose co-transporter-2 inhibitors as adjuncts to insulin therapy in Type 2 diabetes, with special reference to IDegLira.

    PubMed

    Wilding, J P H; Bain, S C

    2016-07-01

    The progressive nature of Type 2 diabetes necessitates treatment intensification over time in order to maintain glycaemic control, with many patients ultimately requiring insulin therapy. While insulin has unlimited potential efficacy, its initiation is often delayed and improvements in glycaemic control are typically accompanied by weight gain and an increased risk of hypoglycaemia, particularly as HbA1c approaches and falls below target levels. This may account for the sub-optimal control often achieved after insulin initiation. Combining insulin with antihyperglycaemic therapies that have a low risk of hypoglycaemia and are weight-neutral or result in weight loss is a therapeutic strategy with the potential to improve Type 2 diabetes management. Although the effects differ with each individual class of therapy, clinical trials have shown that adding a glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor to insulin regimens can offer a significant reduction in HbA1c without substantially increasing hypoglycaemia risk, or weight. The evidence and merit of each approach are reviewed in this paper. Once-daily co-formulations of a basal insulin and a glucagon-like peptide-1 receptor agonist have been developed (insulin degludec/liraglutide) or are under development (lixisenatide/insulin glargine). Insulin degludec/liraglutide phase III trials and a lixisenatide/insulin glargine phase II trial have shown robust HbA1c reductions, with weight loss and a low risk of hypoglycaemia. With insulin degludec/liraglutide now approved in Europe, an important consideration will be the types of patients who may benefit most from a fixed-ratio combination; this is discussed in the present review, and we also take a look toward future developments in the field. PMID:26525806

  1. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats

    PubMed Central

    EL-SALHY, MAGDY; UMEZAWA, KAZUO

    2016-01-01

    The aim of the present study was to elucidate the anti-inflammatory effects of the two novel anti-inflammatory substances, 3-[(dodecylthiocarbonyl)-methyl]-glutarimide (DTCM-G) and dehydroxymethylepoxyquinomicin (DHMEQ), on DSS-induced colitis in rats. For this purpose, rats with dextran sulfate sodium (DSS)-induced colitis were randomly divided into 3 groups with 10 animals in each group as follows: i) the control group, which received 0.5 ml of 0.5% carboxymethyl cellulose (CMC; vehicle), ii) rats that received DTCM-G (20 mg/kg body weight in 0.5% CMC; the DTCM-G group), and iii) rats that received DHMEQ (15 mg/kg body weight in 0.5% CMC; the DHMEQ group). The animals were sacrificed after the 5-day treatment period, and tissue samples were taken from their colons and sectioned for histological evaluation. The tissue sections were stained with hematoxylin and eosin, and immunostained for leukocytes, lymphocytes, macrophages/monocytes and mast cells. The disease activity index (DAI), histological grading of colitis, and densities of several types of submucosal immune cells were compared between the controls, and the DTCM-G and DHMEQ groups. The DAI values were significantly lower in both the DTCM-G and DHMEQ groups than in the control group. The total scores for the histological grading of colitis were also significantly lower in the DTCM-G and DHMEQ groups than in the control group. The submucosal densities of leucocytes, lymphocytes, macrophages/monocytes and mast cells were significantly lower in the DTCM-G and DHMEQ groups than in the control group. Our findings indicate that the anti-inflammatory and anticancer effects of DTCM-G and DHMEQ, and the absence of any associated toxicity render them excellent therapeutic candidates for clinical use in the treatment of colitis. PMID:27082818

  2. Effects of A Voltage Sensitive Calcium Channel Blocker and A Sodium-Calcium Exchanger Inhibitor on Apoptosis of Motor Neurons in Adult Spinal Cord Slices

    PubMed Central

    Momeni, Hamid Reza; Jarahzadeh, Mahsa

    2012-01-01

    Objective: The apoptosis of motor neurons is a critical phenomenon in spinal cord injuries. Adult spinal cord slices were used to investigate whether voltage sensitive calcium channels and Na+/Ca2+ exchangers play a role in the apoptosis of motor neurons. Materials and Methods: In this experimental research, the thoracic region of the adult mouse spinal cord was sliced using a tissue chopper and the slices were incubated in a culture medium in the presence or absence of N/L type voltage sensitive calcium channels blocker (loperamide, 100 µM) or Na+/Ca2+ exchangers inhibitor(bepridil, 20 µM) for 6 hours. 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyl tetrazolium (MTT) staining was used to assess slice viability while morphological features of apoptosis in motor neurons were studied using fluorescent staining. Results: After 6 hours in culture, loperamideand bepridil not only increased slice viability, but also prevented motor neuron apoptosis and significantly increased the percentage of viable motor neurons in the ventral horns of the spinal cord. Conclusion: The results of this study suggest that voltage sensitive calcium channels and Na+/Ca2+ exchanger might be involved in the apoptosis of motor neurons in adult spinal cord slices. PMID:23508879

  3. Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

    PubMed Central

    Montero-Melendez, T; Dalli, J; Perretti, M

    2013-01-01

    Despite several therapies being currently available to treat inflammatory diseases, new drugs to treat chronic conditions with less side effects and lower production costs are still needed. An innovative approach to drug discovery, the Connectivity Map (CMap), shows how integrating genome-wide gene expression data of drugs and diseases can accelerate this process. Comparison of genome-wide gene expression data generated with annexin A1 (AnxA1) with the CMap revealed significant alignment with gene profiles elicited by histone deacetylase inhibitors (HDACIs), what made us to hypothesize that AnxA1 might mediate the anti-inflammatory actions of HDACIs. Addition of HDACIs (valproic acid, sodium butyrate and thricostatin A) to mouse macrophages caused externalization of AnxA1 with concomitant inhibition of cytokine gene expression and release, events that occurred independently as this inhibition was retained in AnxA1 null macrophages. In contrast, novel AnxA1-mediated functions for HDACIs could be unveiled, including promotion of neutrophil apoptosis and macrophage phagocytosis, both steps crucial for effective resolution of inflammation. In a model of acute resolving inflammation, administration of valproic acid and sodium butyrate to mice at the peak of disease accelerated resolution processes in wild type, but much more modestly in AnxA1 null mice. Deeper analyses revealed a role for endogenous AnxA1 in the induction of neutrophil death in vivo by HDACIs. In summary, interrogation of the CMap revealed an unexpected association between HDACIs and AnxA1 that translated in mechanistic findings with particular impact on the processes that regulate the resolution of inflammation. We propose non-genomic modulation of AnxA1 in immune cells as a novel mechanism of action for HDACIs, which may underlie their reported efficacy in models of chronic inflammatory pathologies. PMID:23222458

  4. Sodium Oxybate

    MedlinePlus

    ... if you use or have ever used street drugs, or if you have overused prescription medications. Sodium oxybate may be harmful when taken by people other than the person for whom it was prescribed. Do not sell or give your sodium oxybate to anyone else; selling or sharing it is against the law. Store ...

  5. Anti-inflammatory effects of novel AP-1 and NF-κB inhibitors in dextran-sulfate-sodium-induced colitis in rats.

    PubMed

    El-Salhy, Magdy; Umezawa, Kazuo

    2016-06-01

    The aim of the present study was to elucidate the anti-inflammatory effects of the two novel anti-inflammatory substances, 3-[(dodecylthiocarbonyl)‑methyl]-glutarimide (DTCM-G) and dehydroxymethylepoxyquinomicin (DHMEQ), on DSS-induced colitis in rats. For this purpose, rats with dextran sulfate sodium (DSS)-induced colitis were randomly divided into 3 groups with 10 animals in each group as follows: i) the control group, which received 0.5 ml of 0.5% carboxymethyl cellulose (CMC; vehicle), ii) rats that received DTCM-G (20 mg/kg body weight in 0.5% CMC; the DTCM-G group), and iii) rats that received DHMEQ (15 mg/kg body weight in 0.5% CMC; the DHMEQ group). The animals were sacrificed after the 5-day treatment period, and tissue samples were taken from their colons and sectioned for histological evaluation. The tissue sections were stained with hematoxylin and eosin, and immunostained for leukocytes, lymphocytes, macrophages/monocytes and mast cells. The disease activity index (DAI), histological grading of colitis, and densities of several types of submucosal immune cells were compared between the controls, and the DTCM-G and DHMEQ groups. The DAI values were significantly lower in both the DTCM-G and DHMEQ groups than in the control group. The total scores for the histological grading of colitis were also significantly lower in the DTCM-G and DHMEQ groups than in the control group. The submucosal densities of leucocytes, lymphocytes, macrophages/monocytes and mast cells were significantly lower in the DTCM-G and DHMEQ groups than in the control group. Our findings indicate that the anti-inflammatory and anticancer effects of DTCM-G and DHMEQ, and the absence of any associated toxicity render them excellent therapeutic candidates for clinical use in the treatment of colitis. PMID:27082818

  6. Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF

    SciTech Connect

    Belakavadi, Madesh . E-mail: belakama@umdnj.edu; Prabhakar, B.T.; Salimath, Bharathi P.

    2005-10-07

    Butyrate, a short-chain fatty acid produced in the colon, induces cell cycle arrest, differentiation, and apoptosis in transformed cell lines. In this report, we study the effects of butyrate (BuA) on the growth of Ehrlich ascites tumor (EAT) cells in vivo. BuA, when injected intraperitoneally (i.p) into mice, inhibited proliferation of EAT cells. Further, induction of apoptosis in EAT cells was monitored by nuclear condensation, annexin-V staining, DNA fragmentation, and translocation of caspase-activated DNase into nucleus upon BuA-treatment. Ac-DEVD-CHO, a caspase-3 inhibitor, completely inhibited BuA-induced apoptosis, indicating that activation of caspase-3 mediates the apoptotic pathway in EAT cells. The proapoptotic effect of BuA also reflects on the antiangiogenic pathway in EAT cells. The antiangiogenic effect of BuA in vivo was demonstrated by the downregulation of the secretion of VEGF in EAT cells. CD31 immunohistochemical staining of peritoneum sections clearly indicated a potential angioinhibitory effect of BuA in EAT cells. These results suggest that BuA, besides regulating other fundamental cellular processes, is able to modulate the expression/secretion of the key angiogenic growth factor VEGF in EAT cells.

  7. Effect of butyric acid on the performance and carcass yield of broiler chickens.

    PubMed

    Leeson, S; Namkung, H; Antongiovanni, M; Lee, E H

    2005-09-01

    Short-chain fatty acids such as butyrate are considered potential alternatives to antibiotic growth promoters. The efficacy of butyric acid on performance and carcass characteristics of broiler chickens was tested in two studies. The effect of dietary butyrate on the ability to withstand coccidial oocyte challenge also was investigated. In experiment 1, male broiler chickens were fed diets supplemented with 0 or 11 ppm virginiamycin or 0.2 or 0.4% butyric acid (as mono-, di-, and triglyceride). In experiment 2, broilers were fed bacitracin methylene disalicylate or 0.1 or 0.2% butyric acid. In another trial, birds vaccinated against coccidiosis were challenged with oocytes at 21 d and examined 6 d later. In experiment 1, diet treatments had no effect on body weight gain. Feed intake of the birds fed 0.4% butyric acid was decreased (P < 0.01) compared with birds fed the nonmedicated diet during the starter period, whereas birds fed 0.2% butyric acid had similar feed intake to the control birds. In experiment 2, diet treatments did not affect the performance of broiler chicks while carcass weight and breast meat yield increased (P < 0.01) in birds fed 0.2% butyric acid. With oocyte challenge, birds that had received butyric acid before challenge showed higher growth rate following the challenge compared with birds that received nonmedicated feed. Bacitracin decreased (P < 0.05%) duodenal villi crypt depth, whereas villus length was similar in birds fed butyric acid or the nonmedicated control diet. These results show that 0.2% butyric acid can help to maintain the performance and carcass quality of broilers, especially in vaccinated birds challenged with coccidiosis. PMID:16206563

  8. Acetylcarnitine potentiates the anticarcinogenic effects of butyrate on SW480 colon cancer cells.

    PubMed

    Elimrani, Ihsan; Dionne, Serge; Saragosti, Dan; Qureshi, Ijaz; Levy, Emile; Delvin, Edgar; Seidman, Ernest G

    2015-08-01

    Butyrate is a potent anticarcinogenic compound against colon cancer cells in vitro. However, its rapid metabolism is hypothesized to limit its anticancer benefits in colonic epithelial cells. Carnitine, a potent antioxidant, is essential to fatty acid oxidation. The aims of this study were to identify a colon cancer cell line capable of transporting carnitine. We evaluated the effect of carnitine and acetylcarnitine (ALCAR) on the response of colon carcinoma cells to butyrate. We explored the mechanisms underlying the anticarcinogenic benefit. SW480 cells were incubated with butyrate ± carnitine or ALCAR. Carnitine uptake was assessed using [3H]-carnitine. Apoptosis and cell viability were assessed using an ELISA kit and flow cytometry, respectively. Modulation of proteins implicated in carnitine transport, cell death and proliferation were assessed by western blotting. SW480 cells were found to transport carnitine primarily via the OCTN2 transporter. Butyrate induced SW480 cell death occurred at concentrations of 2 mM and higher. Cells treated with the combination of butyrate (3 mM) with ALCAR exhibited increased mortality. The addition of carnitine or ALCAR also increased butyrate-induced apoptosis. Butyrate increased levels of cyclin D1, p21 and PARP p86, but decreased Bcl-XL and survivin levels. Butyrate also downregulated dephospho-β-catenin and increased acetylated histone H4 levels. Butyrate and carnitine decreased survivin levels by ≥25%. ALCAR independently induced a 20% decrease in p21. These results demonstrate that butyrate and ALCAR are potentially beneficial anticarcinogenic nutrients that inhibit colon cancer cell survival in vitro. The combination of both agents may have superior anticarcinogenic properties than butyrate alone. PMID:26043725

  9. Butyrate enhances antibacterial effects while suppressing other features of alternative activation in IL-4-induced macrophages.

    PubMed

    Fernando, Maria R; Saxena, Alpana; Reyes, José-Luis; McKay, Derek M

    2016-05-15

    The short-chain fatty acid butyrate is produced by fermentation of dietary fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 [M(IL-4)s] can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1 and significantly suppressed LPS-induced nitric oxide, IL-12p40, and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared with M(IL-4) and this was not accompanied by enhanced proinflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4 + butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T-cell marker Foxp3. However, Tregs cocultured with M(IL-4 + butyrate) produced less IL-17A than Tregs cocultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can limit T-cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis. PMID:27012776

  10. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn's disease

    PubMed Central

    Segain, J; de la Bletiere, D R.; Bourreille, A; Leray, V; Gervois, N; Rosales, C; Ferrier, L; Bonnet, C; Blottiere, H; Galmiche, J

    2000-01-01

    BACKGROUND/AIM—Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFκB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression.
METHODS—Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFκB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFκB inhibitory protein (IκBα) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis.
RESULTS—Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFκB from the cytoplasm to the nucleus. LPS induced NFκB transcriptional activity was decreased by butyrate while IκBα levels were stable. Butyrate treatment also improved TNBS induced colitis.
CONCLUSIONS—Butyrate decreases proinflammatory cytokine expression via inhibition of NFκB activation and IκBα degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.


Keywords: inflammation; butyrate; Crohn's disease; nuclear factor kappa B; cytokines PMID:10940278

  11. Valproic Acid and Other HDAC Inhibitors Induce Microglial Apoptosis and Attenuate Lipopolysaccharide- induced Dopaminergic Neurotoxicity

    PubMed Central

    Chen, Po See; Wang, Chao-Chuan; Bortner, Carl D.; Peng, Giia-Sheun; Wu, Xuefei; Pang, Hao; Lu, Ru-Band; Gean, Po-Wu; Chuang, De-Maw; Hong, Jau-Shyong

    2009-01-01

    Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation. Other HDAC inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson’s disease. PMID:17850978

  12. TRAPPING YELLOWJACKETS (HYMENOPTERA: VESPIDAE) WITH HEPTYL BUTYRATE EMITTED FROM CONTROLLED-RELEASE DISPENSERS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numbers of workers of Vespula pensylvanica (Saussure) (western yellowjacket) and V. atropilosa (Sladen) trapped with heptyl butyrate in Washington increased with increased release of the attractant from vial dispensers, up to an estimated 2.3 milligrams heptyl butyrate per hour. Vespula germanica F...

  13. Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat.

    PubMed Central

    Butzner, J D; Parmar, R; Bell, C J; Dalal, V

    1996-01-01

    BACKGROUND--The short chain fatty acid (SCFA) butyrate provides energy for colonocytes, stimulates colonic fluid and electrolyte absorption and is recognised as an effective treatment for multiple types of colitis. AIM--To examine the impact of butyrate enema therapy on the clinical course, severity of inflammation, and SCFA stimulated Na+ absorption in a chronic experimental colitis. METHODS--Distal colitis was induced in rats with a trinitrobenzenesulphonic acid (TNBS) enema. Five days after induction, rats were divided into groups to receive: no treatment, saline enemas, or 100 mM Na-butyrate enemas daily. On day 24, colonic damage score and tissue myeloperoxidase (MPO) activity were evaluated. Colon was mounted in Ussing chambers and Na+ transport and electrical activities were measured during a basal period and after stimulation with 25 mM butyrate. RESULTS--In the untreated and the saline enema treated TNBS groups, diarrhoea and extensive colonic damage were seen, associated with increased tissue MPO activities and absent butyrate stimulated Na+ absorption. In contrast, in the butyrate enema treated TNBS group, diarrhoea ceased, colonic damage score improved, and tissue MPO activity as well as butyrate stimulated Na+ absorption recovered to control values. CONCLUSION--Butyrate enema therapy stimulated colonic repair, as evidenced by clinical recovery, decreased inflammation, and restoration of SCFA stimulated electrolyte absorption. PMID:8707089

  14. Butyric acid from anaerobic fermentation of lignocellulosic biomass hydrolysates by Clostridium sp. strain RPT-4213

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel Clostridium sp. strain RPT-4213 was found producing butyrate under strict anaerobic conditions. This strain produced 9.47 g L-1 butyric acid from MRS media (0.48 g/g glucose). RPT-4213 was also used to ferment dilute acid pretreated hydrolysates including wheat straw (WSH), corn fiber (CFH...

  15. Effect of butyrate on immune response of a chicken macrophage cell line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyric acid is a major short chain fatty acid (SCFA) produced in the gastrointestinal tract by anaerobic bacterial fermentation which has been demonstrated to have beneficial health effects in many species including poultry. To understand the immunomodulating effects of butyrate on chicken macropha...

  16. Butyric acid stimulates bovine neutrophil functions and potentiates the effect of platelet activating factor.

    PubMed

    Carretta, M D; Hidalgo, A I; Burgos, J; Opazo, L; Castro, L; Hidalgo, M A; Figueroa, C D; Taubert, A; Hermosilla, C; Burgos, R A

    2016-08-01

    Increased short-chain fatty acid (SCFA) production is associated with subacute ruminal acidosis (SARA) and activation of inflammatory processes. In humans and rodents, SCFAs modulate inflammatory responses in the gut via free fatty acid receptor 2 (FFA2). In bovines, butyric acid is one of the most potent FFA2 agonists. Its expression in bovine neutrophils has recently been demonstrated, suggesting a role in innate immune response in cattle. This study aimed to evaluate if butyric acid modulates oxidative and non-oxidative functions or if it can potentiate other inflammatory mediators in bovine neutrophils. Our results showed that butyric acid can activate bovine neutrophils, inducing calcium (Ca(2+)) influx and mitogen-activated protein kinase (MAPK) phosphorylation, two second messengers involved in FFA2 activation. Ca(2+) influx induced by butyric acid was dependent on the extracellular and intracellular Ca(2+) source and phospholipase C (PLC) activation. Butyric acid alone had no significant effect on reactive oxygen species (ROS) production and chemotaxis; however, a priming effect on platelet-activating factor (PAF), a potent inflammatory mediator, was observed. Butyric acid increased CD63 expression and induced the release of neutrophil granule markers matrix metalloproteinase-9 (MMP-9) and lactoferrin. Finally, we observed that butyric acid induced neutrophil extracellular trap (NET) formation without affecting cellular viability. These findings suggest that butyric acid, a component of the ruminal fermentative process, can modulate the innate immune response of ruminants. PMID:27288853

  17. Bioinformatic dissecting of TP53 regulation pathway underlying butyrate-induced histone modification in epigenetic regulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate affects cell proliferation, differentiation and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by IPA in our RNA sequencing data set. The TP53 signaling pathway pl...

  18. Butyrate production from dietary fibre and protection against large bowel cancer in a rat model.

    PubMed Central

    McIntyre, A; Gibson, P R; Young, G P

    1993-01-01

    Butyrate slows the growth of cancer cells cultured in vitro. To determine the relevance of the fermentative production of butyrate in vivo, colonic butyrate concentrations were manipulated by feeding different dietary fibres and were related to tumour development in the rat dimethylhydrazine model of large bowel cancer. It has previously been shown that guar gum and oat bran, while highly fermentable, are associated with low butyrate levels in the distal colon, while wheat bran causes significantly higher concentrations. Diets containing these fibres (nominally 10% w:w) were administered for 3 weeks before, for 10 weeks during, and for 20 weeks after dimethylhydrazine administration, after which animals were killed and examined for tumours. Significantly fewer tumours were seen in the rats fed wheat bran compared with those fed guar or oat bran, and the total tumour mass was lowest in rats fed wheat bran. Rats on a 'no added fibre diet' had an intermediate tumour mass. Regression analysis, performed regardless of dietary group, showed that the concentration in stools of butyrate but not of acetate or stool volume, correlated significantly (and negatively) with tumour mass. These findings indicate that fibre which is associated with high butyrate concentrations in the distal large bowel is protective against large bowel cancer, while soluble fibres that do not raise distal butyrate concentrations, are not protective. Thus, butyrate production in vivo does bear a significant relationship to suppression of tumour formation. PMID:8386131

  19. Conversion of N-butyrate to N-butanol with Continuous Fermentation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of our study is to optimize n-butanol production from n-butyrate, using pure cultures of solventogenic Clostridia. In addition to butyrate as a substrate, glucose was used as a source of energy and to provide reducing equivalents to facilitate the conversion. To prevent product inhibition...

  20. Butyric acid from anaerobic fermentation of lignocellulosic biomass hydrolysates by Clostridium tyrobutyricum strain RPT-4213

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A newly isolated Clostridium sp. strain RPT-4213 was found to produce butyrate under anaerobic conditions. Fermentations using Lactobacilli MRS Broth produced 9.47 g L-1 butyric acid from glucose (0.48 g/g glucose). However, the strain was not capable of utilizing five carbon sugars. To assess the a...

  1. Butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1 with high butyric acid yield and selectivity.

    PubMed

    Kim, Minsun; Kim, Ki-Yeon; Lee, Kyung Min; Youn, Sung Hun; Lee, Sun-Mi; Woo, Han Min; Oh, Min-Kyu; Um, Youngsoon

    2016-10-01

    The aim of this work was to study the butyric acid production from softwood hydrolysate by acetate-consuming Clostridium sp. S1. Results showed that Clostridium sp. S1 produced butyric acid by simultaneously utilizing glucose and mannose in softwood hydrolysate and, more remarkably, it consumed acetic acid in hydrolysate. Clostridium sp. S1 utilized each of glucose, mannose, and xylose as well as mixed sugars simultaneously with partially repressed xylose utilization. When softwood (Japanese larch) hydrolysate containing glucose and mannose as the main sugars was used, Clostridium sp. S1 produced 21.17g/L butyric acid with the yield of 0.47g/g sugar and the selectivity of 1 (g butyric acid/g total acids) owing to the consumption of acetic acid in hydrolysate. The results demonstrate potential of Clostridium sp. S1 to produce butyric acid selectively and effectively from hydrolysate not only by utilizing mixed sugars simultaneously but also by converting acetic acid to butyric acid. PMID:27474955

  2. [Pharmacological study on hydrocortisone 17-butyrate 21-propionate (author's transl)].

    PubMed

    Otomo, S; Higuchi, S; Nakaike, S; Takeshita, K; Tanaka, M; Gotoh, Y; Osada, Y; Tsuchida, K; Inoue, K; Kyogoku, K; Tarumoto, Y; Sasajima, M; Ohzeki, M

    1981-12-01

    The topical and systemic anti-inflammatory activities of hydrocortisone 17-butyrate 21-propionate (HBP) were studied. The systemic anti-inflammatory activities of HBP and reference steroids were examined for their effects on dinitrochlorobenzene dermatitis, carrageenin edema, cotton pellet granuloma and adjuvant arthritis in rats and by the delayed allergic edema test in mice. The topical anti-inflammatory activities of these steroids were examined for their effects on croton oil dermatitis, croton oil ear edema, carrageenin edema and cotton pellet granuloma in rats. Furthermore, effects of these steroids on liver glycogen deposition in mice, thymolysis, and decrease of serum corticosterone level in rats were examined. Systemically administered HBP was less potent than betamethasone 17-valerate (BV), but was almost equal to hydrocortisone 17-butyrate (HB) in anti-inflammatory activity, and its effects on liver glycogen deposition, thymolysis, and the decrease of serum corticosterone level. However, the topical anti-inflammatory activity of HBP was more potent than that of BV and HB, although in the same experiment, thymolytic activity of HBP was less potent than that of BV, but was almost equal to HB. The inhibitory effect of HBP on hypotonic induced hemolysis was weaker than that of BV, but was stronger than that of HB in vitro. The affinity of HBP was higher than that of BV and HB to polymorphonuclear leucocytes used as the inflammatory cells in vitro. On the other hand no marked difference was observed in the affinity to erythrocytes used as the non-inflammatory cells in vitro. These results suggest that HBP is a useful drug which has superior topical anti-inflammatory activity, but has a weak systemic effect. PMID:7333567

  3. Butyrate plays differential roles in cellular signaling in cancerous HCT116 and noncancerous NCM460 colon cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits chemoprevention effects in colon. However, the mechanistic action of butyrate at the cellular level remains to be determined. We hypothesize that butyrate plays differential roles in cancerous and non-cancerous cells through si...

  4. In vitro dissolution and in vivo absorption of calcium [1-14C]butyrate in free or protected forms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate is a by-product of microbial carbohydrate fermentation that occurs primarily in the large intestine. When added to feed, butyrate quickly disappears in the upper digestive tract. Because butyrate is important for the epithelial cell development and for mucosal integrity, and for animal grow...

  5. Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice

    PubMed Central

    Terasaki, Michishige; Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Nagashima, Masaharu; Kushima, Hideki; Watanabe, Takuya; Hirano, Tsutomu

    2015-01-01

    Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe−/−) mice, streptozotocin-induced diabetic Apoe−/− mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe−/− mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe−/− mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe−/− mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo. PMID:26606676

  6. The Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin Improves Diabetes-Induced Vascular Dysfunction in the Streptozotocin Diabetes Rat Model by Interfering with Oxidative Stress and Glucotoxicity

    PubMed Central

    Welschof, Philipp; Jansen, Thomas; Hausding, Michael; Mikhed, Yuliya; Stamm, Paul; Mader, Michael; Zinßius, Elena; Agdauletova, Saule; Gottschlich, Anna; Steven, Sebastian; Schulz, Eberhard; Bottari, Serge P.; Mayoux, Eric; Münzel, Thomas; Daiber, Andreas

    2014-01-01

    Objective In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. Methods Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE). Results Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy. Conclusions Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs. PMID:25402275

  7. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

    PubMed

    Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

    2014-01-01

    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. PMID:25061325

  8. Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage-Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice.

    PubMed

    Terasaki, Michishige; Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Nagashima, Masaharu; Kushima, Hideki; Watanabe, Takuya; Hirano, Tsutomu

    2015-01-01

    Direct associations between hyperglycemia and atherosclerosis remain unclear. We investigated the association between the amelioration of glycemia by sodium-glucose cotransporter 2 inhibitors (SGLT2is) and macrophage-driven atherosclerosis in diabetic mice. We administered dapagliflozin or ipragliflozin (1.0 mg/kg/day) for 4-weeks to apolipoprotein E-null (Apoe-/-) mice, streptozotocin-induced diabetic Apoe-/- mice, and diabetic db/db mice. We then determined aortic atherosclerosis, oxidized low-density lipoprotein (LDL)-induced foam cell formation, and related gene expression in exudate peritoneal macrophages. Dapagliflozin substantially decreased glycated hemoglobin (HbA1c) and glucose tolerance without affecting body weight, blood pressure, plasma insulin, and lipids in diabetic Apoe-/- mice. Aortic atherosclerotic lesions, atheromatous plaque size, and macrophage infiltration in the aortic root increased in diabetic Apoe-/- mice; dapagliflozin attenuated these changes by 33%, 27%, and 20%, respectively. Atherosclerotic lesions or foam cell formation highly correlated with HbA1c. Dapagliflozin did not affect atherosclerosis or plasma parameters in non-diabetic Apoe-/- mice. In db/db mice, foam cell formation increased by 4-fold compared with C57/BL6 mice, whereas ipragliflozin decreased it by 31%. Foam cell formation exhibited a strong correlation with HbA1c. Gene expression of lectin-like ox-LDL receptor-1 and acyl-coenzyme A:cholesterol acyltransferase 1 was upregulated, whereas that of ATP-binding cassette transporter A1 was downregulated in the peritoneal macrophages of both types of diabetic mice. SGLT2i normalized these gene expressions. Our study is the first to demonstrate that SGLT2i exerts anti-atherogenic effects by pure glucose lowering independent of insulin action in diabetic mice through suppressing macrophage foam cell formation, suggesting that foam cell formation is highly sensitive to glycemia ex vivo. PMID:26606676

  9. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet

    PubMed Central

    Vickers, Steven P; Cheetham, Sharon C; Headland, Katie R; Dickinson, Keith; Grempler, Rolf; Mayoux, Eric; Mark, Michael; Klein, Thomas

    2014-01-01

    The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone, and significantly improved glucose tolerance, plasma insulin, and leptin compared to vehicle-treated controls. The effect of sibutramine to improve glycemic control in an oral glucose-tolerance test was also significantly increased, with empagliflozin and combination treatment leading to a reduction in carcass fat greater than that observed with either drug alone. These data demonstrate that empagliflozin reduces body weight in cafeteria-fed obese rats. In combination studies, empagliflozin further improved the body-weight or body-fat loss of animals in comparison to orlistat or sibutramine alone. Such studies may indicate improved strategies for the treatment of obese patients with prediabetes or type 2 diabetes. PMID:25061325

  10. Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition.

    PubMed

    Xiong, Haitao; Guo, Bingxiu; Gan, Zhenshun; Song, Deguang; Lu, Zeqing; Yi, Hongbo; Wu, Yueming; Wang, Yizhen; Du, Huahua

    2016-01-01

    Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition. PMID:27230284

  11. Butyrate upregulates endogenous host defense peptides to enhance disease resistance in piglets via histone deacetylase inhibition

    PubMed Central

    Xiong, Haitao; Guo, Bingxiu; Gan, Zhenshun; Song, Deguang; Lu, Zeqing; Yi, Hongbo; Wu, Yueming; Wang, Yizhen; Du, Huahua

    2016-01-01

    Butyrate has been used to treat different inflammatory disease with positive outcomes, the mechanisms by which butyrate exerts its anti-inflammatory effects remain largely undefined. Here we proposed a new mechanism that butyrate manipulate endogenous host defense peptides (HDPs) which contributes to the elimination of Escherichia coli O157:H7, and thus affects the alleviation of inflammation. An experiment in piglets treated with butyrate (0.2% of diets) 2 days before E. coli O157:H7 challenge was designed to investigate porcine HDP expression, inflammation and E. coli O157:H7 load in feces. The mechanisms underlying butyrate-induced HDP gene expression and the antibacterial activity and bacterial clearance of macrophage 3D4/2 cells in vitro were examined. Butyrate treatment (i) alleviated the clinical symptoms of E. coli O157:H7-induced hemolytic uremic syndrome (HUS) and the severity of intestinal inflammation; (ii) reduced the E. coli O157:H7 load in feces; (iii) significantly upregulated multiple, but not all, HDPs in vitro and in vivo via histone deacetylase (HDAC) inhibition; and (iv) enhanced the antibacterial activity and bacterial clearance of 3D4/2 cells. Our findings indicate that butyrate enhances disease resistance, promotes the clearance of E. coli O157:H7, and alleviates the clinical symptoms of HUS and inflammation, partially, by affecting HDP expression via HDAC inhibition. PMID:27230284

  12. Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea

    PubMed Central

    2013-01-01

    Background Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by life-long, severe diarrhea with intestinal Cl- malabsorption. It results from a reduced activity of the down regulated in adenoma exchanger (DRA), due to mutations in the solute carrier family 26, member 3 (SLC26A3) gene. Currently available therapies are not able to limit the severity of diarrhea in CLD. Conflicting results have been reported on the therapeutic efficacy of oral butyrate. Methods We investigated the effect of oral butyrate (100 mg/kg/day) in seven CLD children with different SLC26A3 genotypes. Nasal epithelial cells were obtained to assess the effect of butyrate on the expression of the two main Cl- transporters: DRA and putative anion transporter-1 (PAT-1). Results A variable clinical response to butyrate was observed regarding the stool pattern and fecal ion loss. The best response was observed in subjects with missense and deletion mutations. Variable response to butyrate was also observed on SLC26A3 (DRA) and SLC26A6 (PAT1) gene expression in nasal epithelial cells of CLD patients. Conclusions We demonstrate a genotype-dependency for butyrate therapeutic efficacy in CLD. The effect of butyrate is related in part on a different modulation of the expression of the two main apical membrane Cl- exchangers of epithelial cells, members of the SLC26 anion family. Trial registration Australian New Zealand Clinical trial Registry ACTRN12613000450718. PMID:24350656

  13. Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion.

    PubMed

    Liu, Bin; Qian, Jianmin; Wang, Qingbao; Wang, Fangrui; Ma, Zhenyu; Qiao, Yingli

    2014-01-01

    Hepatic ischemia/reperfusion (I/R) injury is an unavoidable consequence of major liver surgery, especially in liver transplantation with bowel congestion, during which endotoxemia is often evident. The inflammatory response aggravated by endotoxin after I/R contributes to liver dysfunction and failure. The purpose of the present study was to investigate the protective effect of butyrate, a naturally occurring four-carbon fatty acid in the body and a dietary component of foods such as cheese and butter, on hepatic injury complicated by enterogenous endotoxin, as well as to examine the underlying mechanisms involved. SD rats were subjected to a total hepatic ischemia for 30 min after pretreatment with either vehicle or butyrate, followed by 6 h and 24 h of reperfusion. Butyrate preconditioning markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathological changes. The inflammatory factors levels, macrophages activation, TLR4 expression, and neutrophil infiltration in live were attenuated by butyrate. Butyrate also maintained the intestinal barrier structures, reversed the aberrant expression of ZO-1, and decreased the endotoxin translocation. We conclude that butyrate inhibition of endotoxin translocation, macrophages activation, inflammatory factors production, and neutrophil infiltration is involved in the alleviation of total hepatic I/R liver injury in rats. This suggests that butyrate should potentially be utilized in liver transplantation. PMID:25171217

  14. Destructive effects of butyrate on the cell envelope of Helicobacter pylori.

    PubMed

    Yonezawa, Hideo; Osaki, Takako; Hanawa, Tomoko; Kurata, Satoshi; Zaman, Cynthia; Woo, Timothy Derk Hoong; Takahashi, Motomichi; Matsubara, Sachie; Kawakami, Hayato; Ochiai, Kuniyasu; Kamiya, Shigeru

    2012-04-01

    Helicobacter pylori can be found in the oral cavity and is mostly detected by the use of PCR techniques. Growth of H. pylori is influenced by various factors in the mouth, such as the oral microflora, saliva and other antimicrobial substances, all of which make colonization of the oral cavity by H. pylori difficult. In the present study, we analysed the effect of the cell supernatant of a representative periodontal bacterium Porphyromonas gingivalis on H. pylori and found that the cell supernatant destroyed the H. pylori cell envelope. As P. gingivalis produces butyric acid, we focused our research on the effects of butyrate and found that it significantly inhibited the growth of H. pylori. H. pylori cytoplasmic proteins and DNA were detected in the extracellular environment after treatment with butyrate, suggesting that the integrity of the cell envelope was compromised and indicating that butyrate has a bactericidal effect on H. pylori. In addition, levels of extracellular H. pylori DNA increased following treatment with the cell supernatant of butyric acid-producing bacteria, indicating that the cell supernatant also has a bactericidal effect and that this may be due to its butyric acid content. In conclusion, butyric acid-producing bacteria may play a role in affecting H. pylori colonization of the oral cavity. PMID:22194341

  15. In vivo measurement of colonic butyrate metabolism in patients with quiescent ulcerative colitis

    PubMed Central

    Simpson, E; Chapman, M; Dawson, J; Berry, D; Macdonald, I; Cole, A

    2000-01-01

    BACKGROUND—Butyrate, a short chain fatty acid produced by bacterial fermentation, is a major fuel source for the colonocyte. In vitro work has shown that ulcerative colitis may be characterised by a metabolic defect in colonocyte butyrate oxidation.
AIMS—To investigate the rate of metabolism of rectally administered butyrate in patients with quiescent colitis.
METHODS—[1-13C]-butyrate enemas were administered to 11 patients with long standing quiescent ulcerative colitis and to 10 control patients. The rate of production of 13CO2 in exhaled breath over four hours was measured by isotope ratio mass spectrometry combined with indirect calorimetry in order to measure CO2 production. This allowed calculation of the patients' resting energy expenditure and respiratory quotient.
RESULTS—Over a four hour period, 325 (SEM 21) µmol 13CO2 was recovered in breath samples from the colitis group compared with 322 (17) µmol from the control group (NS). The respiratory quotient of the colitic group was significantly lower than that of the control group.
CONCLUSION—There was no difference in the rate of metabolism of butyrate between the two groups. It is unlikely that there is a primary metabolic defect of butyrate metabolism in patients with quiescent ulcerative colitis.


Keywords: ulcerative colitis; in vivo butyrate metabolism PMID:10601058

  16. Butyrate enemas upregulate Muc genes expression but decrease adherent mucus thickness in mice colon.

    PubMed

    Gaudier, E; Rival, M; Buisine, M-P; Robineau, I; Hoebler, C

    2009-01-01

    Colonic mucosal protection is provided by the mucus gel, mainly composed of mucins. Several factors can modulate the formation and the secretion of mucins, and among them butyrate, an end-product of carbohydrate fermentation. However, the specific effect of butyrate on the various colonic mucins, and the consequences in terms of the mucus layer thickness are not known. Our aim was to determine whether butyrate modulates colonic MUC genes expression in vivo and whether this results in changes in mucus synthesis and mucus layer thickness. Mice received daily for 7 days rectal enemas of butyrate (100 mM) versus saline. We demonstrated that butyrate stimulated the gene expression of both secreted (Muc2) and membrane-linked (Muc1, Muc3, Muc4) mucins. Butyrate especially induced a 6-fold increase in Muc2 gene expression in proximal colon. However, butyrate enemas did not modify the number of epithelial cells containing the protein Muc2, and caused a 2-fold decrease in the thickness of adherent mucus layer. Further studies should help understanding whether this last phenomenon, i.e. the decrease in adherent mucus gel thickness, results in a diminished protective function or not. PMID:18198997

  17. Acifluorfen, sodium

    Integrated Risk Information System (IRIS)

    Acifluorfen , sodium ; CASRN 62476 - 59 - 9 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcino

  18. Sodium diethyldithiocarbamate

    Integrated Risk Information System (IRIS)

    Sodium diethyldithiocarbamate ; CASRN 148 - 18 - 5 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Non

  19. Sodium fluoroacetate

    Integrated Risk Information System (IRIS)

    Sodium fluoroacetate ; CASRN 62 - 74 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogen

  20. Sodium azide

    Integrated Risk Information System (IRIS)

    Sodium azide ; CASRN 26628 - 22 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Ef

  1. Sodium cyanide

    Integrated Risk Information System (IRIS)

    Jump to main content . Integrated Risk Information System Recent Additions | Contact Us Search : All EPA IRIS • You are here : EPA Home • Research • Environmental Assessment • IRIS • IRIS Summaries Redirect Page As of September 28 , 2010 , the assessment summary for sodium cyanide is included in the

  2. n-Butyrate inhibits Jun NH(2)-terminal kinase activation and cytokine transcription in mast cells

    SciTech Connect

    Diakos, Christos; Prieschl, Eva E.; Saeemann, Marcus D.; Boehmig, Georg A.; Csonga, Robert; Sobanov, Yury; Baumruker, Thomas; Zlabinger, Gerhard J. . E-mail: gerhard.zlabinger@meduniwien.ac.at

    2006-10-20

    Mast cells are well known to contribute to type I allergic conditions but only recently have been brought in association with chronic relapsing/remitting autoimmune diseases such as celiac disease and ulcerative colitis. Since the bacterial metabolite n-butyrate is considered to counteract intestinal inflammation we investigated the effects of this short chain fatty acid on mast cell activation. Using RNAse protection assays and reporter gene technology we show that n-butyrate downregulates TNF-{alpha} transcription. This correlates with an impaired activation of the Jun NH(2)-terminal kinase (JNK) but not other MAP kinases such as ERK and p38 that are largely unaffected by n-butyrate. As a consequence, we observed a decreased nuclear activity of AP-1 and NF-AT transcription factors. These results indicate that n-butyrate inhibits critical inflammatory mediators in mast cells by relatively selectively targeting the JNK signalling.

  3. ALA-Butyrate prodrugs for Photo-Dynamic Therapy

    NASA Astrophysics Data System (ADS)

    Berkovitch, G.; Nudelman, A.; Ehenberg, B.; Rephaeli, A.; Malik, Z.

    2010-05-01

    The use of 5-aminolevulinic acid (ALA) administration has led to many applications of photodynamic therapy (PDT) in cancer. However, the hydrophilic nature of ALA limits its ability to penetrate the cells and tissues, and therefore the need for ALA derivatives became an urgent research target. In this study we investigated the activity of novel multifunctional acyloxyalkyl ester prodrugs of ALA that upon metabolic hydrolysis release active components such as, formaldehyde, and the histone deacetylase inhibitory moiety, butyric acid. Evaluation of these prodrugs under photo-irradiation conditions showed that butyryloxyethyl 5-amino-4-oxopentanoate (ALA-BAC) generated the most efficient photodynamic destruction compared to ALA. ALA-BAC stimulated a rapid biosynthesis of protoporphyrin IX (PpIX) in human glioblastoma U-251 cells which resulted in generation of intracellular ROS, reduction of mitochondrial activity, leading to apoptotic and necrotic death of the cells. The apoptotic cell death induced by ALA / ALA-BAC followed by PDT equally activate intrinsic and extrinsic apoptotic signals and both pathways may occur simultaneously. The main advantage of ALA-BAC over ALA stems from its ability to induce photo-damage at a significantly lower dose than ALA.

  4. Ultrasound assisted synthesis of methyl butyrate using heterogeneous catalyst.

    PubMed

    Dange, P N; Kulkarni, A V; Rathod, V K

    2015-09-01

    Ultrasound assisted esterification of butyric acid with methanol was investigated in an ultrasound irradiated isothermal batch reactor using acid ion-exchange resin (amberlyst-15) as a catalyst. Effect of parameters such as temperature (323-353 K), catalyst loading (0-8.5%w/w), alcohol to acid ratio, M (2-6), ultrasound power (0-145 W), duty cycle (0-85%) and amount of molecular sieves added (0-11%w/w) on the rate of reaction was studied. At optimized parameters, a maximum conversion of 91.64% was obtained in 120 min in presence of ultrasound. Experimental kinetic data were correlated by using Eley-Rideal (ER) and Langmuir-Hinshelwood-Hougen-Watson (LHH W) models taking into account reverse reaction. Studies showed that single site LHHW with reactants and products both adsorbing on catalyst surface was most suited for the obtained experimental data. Activation energy determined based on heterogeneous kinetics was in the range 49.31-57.54 kJ/mol while it was 18.29 kJ/mol using homogeneous model. PMID:25825149

  5. Comparative pharmaceutical evaluation of brand and generic clobetasone butyrate ointments.

    PubMed

    Yamamoto, Yoshihisa; Fukami, Toshiro; Koide, Tatsuo; Onuki, Yoshinori; Suzuki, Toyofumi; Metori, Koichi; Katori, Noriko; Hiyama, Yukio; Tomono, Kazuo

    2014-03-10

    In the present study, we performed comprehensive pharmaceutical evaluation among an original clobetasone butyrate (CLB) ointment product and three generic products. Although spherocrystal images were observed under a polarizing microscope for only Kindavate®, the original product, distribution of active and inactive ingredients was chemically equivalent between the original and generic medicine by the attenuated total reflection infrared spectroscopy. These results suggest that the spherocrystals observed in Kindavate® are composed of hydrocarbon. On GC/MS, it was revealed that linear alkanes having 25-27 carbon atoms are densely present in Sun White®, the base used in Kindavate®. On the other hand, linear alkanes having 22-31 carbon atoms were broadly distributed in most other white petrolatums. In the CLB ointment products, the distribution equivalent of linear alkane to Sun White® was observed only in Kindavate®. Thus, the GC/MS method is extremely useful for identification of white petrolatum used in the ointment. A similar amount of CLB among the pharmaceutical products was detected in the skin tissue by skin accumulation test, although there were the differences in rheological properties and the quality of white petrolatum. The present results will be very useful for pharmacists in selecting medicine products that match the needs of the patient. Such pharmaceutical information will help spread objective knowledge about products in the future, and will contribute to the appropriate selection of medication. PMID:24406671

  6. Butyrate-mediated acquisition of chemoresistance by human colon cancer cells.

    PubMed

    Kang, Hyang Ri; Choi, Hyeon Gyeom; Jeon, Chae Kyung; Lim, Soo-Jeong; Kim, So Hee

    2016-08-01

    Butyrate is a short-chain fatty acid produced by the intestinal microflora and it not only induces apoptosis but also inhibits the proliferation of cancer cells. Recently, it has been reported that butyrate may cause resistance in colon cancer cells. Therefore, we investigated the effects of increased resistance to butyrate in HCT116 colon cancer cells. We established HCT116 cells resistant to butyrate (HCT116/BR) by treating HCT116 parental cells (HCT116/PT) with increasing concentrations of butyrate to a maximum of 1.6 mM for 3 months. The butyrate concentrations that inhibited cell growth by 50% (IC50) were 0.508 and 5.50 mM in HCT116/PT and HCT116/BR cells. The values after treatment with paclitaxel, 5-fluorouracil (5-FU), doxorubicin and trichostatin A (TSA) were 2.42, 2.36, 4.31 and 11.3-fold higher, respectively, in HCT116/BR cells compared with HCT116/PT cells. The protein expression of drug efflux pumps, such as P-glycoprotein (P-gp), breast cancer-resistant protein (BCRP) and the multidrug resistance associated protein 1 (MRP1), did not differ between HCT116/PT and HCT116/BR cells. The expression level of the anti-apoptotic Bcl-xL protein was increased while those of pro-apoptotic Bax and Bim proteins were reduced in HCT116/BR cells. There were no significant differences in cell motility and invasion. This study suggests that exposure of colon cancer cells to butyrate results in development of resistance to butyrate, which may play a role in the acquisition of chemoresistance in colon cancer. PMID:27277338

  7. 4,4,4-trifluoro-3-(indole-3-)butyric acid promotes root elongation in Lactuca sativa independent of ethylene synthesis and pH

    NASA Technical Reports Server (NTRS)

    Zhang, Nenggang; Hasenstein, Karl H.

    2002-01-01

    We studied the mode of action of 4,4,4-trifluoro-3- (indole-3-) butyric acid (TFIBA), a recently described root growth stimulator, on primary root growth of Lactuca sativa L. seedlings. TFIBA (100 micromoles) promoted elongation of primary roots by 40% in 72 h but inhibited hypocotyl growth by 35%. TFIBA induced root growth was independent of pH. TFIBA did not affect ethylene production, but reduced the inhibitory effect of ethylene on root elongation. TFIBA promoted root growth even in the presence of the ethylene biosynthesis inhibitor L-alpha-(2-aminoethoxyvinyl)glycine. TFIBA and the ethylene-binding inhibitor silver thiosulphate (STS) had a similar effect on root elongation. The results indicate that TFIBA-stimulated root elongation was neither pH-dependent nor related to inhibition of ethylene synthesis, but was possibly related to ethylene action.

  8. Test Your Sodium Smarts

    MedlinePlus

    ... You may be surprised to learn how much sodium is in many foods. Sodium, including sodium chloride ... foods with little or no salt. Test your sodium smarts by answering these 10 questions about which ...

  9. Low sodium level

    MedlinePlus

    Low sodium level is a condition in which the amount of sodium (salt) in the blood is lower ... and this causes many of the symptoms of low sodium. With low sodium level (hyponatremia), the imbalance of ...

  10. Low sodium diet (image)

    MedlinePlus

    ... for you. Look for these words on labels: low-sodium, sodium-free, no salt added, sodium-reduced, or ... for you. Look for these words on labels: low-sodium, sodium-free, no salt added, sodium-reduced, or ...

  11. Gamma amino butyric acid accumulation in medicinal plants without stress

    PubMed Central

    Anju, P.; Moothedath, Ismail; Rema Shree, Azhimala Bhaskaranpillai

    2014-01-01

    Introduction: Gamma amino butyric acid (GABA) is an important ubiquitous four carbon nonprotein amino acid with an amino group attached to gamma carbon instead of beta carbon. It exists in different organisms including bacteria, plants, and animals and plays a crucial role in humans by regulating neuronal excitability throughout the nervous system. It is directly responsible for the regulation of muscle tone and also effective in lowering stress, blood pressure, and hypertension. Aim and Objective: The aim of the study was to develop the fingerprint profile of selected medicinally and economically important plants having central nervous system (CNS) activity and to determine the quantity of GABA in the selected plants grown under natural conditions without any added stress. Materials and Methods: The high-performance thin layer chromatography analysis was performed on precoated silica gel plate 60F–254 plate (20 cm × 10 cm) in the form of bands with width 8 mm using Hamilton syringe (100 μl) using n-butanol, acetic acid, and water in the proportion 5:2:2 as mobile phase in a CAMAG chamber which was previously saturated for 30 min. CAMAG TLC scanner 3 was used for the densitometric scanning at 550 nm. Specific marker compounds were used for the quantification. Results and Conclusion: Among the screened medicinal plants, Zingiber officinale and Solanum torvum were found to have GABA. The percentage of GABA present in Z. officinale and S. torvum were found to be 0.0114% and 0.0119%, respectively. The present work confirmed that among the selected CNS active medicinal plants, only two plants contain GABA. We found a negative correlation with plant having CNS activity and accumulation of GABA. The GABA shunt is a conserved pathway in eukaryotes and prokaryotes but, although the role of GABA as a neurotransmitter in mammals is clearly established, its role in plants is still vague. PMID:25861139

  12. Butyrate delivered by butyrylated starch increases distal colonic epithelial apoptosis in carcinogen-treated rats.

    PubMed

    Clarke, Julie M; Young, Graeme P; Topping, David L; Bird, Anthony R; Cobiac, Lynne; Scherer, Benjamin L; Winkler, Jessica G; Lockett, Trevor J

    2012-01-01

    Animal studies show that increasing large bowel butyrate concentration through ingestion of butyrylated or resistant starches opposes carcinogen-induced tumorigenesis, which is consistent with population data linking greater fiber consumption with lowered colorectal cancer (CRC) risk. Butyrate has been shown to regulate the apoptotic response to DNA damage. This study examined the impact of increasing large bowel butyrate concentration by dietary butyrylated starch on the colonic epithelium of rats treated with the genotoxic carcinogen azoxymethane (AOM). Four groups of 10 male rats were fed AIN-93G based-diets containing either low amylose maize starch (LAMS), LAMS with 3% tributyrin, 10% high amylose maize starch (HAMS) or 10% butyrylated HAMS (HAMSB). HAMS and HAMSB starches were cooked by heating in water. After 4 weeks, rats were injected once with AOM and killed 6 h later. Rates of apoptosis and proliferation were measured in colonic epithelium. Short-chain fatty acid concentrations in large bowel digesta and hepatic portal venous plasma were higher in HAMSB than all other groups. Apoptotic rates in the distal colon were increased by HAMSB and correlated with luminal butyrate concentrations but cellular proliferation rates were unaffected by diet. The increase in apoptosis was most marked in the base and proliferative zone of the crypt. Regulation of luminal butyrate using HAMSB increases the rates of apoptotic deletion of DNA-damaged colonocytes. We propose this pro-apoptotic function of butyrate plays a major role reducing tumour formation in the AOM-treated rat and that these data support a potential protective role of butyrate in CRC. PMID:22080572

  13. Butyrate modulates antioxidant enzyme expression in malignant and non-malignant human colon tissues.

    PubMed

    Jahns, Franziska; Wilhelm, Anne; Jablonowski, Nadja; Mothes, Henning; Greulich, Karl Otto; Glei, Michael

    2015-04-01

    The induction of antioxidant enzymes is an important mechanism in colon cancer chemoprevention, but the response of human colon tissue to butyrate, a gut fermentation product derived from dietary fiber, remains largely unknown. Therefore, our study investigated the effect of a butyrate treatment on catalase (CAT) and superoxide dismutase (SOD2) in matched human colon tissues of different transformation stages (n = 3-15 in each group) ex vivo. By performing quantitative real-time PCR, Western blot, and spectrophotometric measurements, we found an increase in SOD2 at expression and activity level in colonic adenocarcinomas (mRNA: 1.96-fold; protein: 1.41-fold, activity: 1.8-fold; P < 0.05). No difference was detectable for CAT between normal, adenoma, and carcinoma colon tissues. Treatment of normal colon epithelium (12 h) with a physiologically relevant concentration of butyrate (10 mM) resulted in a significant increase (P < 0.05) in CAT mRNA (1.24-fold) and protein (1.39-fold), without affecting the enzymatic activity. Consequently, preliminary experiments failed to show any protective effect of butyrate against H2 O2 -mediated DNA damage. Despite a significantly lowered SOD2 transcript (0.51-fold, P < 0.01) and, to a lesser extent, protein level (0.86-fold) after butyrate exposure of normal colon cells, the catalytic activity was significantly enhanced (1.19-fold, P < 0.05), suggesting an increased protection against tissue superoxide radicals. In malignant tissues, greater variations in response to butyrate were observed. Furthermore, both enzymes showed an age-dependent decrease in activity in normal colon epithelium (CAT: r = -0.49, P = 0.09; SOD2: r = -0.58, P = 0.049). In conclusion, butyrate exhibited potential antioxidant features ex vivo but cellular consequences need to be investigated more in depth. PMID:24677319

  14. Efficient production of butyric acid from Jerusalem artichoke by immobilized Clostridium tyrobutyricum in a fibrous-bed bioreactor.

    PubMed

    Huang, Jin; Cai, Jin; Wang, Jin; Zhu, Xiangcheng; Huang, Lei; Yang, Shang-Tian; Xu, Zhinan

    2011-02-01

    Butyric acid is an important specialty chemical with wide industrial applications. The feasible large-scale fermentation for the economical production of butyric acid requires low-cost substrate and efficient process. In the present study, butyric acid production by immobilized Clostridium tyrobutyricum was successfully performed in a fibrous-bed bioreactor using Jerusalem artichoke as the substrate. Repeated-batch fermentation was carried out to produce butyric acid with a high butyrate yield (0.44 g/g), high productivity (2.75 g/L/h) and a butyrate concentration of 27.5 g/L. Furthermore, fed-batch fermentation using sulfuric acid pretreated Jerusalem artichoke hydrolysate resulted in a high butyric acid concentration of 60.4 g/L, with the yield of 0.38 g/g and the selectivity of ∼ 85.1 (85.1g butyric acid/g acetic acid). Thus, the production of butyric acid from Jerusalem artichoke on a commercial scale could be achieved based on the system developed in this work. PMID:21169015

  15. Oncogenic ras alters sensitivity of mouse colonocytes to butyrate and fatty acid mediated growth arrest and apoptosis.

    PubMed

    Turner, Nancy D; Zhang, Jianhu; Davidson, Laurie A; Lupton, Joanne R; Chapkin, Robert S

    2002-12-01

    Docosahexaenoic acid (DHA) and butyrate favorably modulate colonocyte proliferation and apoptosis. In order to elucidate how oncogenic Ras modulates responses to these chemopreventive nutrients, we incubated isogenic non-transformed and Ras malignant transformed mouse colon cells with butyrate and DHA or linoleic acid (LA). Combining DHA with 1mM butyrate decreased proliferation relative to LA or no PUFA treatment in both cell lines. At a higher butyrate dose (5mM), caspase 3 activity was elevated to a greater extent in Ras transformed cells. Only non-transformed cells were sensitive to the apoptogenic effects of DHA, indicating that Ras transformation alters sensitivity to dietary chemopreventive agents. PMID:12183072

  16. Butyrate production in phylogenetically diverse Firmicutes isolated from the chicken caecum

    PubMed Central

    Eeckhaut, Venessa; Van Immerseel, Filip; Croubels, Siska; De Baere, Siegrid; Haesebrouck, Freddy; Ducatelle, Richard; Louis, Petra; Vandamme, Peter

    2011-01-01

    Summary Sixteen butyrate‐producing bacteria were isolated from the caecal content of chickens and analysed phylogenetically. They did not represent a coherent phylogenetic group, but were allied to four different lineages in the Firmicutes phylum. Fourteen strains appeared to represent novel species, based on a level of ≤ 98.5% 16S rRNA gene sequence similarity towards their nearest validly named neighbours. The highest butyrate concentrations were produced by the strains belonging to clostridial clusters IV and XIVa, clusters which are predominant in the chicken caecal microbiota. In only one of the 16 strains tested, the butyrate kinase operon could be amplified, while the butyryl‐CoA : acetate CoA‐transferase gene was detected in eight strains belonging to clostridial clusters IV, XIVa and XIVb. None of the clostridial cluster XVI isolates carried this gene based on degenerate PCR analyses. However, another CoA‐transferase gene more similar to propionate CoA‐transferase was detected in the majority of the clostridial cluster XVI isolates. Since this gene is located directly downstream of the remaining butyrate pathway genes in several human cluster XVI bacteria, it may be involved in butyrate formation in these bacteria. The present study indicates that butyrate producers related to cluster XVI may play a more important role in the chicken gut than in the human gut. PMID:21375722

  17. Butyric acid fermentation in a fibrous bed bioreactor with immobilized Clostridium tyrobutyricum from cane molasses.

    PubMed

    Jiang, Ling; Wang, Jufang; Liang, Shizhong; Wang, Xiaoning; Cen, Peilin; Xu, Zhinan

    2009-07-01

    Butyrate fermentation by immobilized Clostridium tyrobutyricum was successfully carried out in a fibrous bed bioreactor using cane molasses. Batch fermentations were conducted to investigate the influence of pH on the metabolism of the strain, and the results showed that the fermentation gave a highest butyrate production of 26.2 g l(-1) with yield of 0.47 g g(-1) and reactor productivity up to 4.13 g l(-1)h(-1) at pH 6.0. When repeated-batch fermentation was carried out, long-term operation with high butyrate yield, volumetric productivity was achieved. Several cane molasses pretreatment techniques were investigated, and it was found that sulfuric acid treatment gave better results regarding butyrate concentration (34.6+/-0.8 g l(-1)), yield (0.58+/-0.01 g g(-1)), and sugar utilization (90.8+/-0.9%). Also, fed-batch fermentation from cane molasses pretreated with sulfuric acid was performed to further increase the concentration of butyrate up to 55.2 g l(-1). PMID:19297150

  18. Production of Butyrate from Lactate by a Newly Isolated Clostridium sp. BPY5.

    PubMed

    Tao, Yong; Hu, Xiaohong; Zhu, Xiaoyu; Jin, Hong; Xu, Zhancheng; Tang, Qinglan; Li, Xiangzhen

    2016-06-01

    Lactate-utilizing bacteria play important roles in the production of Chinese strong-flavored liquor (CSFL). However, the identity of these bacteria and their lactate-utilizing properties are largely unknown. Here, a lactate-utilizing, butyrate-producing bacterium BPY5 was isolated from an old fermentation pit for CSFL production. The isolate represented a novel species belonging to Clostridium cluster XIVa of family Lachnospiraceae based on phylogenetic analysis using 16S rRNA gene sequences. Strain BPY5 could ferment lactate into butyrate as the major metabolic product. Butyrate was significantly formed at initial lactate concentration from 66 to 104 mM, but substantially declined when initial lactate exceeded 133 mM. At initial lactate concentration of 66 mM, lactate conversion was independent on initial pH from 5.5 to 7.0, but the conversion was completely inhibited when pH dropped below 4.8. Nevertheless, the inhibition on lactate conversion was largely relieved by the addition of acetate, suggesting that exogenous acetate could enhance lactate conversion at low pH condition. Additionally, lactate in CSFL-brewing wastewater was dramatically removed when inoculated with strain BPY5. These results implicate that the isolate may be applied for the industrial production of butyrate or the recovery of butyrate from lactate-containing wastewater. PMID:26842597

  19. New holographic polymeric composition based on plexiglass, polyvinyl butyral, and phenanthrenquinone

    NASA Astrophysics Data System (ADS)

    Matusevich, Vladislav; Tolstik, Elen; Kowarschik, Richard; Egorova, Elena; Matusevich, Yuri I.; Krul, Leonid

    2013-05-01

    The newly developed Plexiglas films containing polyvinyl butyral resins and phenanthrenequinone molecules as photosensitive dopant, which are proposed for the practical application as interlayer of laminated safety glass, are shown for the first time. The injection of the phenanthrenequinone-poly(methyl methacrylate) into the polyvinyl butyral protective interlayer provides a homogenous distribution of the recording holographic medium in the layer and allows fixing the entire surface grating in the laminated glass. In addition, the original properties of polyvinyl butyral as a connecting material were preserved during manufacturing of the laminated glass. This allows a recording of holographic structures directly after baking of the laminated glass, thus reducing the destruction of the gratings due to the elevated temperatures. The diffractive structures in phenanthrenequinone-poly(methyl methacrylate)-polyvinyl butyral polymeric layers with thicknesses of hundreds of microns are sealed between two panels of glass (so-called laminated glass) and are generated by illumination with an Argon-laser of 514 nm. Efficiently fixed and long-term stable holographic gratings recorded in the phenanthrenequinone-poly(methyl methacrylate)-polyvinyl butyral layer enable to produce transparent laminated glass with inserted diffractive elements, which can be used e.g. for Head-up Displays in automobile windshields or as holographic light concentrators for solar cells.

  20. Butyric acid fermentation from pretreated and hydrolysed wheat straw by an adapted Clostridium tyrobutyricum strain

    PubMed Central

    Baroi, G N; Baumann, I; Westermann, P; Gavala, H N

    2015-01-01

    Butyric acid is a valuable building-block for the production of chemicals and materials and nowadays it is produced exclusively from petroleum. The aim of this study was to develop a suitable and robust strain of Clostridium tyrobutyricum that produces butyric acid at a high yield and selectivity from lignocellulosic biomasses. Pretreated (by wet explosion) and enzymatically hydrolysed wheat straw (PHWS), rich in C6 and C5 sugars (71.6 and 55.4 g l−1 of glucose and xylose respectively), was used as substrate. After one year of serial selections, an adapted strain of C. tyrobutyricum was developed. The adapted strain was able to grow in 80% (v v−1) PHWS without addition of yeast extract compared with an initial tolerance to less than 10% PHWS and was able to ferment both glucose and xylose. It is noticeable that the adapted C. tyrobutyricum strain was characterized by a high yield and selectivity to butyric acid. Specifically, the butyric acid yield at 60–80% PHWS lie between 0.37 and 0.46 g g−1 of sugar, while the selectivity for butyric acid was as high as 0.9–1.0 g g−1 of acid. Moreover, the strain exhibited a robust response in regards to growth and product profile at pH 6 and 7. PMID:26230610

  1. Neurological perspectives on voltage-gated sodium channels

    PubMed Central

    Linley, John E.; Baker, Mark D.; Minett, Michael S.; Cregg, Roman; Werdehausen, Robert; Rugiero, François

    2012-01-01

    The activity of voltage-gated sodium channels has long been linked to disorders of neuronal excitability such as epilepsy and chronic pain. Recent genetic studies have now expanded the role of sodium channels in health and disease, to include autism, migraine, multiple sclerosis, cancer as well as muscle and immune system disorders. Transgenic mouse models have proved useful in understanding the physiological role of individual sodium channels, and there has been significant progress in the development of subtype selective inhibitors of sodium channels. This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects. We also discuss recent advances in the development of selective sodium channel inhibitors. PMID:22961543

  2. SGLT2 inhibitors.

    PubMed

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. PMID:26362302

  3. Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by butyrate and phenylbutyrate.

    PubMed

    Linsdell, P

    2001-01-12

    Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is inhibited by a broad range of intracellular organic anions. Here it is shown, using patch clamp recording from CFTR-transfected mammalian cell lines, that the fatty acids butyrate and 4-phenylbutyrate cause a voltage-dependent block of CFTR Cl(-) currents when applied to the cytoplasmic face of membrane patches, with apparent K(d)s (at 0 mV) of 29.6 mM for butyrate and 6.6 mM for 4-phenylbutyrate. At the single channel level, both these fatty acids caused an apparent reduction in CFTR current amplitude, suggesting a kinetically fast blocking mechanism. The concentration-dependence of block suggests that CFTR-mediated Cl(-) currents in vivo may be affected by both 4-phenylbutyrate used in the treatment of various diseases, including cystic fibrosis, and by butyrate produced endogenously within the colonic lumen. PMID:11164382

  4. Different control mechanisms of growth hormone (GH) secretion between gamma-amino- and gamma-hydroxy-butyric acid: neuroendocrine evidence in Parkinson's disease.

    PubMed

    Volpi, R; Chiodera, P; Caffarra, P; Scaglioni, A; Saccani, A; Coiro, V

    1997-10-01

    The observation that baclofen stimulates growth hormone (GH) secretion in normal men, but not in parkinsonian patients led us to test the GH releasing effect of other gamma-amino-butyric acid (GABA)ergic agents with different mechanisms of action in Parkinson's disease. For this purpose 10 normal men and 10 de novo parkinsonian patients were tested with sodium valproate (800 mg PO), gamma-hydroxybutyric acid (GHB) (25 mg/kg body weight PO) and baclofen (10 mg PO). All drugs induced a significant increment in serum GH levels in the normal controls. On the other hand, GH secretion in parkinsonian patients did not change after baclofen or sodium valproate administration, whereas it showed normal responsiveness to GHB. These data suggest that the mechanism underlying the GH response to GHB is different from that (or those) mediating sodium valproate and/or baclofen action. In addition, the former, but not the latter mechanism appears to be preserved in the parkinsonian brain. PMID:9373886

  5. Low sodium level

    MedlinePlus

    Low sodium level is a condition in which the amount of sodium (salt) in the blood is lower than normal. The ... Sodium is found mostly in the body fluids outside the cells. It is very important for maintaining ...

  6. Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells.

    PubMed

    Sonnemann, Jürgen; Hüls, Isabel; Sigler, Michael; Palani, Chithra D; Hong, Le Thi Thu; Völker, Uwe; Kroemer, Heyo K; Beck, James F

    2008-07-01

    Histone deacetylase inhibitors (HDIs) as well as non-steroidal anti-inflammatory drugs including aspirin show promise as antineoplastic agents. The treatment with both HDIs and aspirin can result in hyperacetylation of proteins. In this study, we investigated whether HDIs and aspirin interacted in inducing anticancer activity and histone acetylation. We found that the HDIs, suberoylanilide hydroxamic acid and sodium butyrate, and aspirin cooperated to induce cell death in the ovarian cancer cell line, A2780. The effect was synergistic, as evidenced by CI-isobologram analysis. However, aspirin had no effect on histone acetylation, neither in the absence nor presence of HDIs. To gain insight into the mechanism underlying the synergistic action of HDIs and aspirin, we employed the deacetylated metabolite of aspirin, salicylic acid, and the cyclooxygenase-1- and -2-selective inhibitors, SC-560 and NS-398, respectively. We found that HDIs and salicylic acid interacted synergistically, albeit less efficiently than HDIs and aspirin, to induce cancer cell death, suggesting that the acetyl and the salicyl moiety contributed to the cooperative interaction of aspirin with HDIs. SC-560 and NS-398 had little effect both when applied alone or in conjunction with HDIs, indicating that the combinatorial effect of HDIs and aspirin was not the result of cyclo-oxygenase inhibition. In conclusion, our study demonstrates that HDIs and aspirin synergize to induce cancer cell death and, thus, provides a rationale for a more in-depth exploration into the potential of combining HDIs and aspirin as a strategy for anticancer therapy. PMID:18575740

  7. Effects of butyrate, avilamycin, and a plant extract combination on the intestinal equilibrium of early-weaned pigs.

    PubMed

    Manzanilla, E G; Nofrarías, M; Anguita, M; Castillo, M; Perez, J F; Martín-Orúe, S M; Kamel, C; Gasa, J

    2006-10-01

    We evaluated the effects of 3 additives, sodium butyrate (AC), avilamycin (AB), and a combination of plant extracts (XT), on the productive performance and the intestinal environment of the early-weaned pig. The XT was a standardized mixture with 5% (wt/wt) carvacrol (from Origanum spp.), 3% cinnamaldehyde (from Cinnamonum spp.), and 2% capsicum oleoresin (from Capsicum annum). Pigs (n = 32) weaned at 18 to 22 d of age with an initial BW of 6.0 +/- 0.10 kg were allocated to 8 pens that, in turn, were allocated to 4 treatments. The treatments included a basal diet (CT) or the basal diet supplemented with 0.3% of AC, 0.04% of AB, or 0.03% of XT. Productive performance was determined during the initial 14 d postweaning. On d 19 and 21 of the experiment, the pigs were killed to allow collection of digesta and intestinal tissue to evaluate variables indicative of aspects of the gastrointestinal environment. Treatments AB and AC improved G:F (P = 0.012 and 0.003, respectively) compared with the CT. Butyrate included in the diet was only detected in the stomach but not in cranial jejunum. When compared with CT, AC produced a lower ileal starch digestibility (P = 0.002) and a lower whole-tract OM and starch digestibility (P = 0.001 and 0.003, respectively), related to a lower VFA concentration in the cranial colon (P = 0.082) and a numerically reduced branched VFA percentage in the rectum. The AB treatment diminished propionate production in caudal colon (P = 0.002) and rectum (P = 0.012) compared with CT. The AC group exhibited deeper crypt depth in the jejunum without variations in villus height compared with CT (P = 0.042). The AC and AB groups also increased goblet cell presence in the colon (P = 0.001 and 0.032, respectively). On the other hand, AB and XT diminished intraepithelial lymphocytes in the jejunum (P = 0.003 and 0.034, respectively). The XT increased lymphocyte presence in the colon (P = 0.003). These results show the important influence of AB and AC on

  8. Transport of the two natural auxins, indole-3-butyric acid and indole-3-acetic acid, in Arabidopsis

    NASA Technical Reports Server (NTRS)

    Rashotte, Aaron M.; Poupart, Julie; Waddell, Candace S.; Muday, Gloria K.; Brown, C. S. (Principal Investigator)

    2003-01-01

    Polar transport of the natural auxin indole-3-acetic acid (IAA) is important in a number of plant developmental processes. However, few studies have investigated the polar transport of other endogenous auxins, such as indole-3-butyric acid (IBA), in Arabidopsis. This study details the similarities and differences between IBA and IAA transport in several tissues of Arabidopsis. In the inflorescence axis, no significant IBA movement was detected, whereas IAA is transported in a basipetal direction from the meristem tip. In young seedlings, both IBA and IAA were transported only in a basipetal direction in the hypocotyl. In roots, both auxins moved in two distinct polarities and in specific tissues. The kinetics of IBA and IAA transport appear similar, with transport rates of 8 to 10 mm per hour. In addition, IBA transport, like IAA transport, is saturable at high concentrations of auxin, suggesting that IBA transport is protein mediated. Interestingly, IAA efflux inhibitors and mutations in genes encoding putative IAA transport proteins reduce IAA transport but do not alter IBA movement, suggesting that different auxin transport protein complexes are likely to mediate IBA and IAA transport. Finally, the physiological effects of IBA and IAA on hypocotyl elongation under several light conditions were examined and analyzed in the context of the differences in IBA and IAA transport. Together, these results present a detailed picture of IBA transport and provide the basis for a better understanding of the transport of these two endogenous auxins.

  9. The rib1 Mutant Is Resistant to Indole-3-Butyric Acid, an Endogenous Auxin in Arabidopsis1

    PubMed Central

    Poupart, Julie; Waddell, Candace S.

    2000-01-01

    The presence of indole-3-butyric acid (IBA) as an endogenous auxin in Arabidopsis has been recently demonstrated. However, the in vivo role of IBA remains to be elucidated. We present the characterization of a semi-dominant mutant that is affected in its response to IBA, but shows a wild-type response to indole-3-acetic acid (IAA), the predominant and most studied form of auxin. We have named this mutant rib1 for resistant to IBA. Root elongation assays show that rib1 is specifically resistant to IBA, to the synthetic auxin 2,4-dichlorophenoxyacetic acid, and to auxin transport inhibitors. rib1 does not display increased resistance to IAA, to the synthetic auxin naphthalene acetic acid, or to other classes of plant hormones. rib1 individuals also have other root specific phenotypes including a shortened primary root, an increased number of lateral roots, and a more variable response than wild type to a change in gravitational vector. Adult rib1 plants are morphologically indistinguishable from wild-type plants. These phenotypes suggest that rib1 alters IBA activity in the root, thereby affecting root development and response to environmental stimuli. We propose models in which RIB1 has a function in either IBA transport or response. Our experiments also suggest that IBA does not use the same mechanism to exit cells as does IAA and we propose a model for IBA transport. PMID:11115890

  10. MicroRNA (miRNA) expression is regulated by butyrate induced epigenetic modulation of gene expression in bovine cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We present evidence that butyrate induced histone acetylation regulates miRNA expression. MicroRNA expression microarray profiling revealed that 35 miRNA transcripts are significantly (p <0.05) differentially expressed after cells were treated with 10 mM butyrate. Among them, 11 transcripts are dif...

  11. INDUCTION OF APOPTOSIS BY BUTYRATE CORRELATES WITH INCREASING LEVEL OF PROTEIN UBIQUITINATION IN BOVINE KIDNEY EPITHELIAL CELLS (MDBK)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    While butyrate (BT) is largely regarded as the minor short-chain fatty acid ([butyrate]< [acetate] or [proiponate]) formed during microbial fermatation in ruminants, an increasing body of evidence has clearly shown effects beyond those attributable to its function in nutrition. BT modulates cell d...

  12. Communities stimulated with ethanol to perform direct interspecies electron transfer for syntrophic metabolism of propionate and butyrate.

    PubMed

    Zhao, Zhiqiang; Zhang, Yaobin; Yu, Qilin; Dang, Yan; Li, Yang; Quan, Xie

    2016-10-01

    Direct interspecies electron transfer (DIET) has been considered as an alternative to interspecies H2 transfer (IHT) for syntrophic metabolism, but the microorganisms capable of metabolizing the key intermediates, such as propionate and butyrate, via DIET have yet to be described. A strategy of culturing the enrichments with ethanol as a DIET substrate to stimulate the communities for the syntrophic metabolism of propionate and/or butyrate was proposed in this study. The results showed that the syntrophic propionate and/or butyrate degradation was significantly improved in the ethanol-stimulated reactor when propionate/butyrate was the sole carbon source. The conductivity of the ethanol-stimulated enrichments was as 5 folds (for propionate)/76 folds (for butyrate) as that of the traditional enrichments (never ethanol fed). Microbial community analysis revealed that Geobacter species known to proceed DIET were only detected in the ethanol-stimulated enrichments. Together with the significant increase of Methanosaeta and Methanosarcina species in these enrichments, the potential DIET between Geobacter and Methanosaeta or Methanosarcina species might be established to improve the syntrophic propionate and/or butyrate degradation. Further experiments demonstrated that granular activated carbon (GAC) could improve the syntrophic metabolism of propionate and/or butyrate of the ethanol-stimulated enrichments, while almost no effects on the traditional enrichments. Also, the high H2 partial pressure could inhibit the syntrophic propionate and/or butyrate degradation of the traditional enrichments, but its effect on that of the ethanol-stimulated enrichments was negligible. PMID:27403870

  13. Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior

    PubMed Central

    Ploense, Kyle L.; Kerstetter, Kerry A.; Wade, Matthew A.; Woodward, Nicholas C.; Maliniak, Dan; Reyes, Michael; Uchizono, Russell S.; Bredy, Timothy W.; Kippin, Tod E.

    2014-01-01

    Histone deacetylase inhibitors (HDACIs) strengthen memory following fear conditioning and cocaine-induced conditioned place preference. Here, we examined the effects of two non-specific HDACIs, valproic acid (VPA) and sodium butyrate (NaB), on appetitive learning measured via conditioned stimulus (CS)-induced reinstatement of operant responding. Rats were trained to lever press for food reinforcement and then injected with VPA (50–200 mg/kg, i.p.), NaB (250–1000 mg/kg, i.p.), or saline vehicle (1.0 ml/kg), 2h before receiving pairings of noncontingent presentation of food pellets preceded by a tone+light cue CS. Rats next underwent extinction of operant responding followed by response-contingent re-exposure to the CS. Rats receiving VPA (100 mg/kg) or NaB (1000 mg/kg) prior to conditioning displayed significantly higher cue-induced reinstatement than did saline controls. Rats that receiving either vehicle or VPA (100 mg/kg) prior to a conditioning session with a randomized relation between presentation of food pellets and the CS failed to show subsequent cue-induced reinstatement with no difference between the two groups. These findings indicate that, under certain contexts, HDACIs strengthen memory formation by specifically increasing the associative strength of the CS, not through an increasing motivation to seek reinforcement. PMID:23604166

  14. Butyrate modulates bacterial adherence on LS174T human colorectal cells by stimulating mucin secretion and MAPK signaling pathway

    PubMed Central

    Jung, Tae-Hwan; Park, Jeong Hyeon; Han, Kyoung-Sik

    2015-01-01

    BACKGROUND/OBJECTIVES Fermentation of dietary fiber results in production of various short chain fatty acids in the colon. In particular, butyrate is reported to regulate the physical and functional integrity of the normal colonic mucosa by altering mucin gene expression or the number of goblet cells. The objective of this study was to investigate whether butyrate modulates mucin secretion in LS174T human colorectal cells, thereby influencing the adhesion of probiotics such as Lactobacillus and Bifidobacterium strains and subsequently inhibiting pathogenic bacteria such as E. coli. In addition, possible signaling pathways involved in mucin gene regulation induced by butyrate treatment were also investigated. MATERIALS/METHODS Mucin protein content assay and periodic acid-Schiff (PAS) staining were performed in LS174T cells treated with butyrate at various concentrations. Effects of butyrate on the ability of probiotics to adhere to LS174T cells and their competition with E. coli strains were examined. Real time polymerase chain reaction for mucin gene expression and Taqman array 96-well fast plate-based pathway analysis were performed on butyrate-treated LS174T cells. RESULTS Treatment with butyrate resulted in a dose-dependent increase in mucin protein contents in LS174T cells with peak effects at 6 or 9 mM, which was further confirmed by PAS staining. Increase in mucin protein contents resulted in elevated adherence of probiotics, which subsequently reduced the adherent ability of E. coli. Treatment with butyrate also increased transcriptional levels of MUC3, MUC4, and MUC12, which was accompanied by higher gene expressions of signaling kinases and transcription factors involved in mitogen-activated protein kinase (MAPK) signaling pathways. CONCLUSIONS Based on our results, butyrate is an effective regulator of modulation of mucin protein production at the transcriptional and translational levels, resulting in changes in the adherence of gut microflora. Butyrate

  15. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  16. Morphological development of polypropylene in immiscible blends with cellulose acetate butyrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Isotactic polypropylenes (iPP) with different melt flow indexes were melt blended with cellulose acetate butyrate (CAB) and then prepared into microspheres or nanofibers following a novel process of producing well dispersed CAB/iPP immiscible blends and subsequent removal of the CAB matrix. The morp...

  17. Draft Genome Sequence of the Butyric Acid Producer Clostridium tyrobutyricum Strain CIP I-776 (IFP923)

    PubMed Central

    Clément, Benjamin; Lopes Ferreira, Nicolas

    2016-01-01

    Here, we report the draft genome sequence of Clostridium tyrobutyricum CIP I-776 (IFP923), an efficient producer of butyric acid. The genome consists of a single chromosome of 3.19 Mb and provides useful data concerning the metabolic capacities of the strain. PMID:26941139

  18. Intermediary Metabolism in Clostridium acetobutylicum: Levels of Enzymes Involved in the Formation of Acetate and Butyrate

    PubMed Central

    Hartmanis, Maris G. N.; Gatenbeck, Sten

    1984-01-01

    The levels of seven intermediary enzymes involved in acetate and butyrate formation from acetyl coenzyme A in the saccharolytic anaerobe Clostridium acetobutylicum were investigated as a function of time in solvent-producing batch fermentations. Phosphate acetyltransferase and acetate kinase, which are known to form acetate from acetyl coenzyme A, both showed a decrease in specific activity when the organism reached the solvent formation stage. The three consecutive enzymes thiolase, β-hydroxybutyrylcoenzyme A dehydrogenase, and crotonase exhibited a coordinate expression and a maximal activity after growth had ceased. Only low levels of butyryl coenzyme A dehydrogenase activity were found. Phosphate butyryltransferase activity rapidly decreased after 20 h from 5 to 11 U/mg of protein to below the detection limit (1 mU/mg). Butyrate no longer can be formed, and the metabolic flux may be diverted to butanol. Butyrate kinase showed a 2.5- to 10-fold increase in specific activity after phosphate butyryltransferase activity no longer could be detected. These results suggest that the uptake of acetate and butyrate during solvent formation can not proceed via a complete reversal of the phosphate transferase and kinase reactions. The activities of all enzymes investigated as a function of time in vitro are much higher than the metabolic fluxes through them in vivo. This indicates that none of the maximal activities of the enzymes assayed is rate limiting in C. acetobutylicum. PMID:16346566

  19. Isolation of acetic, propionic and butyric acid-forming bacteria from biogas plants.

    PubMed

    Cibis, Katharina Gabriela; Gneipel, Armin; König, Helmut

    2016-02-20

    In this study, acetic, propionic and butyric acid-forming bacteria were isolated from thermophilic and mesophilic biogas plants (BGP) located in Germany. The fermenters were fed with maize silage and cattle or swine manure. Furthermore, pressurized laboratory fermenters digesting maize silage were sampled. Enrichment cultures for the isolation of acid-forming bacteria were grown in minimal medium supplemented with one of the following carbon sources: Na(+)-dl-lactate, succinate, ethanol, glycerol, glucose or a mixture of amino acids. These substrates could be converted by the isolates to acetic, propionic or butyric acid. In total, 49 isolates were obtained, which belonged to the phyla Firmicutes, Tenericutes or Thermotogae. According to 16S rRNA gene sequences, most isolates were related to Clostridium sporosphaeroides, Defluviitoga tunisiensis and Dendrosporobacter quercicolus. Acetic, propionic or butyric acid were produced in cultures of isolates affiliated to Bacillus thermoamylovorans, Clostridium aminovalericum, Clostridium cochlearium/Clostridium tetani, C. sporosphaeroides, D. quercicolus, Proteiniborus ethanoligenes, Selenomonas bovis and Tepidanaerobacter sp. Isolates related to Thermoanaerobacterium thermosaccharolyticum produced acetic, butyric and lactic acid, and isolates related to D. tunisiensis formed acetic acid. Specific primer sets targeting 16S rRNA gene sequences were designed and used for real-time quantitative PCR (qPCR). The isolates were physiologically characterized and their role in BGP discussed. PMID:26779817

  20. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal

    PubMed Central

    Bui, Thi Phuong Nam; Ritari, Jarmo; Boeren, Sjef; de Waard, Pieter; Plugge, Caroline M.; de Vos, Willem M.

    2015-01-01

    Human intestinal bacteria produce butyrate, which has signalling properties and can be used as energy source by enterocytes thus influencing colonic health. However, the pathways and the identity of bacteria involved in this process remain unclear. Here we describe the isolation from the human intestine of Intestinimonas strain AF211, a bacterium that can convert lysine stoichiometrically into butyrate and acetate when grown in a synthetic medium. Intestinimonas AF211 also converts the Amadori product fructoselysine, which is abundantly formed in heated foods via the Maillard reaction, into butyrate. The butyrogenic pathway includes a specific CoA transferase that is overproduced during growth on lysine. Bacteria related to Intestinimonas AF211 as well as the genetic coding capacity for fructoselysine conversion are abundantly present in colonic samples from some healthy human subjects. Our results indicate that protein can serve as a source of butyrate in the human colon, and its conversion by Intestinimonas AF211 and related butyrogens may protect the host from the undesired side effects of Amadori reaction products. PMID:26620920

  1. Simultaneous Clostridial fermentation, lipase-catalyzed esterification, and ester extraction to enrich diesel with butyl butyrate.

    PubMed

    van den Berg, Corjan; Heeres, Arjan S; van der Wielen, Luuk A M; Straathof, Adrie J J

    2013-01-01

    The recovery of 1-butanol from fermentation broth is energy-intensive since typical concentrations in fermentation broth are below 20 g L(-1). To prevent butanol inhibition and high downstream processing costs, we aimed at producing butyl esters instead of 1-butanol. It is shown that it is possible to perform simultaneously clostridial fermentation, esterification of the formed butanol to butyl butyrate, and extraction of this ester by hexadecane. The very high partition coefficient of butyl butyrate pulls the esterification towards the product side even at fermentation pH and relatively low butanol concentrations. The hexadecane extractant is a model diesel compound and is nontoxic to the cells. If butyl butyrate enriched diesel can directly be used as car fuel, no product recovery is required. A proof-of-principle experiment for the one-pot bio-ester production from glucose led to 5 g L(-1) butyl butyrate in the hexadecane phase. The principle may be extended to a wide range of esters, especially to longer chain ones. PMID:22833369

  2. Perturbation dynamics of the rumen microbiota in response to exogenous butyrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The capacity of the rumen microbiota to produce volatile fatty acids (VFA) has important implications in animal well-being and production. We investigated temporal changes of the rumen microbiota in response to butyrate infusion using pyrosequencing of the 16S rRNA gene. Phyla were identified in ...

  3. 4-(2,4-Dichlorophenoxy)butyric acid (2,4-DB)

    Integrated Risk Information System (IRIS)

    4 - ( 2,4 - Dichlorophenoxy ) butyric acid ( 2,4 - DB ) ; CASRN 94 - 82 - 6 Health assessment information on a chemical substance is included in IRIS only after a comprehensive review of chronic toxicity data by U.S . EPA health scientists from several Program Offices and the Office of Research and

  4. Exploring the Genome of a Butyric Acid Producer, Clostridium butyricum INCQS635

    PubMed Central

    Leite, Fernanda Gomes; Tschoeke, Diogo Antonio; Miranda, Milene; Pereira, Nei; Valle, Rogério; Thompson, Cristiane C.

    2014-01-01

    The draft genome sequence of Clostridium butyricum INCQS635 was obtained by means of ion sequencing. The genome provides further insight into the genetic repertoire involved with metabolic pathways related to the fermentation of different compounds and organic solvents synthesis (i.e., butyric acid) with biofuel applications. PMID:25414496

  5. Exploring the Genome of a Butyric Acid Producer, Clostridium butyricum INCQS635.

    PubMed

    Bruce, Thiago; Leite, Fernanda Gomes; Tschoeke, Diogo Antonio; Miranda, Milene; Pereira, Nei; Valle, Rogério; Thompson, Cristiane C; Thompson, Fabiano L

    2014-01-01

    The draft genome sequence of Clostridium butyricum INCQS635 was obtained by means of ion sequencing. The genome provides further insight into the genetic repertoire involved with metabolic pathways related to the fermentation of different compounds and organic solvents synthesis (i.e., butyric acid) with biofuel applications. PMID:25414496

  6. Enhanced butyrate formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis.

    PubMed

    Rios-Covian, David; Gueimonde, Miguel; Duncan, Sylvia H; Flint, Harry J; de los Reyes-Gavilan, Clara G

    2015-11-01

    Cross-feeding is an important metabolic interaction mechanism of bacterial groups inhabiting the human colon and includes features such as the utilization of acetate by butyrate-producing bacteria as may occur between Bifidobacterium and Faecalibacterium genera. In this study, we assessed the utilization of different carbon sources (glucose, starch, inulin and fructooligosaccharides) by strains of both genera and selected the best suited combinations for evidencing this cross-feeding phenomenon. Co-cultures of Bifidobacterium adolescentis L2-32 with Faecalibacterium prausnitzii S3/L3 with fructooligosaccharides as carbon source, as well as with F. prausnitzii A2-165 in starch, were carried out and the production of short-chain fatty acids was determined. In both co-cultures, acetate levels decreased between 8 and 24 h of incubation and were lower than in the corresponding B. adolescentis monocultures. In contrast, butyrate concentrations were higher in co-cultures as compared to the respective F. prausnitzii monocultures, indicating enhanced formation of butyrate by F. prausnitzii in the presence of the bifidobacteria. Variations in the levels of acetate and butyrate were more pronounced in the co-culture with fructooligosaccharides than with starch. Our results provide a clear demonstration of cross-feeding between B. adolescentis and F. prausnitzii. PMID:26420851

  7. 40 CFR 180.318 - 4-(2-Methyl-4-chlorophenoxy) butyric acid; tolerance for residues.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...)butanoic acid, and its metabolite MCPA, (4-chloro-2-methylphenoxy)acetic acid, in or on the following food... acid; tolerance for residues. 180.318 Section 180.318 Protection of Environment ENVIRONMENTAL... FOOD Specific Tolerances § 180.318 4-(2-Methyl-4-chlorophenoxy) butyric acid; tolerance for...

  8. Allergic contact dermatitis to topical corticosteroids: clobetasol propionate and clobetasone butyrate.

    PubMed

    Dooms-Goossens, A; Vanhee, J; Vanderheyden, D; Gevers, D; Willems, L; Degreef, H

    1983-11-01

    2 case reports are given of patients with positive patch test reactions to clobetasol propionate. One of the patients also reacted to clobetasone butyrate. 30 other steroids that were chemically very closely related to these two 21-chloro-9-alpha-fluoro-corticosteroids, were patch test negative. The literature on contact dermatitis reactions to corticosteroids is reviewed. PMID:6653104

  9. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Consumption of a high fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk while butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit colon cancer preventive effects. To distinguish these opposing effects of DCA and...

  10. Butyrate and deoxycholic acid play common and distinct roles in HCT116 human colon cell proliferation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Consumption of a high fat diet causes an increase in bile acid deoxycholic acid (DCA) in colon lumen and colon cancer risk while butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit colon cancer preventive effects. To distinguish these opposing effects of D...

  11. Production of Butyric Acid and Butanol from Biomass

    SciTech Connect

    David E. Ramey; Shang-Tian Yang

    2005-08-25

    Environmental Energy Inc has shown that BUTANOL REPLACES GASOLINE - 100 pct and has no pollution problems, and further proved it is possible to produce 2.5 gallons of butanol per bushel corn at a production cost of less than $1.00 per gallon. There are 25 pct more Btu-s available and an additional 17 pct more from hydrogen given off, from the same corn when making butanol instead of ethanol that is 42 pct more Btu-s more energy out than it takes to make - that is the plow to tire equation is positive for butanol. Butanol is far safer to handle than gasoline or ethanol. Butanol when substituted for gasoline gives better gas mileage and does not pollute as attested to in 10 states. Butanol should now receive the same recognition as a fuel alcohol in U.S. legislation as ethanol. There are many benefits to this technology in that Butanol replaces gasoline gallon for gallon as demonstrated in a 10,000 miles trip across the United States July-August 2005. No modifications at all were made to a 1992 Buick Park Avenue; essentially your family car can go down the road on Butanol today with no modifications, Butanol replaces gasoline. It is that simple. Since Butanol replaces gasoline more Butanol needs to be made. There are many small farms across America which can grow energy crops and they can easily apply this technology. There is also an abundance of plant biomass present as low-value agricultural commodities or processing wastes requiring proper disposal to avoid pollution problems. One example is in the corn refinery industry with 10 million metric tons of corn byproducts that pose significant environmental problems. Whey lactose presents another waste management problem, 123,000 metric tons US, which can now be turned into automobile fuel. The fibrous bed bioreactor - FBB - with cells immobilized in the fibrous matrix packed in the reactor has been successfully used for several organic acid fermentations, including butyric and propionic acids with greatly increased

  12. Diclofenac sodium.

    PubMed

    Small, R E

    1989-08-01

    The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of diclofenac sodium are reviewed. Diclofenac, the first nonsteroidal anti-inflammatory agent (NSAID) to be approved that is a phenylacetic acid derivative, competes with arachidonic acid for binding to cyclo-oxygenase, resulting in decreased formation of prostaglandins. The drug has both analgesic and antipyretic activities. Diclofenac is efficiently absorbed from the gastrointestinal tract; peak plasma concentrations occur 1.5 to 2.0 hours after ingestion in fasting subjects. Even though diclofenac has a relatively short elimination half-life in plasma (1.5 hours), it persists in synovial fluid. The drug is metabolized in the liver and is eliminated by urinary and biliary excretion. In clinical trials, diclofenac was as effective as aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, and naproxen in improving function and reducing pain in patients with rheumatoid arthritis. For treatment of osteoarthritis, diclofenac was equivalent in efficacy to aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, flurbiprofen, mefenamic acid, and piroxicam. Diclofenac was as effective as indomethacin or sulindac in treating ankylosing spondylitis. The most frequent adverse effects reported for diclofenac were gastrointestinal, but these effects were fewer and less serious than occurred with aspirin or indomethacin; in addition, diclofenac caused fewer central nervous system reactions than indomethacin. Diclofenac is administered in divided doses with meals. The recommended total daily dosage is 100 to 150 mg (osteoarthritis and ankylosing spondylitis) or 150 to 200 mg (rheumatoid arthritis). Diclofenac is effective, but no more so than other NSAIDs. It is structurally distinct and offers another choice in the treatment of rheumatological conditions. PMID:2670397

  13. Sodium blood test

    MedlinePlus

    ... foods. The most common form of sodium is sodium chloride, which is table salt. This test is usually done as part of an electrolyte or basic metabolic panel blood test . Your blood sodium level represents a balance between the sodium and ...

  14. Eumovate (clobetasone butyrate 0.05%) cream: a review of clinical efficacy and safety.

    PubMed

    Goustas, P; Cork, M J; Higson, D

    2003-06-01

    Topical steroid creams and ointments have been available as over-the-counter (OTC) medications for the self treatment of acute dermatitis and other steroid responsive skin disorders for more than ten years. Despite earlier fears, widespread availability and use of these creams is not associated with clinically significant adverse effects. In dermatological practice, hydrocortisone 1% remains the mainstay of treatment for facial eczema, but it is often not effective in eczema affecting other body areas. Eumovate(TM) (clobetasone butyrate 0.05%) cream has recently been made available as a pharmacy medication for the short-term management of acute eczema and allergic dermatitis by adults and children aged 10 or older, based on evidence derived from clinical trials involving over 3500 patients. This review summarises the key efficacy and safety data derived from 29 clinical trials and the post-licensing pharmacovigilance safety information, which supported the reclassification of this product for OTC use. These data show clobetasone butyrate 0.05% is more effective than 1.0% hydrocortisone in the treatment of eczema and more effective than flurandrenolone 0.0125% (p=0.01%) and a potent topical steroid hydrocortisone butyrate (p<0.05), in the treatment of psoriasis. A review of the effect of topical steroids on skin thickness concluded that, following short term application, there was no clinically significant difference between hydrocortisone 1.0% and clobetasone butyrate 0.05% in terms of potential for skin thinning. Similarly, even under extreme conditions, clobetasone butyrate 0.05% has negligible systemic absorption and has almost no effect on HPA axis function. PMID:12775314

  15. Replacement inhibitors for high level waste tank cooling coils

    SciTech Connect

    Wiersma, B.J.; Hsu, T.C.

    1996-10-01

    Sodium chromate has been an effective corrosion inhibitor for the cooling coil systems in Savannah River Site (SRS) waste tanks for over 40 years. Due to age and operating history, cooling coils occasionally fail allowing chromated water to leak into the environment. The costs of reporting and cleaning up chromate spills became significant enough for SRS to consider alternate inhibitors. Confirmatory tests were performed to assess the effectiveness of three alternative corrosion inhibitor systems for the waste tank cooling water systems: (1) sodium molybdate (250 ppm as Mo)/sodium hydroxide (pH 10), (2) sodium molybdate (50 ppm as Mo)/sodium silicate (50 ppm as Si), and (3) sodium nitrite (500 ppm)/ sodium hydroxide (0.01 M). The tests were conducted under stagnant conditions to simulate a worst-case scenario. The results showed that these inhibitors were as effective as chromate at minimizing general corrosion at solution temperatures between 30--70 C. However, the initiation of localized attack in crevice regions, in solutions containing the alternative inhibitors at 70 C, was observed. Also, for the nitrite and the molybdate systems to be effective, suitable biocide is needed. On the other hand, interval coupon tests showed that the molybdate inhibitor systems prevented significant propagation of the localized attack.

  16. Butyrate downregulates α2β1 integrin: a possible role in the induction of apoptosis in colorectal cancer cell lines

    PubMed Central

    Buda, A; Qualtrough, D; Jepson, M A; Martines, D; Paraskeva, C; Pignatelli, M

    2003-01-01

    Background: Integrins mediate cell matrix adhesion and regulate cell growth and survival. In colonic epithelial cells, α2β1 integrin controls glandular differentiation and proliferation. Butyrate stimulates differentiation and induces apoptosis in vitro. Aims: We investigated whether butyrate induction of apoptosis was associated with perturbation of integrin mediated cell matrix adhesion. Methods: Three colonic cancer cell lines (SW1222, SW620, LS174T) were studied. Adhesion to extracellular matrix proteins, expression of α2β1 integrin, and apoptosis were studied in adherent cells after treatment with 4 mM butyrate. Results: Butyrate decreased the attachment to type I collagen in SW620 cells and type I and IV collagen in LS174T cells. The decreased cell attachment was associated with downregulation of α2β1 integrin and increased apoptosis in adherent cells. No changes in α2β1 expression or matrix adhesion were seen in SW1222 cells, which were also found to be less sensitive to butyrate induction of apoptosis. Downregulation of α2β1 integrin preceded the detection of apoptosis. Conclusion: Apoptosis induced by butyrate is associated with downregulation of expression and functional activity of α2β1 integrin. Perturbation of cell matrix adhesion may be a novel mechanism by which butyrate induces apoptosis in colorectal cancer cells. PMID:12692060

  17. Inhibition Of Washed Sludge With Sodium Nitrite

    SciTech Connect

    Congdon, J. W.; Lozier, J. S.

    2012-09-25

    This report describes the results of electrochemical tests used to determine the relationship between the concentration of the aggressive anions in washed sludge and the minimum effective inhibitor concentration. Sodium nitrate was added as the inhibitor because of its compatibility with the DWPF process. A minimum of 0.05M nitrite is required to inhibit the washed sludge simulant solution used in this study. When the worst case compositions and safety margins are considered, it is expected that a minimum operating limit of nearly 0.1M nitrite will be specified. The validity of this limit is dependent on the accuracy of the concentrations and solubility splits previously reported. Sodium nitrite additions to obtain 0.1M nitrite concentrations in washed sludge will necessitate the additional washing of washed precipitate in order to decrease its sodium nitrite inhibitor requirements sufficiently to remain below the sodium limits in the feed to the DWPF. Nitrite will be the controlling anion in "fresh" washed sludge unless the soluble chloride concentration is about ten times higher than predicted by the solubility splits. Inhibition of "aged" washed sludge will not be a problem unless significant chloride dissolution occurs during storage. It will be very important tomonitor the composition of washed sludge during processing and storage.

  18. Relationship of Enhanced Butyrate Production by Colonic Butyrate-Producing Bacteria to Immunomodulatory Effects in Normal Mice Fed an Insoluble Fraction of Brassica rapa L.

    PubMed

    Tanaka, Sachi; Yamamoto, Kana; Yamada, Kazuki; Furuya, Kanon; Uyeno, Yutaka

    2016-05-01

    This study was performed to determine the effects of feeding a fiber-rich fraction of Brassica vegetables on the immune response through changes in enteric bacteria and short-chain fatty acid (SCFA) production in normal mice. The boiled-water-insoluble fraction of Brassica rapa L. (nozawana), which consists mainly of dietary fiber, was chosen as a test material. A total of 31 male C57BL/6J mice were divided into two groups and housed in a specific-pathogen-free facility. The animals were fed either a control diet or the control diet plus the insoluble B. rapa L. fraction for 2 weeks and sacrificed to determine microbiological and SCFA profiles in lower-gut samples and immunological molecules. rRNA-based quantification indicated that the relative population of Bacteroidetes was markedly lower in the colon samples of the insoluble B. rapa L. fraction-fed group than that in the controls. Populations of the Eubacterium rectale group and Faecalibacterium prausnitzii, both of which are representative butyrate-producing bacteria, doubled after 2 weeks of fraction intake, accompanying a marginal increase in the proportion of colonic butyrate. In addition, feeding with the fraction significantly increased levels of the anti-inflammatory cytokine interleukin-10 (IL-10) and tended to increase splenic regulatory T cell numbers but significantly reduced the population of cells expressing activation markers. We demonstrated that inclusion of the boiled-water-insoluble fraction of B. rapa L. can alter the composition of the gut microbiota to decrease the numbers of Bacteroidetes and to increase the numbers of butyrate-producing bacteria, either of which may be involved in the observed shift in the production of splenic IL-10. PMID:26921420

  19. The hypophagic response to heat stress is not mediated by GPR109A or peripheral β-OH butyrate.

    PubMed

    Hepler, Chelsea; Foy, Caroline E; Higgins, Mark R; Renquist, Benjamin J

    2016-05-15

    Rising temperatures resulting from climate change will increase the incidence of heat stress, negatively impacting the labor force and food animal production. Heat stress elevates circulating β-OH butyrate, which induces vasodilation through GPR109a. Interestingly, both heat stress and intraperitoneal β-OH butyrate administration induce hypophagia. Thus, we aimed to investigate the role of β-OH butyrate in heat stress hypophagia in mice. We found that niacin, a β-OH butyrate mimetic that cannot be oxidized to generate ATP, also reduces food intake. Interestingly, the depression in food intake as a result of 8-h intraperitoneal niacin or 48-h heat exposure did not result from changes in hypothalamic expression of orexigenic or anorexigenic signals (AgRP, NPY, or POMC). Genetically eliminating GPR109a expression did not prevent the hypophagic response to heat exposure, intraperitoneal β-OH butyrate (5.7 mmol/kg), or niacin (0.8 mmol/kg). Hepatic vagotomy eliminated the hypophagic response to β-OH butyrate and niacin but did not affect the hypophagic response to heat exposure. We subsequently hypothesized that the hypophagic response to heat stress may depend on direct effects of β-OH butyrate at the central nervous system: β-OH butyrate induced hormonal changes (hyperinsulinemia, hypercorticosteronemia, and hyperleptinemia), or gene expression changes. To test these possibilities, we blocked expression of hepatic hydroxyl methyl glutaryl CoA synthase II (HMGCS2) to prevent hepatic β-OH butyrate synthesis. Mice that lack HMGCS2 maintain a hypophagic response to heat stress. Herein, we establish that the hypophagia of heat stress is independent of GPR109a, the hepatic vagus afferent nerve, and hepatic ketone body synthesis. PMID:26936786

  20. Co-culturing a novel Bacillus strain with Clostridium tyrobutyricum ATCC 25755 to produce butyric acid from sucrose

    PubMed Central

    2013-01-01

    Background Currently, the most promising microorganism used for the bio-production of butyric acid is Clostridium tyrobutyricum ATCC 25755T; however, it is unable to use sucrose as a sole carbon source. Consequently, a newly isolated strain, Bacillus sp. SGP1, that was found to produce a levansucrase enzyme, which hydrolyzes sucrose into fructose and glucose, was used in a co-culture with this strain, permitting C. tyrobutyricum ATCC 25755T to ferment sucrose to butyric acid. Results B. sp. SGP1 alone did not show any butyric acid production and the main metabolite produced was lactic acid. This allowed C. tyrobutyricum ATCC 25755T to utilize the monosaccharides resulting from the activity of levansucrase together with the lactic acid produced by B. sp. SGP1 to generate butyric acid, which was the main fermentative product within the co-culture. Furthermore, the final acetic acid concentration in the co-culture was significantly lower when compared with pure C. tyrobutyricum ATCC 25755T cultures grown on glucose. In fed-batch fermentations, the optimum conditions for the production of butyric acid were around pH 5.50 and a temperature of 37°C. Under these conditions, the final butyrate concentration was 34.2±1.8 g/L with yields of 0.35±0.03 g butyrate/g sucrose and maximum productivity of 0.3±0.04 g/L/h. Conclusions Using this co-culture, sucrose can be utilized as a carbon source for butyric acid production at a relatively high yield. In addition, this co-culture offers also the benefit of a greater selectivity, with butyric acid constituting 92.8% of the acids when the fermentation was terminated. PMID:23452443

  1. Clinical evaluation of clobetasone butyrate eye drops in the treatment of anterior uveitis and its effects on intraocular pressure.

    PubMed Central

    Eilon, L A; Walker, S R

    1981-01-01

    Clobetasone butyrate has been formulated as a new steroid preparation of use in ophthalmology and has been compared with prednisolone phosphate and betamethasone phosphate in the treatment of anterior uveitis. The results from 4 double-blind, between-patient studies have shown that all 3 treatments are effective in reducing the signs and symptoms of this intraocular disease. 87% of those patients receiving clobetasone butyrate had a good or satisfactory response, but no differences in therapeutic efficacy were observed between these 3 steroid treatments. Clobetasone butyrate had little effect on intraocular pressure when compared with dexamethasone or hydrocortisone, both of which cause a significant rise in intraocular pressure. PMID:7028089

  2. Detoxification of lignocellulosic hydrolysates using sodium borohydride.

    PubMed

    Cavka, Adnan; Jönsson, Leif J

    2013-05-01

    Addition of sodium borohydride to a lignocellulose hydrolysate of Norway spruce affected the fermentability when cellulosic ethanol was produced using Saccharomyces cerevisiae. Treatment of the hydrolysate with borohydride improved the ethanol yield on consumed sugar from 0.09 to 0.31 g/g, the balanced ethanol yield from 0.02 to 0.30 g/g, and the ethanol productivity from 0.05 to 0.57 g/(L×h). Treatment of a sugarcane bagasse hydrolysate gave similar results, and the experiments indicate that sodium borohydride is suitable for chemical in situ detoxification. The model inhibitors coniferyl aldehyde, p-benzoquinone, 2,6-dimethoxybenzoquinone, and furfural were efficiently reduced by treatment with sodium borohydride, even under mild reaction conditions (20 °C and pH 6.0). While addition of sodium dithionite to pretreatment liquid from spruce improved enzymatic hydrolysis of cellulose, addition of sodium borohydride did not. This result indicates that the strong hydrophilicity resulting from sulfonation of inhibitors by dithionite treatment was particularly important for alleviating enzyme inhibition. PMID:23567704

  3. Cytoarchitecture of Kirsten sarcoma virus-transformed rat kidney fibroblasts: butyrate-induced reorganization within the actin microfilament network.

    PubMed

    Ryan, M P; Higgins, P J

    1988-10-01

    Murine sarcoma virus-transformed rat fibroblasts (KNRK cells) undergo marked cytoarchitectural reorganization during in vitro exposure to sodium-n-butyrate (NaB) resulting in restoration of (1) a more typical fibroblastoid morphology, (2) proper cell-to-cell orientation, and (3) substratum adherence. Augmented cell spreading, involving greater than 90% of the population, was a function of culture density and time of exposure to NaB (2 mM final concentration). Induced cell spreading reflected a 2.5- to 3.0-fold increase in both total cellular actin content and deposition of actin into the detergent-resistant cytoskeleton. Cytoskeletal actin deposition in response to NaB was accompanied by the formation of occasionally dense, parallel alignments of F-actin-containing microfilaments and by a dramatic increase in the size and incidence of actin-enriched membrane ruffles. Long-term NaB-treated cells exhibited parallel orientations of microfilaments similar to those found in untransformed fibroblasts. Increased cytoskeletal actin occurred within 24 hr of NaB exposure, correlating with the initial reorganization of actin-containing microfilaments detected microscopically, and reflected concomitant 3-fold increases in cellular alpha-actinin and fibronectin content. In contrast, the amount of vimentin, tropomyosin, and tubulin in NaB-treated cells was significantly decreased. NaB-induced morphologic restructuring of sarcoma virus-transformed fibroblasts, thus, impacts on all three basic cytoskeletal systems. Selective increases, however, were evident in particular cytoskeletal proteins (actin, alpha-actinin, fibronectin) implicated in microfilament networking and cell spreading. PMID:2844835

  4. Replacement inhibitors for tank farm cooling coil systems

    SciTech Connect

    Hsu, T.C.

    1995-03-23

    Sodium chromate has been an effective corrosion inhibitor for the cooling coil systems in Savannah River Site (SRS) waste tanks for over 40 years. Due to their age and operating history, cooling coils occasionally fail allowing chromate water to leak into the environment. When the leaks spill 10 lbs. or more of sodium chromate over a 24-hr period, the leak incidents are classified as Unusual Occurrences (UO) per CERCLA (Comprehensive Environmental Response, Compensation and Liability Act). The cost of reporting and cleaning up chromate spills prompted High Level Waste Engineering (HLWE) to initiate a study to investigate alternative tank cooling water inhibitor systems and the associated cost of replacement. Several inhibitor systems were investigated as potential alternatives to sodium chromate. All would have a lesser regulatory impact, if a spill occurred. However, the conversion cost is estimated to be $8.5 million over a period of 8 to 12 months to convert all 5 cooling systems. Although each of the alternative inhibitors examined is effective in preventing corrosion, there is no inhibitor identified that is as effective as chromate. Assuming 3 major leaks a year (the average over the past several years), the cost of maintaining the existing inhibitor was estimated at $0.5 million per year. Since there is no economic or regulatory incentive to replace the sodium chromate with an alternate inhibitor, HLWE recommends that sodium chromate continue to be used as the inhibitor for the waste tank cooling systems.

  5. MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence.

    PubMed

    Cho, Joon-Ho; Dimri, Manjari; Dimri, Goberdhan P

    2015-04-17

    MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process. PMID:25737447

  6. MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence*

    PubMed Central

    Cho, Joon-Ho; Dimri, Manjari; Dimri, Goberdhan P.

    2015-01-01

    MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process. PMID:25737447

  7. Suppression of Neurotensin Receptor Type 1 Expression and Function by Histone Deacetylase Inhibitors in Human Colorectal Cancers*

    PubMed Central

    Wang, Xiaofu; Jackson, Lindsey N.; Johnson, Sara M.; Wang, Qingding; Evers, B. Mark

    2010-01-01

    Neurotensin (NT), a gut peptide, stimulates growth of colorectal cancers (CRCs) which possess the high affinity NT receptor (NTR1). Sodium butyrate (NaBT) is a potent histone deacetylase inhibitor (HDACi) which induces growth arrest, differentiation and apoptosis of CRCs. Previously, we showed that NaBT increases nuclear GSK-3β expression and kinase activity; GSK-3β functions as a negative regulator of ERK signaling. The purpose of our current study was to determine: (a) whether HDACi alters NTR1 expression and function, and (b) the role of GSK-3β/ERK in NTR1 regulation. Human CRCs with NTR1 were treated with various HDACi and NTR1 expression and function were assessed. Treatment with HDACi dramatically decreased endogenous NTR1 mRNA, protein and promoter activity. Overexpression of GSK-3β decreased NTR1 promoter activity (> 30%); inhibition of GSK-3β increased NTR1 expression in CRC cells, indicating that GSK-3β is a negative regulator of ERK and NTR1. Consistent with our previous findings, HDACi significantly decreased phosphorylated ERK while increasing GSK-3β. Selective MEK/ERK inhibitors suppressed NTR1 mRNA expression in a time- and dose-dependent fashion, and reduced NTR1 promoter activity by ~70%. Finally, pretreatment with NaBT prevented NT-mediated COX-2 and c-myc expression and attenuated NT-induced IL-8 expression. HDACi suppresses endogenous NTR1 expression and function in CRC cell lines; this effect is mediated through, at least in part, the GSK-3β/ERK pathway. The down-regulation of NTR1 in CRCs may represent an important mechanism for the anti-cancer effects of HDACi. PMID:20663927

  8. Resorufin butyrate as a soluble and monomeric high-throughput substrate for a triglyceride lipase.

    PubMed

    Lam, Vincent; Henault, Martin; Khougaz, Karine; Fortin, Louis-Jacques; Ouellet, Marc; Melnyk, Roman; Partridge, Anthony

    2012-02-01

    Triglyceride lipases such as lipoprotein lipase, endothelial lipase, and hepatic lipase play key roles in controlling the levels of plasma lipoprotein. Accordingly, small-molecule modulation of these species could alter patient lipid profiles with corresponding health effects. Screening of these enzymes for small-molecule therapeutics has historically involved the use of lipid-based particles to mimic native substrates. However, particle-based artifacts can complicate the discovery of therapeutic molecules. As a simplifying solution, the authors sought to develop an approach involving a soluble and monomeric lipase substrate. Using purified bovine lipoprotein lipase as a model system, they show that the hydrolysis of resorufin butyrate can be fluorescently monitored to give a robust assay (Z' > 0.8). Critically, using parallel approaches, they show that resorufin butyrate is soluble and monomeric under assay conditions. The presented assay should be useful as a simple and inexpensive primary or secondary screen for the discovery of therapeutic lipase modulators. PMID:21956174

  9. Butyrate Infusions in the Ovine Fetus Delay the Biologic Clock for Globin Gene Switching

    NASA Astrophysics Data System (ADS)

    Perrine, Susan P.; Rudolph, Abraham; Faller, Douglas V.; Roman, Christine; Cohen, Ruth A.; Chen, Shao-Jing; Kan, Yuet Wai

    1988-11-01

    The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal β -globin genes. Butyric acid, which is found in increased plasma concentrations in infants of diabetic mothers who have delayed globin gene switching, was infused into catheterized fetal lambs in utero during the time of the normal globin gene switch period. The globin gene switch was significantly delayed in three of four butyrate-treated fetuses compared with controls and was entirely prevented in one fetus in whom the infusion was begun before the globin switch was under way. These data provide a model for investigating and arresting the biologic clock of hemoglobin switching.

  10. Structural Analysis and Quantitative Determination of Clevidipine Butyrate Impurities Using an Advanced RP-HPLC Method.

    PubMed

    Zhou, Yuxia; Zhou, Fan; Yan, Fei; Yang, Feng; Yao, Yuxian; Zou, Qiaogen

    2016-03-01

    Eleven potential impurities, including process-related compounds and degradation products, have been analyzed by comprehensive studies on the manufacturing process of clevidipine butyrate. Possible formation mechanisms could also be devised. MS and NMR techniques have been used for the structural characterization of three previously unreported impurities (Imp-3, Imp-5 and Imp-11). To separate and quantify the potential impurities in a simultaneous fashion, an efficient and advanced RP-HPLC method has been developed. In doing so, four major degradation products (Imp-2, Imp-4, Imp-8 and Imp-10) can be observed under varying stress conditions. This analytical method has been validated according to ICH guidelines with respect to specificity, accuracy, linearity, robustness and stability. The method described has been demonstrated to be applicable in routine quality control processes and stability evaluation studies of clevidipine butyrate. PMID:26489435

  11. Isolation of lipase producer and its performance in enantioselective hydrolysis of glycidyl butyrate.

    PubMed

    Jia, Shi-Ying; Xu, Jian-He; Li, Qing Shan; Yu, Jun Tang

    2003-01-01

    A racemic glycidyl butyrate resolving strain, preliminarily identified as a Rhizopus sp., had been isolated from soil. Its extracellular lipase was found to enantioselectively hydrolyze the (S)-enantiomer of the chiral ester, with optimal activities at pH 5.3 and 42 degrees C. Higher enantioselectivity of the enzyme was observed at lower temperatures, while the best enantioselectivity was obtained at pH 5.5-6.0, with an E value (enantiomeric ratio) of 57. PMID:12495206

  12. An Acute Butyr-Fentanyl Fatality: A Case Report with Postmortem Concentrations.

    PubMed

    McIntyre, Iain M; Trochta, Amber; Gary, Ray D; Wright, Jennifer; Mena, Othon

    2016-03-01

    In this case report, we present an evaluation of the distribution of postmortem concentrations of butyr-fentanyl in a fatality attributed principally to the drug. A man who had a history of intravenous drug abuse was found unresponsive on the bathroom floor of his home. Drug paraphernalia was located on the bathroom counter. Toxicology testing, which initially screened positive for fentanyl by enzyme-linked immunosorbent assay, subsequently confirmed butyr-fentanyl, which was then quantitated by gas chromatography-mass spectrometry-specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. The butyr-fentanyl peripheral blood concentration was quantitated at 58 ng/mL compared with the central blood concentration of 97 ng/mL. The liver concentration was 320 ng/g, the vitreous was 40 ng/mL, the urine was 670 ng/mL and the gastric contained 170 mg. Acetyl-fentanyl was also detected in all biological specimens tested. Peripheral blood concentration was quantitated at 38 ng/mL compared with the central blood concentration of 32 ng/mL. The liver concentration was 110 ng/g, the vitreous was 38 ng/mL, the urine was 540 ng/mL and the gastric contained <70 mg. The only other drug detected was a relatively low concentration of benzoylecgonine. The cause of death was certified as acute butyr-fentanyl, acetyl-fentanyl and cocaine intoxication, and the manner of death was certified as accident. PMID:26683128

  13. Diclofenac sodium overdose

    MedlinePlus

    Diclofenac sodium is a prescription medicine used to relieve pain and swelling. It is a nonsteroidal anti-inflammatory drug (NSAID). Diclofenac sodium overdose occurs when someone takes more than the ...

  14. Sodium Ferric Gluconate Injection

    MedlinePlus

    Sodium ferric gluconate injection is used to treat iron-deficiency anemia (a lower than normal number of ... are also receiving the medication epoetin (Epogen, Procrit). Sodium ferric gluconate injection is in a class of ...

  15. Docusate Sodium and Pregnancy

    MedlinePlus

    ... live chat Live Help Fact Sheets Share Docusate Sodium Friday, 01 April 2016 In every pregnancy, a ... This sheet talks about whether exposure to docusate sodium may increase the risk for birth defects over ...

  16. Sodium carbonate poisoning

    MedlinePlus

    Sodium carbonate (known as washing soda or soda ash) is a chemical found in many household and ... products. This article focuses on poisoning due to sodium carbonate. This article is for information only. Do ...

  17. Diclofenac sodium overdose

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/002630.htm Diclofenac sodium overdose To use the sharing features on this page, please enable JavaScript. Diclofenac sodium is a prescription medicine used to relieve pain ...

  18. Fractional excretion of sodium

    MedlinePlus

    FE sodium; FENa ... to a lab. There, they are examined for salt (sodium) and creatinine levels. Creatinine is a chemical waste ... your normal foods with a normal amount of salt, unless otherwise instructed by your health care provider. ...

  19. Sodium blood test

    MedlinePlus

    ... able to conserve water) Too much salt or sodium bicarbonate in the diet Use of certain medicines, including corticosteroids, laxatives, lithium, and medicines such as ibuprofen or naproxen Lower than normal sodium level is called hyponatremia. It may be due ...

  20. CFTR Inhibitors

    PubMed Central

    Verkman, Alan S.; Synder, David; Tradtrantip, Lukmanee; Thiagarajah, Jay R.; Anderson, Marc O.

    2014-01-01

    The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cAMP-regulated Cl− channel whose major function is to facilitate epithelial fluid secretion. Loss-of-function mutations in CFTR cause the genetic disease cystic fibrosis. CFTR is required for transepithelial fluid transport in certain secretory diarrheas, such as cholera, and for cyst expansion in autosomal dominant polycystic kidney disease. High-throughput screening has yielded CFTR inhibitors of the thiazolidinone, glycine hydrazide and quinoxalinedione chemical classes. The glycine hydrazides target the extracellular CFTR pore, whereas the thiazolidinones and quinoxalinediones act at the cytoplasmic surface. These inhibitors have been widely used in cystic fibrosis research to study CFTR function at the cell and organ levels. The most potent CFTR inhibitor has IC50 of approximately 4 nM. Studies in animal models support the development of CFTR inhibitors for antisecretory therapy of enterotoxin-mediated diarrheas and polycystic kidney disease. PMID:23331030

  1. Impact of butyrate on microbial selection in enhanced biological phosphorus removal systems.

    PubMed

    Begum, Shamim A; Batista, Jacimaria R

    2014-01-01

    Microbial selection in an enhanced biological phosphorus removal system was investigated in a laboratory-scale sequencing batch reactor fed exclusively with butyrate as a carbon source. As reported in the few previous studies, butyrate uptake was slow and phosphorus (P) release occurred during the entire anaerobic period. Polyphosphate-accumulating organism (PAO), i.e. Candidatus Accumulibacter phosphatis (named as Accumulibacter), glycogen-accumulating organisms (GAOs), i.e. Candidatus Competibacter phosphatis (named as Competibacter) and Defluviicoccus-related, tetrad-forming alphaproteobacteria (named as Defluviicoccus) were identified using fluorescence in situ hybridization analysis. The results show that Accumulibacter and Defluviicoccus were selected in the butyrate-fed reactor, whereas Competibacter was not selected. P removal was efficient at the beginning of the experiment with an increasing percentage relative abundance (% RA) of PAOs. The % RA of Accumulibacter and Defluviicoccus increased from 13% to 50% and 8% to 16%, respectively, and the % RA of Competibacter decreased from 8% to 2% during the experiment. After 6 weeks, P removal deteriorated with the poor correlation between the percentage of P removal and % RA of GAOs. PMID:25189844

  2. Analysis of the key enzymes of butyric and acetic acid fermentation in biogas reactors

    PubMed Central

    Gabris, Christina; Bengelsdorf, Frank R; Dürre, Peter

    2015-01-01

    This study aimed at the investigation of the mechanisms of acidogenesis, which is a key process during anaerobic digestion. To expose possible bottlenecks, specific activities of the key enzymes of acidification, such as acetate kinase (Ack, 0.23–0.99 U mg−1 protein), butyrate kinase (Buk, < 0.03 U mg−1 protein) and butyryl-CoA:acetate-CoA transferase (But, 3.24–7.64 U mg−1 protein), were determined in cell free extracts of biogas reactor content from three different biogas reactors. Furthermore, the detection of Ack was successful via Western blot analysis. Quantification of corresponding functional genes encoding Buk (buk) and But (but) was not feasible, although an amplification was possible. Thus, phylogenetic trees were constructed based on respective gene fragments. Four new clades of possible butyrate-producing bacteria were postulated, as well as bacteria of the genera Roseburia or Clostridium identified. The low Buk activity was in contrast to the high specific But activity in the analysed samples. Butyrate formation via Buk activity does barely occur in the investigated biogas reactor. Specific enzyme activities (Ack, Buk and But) in samples drawn from three different biogas reactors correlated with ammonia and ammonium concentrations (NH3 and NH4+-N), and a negative dependency can be postulated. Thus, high concentrations of NH3 and NH4+-N may lead to a bottleneck in acidogenesis due to decreased specific acidogenic enzyme activities. PMID:26086956

  3. Converting Carbon Dioxide to Butyrate with an Engineered Strain of Clostridium ljungdahlii

    PubMed Central

    Nevin, Kelly P.; Woodard, Trevor L.; Lovley, Derek R.

    2014-01-01

    ABSTRACT Microbial conversion of carbon dioxide to organic commodities via syngas metabolism or microbial electrosynthesis is an attractive option for production of renewable biocommodities. The recent development of an initial genetic toolbox for the acetogen Clostridium ljungdahlii has suggested that C. ljungdahlii may be an effective chassis for such conversions. This possibility was evaluated by engineering a strain to produce butyrate, a valuable commodity that is not a natural product of C. ljungdahlii metabolism. Heterologous genes required for butyrate production from acetyl-coenzyme A (CoA) were identified and introduced initially on plasmids and in subsequent strain designs integrated into the C. ljungdahlii chromosome. Iterative strain designs involved increasing translation of a key enzyme by modifying a ribosome binding site, inactivating the gene encoding the first step in the conversion of acetyl-CoA to acetate, disrupting the gene which encodes the primary bifunctional aldehyde/alcohol dehydrogenase for ethanol production, and interrupting the gene for a CoA transferase that potentially represented an alternative route for the production of acetate. These modifications yielded a strain in which ca. 50 or 70% of the carbon and electron flow was diverted to the production of butyrate with H2 or CO as the electron donor, respectively. These results demonstrate the possibility of producing high-value commodities from carbon dioxide with C. ljungdahlii as the catalyst. PMID:25336453

  4. Severity of atopic disease inversely correlates with intestinal microbiota diversity and butyrate-producing bacteria.

    PubMed

    Nylund, L; Nermes, M; Isolauri, E; Salminen, S; de Vos, W M; Satokari, R

    2015-02-01

    The reports on atopic diseases and microbiota in early childhood remain contradictory, and both decreased and increased microbiota diversity have been associated with atopic eczema. In this study, the intestinal microbiota signatures associated with the severity of eczema in 6-month-old infants were characterized. Further, the changes in intestinal microbiota composition related to the improvement of this disease 3 months later were assessed. The severity of eczema correlated inversely with microbiota diversity (r = -0.54, P = 0.002) and with the abundance of butyrate-producing bacteria (r = -0.52, P = 0.005). During the 3-month follow-up, microbiota diversity increased (P < 0.001) and scoring atopic dermatitis values decreased (P < 0.001) in all infants. This decrease coincided with the increase in bacteria related to butyrate-producing Coprococcus eutactus (r = -0.59, P = 0.02). In conclusion, the high diversity of microbiota and high abundance of butyrate-producing bacteria were associated with milder eczema, thus suggesting they have a role in alleviating symptoms of atopic eczema. PMID:25413686

  5. Analysis of the key enzymes of butyric and acetic acid fermentation in biogas reactors.

    PubMed

    Gabris, Christina; Bengelsdorf, Frank R; Dürre, Peter

    2015-09-01

    This study aimed at the investigation of the mechanisms of acidogenesis, which is a key process during anaerobic digestion. To expose possible bottlenecks, specific activities of the key enzymes of acidification, such as acetate kinase (Ack, 0.23-0.99 U mg(-1) protein), butyrate kinase (Buk, < 0.03 U mg(-1) protein) and butyryl-CoA:acetate-CoA transferase (But, 3.24-7.64 U mg(-1) protein), were determined in cell free extracts of biogas reactor content from three different biogas reactors. Furthermore, the detection of Ack was successful via Western blot analysis. Quantification of corresponding functional genes encoding Buk (buk) and But (but) was not feasible, although an amplification was possible. Thus, phylogenetic trees were constructed based on respective gene fragments. Four new clades of possible butyrate-producing bacteria were postulated, as well as bacteria of the genera Roseburia or Clostridium identified. The low Buk activity was in contrast to the high specific But activity in the analysed samples. Butyrate formation via Buk activity does barely occur in the investigated biogas reactor. Specific enzyme activities (Ack, Buk and But) in samples drawn from three different biogas reactors correlated with ammonia and ammonium concentrations (NH₃ and NH₄(+)-N), and a negative dependency can be postulated. Thus, high concentrations of NH₃ and NH₄(+)-N may lead to a bottleneck in acidogenesis due to decreased specific acidogenic enzyme activities. PMID:26086956

  6. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition.

    PubMed

    Chang, Pamela V; Hao, Liming; Offermanns, Stefan; Medzhitov, Ruslan

    2014-02-11

    Given the trillions of microbes that inhabit the mammalian intestines, the host immune system must constantly maintain a balance between tolerance to commensals and immunity against pathogens to avoid unnecessary immune responses against otherwise harmless bacteria. Misregulated responses can lead to inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. The mechanisms by which the immune system maintains this critical balance remain largely undefined. Here, we demonstrate that the short-chain fatty acid n-butyrate, which is secreted in high amounts by commensal bacteria, can modulate the function of intestinal macrophages, the most abundant immune cell type in the lamina propria. Treatment of macrophages with n-butyrate led to the down-regulation of lipopolysaccharide-induced proinflammatory mediators, including nitric oxide, IL-6, and IL-12, but did not affect levels of TNF-α or MCP-1. These effects were independent of toll-like receptor signaling and activation of G-protein-coupled receptors, two pathways that could be affected by short-chain fatty acids. In this study, we provide several lines of evidence that suggest that these effects are due to the inhibition of histone deacetylases by n-butyrate. These findings elucidate a pathway in which the host may maintain tolerance to intestinal microbiota by rendering lamina propria macrophages hyporesponsive to commensal bacteria through the down-regulation of proinflammatory effectors. PMID:24390544

  7. The rib1 Mutant of Arabidopsis Has Alterations in Indole-3-Butyric Acid Transport, Hypocotyl Elongation, and Root Architecture1

    PubMed Central

    Poupart, Julie; Rashotte, Aaron M.; Muday, Gloria K.; Waddell, Candace S.

    2005-01-01

    Polar transport of the auxin indole-3-butyric acid (IBA) has recently been shown to occur in Arabidopsis (Arabidopis thaliana) seedlings, yet the physiological importance of this process has yet to be fully resolved. Here we describe the first demonstration of altered IBA transport in an Arabidopsis mutant, and show that the resistant to IBA (rib1) mutation results in alterations in growth, development, and response to exogenous auxin consistent with an important physiological role for IBA transport. Both hypocotyl and root IBA basipetal transport are decreased in rib1 and root acropetal IBA transport is increased. While indole-3-acetic acid (IAA) transport levels are not different in rib1 compared to wild type, root acropetal IAA transport is insensitive to the IAA efflux inhibitor naphthylphthalamic acid in rib1, as is the dependent physiological process of lateral root formation. These observed changes in IBA transport are accompanied by altered rib1 phenotypes. Previously, rib1 roots were shown to be less sensitive to growth inhibition by IBA, but to have a wild-type response to IAA in root elongation. rib1 is also less sensitive to IBA in stimulation of lateral root formation and in hypocotyl elongation under most, but not all, light and sucrose conditions. rib1 has wild-type responses to IAA, except under one set of conditions, low light and 1.5% sucrose, in which both hypocotyl elongation and lateral root formation show altered IAA response. Taken together, our results support a model in which endogenous IBA influences wild-type seedling morphology. Modifications in IBA distribution in seedlings affect hypocotyl and root elongation, as well as lateral root formation. PMID:16258013

  8. Increased growth of Bifidobacterium and Eubacterium by germinated barley foodstuff, accompanied by enhanced butyrate production in healthy volunteers.

    PubMed

    Kanauchi, O; Fujiyama, Y; Mitsuyama, K; Araki, Y; Ishii, T; Nakamura, T; Hitomi, Y; Agata, K; Saiki, T; Andoh, A; Toyonaga, A; Bamba, T

    1999-02-01

    Germinated barley foodstuff (GBF) derived from the aleurone and scutellum fractions of germinated barley mainly consists of low-lignified hemicellulose and glutamine-rich protein. GBF improves the proliferation of intestinal epithelial cells and defecation, through the bacterial production of short chain fatty acids (SCFA), especially butyrate. In this study we investigated the mechanism of production of butyrate by microflora in humans and in vitro. Daily administration of 9 g GBF for 14 successive days significantly increased fecal butyrate content. Fecal Bifidobacterium and Eubacterium were also significantly increased by GBF administration in healthy volunteers. Ten anaerobic micro-organisms selected from intestinal microflora were cultured in vitro in the medium containing GBF as a sole carbon source (GBF medium). After a 3-day incubation, 7 strains (Bifidobacterium breve, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei subsp. casei, Bacteroides ovatus, Clostridium butyricum, and Eubacterium limosum) lowered the medium pH producing SCFA. Eubacterium grown together with Bifidobacterium in GBF medium efficiently produced butyrate. On the other hand, GBF changed the intestinal microflora and increased probiotics such as Bifidobacterium in the intestinal tract. As a result, butyrate was produced by the mutual action of Eubacterium and Bifidobacterium. This butyrate is considered to enhance the proliferation of colonic epithelial cells. PMID:9917526

  9. Butyrate produced by commensal bacteria potentiates phorbol esters induced AP-1 response in human intestinal epithelial cells.

    PubMed

    Nepelska, Malgorzata; Cultrone, Antonietta; Béguet-Crespel, Fabienne; Le Roux, Karine; Doré, Joël; Arulampalam, Vermulugesan; Blottière, Hervé M

    2012-01-01

    The human intestine is a balanced ecosystem well suited for bacterial survival, colonization and growth, which has evolved to be beneficial both for the host and the commensal bacteria. Here, we investigated the effect of bacterial metabolites produced by commensal bacteria on AP-1 signaling pathway, which has a plethora of effects on host physiology. Using intestinal epithelial cell lines, HT-29 and Caco-2, stably transfected with AP-1-dependent luciferase reporter gene, we tested the effect of culture supernatant from 49 commensal strains. We observed that several bacteria were able to activate the AP-1 pathway and this was correlated to the amount of short chain fatty acids (SCFAs) produced. Besides being a major source of energy for epithelial cells, SCFAs have been shown to regulate several signaling pathways in these cells. We show that propionate and butyrate are potent activators of the AP-1 pathway, butyrate being the more efficient of the two. We also observed a strong synergistic activation of AP-1 pathway when using butyrate with PMA, a PKC activator. Moreover, butyrate enhanced the PMA-induced expression of c-fos and ERK1/2 phosphorylation, but not p38 and JNK. In conclusion, we showed that SCFAs especially butyrate regulate the AP-1 signaling pathway, a feature that may contribute to the physiological impact of the gut microbiota on the host. Our results provide support for the involvement of butyrate in modulating the action of PKC in colon cancer cells. PMID:23300800

  10. Proboscis conditioning experiments with honeybees, Apis mellifera caucasica, with butyric acid and DEET mixture as conditioned and unconditioned stimuli.

    PubMed

    Abramson, Charles I; Giray, Tugrul; Mixson, T Andrew; Nolf, Sondra L; Wells, Harrington; Kence, Aykut; Kence, Meral

    2010-01-01

    Three experiments are described investigating whether olfactory repellents DEET and butyric acid can support the classical conditioning of proboscis extension in the honeybee, Apis mellifera caucasica (Hymenoptera: Apidae). In the first experiment DEET and butyric acid readily led to standard acquisition and extinction effects, which are comparable to the use of cinnamon as a conditioned stimulus. These results demonstrate that the odor of DEET or butyric acid is not intrinsically repellent to honey bees. In a second experiment, with DEET and butyric acid mixed with sucrose as an unconditioned stimulus, proboscis conditioning was not established. After several trials, few animals responded to the unconditioned stimulus. These results demonstrate that these chemicals are gustatory repellents when in direct contact. In the last experiment a conditioned suppression paradigm was used. Exposing animals to butyric acid or DEET when the proboscis was extended by direct sucrose stimulation or by learning revealed that retraction of the proboscis was similar to another novel odor, lavender, and in all cases greatest when the animal was not permitted to feed. These results again demonstrate that DEET or butyric acid are not olfactory repellents, and in addition, conditioned suppression is influenced by feeding state of the bee. PMID:20879917

  11. Corrosion inhibitors from expired drugs.

    PubMed

    Vaszilcsin, Nicolae; Ordodi, Valentin; Borza, Alexandra

    2012-07-15

    This paper presents a method of expired or unused drugs valorization as corrosion inhibitors for metals in various media. Cyclic voltammograms were drawn on platinum in order to assess the stability of pharmaceutically active substances from drugs at the metal-corrosive environment interface. Tafel slope method was used to determine corrosion rates of steel in the absence and presence of inhibitors. Expired Carbamazepine and Paracetamol tablets were used to obtain corrosion inhibitors. For the former, the corrosion inhibition of carbon steel in 0.1 mol L(-1) sulfuric acid solution was about 90%, whereas for the latter, the corrosion inhibition efficiency of the same material in the 0.25 mol L(-1) acetic acid-0.25 mol L(-1) sodium acetate buffer solution was about 85%. PMID:22561212

  12. Effects of sodium bicarbonate and sodium sesquicarbonate on animal performance, ruminal metabolism, and systemic acid-base status.

    PubMed

    Ghorbani, G R; Jackson, J A; Hemken, R W

    1989-08-01

    Six rumen-fistulated lactating Holstein cows were arranged in a replicated 3 x 3 latin square design with 3-wk periods and offered diets containing concentrate and corn silage in a 60:40 ratio (DM basis). Treatments were: 1) basal diet, 2) basal diet with 1% NaHCO3, and 3) basal diet with 1% sodium sesquicarbonate. There were no differences among treatments in milk production, milk protein, or 3.5% FCM, but sodium sesquicarbonate increased milk fat percentage (3.89, 3.94, 4.06%) compared with that of the control. Rumen pH was higher for cows fed buffered diets than for control cows. Urine pH was higher for cows fed NaHCO3 diet than for those fed sodium sesquicarbonate and control diets. No differences were detected among treatment means for molar percentage of isobutyrate, isovalerate, or total VFA, Dietary sesquicarbonate addition increased molar percentage of acetate, decreased propionate, and resulted in a higher acetate:propionate ratio compared with the cows fed NaHCO3. However, molar percentage of butyrate and valerate decreased in cows fed sodium sesquicarbonate when compared with those fed the control diet. No differences among treatment means were detected for blood pH, pCO2, or HCO3. PMID:2551941

  13. Rechargeable sodium alloy anode

    SciTech Connect

    Jow, T.R.

    1988-06-28

    A secondary battery is described comprising: (a) an anode which comprises an alloy of sodium and one or metals selected from the group consisting of tin, lead antimony, bismuth, selenium and tellerium, (b) an electrolyte comprising one or more organic solvents and one or more sodium salts dissolved therein forming dissolved sodium cations in solution; and (c) a cathode; the sodium cations from the electrolyte alloying with the one or more metals of the alloy in the anode during the charging of the battery and sodium in the alloy disoloving in the electrolyte during the discharging of the battery.

  14. Reassessing the Effects of Histone Deacetylase Inhibitors on Hippocampal Memory and Cognitive Aging

    PubMed Central

    Castellano, James F.; Fletcher, Bonnie R.; Patzke, Holger; Long, Jeffrey M.; Sewal, Angila; Kim, David H.; Kelley-Bell, Bennett; Rapp, Peter R.

    2014-01-01

    Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 hours at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-hour retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. PMID:24753063

  15. Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging.

    PubMed

    Castellano, James F; Fletcher, Bonnie R; Patzke, Holger; Long, Jeffrey M; Sewal, Angila; Kim, David H; Kelley-Bell, Bennett; Rapp, Peter R

    2014-08-01

    Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. PMID:24753063

  16. Heart failure: SGLT2 inhibitors and heart failure -- clinical implications.

    PubMed

    Raz, Itamar; Cahn, Avivit

    2016-04-01

    The latest findings from the EMPA-REG OUTCOME trial show a 34% reduction in hospitalization for heart failure or cardiovascular death in patients receiving empagliflozin, a sodium/glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo. These outstanding results call for discussion of the clinical implications, and in-depth studies of the mechanisms of action of SGLT2 inhibitors. PMID:26961066

  17. Corrosion inhibitors for solar-heating and cooling

    NASA Technical Reports Server (NTRS)

    Humphries, T. S.

    1979-01-01

    Report describes results of tests conducted to evaluate abilities of 12 candidate corrosion inhibitors to protect aluminum, steel, copper, or stainless steel at typical conditions encountered in solar heating and cooling systems. Inhibitors are based on sodium salts including nitrates, borates, silicates, and phosphates.

  18. Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region.

    PubMed

    Kalina, Uwe; Koyama, Noriko; Hosoda, Tomoko; Nuernberger, Heike; Sato, Kazuto; Hoelzer, Dieter; Herweck, Frank; Manigold, Tobias; Singer, Manfred V; Rossol, Siegbert; Böcker, Ulrich

    2002-09-01

    Expression of IL-18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell-mediated chronic intestinal inflammation and anti-tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL-18 in IEC in vitro and in vivo. Expression of IL-18 mRNA and protein in human carcinoma-derived HT-29 and Caco-2 cells was analyzed by reverse transcription-PCR and Western blot. Transcriptional regulation of IL-18 gene expression was determined by transient transfection of wild-type and mutated IL-18 promoter. Further, in vivo expression of IL-18 in the intestine from butyrate-treated and untreated mice was assessed by immunohistochemistry. IL-18 mRNA and the IL-18 protein were expressed in IEC, while IL-18 secretion was not observed. Butyrate and acetate increased intracellular IL-18 content in a time- and dose-dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL-18 promoter, indicating that IL-18 is regulated at the transcriptional level by SCFA. Furthermore, a 108-bp sequence in the proximal region was identified to be essential for IL-18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL-18 protein expression in IEC from butyrate-treated mice. In conclusion, SCFA up-regulate IL-18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions. PMID:12207348

  19. Diet is a major factor governing the fecal butyrate-producing community structure across Mammalia, Aves and Reptilia

    PubMed Central

    Vital, Marius; Gao, Jiarong; Rizzo, Mike; Harrison, Tara; Tiedje, James M

    2015-01-01

    Butyrate-producing bacteria have an important role in maintaining host health. They are well studied in human and medically associated animal models; however, much less is known for other Vertebrata. We investigated the butyrate-producing community in hindgut-fermenting Mammalia (n=38), Aves (n=8) and Reptilia (n=8) using a gene-targeted pyrosequencing approach of the terminal genes of the main butyrate-synthesis pathways, namely butyryl-CoA:acetate CoA-transferase (but) and butyrate kinase (buk). Most animals exhibit high gene abundances, and clear diet-specific signatures were detected with but genes significantly enriched in omnivores and herbivores compared with carnivores. But dominated the butyrate-producing community in these two groups, whereas buk was more abundant in many carnivorous animals. Clustering of protein sequences (5% cutoff) of the combined communities (but and buk) placed carnivores apart from other diet groups, except for noncarnivorous Carnivora, which clustered together with carnivores. The majority of clusters (but: 5141 and buk: 2924) did not show close relation to any reference sequences from public databases (identity <90%) demonstrating a large ‘unknown diversity'. Each diet group had abundant signature taxa, where buk genes linked to Clostridium perfringens dominated in carnivores and but genes associated with Ruminococcaceae bacterium D16 were specific for herbivores and omnivores. Whereas 16S rRNA gene analysis showed similar overall patterns, it was unable to reveal communities at the same depth and resolution as the functional gene-targeted approach. This study demonstrates that butyrate producers are abundant across vertebrates exhibiting great functional redundancy and that diet is the primary determinant governing the composition of the butyrate-producing guild. PMID:25343515

  20. Steering Endogenous Butyrate Production in the Intestinal Tract of Broilers as a Tool to Improve Gut Health.

    PubMed

    Onrust, Lonneke; Ducatelle, Richard; Van Driessche, Karolien; De Maesschalck, Celine; Vermeulen, Karen; Haesebrouck, Freddy; Eeckhaut, Venessa; Van Immerseel, Filip

    2015-01-01

    The ban on antimicrobial growth promoters and efforts to reduce therapeutic antibiotic usage has led to major problems of gastrointestinal dysbiosis in livestock production in Europe. Control of dysbiosis without the use of antibiotics requires a thorough understanding of the interaction between the microbiota and the host mucosa. The gut microbiota of the healthy chicken is highly diverse, producing various metabolic end products, including gases and fermentation acids. The distal gut knows an abundance of bacteria from within the Firmicutes Clostridium clusters IV and XIVa that produce butyric acid, which is one of the metabolites that are sensed by the host as a signal. The host responds by strengthening the epithelial barrier, reducing inflammation, and increasing the production of mucins and antimicrobial peptides. Stimulating the colonization and growth of butyrate-producing bacteria thus may help optimizing gut health. Various strategies are available to stimulate butyrate production in the distal gut. These include delivery of prebiotic substrates that are broken down by bacteria into smaller molecules which are then used by butyrate producers, a concept called cross-feeding. Xylo-oligosaccharides (XOS) are such compounds as they can be converted to lactate, which is further metabolized to butyrate. Probiotic lactic acid producers can be supplied to support the cross-feeding reactions. Direct feeding of butyrate-producing Clostridium cluster IV and XIVa strains are a future tool provided that large scale production of strictly anaerobic bacteria can be optimized. Current results of strategies that promote butyrate production in the gut are promising. Nevertheless, our current understanding of the intestinal ecosystem is still insufficient, and further research efforts are needed to fully exploit the capacity of these strategies. PMID:26734618

  1. Diet is a major factor governing the fecal butyrate-producing community structure across Mammalia, Aves and Reptilia.

    PubMed

    Vital, Marius; Gao, Jiarong; Rizzo, Mike; Harrison, Tara; Tiedje, James M

    2015-04-01

    Butyrate-producing bacteria have an important role in maintaining host health. They are well studied in human and medically associated animal models; however, much less is known for other Vertebrata. We investigated the butyrate-producing community in hindgut-fermenting Mammalia (n = 38), Aves (n = 8) and Reptilia (n = 8) using a gene-targeted pyrosequencing approach of the terminal genes of the main butyrate-synthesis pathways, namely butyryl-CoA:acetate CoA-transferase (but) and butyrate kinase (buk). Most animals exhibit high gene abundances, and clear diet-specific signatures were detected with but genes significantly enriched in omnivores and herbivores compared with carnivores. But dominated the butyrate-producing community in these two groups, whereas buk was more abundant in many carnivorous animals. Clustering of protein sequences (5% cutoff) of the combined communities (but and buk) placed carnivores apart from other diet groups, except for noncarnivorous Carnivora, which clustered together with carnivores. The majority of clusters (but: 5141 and buk: 2924) did not show close relation to any reference sequences from public databases (identity <90%) demonstrating a large 'unknown diversity'. Each diet group had abundant signature taxa, where buk genes linked to Clostridium perfringens dominated in carnivores and but genes associated with Ruminococcaceae bacterium D16 were specific for herbivores and omnivores. Whereas 16S rRNA gene analysis showed similar overall patterns, it was unable to reveal communities at the same depth and resolution as the functional gene-targeted approach. This study demonstrates that butyrate producers are abundant across vertebrates exhibiting great functional redundancy and that diet is the primary determinant governing the composition of the butyrate-producing guild. PMID:25343515

  2. Steering Endogenous Butyrate Production in the Intestinal Tract of Broilers as a Tool to Improve Gut Health

    PubMed Central

    Onrust, Lonneke; Ducatelle, Richard; Van Driessche, Karolien; De Maesschalck, Celine; Vermeulen, Karen; Haesebrouck, Freddy; Eeckhaut, Venessa; Van Immerseel, Filip

    2015-01-01

    The ban on antimicrobial growth promoters and efforts to reduce therapeutic antibiotic usage has led to major problems of gastrointestinal dysbiosis in livestock production in Europe. Control of dysbiosis without the use of antibiotics requires a thorough understanding of the interaction between the microbiota and the host mucosa. The gut microbiota of the healthy chicken is highly diverse, producing various metabolic end products, including gases and fermentation acids. The distal gut knows an abundance of bacteria from within the Firmicutes Clostridium clusters IV and XIVa that produce butyric acid, which is one of the metabolites that are sensed by the host as a signal. The host responds by strengthening the epithelial barrier, reducing inflammation, and increasing the production of mucins and antimicrobial peptides. Stimulating the colonization and growth of butyrate-producing bacteria thus may help optimizing gut health. Various strategies are available to stimulate butyrate production in the distal gut. These include delivery of prebiotic substrates that are broken down by bacteria into smaller molecules which are then used by butyrate producers, a concept called cross-feeding. Xylo-oligosaccharides (XOS) are such compounds as they can be converted to lactate, which is further metabolized to butyrate. Probiotic lactic acid producers can be supplied to support the cross-feeding reactions. Direct feeding of butyrate-producing Clostridium cluster IV and XIVa strains are a future tool provided that large scale production of strictly anaerobic bacteria can be optimized. Current results of strategies that promote butyrate production in the gut are promising. Nevertheless, our current understanding of the intestinal ecosystem is still insufficient, and further research efforts are needed to fully exploit the capacity of these strategies. PMID:26734618

  3. Modelling Cometary Sodium Tails

    NASA Astrophysics Data System (ADS)

    Birkett, K. S.; Jones, G. H.; Coates, A. J.

    2013-12-01

    Neutral sodium is readily observed in cometary spectra and can be seen to form its own distinct tail at high activity comets. Solar radiation pressure accelerates the sodium atoms antisunward and, as strong sodium absorption lines are present in the solar spectrum, the magnitude of this force is dependent upon the Doppler shift of the incident solar radiation. Therefore the heliocentric velocity of the sodium atom directly determines its acceleration. This can produce unique effects, such as a stagnation region. Sodium is relatively easy to detect and so can potentially be used to trace mechanisms in the coma that are otherwise difficult to observe. The source of neutral sodium in the tail currently remains unknown. We have therefore developed a new, three dimensional Monte-Carlo model of neutral cometary sodium in order to facilitate testing of different source production functions. It includes weightings due to neutral sodium lifetime, variation of cometary sodium emission due to Fraunhofer absorption lines and solar flux variation with heliocentric distance. The Swings and Greenstein effects, which can have particularly dramatic effects in near-Sun comets, are also considered comprehensively. Preliminary results from this model are presented, focusing on a comparison of predictions of the neutral sodium tail of Comet C/2012 S1 (ISON) with initial observations.

  4. Use of Additives to Improve Performance of Methyl Butyrate-Based Lithium-Ion Electrolytes

    NASA Technical Reports Server (NTRS)

    Smart, Marshall C.; Bugga, Ratnakumar V.

    2011-01-01

    This work addresses the need for robust rechargeable batteries that can operate well over a wide temperature range. To this end, a number of electrolyte formulations have been developed that incorporate the use of electrolyte additives to improve the high-temperature resilience, low-temperature power capability, and life characteristics of methyl butyrate-based electrolyte solutions. These electrolyte additives include mono-fluoroethylene carbonate (FEC), lithium oxalate, vinylene carbonate (VC), and lithium bis(oxalato)borate (LiBOB), which have been shown to result in improved high-temperature resilience of all carbonate-based electrolytes. Improved performance has been demonstrated of Li-ion cells with methyl butyrate-based electrolytes, including 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %); 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %) + 2% FEC; 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %) + 4% FEC; 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %) + lithium oxalate; 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %) + 2% VC; and 1.20M LiPF6 in EC+EMC+MB (20:20:60 v/v %) + 0.10M LiBOB. These electrolytes have been shown to improve performance in MCMB-LiNiCoO2 and graphite-LiNi1/3Co1/3Mn1/3O2 experimental Li-ion cells. A number of LiPF6-based mixed carbonate electrolyte formulations have been developed that contain ester co-solvents, which have been optimized for operation at low temperature, while still providing reasonable performance at high temperature. For example, a number of ester co-solvents were investigated, including methyl propionate (MP), ethyl propionate (EP), methyl butyrate (MB), ethyl butyrate (EB), propyl butyrate (PB), and butyl butyrate (BB) in multi-component electrolytes of the following composition: 1.0M LiPF6 in ethylene carbonate (EC) + ethyl methyl carbonate (EMC) + X (20:60:20 v/v %) [where X = ester co-solvent]. ["Optimized Car bon ate and Ester-Based Li-Ion Electrolytes", NASA Tech Briefs, Vol. 32, No. 4 (April 2008), p. 56.] Focusing upon improved rate

  5. Butyrivibrio hungatei sp. nov. and Pseudobutyrivibrio xylanivorans sp. nov., butyrate-producing bacteria from the rumen.

    PubMed

    Kopecný, Jan; Zorec, Masa; Mrázek, Jakub; Kobayashi, Yasuo; Marinsek-Logar, Romana

    2003-01-01

    Two novel Gram-negative, anaerobic, non-spore-forming, butyrate-producing bacterial species, strains Mz 5T and JK 615T, were isolated from the rumen fluid of cow and sheep. Both strains were curved rods that were motile by means of single polar or subpolar flagellum and common in the rumen microbial ecosystem. Strain Mz 5T produced high xylanase, proteinase, pectin hydrolase and DNase activities; 1,4-beta-endoglucanase was also detected in the culture medium. The bacterium utilized a wide range of carbohydrates. Glucose was fermented to formate, butyrate, lactate, succinate and ethanol. The DNA G + C content was 42.1 mol%. The complete 16S rDNA sequence was obtained and phylogenetic relationships were determined. Strain Mz 5T and related isolates were located in clostridial cluster XIVa and were closely related to Pseudobutyrivibrio ruminis, Butyrivibrio crossotus, Roseburia cecicola and Eubacterium rectale. The name proposed for this novel bacterium is Pseudobutyrivibrio xylanivorans; the type strain is Mz 5T (=DSM 14809T =ATCC BAA-455T). Strain JK 615T produced no fibrolytic activity, but utilized a wide range of carbohydrates. Glucose was fermented to formate, acetate, butyrate and ethanol. The DNA G + C content was 44-8 mol%. The complete 16S rDNA sequence was obtained and phylogenetic relationships were determined. Strain JK 615T was located in clostridial cluster XIVa and was closely related to Clostridium proteoclasticum, Butyrivibrio fibrisolvens and Eubacterium halii. The name proposed for this novel bacterium is Butyrivibrio hungatei; the type strain is JK 615T (=DSM 14810T =ATCC BAA-456T). PMID:12656174

  6. Direct interspecies electron transfer accelerates syntrophic oxidation of butyrate in paddy soil enrichments.

    PubMed

    Li, Huijuan; Chang, Jiali; Liu, Pengfei; Fu, Li; Ding, Dewen; Lu, Yahai

    2015-05-01

    Syntrophic interaction occurs during anaerobic fermentation of organic substances forming methane as the final product. H2 and formate are known to serve as the electron carriers in this process. Recently, it has been shown that direct interspecies electron transfer (DIET) occurs for syntrophic CH4 production from ethanol and acetate. Here, we constructed paddy soil enrichments to determine the involvement of DIET in syntrophic butyrate oxidation and CH4 production. The results showed that CH4 production was significantly accelerated in the presence of nanoFe3 O4 in all continuous transfers. This acceleration increased with the increase of nanoFe3 O4 concentration but was dismissed when Fe3 O4 was coated with silica that insulated the mineral from electrical conduction. NanoFe3 O4 particles were found closely attached to the cell surfaces of different morphology, thus bridging cell connections. Molecular approaches, including DNA-based stable isotope probing, revealed that the bacterial Syntrophomonadaceae and Geobacteraceae, and the archaeal Methanosarcinaceae, Methanocellales and Methanobacteriales, were involved in the syntrophic butyrate oxidation and CH4 production. Among them, the growth of Geobacteraceae strictly relied on the presence of nanoFe3 O4 and its electrical conductivity in particular. Other organisms, except Methanobacteriales, were present in enrichments regardless of nanoFe3 O4 amendment. Collectively, our study demonstrated that the nanoFe3 O4 -facilitated DIET occurred in syntrophic CH4 production from butyrate, and Geobacter species played the key role in this process in the paddy soil enrichments. PMID:25059331

  7. Tarsi of Male Heliothine Moths Contain Aldehydes and Butyrate Esters as Potential Pheromone Components.

    PubMed

    Choi, Man-Yeon; Ahn, Seung-Joon; Park, Kye-Chung; Meer, Robert Vander; Cardé, Ring T; Jurenka, Russell

    2016-05-01

    The Noctuidae are one of the most speciose moth families and include the genera Helicoverpa and Heliothis. Females use (Z)-11-hexadecenal as the major component of their sex pheromones except for Helicoverpa assulta and Helicoverpa gelotopoeon, both of which utilize (Z)-9-hexadecenal. The minor compounds found in heliothine sex pheromone glands vary with species, but hexadecanal has been found in the pheromone gland of almost all heliothine females so far investigated. In this study, we found a large amount (0.5-1.5 μg) of hexadecanal and octadecanal on the legs of males of four heliothine species, Helicoverpa zea, Helicoverpa armigera, H. assulta, and Heliothis virescens. The hexadecanal was found on and released from the tarsi, and was in much lower levels or not detected on the remaining parts of the leg (tibia, femur, trochanter, and coxa). Lower amounts (0.05-0.5 μg) of hexadecanal were found on female tarsi. This is the first known sex pheromone compound to be identified from the legs of nocturnal moths. Large amounts of butyrate esters (about 16 μg) also were found on tarsi of males with lower amounts on female tarsi. Males deposited the butyrate esters while walking on a glass surface. Decapitation did not reduce the levels of hexadecanal on the tarsi of H. zea males, indicating that hexadecanal production is not under the same neuroendocrine regulation system as the production of female sex pheromone. Based on electroantennogram studies, female antennae had a relatively high response to hexadecanal compared to male antennae. We consider the possible role of aldehydes and butyrate esters as courtship signals in heliothine moths. PMID:27155602

  8. Sodium remote from Io

    NASA Astrophysics Data System (ADS)

    Brown, R. A.; Schneider, N. M.

    1981-12-01

    Measurements of sodium emission lines originating in the middle Jupiter magnetosphere are measured, confirming the wide dispersal of neutral sodium in the Jovian system in at least two distinct manifestations. Candidate neutral transport processes in the context of the observed kinematical signatures are discussed. It is argued that the normal emission feature is produced by sodium atoms on bound elliptical orbits originating in the Io sodium cloud but with apojove in the field of view. Observations of the fast sodium feature indicate that atoms episodically acquire a broad range of line-of-sight velocities above the Jupiter gravitational escape speed and far above the speeds characteristic of surface-sputtered atoms. Three suggested reactions are distinguished according to (1) production rates based on estimated plasmaspheric properties, (2) kinematical signature, and (3) the timing of occurrences of the fast sodium feature.

  9. Oral butyrate reduces oxidative stress in atherosclerotic lesion sites by a mechanism involving NADPH oxidase down-regulation in endothelial cells.

    PubMed

    Aguilar, Edenil C; Santos, Lana Claudinez Dos; Leonel, Alda J; de Oliveira, Jamil Silvano; Santos, Elândia Aparecida; Navia-Pelaez, Juliana M; da Silva, Josiane Fernandes; Mendes, Bárbara Pinheiro; Capettini, Luciano S A; Teixeira, Lilian G; Lemos, Virginia S; Alvarez-Leite, Jacqueline I

    2016-08-01

    Butyrate is a 4-carbon fatty acid that has antiinflammatory and antioxidative properties. It has been demonstrated that butyrate is able to reduce atherosclerotic development in animal models by reducing inflammatory factors. However, the contribution of its antioxidative effects of butyrate on atherogenesis has not yet been studied. We investigated the influence of butyrate on oxidative status, reactive oxygen species (ROS) release and oxidative enzymes (NADPH oxidase and iNOS) in atherosclerotic lesions of ApoE(-/-) mice and in oxLDL-stimulated peritoneal macrophages and endothelial cells (EA.hy926). The lesion area in aorta was reduced while in the aortic valve, although lesion area was unaltered, superoxide production and protein nitrosylation were reduced in butyrate-supplemented mice. Peritoneal macrophages from the butyrate group presented a lower free radical release after zymosan stimulus. When endothelial cells were pretreated with butyrate before oxLDL stimulus, the CCL-2 and superoxide ion productions and NADPH oxidase subunit p22phox were reduced. In macrophage cultures, in addition to a reduction in ROS release, nitric oxide and iNOS expression were down-regulated. The data suggest that one mechanism related to the effect of butyrate on atherosclerotic development is the reduction of oxidative stress in the lesion site. The reduction of oxidative stress related to NADPH oxidase and iNOS expression levels associated to butyrate supplementation attenuates endothelium dysfunction and macrophage migration and activation in the lesion site. PMID:27261536

  10. Protective activity of butyrate on hydrogen peroxide-induced DNA damage in isolated human colonocytes and HT29 tumour cells.

    PubMed

    Rosignoli, P; Fabiani, R; De Bartolomeo, A; Spinozzi, F; Agea, E; Pelli, M A; Morozzi, G

    2001-10-01

    Epidemiological studies support the involvement of short-chain fatty acids (SCFA) in colon physiology and the protective role of butyrate on colon carcinogenesis. Among the possible mechanisms by which butyrate may exert its anti-carcinogenicity an antioxidant activity has been recently suggested. We investigated the effects of butyrate and mixtures of SCFA (butyrate, propionate and acetate) on DNA damage induced by H(2)O(2) in isolated human colonocytes and in two human colon tumour cell lines (HT29 and HT29 19A). Human colonocytes were isolated from endoscopically obtained samples and the DNA damage was assessed by the comet assay. H(2)O(2) induced DNA damage in normal colonocytes in a dose-dependent manner which was statistically significant at concentrations over 10 microM. At 15 microM H(2)O(2) DNA damage in HT29 and HT29 19A cells was significantly lower than that observed in normal colonocytes (P < 0.01). Pre-incubation of the cells with physiological concentrations of butyrate (6.25 and 12.5 mM) reduced H(2)O(2) (15 microM) induced damage by 33 and 51% in human colonocytes, 45 and 75% in HT29 and 30 and 80% in HT29 19A, respectively. Treatment of cells with a mixture of 25 mM acetate + 10.4 mM propionate + 6.25 mM butyrate did not induce DNA damage, while a mixture of 50 mM acetate + 20.8 mM propionate + 12.5 mM butyrate was weakly genotoxic only towards normal colonocytes. However, both mixtures were able to reduce the H(2)O(2)-induced DNA damage by about 50% in all cell types. The reported protective effect of butyrate might be important in pathogenetic mechanisms mediated by reactive oxygen species, and aids understanding of the apparent protection toward colorectal cancer exerted by dietary fibres, which enhance the butyrate bioavailability in the colonic mucosa. PMID:11577008

  11. Butyrate Induced IGF2 Activation Correlated with Distinct Chromatin Signatures Due to Histone Modification.

    PubMed

    Shin, Joo Heon; Li, Robert W; Gao, Yuan; Bickhart, Derek M; Liu, George E; Li, Weizhong; Wu, Sitao; Li, Cong-Jun

    2013-01-01

    Histone modification has emerged as a very important mechanism regulating the transcriptional status of the genome. Insulin-like growth factor 2 (IGF2) is a peptide hormone controlling various cellular processes, including proliferation and apoptosis. H19 gene is closely linked to IGF2 gene, and IGF2 and H19 are reciprocally regulated imprinted genes. The epigenetic signature of H19 promoter (hypermethylation) on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2.46 Our previous studies demonstrate that butyrate regulates the expression of IGF2 as well as genes encoding IGF Binding proteins. To obtain further understanding of histone modification and its regulatory potentials in controlling IGF2/H19 gene expression, we investigated the histone modification status of some key histones associated with the expression of IGF2/H19 genes in bovine cells using RNA-seq in combination with Chip-seq technology. A high-resolution map of the major chromatin modification at the IGF2/H19 locus induced by butyrate was constructed to illustrate the fundamental association of the chromatin modification landscape that may play a role in the activation of the IGF2 gene. High-definition epigenomic landscape mapping revealed that IGF2 and H19 have distinct chromatin modification patterns at their coding and promoter regions, such as TSSs and TTSs. Moreover, the correlation between the differentially methylated regions (DMRs) of IGF2/H19 locus and histone modification (acetylation and methylation) indicated that epigenetic signatures/markers of DNA methylation, histone methylation and histone acetylation were differentially distributed on the expressed IGF2 and silenced H19 genes. Our evidence also suggests that butyrate-induced regional changes of histone acetylation statusin the upstream regulation domain of H19 may be related to the reduced expression of H19 and strong activation of IGF2. Our results provided insights into the mechanism

  12. Converting carbon dioxide to butyrate with an engineered strain of Clostridium ljungdahlii.

    PubMed

    Ueki, Toshiyuki; Nevin, Kelly P; Woodard, Trevor L; Lovley, Derek R

    2014-01-01

    Microbial conversion of carbon dioxide to organic commodities via syngas metabolism or microbial electrosynthesis is an attractive option for production of renewable biocommodities. The recent development of an initial genetic toolbox for the acetogen Clostridium ljungdahlii has suggested that C. ljungdahlii may be an effective chassis for such conversions. This possibility was evaluated by engineering a strain to produce butyrate, a valuable commodity that is not a natural product of C. ljungdahlii metabolism. Heterologous genes required for butyrate production from acetyl-coenzyme A (CoA) were identified and introduced initially on plasmids and in subsequent strain designs integrated into the C. ljungdahlii chromosome. Iterative strain designs involved increasing translation of a key enzyme by modifying a ribosome binding site, inactivating the gene encoding the first step in the conversion of acetyl-CoA to acetate, disrupting the gene which encodes the primary bifunctional aldehyde/alcohol dehydrogenase for ethanol production, and interrupting the gene for a CoA transferase that potentially represented an alternative route for the production of acetate. These modifications yielded a strain in which ca. 50 or 70% of the carbon and electron flow was diverted to the production of butyrate with H2 or CO as the electron donor, respectively. These results demonstrate the possibility of producing high-value commodities from carbon dioxide with C. ljungdahlii as the catalyst. Importance: The development of a microbial chassis for efficient conversion of carbon dioxide directly to desired organic products would greatly advance the environmentally sustainable production of biofuels and other commodities. Clostridium ljungdahlii is an effective catalyst for microbial electrosynthesis, a technology in which electricity generated with renewable technologies, such as solar or wind, powers the conversion of carbon dioxide and water to organic products. Other electron donors

  13. Discoloration of poly(vinyl butyral) in cells exposed to real and simulated solar environments

    NASA Technical Reports Server (NTRS)

    Kim, Q.; Shumka, A.

    1984-01-01

    The discoloration of poly(vinl butyral) (PVB) films used in solar cell modules is described. Transmission absorption, Fourier transformation IR absorption and atomic absorption spectroscopy as well as scanning electron microscopy were used for this study. The discoloration of the PVB has been found to be affected by oxygen, moisture, temperature and light. However, the most severe discoloration observed is clearly associated with the migration of positive silver ions, which can be accelerated in the presence of electric fields. The metallization is the source of the silver, and the data are consistent with an interfacial reaction between the silver and PVB followed by transport into the polymer.

  14. In Vitro Effects of Dietary Inulin on Human Fecal Microbiota and Butyrate Production.

    PubMed

    Jung, Tae-Hwan; Jeon, Woo-Min; Han, Kyoung-Sik

    2015-09-01

    Administration of dietary fibers has various health benefits, mainly by increasing numbers of beneficial bacteria and enhancing production of short-chain fatty acids in the colon. There has been growing interest in the addition of dietary fiber to human diet, due to its prebiotic effects. This study aimed to evaluate the prebiotic activity of inulin using an in vitro batch fermentation system with human fecal microbiota. Fermentation of inulin resulted in a significantly greater ratio of Lactobacillus or Bifidobacteria to Enterobacteria strains as an index of healthy human intestine and elevated butyrate concentration, which are related to improvement of gut health. PMID:26095388

  15. Converting Carbon Dioxide to Butyrate with an Engineered Strain of Clostridium ljungdahlii

    SciTech Connect

    Ueki, T; Nevin, KP; Woodard, TL; Lovley, DR

    2014-08-26

    Microbial conversion of carbon dioxide to organic commodities via syngas metabolism or microbial electrosynthesis is an attractive option for production of renewable biocommodities. The recent development of an initial genetic toolbox for the acetogen Clostridium ljungdahlii has suggested that C. ljungdahlii may be an effective chassis for such conversions. This possibility was evaluated by engineering a strain to produce butyrate, a valuable commodity that is not a natural product of C. ljungdahlii metabolism. Heterologous genes required for butyrate production from acetyl-coenzyme A (CoA) were identified and introduced initially on plasmids and in subsequent strain designs integrated into the C. ljungdahlii chromosome. Iterative strain designs involved increasing translation of a key enzyme by modifying a ribosome binding site, inactivating the gene encoding the first step in the conversion of acetyl-CoA to acetate, disrupting the gene which encodes the primary bifunctional aldehyde/alcohol dehydrogenase for ethanol production, and interrupting the gene for a CoA transferase that potentially represented an alternative route for the production of acetate. These modifications yielded a strain in which ca. 50 or 70% of the carbon and electron flow was diverted to the production of butyrate with H-2 or CO as the electron donor, respectively. These results demonstrate the possibility of producing high-value commodities from carbon dioxide with C. ljungdahlii as the catalyst. IMPORTANCE The development of a microbial chassis for efficient conversion of carbon dioxide directly to desired organic products would greatly advance the environmentally sustainable production of biofuels and other commodities. Clostridium ljungdahlii is an effective catalyst for microbial electrosynthesis, a technology in which electricity generated with renewable technologies, such as solar or wind, powers the conversion of carbon dioxide and water to organic products. Other electron donors

  16. Sterically controlled azomethine ylide cycloaddition polymerization of phenyl-C61-butyric acid methyl ester.

    PubMed

    Stephen, Meera; Ramanitra, Hasina H; Santos Silva, Hugo; Dowland, Simon; Bégué, Didier; Genevičius, Kristijonas; Arlauskas, Kęstutis; Juška, Gytis; Morse, Graham E; Distler, Andreas; Hiorns, Roger C

    2016-05-01

    Phenyl-C61-butyric acid methyl ester (PCBM) is polymerized simply using a one-pot reaction to yield soluble, high molecular weight polymers. The sterically controlled azomethine ylide cycloaddition polymerization (SACAP) is demonstrated to be highly adaptable and yields polymers with probable Mn≈ 24 600 g mol(-1) and Mw≈ 73 800 g mol(-1). Products are metal-free and of possible benefit to organic and hybrid photovoltaics and electronics as they form thin films from solution and have raised LUMOs. The promising electronic properties of this new polymer are discussed. PMID:27066898

  17. Inhibition of Sodium Benzoate on Stainless Steel in Tropical Seawater

    SciTech Connect

    Seoh, S. Y.; Senin, H. B.; Nik, W. N. Wan; Amin, M. M.

    2007-05-09

    The inhibition of sodium benzoate for stainless steel controlling corrosion was studied in seawater at room temperature. Three sets of sample have been immersed in seawater containing sodium benzoate with the concentrations of 0.3M, 0.6M and 1.0M respectively. One set of sample has been immersed in seawater without adding any sodium benzoate. It was found that the highest corrosion rate was observed for the stainless steel with no inhibitor was added to the seawater. As the concentration of sodium benzoate being increased, the corrosion rate is decreases. Results show that by the addition of 1.0M of sodium benzoate in seawater samples, it giving {>=} 90% efficiencies.

  18. Vancomycin treatment and butyrate supplementation modulate gut microbe composition and severity of neointimal hyperplasia after arterial injury.

    PubMed

    Ho, Karen J; Xiong, Liqun; Hubert, Nathaniel J; Nadimpalli, Anuradha; Wun, Kelly; Chang, Eugene B; Kibbe, Melina R

    2015-12-01

    Gut microbial metabolites are increasingly recognized as determinants of health and disease. However, whether host -: microbe crosstalk influences peripheral arteries is not understood. Neointimal hyperplasia, a proliferative and inflammatory response to arterial injury, frequently limits the long-term benefits of cardiovascular interventions such as angioplasty, stenting, and bypass surgery. Our goal is to assess the effect of butyrate, one of the principal short chain fatty acids produced by microbial fermentation of dietary fiber, on neointimal hyperplasia development after angioplasty. Treatment of male Lewis Inbred rats with oral vancomycin for 4 weeks changed the composition of gut microbes as assessed by 16S rRNA-based taxonomic profiling and decreased the concentration of circulating butyrate by 69%. In addition, rats treated with oral vancomycin had exacerbated neointimal hyperplasia development after carotid angioplasty. Oral supplementation of butyrate reversed these changes. Butyrate also inhibited vascular smooth muscle cell proliferation, migration, and cell cycle progression in a dose-dependent manner in vitro. Our results suggest for the first time that gut microbial composition is associated with the severity of arterial remodeling after injury, potentially through an inhibitory effect of butyrate on VSMC. PMID:26660548

  19. Butyric acid production from sugarcane bagasse hydrolysate by Clostridium tyrobutyricum immobilized in a fibrous-bed bioreactor.

    PubMed

    Wei, Dong; Liu, Xiaoguang; Yang, Shang-Tian

    2013-02-01

    A fermentation process using Clostridium tyrobutyricum immobilized in a fibrous-bed bioreactor (FBB) was developed for butyric acid production from sugarcane bagasse (SCB) hydrolysate. SCB was first treated with dilute acid and then hydrolyzed with cellulases. The hydrolysate containing glucose and xylose was used as carbon source for the fermentation without detoxification. The bacterium was able to grow at a specific growth rate of ∼0.06 h(-1) in media containing 15-20% (w/v) SCB in serum bottles. In batch cultures in the FBB, both glucose and xylose in the SCB hydrolysate were simultaneously converted to butyrate with a high yield (0.45-0.54 g/gsugar) and productivity (0.48-0.60 g/Lh). A final butyrate concentration of 20.9 g/L was obtained in a fed-batch culture, with an overall productivity of 0.51 g/Lh and butyrate yield of 0.48 g/g sugar consumed. This work demonstrated the feasibility of using SCB as a low-cost feedstock to produce butyric acid. PMID:23270719

  20. Fed-batch strategies using butyrate for high cell density cultivation of Pseudomonas putida and its use as a biocatalyst.

    PubMed

    Cerrone, Federico; Duane, Gearoid; Casey, Eoin; Davis, Reeta; Belton, Ian; Kenny, Shane T; Guzik, Maciej W; Woods, Trevor; Babu, Ramesh P; O'Connor, Kevin

    2014-11-01

    A mathematically based fed-batch bioprocess demonstrated the suitability of using a relatively cheap and renewable substrate (butyric acid) for Pseudomonas putida CA-3 high cell density cultivation. Butyric acid fine-tuned addition is critical to extend the fermentation run and avoid oxygen consumption while maximising the biomass volumetric productivity. A conservative submaximal growth rate (μ of 0.25 h(-1)) achieved 71.3 g L(-1) of biomass after 42 h of fed-batch growth. When a more ambitious feed rate was supplied in order to match a μ of 0.35 h(-1), the volumetric productivity was increased to 2.0 g L(-1) h(-1), corresponding to a run of 25 h and 50 g L(-1) of biomass. Both results represent the highest biomass and the best biomass volumetric productivity with butyrate as a sole carbon source. However, medium chain length polyhydroxyalkanoate (mcl-PHA) accumulation with butyrate grown cells is low (4 %). To achieve a higher mcl-PHA volumetric productivity, decanoate was supplied to butyrate grown cells. This strategy resulted in a PHA volumetric productivity of 4.57 g L(-1) h(-1) in the PHA production phase and 1.63 g L(-1) h(-1)over the lifetime of the fermentation, with a maximum mcl-PHA accumulation of 65 % of the cell dry weight. PMID:25104034

  1. Sodium Polystyrene Sulfonate

    MedlinePlus

    ... allergic to sodium polystyrene sulfonate, other polystyrene sulfonate resins, any other medications, or any of the ingredients ... salt substitutes containing potassium or foods that are high in potassium.

  2. [Proteasome inhibitor].

    PubMed

    Yagi, Hideo

    2014-06-01

    The ubiquitin-proteasome system plays an essential role in degradation of eukaryotic intracellular protein, including cell cycle regulation, cell growth and proliferation, and survival. Cancer cells generally have higher level of proteasome activity compared with normal cells, suggesting proteasome inhibition could be therapeutic target in oncology. Bortezomib, the first proteasome inhibitor introduced into the clinic, is approved for the treatment of patients with multiple myeloma (MM). Although it was approved as single agent in the relapsed setting, bortezomib is now predominantly used in combination with conventional and novel targeted agents because bortezomib has demonstrated additive and synergistic activity in preclinical studies. Recently, several second-generation proteasome inhibitors, such as carfilzomib and MLN9708, have been developed and entered into clinical trials. These agents were investigated in frontline MM in combination with lenalidomide and low-dose dexamethasone. These studies demonstrated positive efficacy and safety, and it is expected that they will be approved in near future. PMID:25016815

  3. Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella.

    PubMed

    Rivera-Chávez, Fabian; Zhang, Lillian F; Faber, Franziska; Lopez, Christopher A; Byndloss, Mariana X; Olsan, Erin E; Xu, Gege; Velazquez, Eric M; Lebrilla, Carlito B; Winter, Sebastian E; Bäumler, Andreas J

    2016-04-13

    The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment. Clostridia depletion and aerobic Salmonella expansion were also observed in the absence of streptomycin treatment in genetically resistant mice but proceeded with slower kinetics and required the presence of functional Salmonella type III secretion systems. The Salmonella cytochrome bd-II oxidase synergized with nitrate reductases to drive luminal expansion, and both were required for fecal-oral transmission. We conclude that Salmonella virulence factors and antibiotic treatment promote pathogen expansion through the same mechanism: depletion of butyrate-producing Clostridia to elevate epithelial oxygenation, allowing aerobic Salmonella growth. PMID:27078066

  4. Postnatal development of the myenteric glial network and its modulation by butyrate.

    PubMed

    Cossais, François; Durand, Tony; Chevalier, Julien; Boudaud, Marie; Kermarrec, Laetitia; Aubert, Philippe; Neveu, Isabelle; Naveilhan, Philippe; Neunlist, Michel

    2016-06-01

    The postnatal period is crucial for the development of gastrointestinal (GI) functions. The enteric nervous system is a key regulator of GI functions, and increasing evidences indicate that 1) postnatal maturation of enteric neurons affect the development of GI functions, and 2) microbiota-derived short-chain fatty acids can be involved in this maturation. Although enteric glial cells (EGC) are central regulators of GI functions, the postnatal evolution of their phenotype remains poorly defined. We thus characterized the postnatal evolution of EGC phenotype in the colon of rat pups and studied the effect of short-chain fatty acids on their maturation. We showed an increased expression of the glial markers GFAP and S100β during the first postnatal week. As demonstrated by immunohistochemistry, a structured myenteric glial network was observed at 36 days in the rat colons. Butyrate inhibited EGC proliferation in vivo and in vitro but had no effect on glial marker expression. These results indicate that the EGC myenteric network continues to develop after birth, and luminal factors such as butyrate endogenously produced in the colon may affect this development. PMID:27056724

  5. Reduction of butyrate- and methane-producing microorganisms in patients with Irritable Bowel Syndrome

    PubMed Central

    Pozuelo, Marta; Panda, Suchita; Santiago, Alba; Mendez, Sara; Accarino, Anna; Santos, Javier; Guarner, Francisco; Azpiroz, Fernando; Manichanh, Chaysavanh

    2015-01-01

    The pathophysiology of irritable bowel syndrome (IBS) remains unclear. Here we investigated the microbiome of a large cohort of patients to identify specific signatures for IBS subtypes. We examined the microbiome of 113 patients with IBS and 66 healthy controls. A subset of these participants provided two samples one month apart. We analyzed a total of 273 fecal samples, generating more than 20 million 16S rRNA sequences. In patients with IBS, a significantly lower microbial diversity was associated with a lower relative abundance of butyrate-producing bacteria (P = 0.002; q < 0.06), in particular in patients with IBS-D and IBS-M. IBS patients who did not receive any treatment harboured a lower abundance of Methanobacteria compared to healthy controls (P = 0.005; q = 0.05). Furthermore, significant correlations were observed between several bacterial taxa and sensation of flatulence and abdominal pain (P < 0.05). Altogether, our findings showed that IBS-M and IBS-D patients are characterized by a reduction of butyrate producing bacteria, known to improve intestinal barrier function, and a reduction of methane producing microorganisms a major mechanism of hydrogen disposal in the human colon, which could explain excess of abdominal gas in IBS. PMID:26239401

  6. Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development.

    PubMed

    Uchiyama, Kazuhiko; Sakiyama, Toshio; Hasebe, Takumu; Musch, Mark W; Miyoshi, Hiroyuki; Nakagawa, Yasushi; He, Tong-Chuan; Lichtenstein, Lev; Naito, Yuji; Itoh, Yoshito; Yoshikawa, Toshikazu; Jabri, Bana; Stappenbeck, Thaddeus; Chang, Eugene B

    2016-01-01

    Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation. PMID:27561676

  7. Prebiotic stimulation of human colonic butyrate-producing bacteria and bifidobacteria, in vitro.

    PubMed

    Scott, Karen P; Martin, Jennifer C; Duncan, Sylvia H; Flint, Harry J

    2014-01-01

    Dietary macronutrients affect the composition of the gut microbiota, and prebiotics are used to improve and maintain a healthy gut. The impact of prebiotics on dominant gut bacteria other than bifidobacteria, however, is under-researched. Here, we report carbohydrate utilisation patterns for representative butyrate-producing anaerobes, belonging to the Gram-positive Firmicutes families Lachnospiraceae and Ruminococcaceae, by comparison with selected Bacteroides and Bifidobacterium species. Growth assessments using anaerobic Hungate tubes and a new rapid microtitre plate assay were generally in good agreement. The Bacteroides strains tested showed some growth on basal medium with no added carbohydrates, utilising peptides in the growth medium. The butyrate-producing strains exhibited different growth profiles on the substrates, which included starch, inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS) and xylooligosaccharides (XOS). Eleven were able to grow on short-chain FOS, but this number decreased as the chain length of the fructan substrates increased. Long-chain inulin was utilised by Roseburia inulinivorans, but by none of the Bifidobacterium species examined here. XOS was a more selective growth substrate than FOS, with only six of the 11 Firmicutes strains able to use XOS for growth. These results illustrate the selectivity of different prebiotics and help to explain why some are butyrogenic. PMID:23909466

  8. Dietary toxicity of calcium beta-hydroxy-beta-methyl butyrate (CaHMB).

    PubMed

    Baxter, J H; Carlos, J L; Thurmond, J; Rehani, R N; Bultman, J; Frost, D

    2005-12-01

    HMB, 3-hydroxy-3-methyl butyrate, is of interest as a dietary supplement and a possible component of functional and medical foods. The purpose of this study was to evaluate the toxicity of the calcium salt of HMB, calcium 3-hydroxy-3-methyl butyrate (CaHMB, monohydrate, food grade), when administered daily in the diet of rats for at least 90 days. Male and female Crl:CD (SD)IGS BR animals were assigned to four groups. Each group received diets containing the carrier or 1%, 2%, or 5% of CaHMB mixed with diet. Assessment of toxicity was based on mortality, clinical observations, body weights, food consumption, and clinical and anatomic pathology evaluations. Administration of CaHMB in basal diet for 91 days was tolerated well. There were no unscheduled sacrifices or deaths. There were no CaHMB-related adverse effects on clinical observations, body weights, food consumption, clinical chemistry, hematology, absolute or relative organ weights, or macroscopic or microscopic observations. A statistically significant increase in inorganic phosphorous was observed in male animals in the 5% feeding group; however, this effect was not considered adverse. Based on the results of this study, the no-observed-adverse-effect level (NOAEL) was considered to be 5% of CaHMB mixed with diet (3.49 g/kg BW for males and 4.16 g/kg BW for females). PMID:16006030

  9. Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development

    PubMed Central

    Uchiyama, Kazuhiko; Sakiyama, Toshio; Hasebe, Takumu; Musch, Mark W.; Miyoshi, Hiroyuki; Nakagawa, Yasushi; He, Tong-Chuan; Lichtenstein, Lev; Naito, Yuji; Itoh, Yoshito; Yoshikawa, Toshikazu; Jabri, Bana; Stappenbeck, Thaddeus; Chang, Eugene B.

    2016-01-01

    Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation. PMID:27561676

  10. Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate

    PubMed Central

    Liu, Jiaming; Sun, Jing; Wang, Fangyan; Yu, Xichong; Ling, Zongxin; Li, Haixiao; Zhang, Huiqing; Jin, Jiangtao; Chen, Wenqian; Pang, Mengqi; Yu, Junjie; He, Yiwen; Xu, Jiru

    2015-01-01

    Probiotics actively participate in neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and vascular dementia (VaD) remains unclear. We used a mouse model of VaD induced by a permanent right unilateral common carotid arteries occlusion (rUCCAO) to investigate the neuroprotective effects and possible underlying mechanisms of Clostridium butyricum. Following rUCCAO, C. butyricum was intragastrically administered for 6 successive weeks. Cognitive function was estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The BDNF-PI3K/Akt pathway-related proteins were assessed by western blot and immunohistochemistry. The diversity of gut microbiota and the levels of butyrate in the feces and the brains were determined. The results showed that C. butyricum significantly attenuated the cognitive dysfunction and histopathological changes in VaD mice. C. butyricum not only increased the levels of BDNF and Bcl-2 and decreased level of Bax but also induced Akt phosphorylation (p-Akt) and ultimately reduced neuronal apoptosis. Moreover, C. butyricum could regulate the gut microbiota and restore the butyrate content in the feces and the brains. These results suggest that C. butyricum might be effective in the treatment of VaD by regulating the gut-brain axis and that it can be considered a new therapeutic strategy against VaD. PMID:26523278

  11. Thermophysical properties of sodium

    NASA Technical Reports Server (NTRS)

    Golden, G. H.; Tokar, J. V.

    1969-01-01

    Assessment is given of physical and thermodynamic properties of sodium. FORTRAN subroutine computes enthalphy and entropy of sodium in given state, and composition, molecular weight, volume, and compressibility factor of corresponding vapor. Tabular results for saturated liquid and vapor are presented for a 500-2500 degree F range.

  12. Butyrate attenuates lipopolysaccharide-induced inflammation in intestinal cells and Crohn's mucosa through modulation of antioxidant defense machinery.

    PubMed

    Russo, Ilaria; Luciani, Alessandro; De Cicco, Paola; Troncone, Edoardo; Ciacci, Carolina

    2012-01-01

    Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CrD). High levels of Reactive Oxygen Species (ROS) induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB), which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia coli (EC-LPS) in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2) mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa. PMID:22412931

  13. Only fibres promoting a stable butyrate producing colonic ecosystem decrease the rate of aberrant crypt foci in rats

    PubMed Central

    Perrin, P; Pierre, F; Patry, Y; Champ, M; Berreur, M; Pradal, G; Bornet, F; Meflah, K; Menanteau, J

    2001-01-01

    BACKGROUND—Dietary fibres have been proposed as protective agents against colon cancer but results of both epidemiological and experimental studies are inconclusive.
AIMS—Hypothesising that protection against colon cancer may be restricted to butyrate producing fibres, we investigated the factors needed for long term stable butyrate production and its relation to susceptibility to colon cancer.
METHODS—A two part randomised blinded study in rats, mimicking a prospective study in humans, was performed using a low fibre control diet (CD) and three high fibre diets: starch free wheat bran (WB), type III resistant starch (RS), and short chain fructo-oligosaccharides (FOS). Using a randomised block design, 96 inbred rats were fed for two, 16, 30, or 44 days to determine the period of adaptation to the diets, fermentation profiles, and effects on the colon, including mucosal proliferation on day 44. Subsequently, 36 rats fed the same diets for 44 days were injected with azoxymethane and checked for aberrant crypt foci 30 days later.
RESULTS—After fermentation had stabilised (44 days), only RS and FOS produced large amounts of butyrate, with a trophic effect in the large intestine. No difference in mucosal proliferation between the diets was noted at this time. In the subsequent experiment one month later, fewer aberrant crypt foci were present in rats fed high butyrate producing diets (RS, p=0.022; FOS, p=0.043).
CONCLUSION—A stable butyrate producing colonic ecosystem related to selected fibres appears to be less conducive to colon carcinogenesis.


Keywords: fibre; fermentation; butyrate; colon carcinogenesis; aberrant crypt foci; rat PMID:11115823

  14. Inhibition of mild steel corrosion by sodium dodecyl benzene sulfonate and sodium oleate in acidic solutions

    SciTech Connect

    Luo, H.; Han, K.N.; Guan, Y.C.

    1998-08-01

    Inhibition of mild steel corrosion by sodium dodecyl benzene sulfonate (C{sub 12}H{sub 25}C{sub 6}H{sub 4}SO{sub 3}Na [SDBS]) and sodium oleate (CH{sub 3}[CH{sub 2}]{sub 7}CH{double_bond}CH[CH{sub 2}]{sub 7}COONa) in acidic solutions was investigated using a potentiostat, a lock-in amplifier, a contact angle goniometer, A fourier transform infrared (FTIR) spectrometer, and an ultraviolet (UV)/visible spectrophotometer. In the presence of the organic inhibitors, the corrosion rate was reduced significantly, Anionic SDBS was adsorbed on the positively charged mild steel surface through the electrostatic attraction. However, for sodium oleate, the soluble oleic acid (CH{sub 3}[CH{sub 2}]{sub 7}CH{double_bond}CH[CH]{sub 7}COOH) chemisorbed on the steel surface at the first stage. Then, insoluble colloid adsorbed on the chemisorbed surface through van der Waals forces.

  15. Direct hydrogenation of biomass-derived butyric acid to n-butanol over a ruthenium-tin bimetallic catalyst.

    PubMed

    Lee, Jong-Min; Upare, Pravin P; Chang, Jong-San; Hwang, Young Kyu; Lee, Jeong Ho; Hwang, Dong Won; Hong, Do-Young; Lee, Seung Hwan; Jeong, Myung-Geun; Kim, Young Dok; Kwon, Young-Uk

    2014-11-01

    Catalytic hydrogenation of organic carboxylic acids and their esters, for example, cellulosic ethanol from fermentation of acetic acid and hydrogenation of ethyl acetate is a promising possibility for future biorefinery concepts. A hybrid conversion process based on selective hydrogenation of butyric acid combined with fermentation of glucose has been developed for producing biobutanol. ZnO-supported Ru-Sn bimetallic catalysts exhibits unprecedentedly superior performance in the vapor-phase hydrogenation of biomass-derived butyric acid to n-butanol (>98% yield) for 3500 h without deactivation. PMID:25123894

  16. Clinical evaluation of clobetasone butyrate: a comparative study of its effects in postoperative inflammation and on intraocular pressure.

    PubMed Central

    Ramsell, T G; Bartholomew, R S; Walker, S R

    1980-01-01

    Clobetasone butyrate, a new corticosteroid with a high topical activity, has been compared with prednisolone phosphate and a placebo in the treatment of inflammation following cataract extraction. These 2 steroids were more effective in relieving postoperative inflammation than placebo (P less than 0.05), though no obvious clinical differences between the 2 compounds emerged from this investigation. However, a single-blind comparative study against betamethasone phosphate in patients suspected of having steroid-induced glaucoma showed that, while betamethasone phosphate significantly raised intraocular pressure, clobetasone butyrate had only a minimal effect, and this difference was statistically significant (P less than 0.02). PMID:6986899

  17. Catalytic and inhibiting effects of lithium peroxide and hydroxide on sodium chlorate decomposition

    SciTech Connect

    Cannon, J.C.; Zhang, Y.

    1995-09-01

    Chemical oxygen generators based on sodium chlorate and lithium perchlorate are used in airplanes, submarines, diving, and mine rescue. Catalytic decomposition of sodium chlorate in the presence of cobalt oxide, lithium peroxide, and lithium hydroxide is studied using thermal gravimetric analysis. Lithium peroxide and hydroxide are both moderately active catalysts for the decomposition of sodium chlorate when used alone, and inhibitors when used with the more active catalyst cobalt oxide.

  18. Decode the Sodium Label Lingo

    MedlinePlus

    ... For Preschooler For Gradeschooler For Teen Decode the Sodium Label Lingo Published January 24, 2013 Print Email Reading food labels can help you slash sodium. Here's how to decipher them. "Sodium free" or " ...

  19. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress

    PubMed Central

    Tong, Ling-chang; Wang, Yue; Wang, Zhi-bin; Liu, Wei-ye; Sun, Sheng; Li, Ling; Su, Ding-feng; Zhang, Li-chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7–14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  20. Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress.

    PubMed

    Tong, Ling-Chang; Wang, Yue; Wang, Zhi-Bin; Liu, Wei-Ye; Sun, Sheng; Li, Ling; Su, Ding-Feng; Zhang, Li-Chao

    2016-01-01

    Propionate is a short chain fatty acid that is abundant as butyrate in the gut and blood. However, propionate has not been studied as extensively as butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced colitis mice. Animals in DSS group received drinking water from 1 to 6 days and DSS [3% (w/v) dissolved in double distilled water] instead of drinking water from 7 to 14 days. Animals in DSS+propionate (DSS+Prop) group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7-14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin, and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase and catalase level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway. PMID:27574508

  1. METHOD FOR REMOVING SODIUM OXIDE FROM LIQUID SODIUM

    DOEpatents

    Bruggeman, W.H.; Voorhees, B.G.

    1957-12-01

    A method is described for removing sodium oxide from a fluent stream of liquid sodium by coldtrapping the sodium oxide. Apparatus utilizing this method is disclosed in United States Patent No. 2,745,552. Sodium will remain in a molten state at temperatures below that at which sodium oxide will crystallize out and form solid deposits, therefore, the contaminated stream of sodium is cooled to a temperature at which the solubility of sodium oxide in sodium is substantially decreased. Thereafter the stream of sodium is passed through a bed of stainless steel wool maintained at a temperature below that of the stream. The stream is kept in contact with the wool until the sodium oxide is removed by crystal growth on the wool, then the stream is reheated and returned to the system. This method is useful in purifying reactor coolants where the sodium oxide would otherwise deposit out on the walls and eventually plug the coolant tubes.

  2. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study

    PubMed Central

    2014-01-01

    Background In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus. Methods The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24. Results Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was −0.028% (−0.192 to 0.137) in the placebo group, compared with −0.797% (−0.960 to −0.634) in the tofogliflozin 10 mg group, −1.017% (−1.178 to −0.856) in the tofogliflozin 20 mg group, and −0.870% (−1.031 to −0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were

  3. Poly-3-hydroxy butyric acid interaction with the transgenic flax fibers: FT-IR and Raman spectra of the composite extracted from a GM flax.

    PubMed

    Wróbel-Kwiatkowska, Magdalena; Zuk, Magdalena; Szopa, Jan; Dymińska, Lucyna; Maczka, Mirosław; Hanuza, Jerzy

    2009-07-15

    The FT-IR and FT-Raman studies have been performed on commercial 3-hydroxy-butyric acid, commercial poly-3-hydroxy butyric acid as well as poly-3-hydroxy butyric acid (PHB) produced by bacteria. The data were compared to those obtained for poly-3-hydroxy butyric acid extracted from natural and genetically modified flax. Genetically modified flax was generated by expression of three bacterial genes coding for synthesis of poly-3-hydroxy butyric acid. Thus transgenic flaxes were enhanced with different amount of the PHB. The discussion of polymer structure and vibrational properties has been done in order to get insight into differences among these materials. The interaction between the cellulose of flax fibers and embedded poly-3-hydroxybutyric acid has been also discussed. The spectroscopic data provide evidences for structural changes in cellulose and in PHB when synthesized in fibers. Based on this data it is suggesting that cellulose and PHB interact by hydrogen and ester bonds. PMID:19328737

  4. Poly-3-hydroxy butyric acid interaction with the transgenic flax fibers: FT-IR and Raman spectra of the composite extracted from a GM flax

    NASA Astrophysics Data System (ADS)

    Wróbel-Kwiatkowska, Magdalena; Żuk, Magdalena; Szopa, Jan; Dymińska, Lucyna; Mączka, Mirosław; Hanuza, Jerzy

    2009-07-01

    The FT-IR and FT-Raman studies have been performed on commercial 3-hydroxy-butyric acid, commercial poly-3-hydroxy butyric acid as well as poly-3-hydroxy butyric acid (PHB) produced by bacteria. The data were compared to those obtained for poly-3-hydroxy butyric acid extracted from natural and genetically modified flax. Genetically modified flax was generated by expression of three bacterial genes coding for synthesis of poly-3-hydroxy butyric acid. Thus transgenic flaxes were enhanced with different amount of the PHB. The discussion of polymer structure and vibrational properties has been done in order to get insight into differences among these materials. The interaction between the cellulose of flax fibers and embedded poly-3-hydroxybutyric acid has been also discussed. The spectroscopic data provide evidences for structural changes in cellulose and in PHB when synthesized in fibers. Based on this data it is suggesting that cellulose and PHB interact by hydrogen and ester bonds.

  5. Submersible sodium pump

    DOEpatents

    Brynsvold, Glen V.; Lopez, John T.; Olich, Eugene E.; West, Calvin W.

    1989-01-01

    An electromagnetic submerged pump has an outer cylindrical stator with an inner cylindrical conductive core for the submerged pumping of sodium in the cylindrical interstitial volume defined between the stator and core. The cylindrical interstitial volume is typically vertically oriented, and defines an inlet at the bottom and an outlet at the top. The outer stator generates upwardly conveyed toroidal magnetic fields, which fields convey preferably from the bottom of the pump to the top of the pump liquid sodium in the cold leg of a sodium cooled nuclear reactor. The outer cylindrical stator has a vertically disposed duct surrounded by alternately stacked layers of coil units and laminates.

  6. SODIUM DEUTERIUM REACTOR

    DOEpatents

    Oppenheimer, E.D.; Weisberg, R.A.

    1963-02-26

    This patent relates to a barrier system for a sodium heavy water reactor capable of insuring absolute separation of the metal and water. Relatively cold D/sub 2/O moderator and reflector is contained in a calandria into which is immersed the fuel containing tubes. The fuel elements are cooled by the sodium which flows within the tubes and surrounds the fuel elements. The fuel containing tubes are surrounded by concentric barrier tubes forming annular spaces through which pass inert gases at substantially atmospheric pressure. Header rooms above and below the calandria are provided for supplying and withdrawing the sodium and inert gases in the calandria region. (AEC)

  7. Submersible sodium pump

    DOEpatents

    Brynsvold, G.V.; Lopez, J.T.; Olich, E.E.; West, C.W.

    1989-11-21

    An electromagnetic submerged pump has an outer cylindrical stator with an inner cylindrical conductive core for the submerged pumping of sodium in the cylindrical interstitial volume defined between the stator and core. The cylindrical interstitial volume is typically vertically oriented, and defines an inlet at the bottom and an outlet at the top. The outer stator generates upwardly conveyed toroidal magnetic fields, which fields convey preferably from the bottom of the pump to the top of the pump liquid sodium in the cold leg of a sodium cooled nuclear reactor. The outer cylindrical stator has a vertically disposed duct surrounded by alternately stacked layers of coil units and laminates. 14 figs.

  8. Small-Molecule Inhibitors of Urea Transporters

    PubMed Central

    Verkman, Alan S.; Esteva-Font, Cristina; Cil, Onur; Anderson, Marc O.; Li, Fei; Li, Min; Lei, Tianluo; Ren, Huiwen; Yang, Baoxue

    2015-01-01

    Urea transporter (UT) proteins, which include isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, facilitate urinary concentrating function. Inhibitors of urea transporter function have potential clinical applications as sodium-sparing diuretics, or ‘urearetics,’ in edema from different etiologies, such as congestive heart failure and cirrhosis, as well as in syndrome of inappropriate antidiuretic hormone (SIADH). High-throughput screening of drug-like small molecules has identified UT-A and UT-B inhibitors with nanomolar potency. Inhibitors have been identified with different UT-A versus UT-B selectivity profiles and putative binding sites on UT proteins. Studies in rodent models support the utility of UT inhibitors in reducing urinary concentration, though testing in clinically relevant animal models of edema has not yet been done. PMID:25298345

  9. The combined use of ultrasound and molecular sieves improves the synthesis of ethyl butyrate catalyzed by immobilized Thermomyces lanuginosus lipase.

    PubMed

    Paludo, Natalia; Alves, Joana S; Altmann, Cintia; Ayub, Marco A Z; Fernandez-Lafuente, Roberto; Rodrigues, Rafael C

    2015-01-01

    In this work, the combined use of ultrasound energy and molecular sieves was investigated for the synthesis of ethyl butyrate, ester with mango and banana notes, catalyzed by the immobilized lipase from Thermomyces lanuginosus (Lipozyme TL-IM). Initially, the best concentrations of biocatalysts (35%) and butyric acid (0.7M) were tested using ultrasound as an alternative to mechanical agitation. The amount of acid in the reaction could be increased by 2-fold when compared to previous works where mechanical agitation was used. In the next step, substrate molar ratio and reaction temperature were optimized and the best conditions were at their lowest levels: 1:1 (acid:alcohol), and 30°C, reaching 61% of conversion in 6h. Molecular sieves (3Å) were added to optimized reaction medium in order to remove the formed water and improve the maximum yield. The reaction yield increased 1.5 times, reaching 90% of conversion in 6h, when 60mg of molecular sieves per mmol of butyric acid was used. Finally, the reuse of Lipozyme TL-IM for the ultrasound-assisted synthesis of ethyl butyrate was verified for 10 batches, without any appreciable loss of activity, whereas in systems using mechanical agitation, the biocatalyst was completely inactivated after 5 batches. These results suggest that the combined use of ultrasound and molecular sieves greatly improve esterification reactions by stabilizing the enzyme and increasing yields. PMID:24844439

  10. Preparation, release and physicochemical characterisation of ethyl butyrate and hexanal inclusion complexes with β- and γ-cyclodextrin.

    PubMed

    Zhang, Yang; Zhou, Yibin; Cao, Shengnan; Li, Songnan; Jin, Shanshan; Zhang, Shu

    2015-01-01

    Complexes of ethyl butyrate and hexanal encapsulated by β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) were prepared by coprecipitation, and gas chromatography was used to quantity the flavour compounds in the complexes. The ethyl butyrate-γ-CD complex had the highest inclusion ratio (12.20%) followed by the ethyl butyrate-β-CD, hexanal-β-CD and hexanal-γ-CD complexes (11.29, 4.41 and 3.33%, respectively). Release experiments were performed under different relative humidities (RH 93, 75 and 52%) and temperatures (4 and 25 °C). The flavour release behaviours of the complexes were described by the Avrami equation. The rate of flavour release was enhanced with both increasing temperature and RH, although the effect of RH was stronger. Physicochemical characterisation using FT-IR, XRD, DSC and SEM analyses demonstrated that crystalline complexes were formed. Both β-CD and γ-CD were able to encapsulate ethyl butyrate and hexanal, and lower RH and temperature were more suitable for the storage of these complexes. PMID:26471403

  11. Effect of abomasal butyrate infusion on net nutrient flux across the portal-drained viscera and liver of growing lambs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of this experiment was to determine if supplying butyrate to the post-ruminal gastrointestinal tract of growing lambs alters blood flow and nutrient flux across the portal-drained viscera (PDV) and hepatic tissues. Polled Dorset wether lambs (n = 10; initial BW = 55 ± 3.3 kg) had cathet...

  12. Fabrication of Tunable Submicro- or Nano-structured Polyethylene Materials form Immiscible Blends with Cellulose Acetate Butyrate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low density polyethylene (LDPE) was prepared into micro- or submicro-spheres or nanofibers via melt blending or extrusion of cellulose acetate butyrate (CAB)/LDPE immiscible blends and subsequent removal of the CAB matrix. The sizes of the PE spheres or fibers can be successfully controlled by varyi...

  13. Pathways analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ruminant species have evolved to metabolize the short-chain volatile fatty acids (VFA), acetate, propionate, and butyrate to fulfill up to 70% of their nutrient energy requirements. The inherent VFA dependence of ruminant cells was exploited in order to add a level of increased sensitivity to the s...

  14. Lipase in biphasic alginate beads as a biocatalyst for esterification of butyric acid and butanol in aqueous media.

    PubMed

    Ng, Choong Hey; Yang, Kun-Lin

    2016-01-01

    Esterification of organic acids and alcohols in aqueous media is very inefficient due to thermodynamic constraints. However, fermentation processes used to produce organic acids and alcohols are often conducted in aqueous media. To produce esters in aqueous media, biphasic alginate beads with immobilized lipase are developed for in situ esterification of butanol and butyric acid. The biphasic beads contain a solid matrix of calcium alginate and hexadecane together with 5 mg/mL of lipase as the biocatalyst. Hexadecane in the biphasic beads serves as an organic phase to facilitate the esterification reaction. Under optimized conditions, the beads are able to catalyze the production of 0.16 mmol of butyl butyrate from 0.5 mmol of butyric acid and 1.5 mmol of butanol. In contrast, when monophasic beads (without hexadecane) are used, only trace amount of butyl butyrate is produced. One main application of biphasic beads is in simultaneous fermentation and esterification (SFE) because the organic phase inside the beads is very stable and does not leach out into the culture medium. SFE is successfully conducted with an esterification yield of 6.32% using biphasic beads containing iso-octane even though the solvent is proven toxic to the butanol-producing Clostridium spp. PMID:26672465

  15. Butyrate Induced Cell Cycle Arrest in Bovine Cells through Targeting Gene Expression relevance to DNA Replication Apparatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using both real-time RT-PCR and Western blot analysis in bovine kidney epithelial cells, we systematically investigated the gene expression relevance to DNA replication apparatus targeted by butyrate. The real-time PCR and Western blot data generally confirmed the microarray analysis. From the quan...

  16. ChIp-seq of bovine cells (MDBK) to study butyrate-induced histone modification with 10 datasets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Next-generation sequencing was combined with chromatin immunoprecipitation (ChIP) technology to analyze histone modification (acetylation) induced by butyrate and to map the epigenomic landscape of normal histone H3, H4 in rumen cells of the cow. Ten variants of histone H3 and H4 modification were m...

  17. Effects of dietary humic and butyric acid on growth performance and response to lipopolysaccharide in young pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Humic acid (MFG) and fat protected butyric acid (BA) has been shown to modulate energy metabolism and inflammation. Therefore, the objectives of this study were to determine the effects of MFG and BA, alone and in combination, on growth performance and response to lipopolysaccharide (LPS) induced in...

  18. [Susceptibility of spore-forming butyric acid bacteria to antimicrobial agents].

    PubMed

    Kaneko, Naofumi; Nakayama, Tomohiro; Ichikawa, Nobuhiro

    2012-01-01

    Antimicrobial agents occasionally cause certain adverse effects, such as diarrhea and loose stool, by altering the composition of the intestinal flora. Antibiotic-resistant lactic acid bacteria are used to prevent these adverse effects. Although these bacteria are not resistant to several recently introduced antimicrobial agents, bacterial preparations are still sometimes prescribed concomitantly with these antimicrobial agents. In this study, we investigated whether the administration of the spore-forming butyric acid bacteria Clostridium butyricum improves the adverse clinical effects by preventing diarrhea. Inhibition of C. butyricum growth was observed with 17 of the 20 antimicrobial agents used. However, dilution of 11 of these 17 agents resulted in the regrowth of C. butyricum. These results suggest that C. butyricum may survive exposure to several antibiotic agents by forming spores. Further, a decrease in the antimicrobial agent concentration in the gastrointestinal tract permits the vegetative growth of C. butyricum, which functions as a probiotic. PMID:22790032

  19. Production of γ-Amino Butyric Acid in Tea Leaves wit Treatment of Lactic Acid Bacteria

    NASA Astrophysics Data System (ADS)

    Watanabe, Yuko; Hayakawa, Kiyoshi; Ueno, Hiroshi

    Lactic acid bacteria was searched for producing termented tea that contained a lot of γ-amino butyric acid(GABA). Also examined were the growth condition, GABA production and changes in catechin contents in the tea leaves. Lactobacillus brevis L12 was found to be suitable for the production of fermented tea since it gave as much GABA as gabaron tea when tea leaves being suspended with water at 10% and incubated for 4 days at 25°C. The amount of GABA produced was more than calculated based upon the content of glutamic acid in tea leaves. It is probable to assume that glutamate derived from glutamine and theanine is converted into GABA.

  20. Polyethylene-supported polyvinylidene fluoride-cellulose acetate butyrate blended polymer electrolyte for lithium ion battery

    NASA Astrophysics Data System (ADS)

    Liu, Jiansheng; Li, Weishan; Zuo, Xiaoxi; Liu, Shengqi; Li, Zhao

    2013-03-01

    The polyethylene (PE)-supported polymer membranes based on the blended polyvinylidene fluoride (PVDF) and cellulose acetate butyrate (CAB) are prepared for gel polymer electrolyte (GPE) of lithium ion battery. The performances of the prepared membranes and the resulting GPEs are investigated by scanning electron microscopy, electrochemical impedance spectroscopy, linear potential sweep, and charge-discharge test. The effect of the ratio of PVDF to CAB on the performance of the prepared membranes is considered. It is found that the GPE based on the blended polymer with PVDF:CAB = 2:1 (in weight) has the largest ionic conductivity (2.48 × 10-3 S cm-1) and shows good compatibility with anode and cathode of lithium ion battery. The LiCoO2/graphite battery using this GPE exhibits superior cyclic stability at room temperature, storage performance at elevated temperature, and rate performance.

  1. Sodium hypochlorite poisoning

    MedlinePlus

    ... poisoning, especially if the product is mixed with ammonia. This article is for information only. Do NOT ... hypochlorite, which may cause severe injury. NEVER mix ammonia with sodium hypochlorite (bleach or bleach-containing products). ...

  2. Sodium bisulfate poisoning

    MedlinePlus

    ... in large amounts. This article discusses poisoning from swallowing sodium bisulfate. This article is for information only. ... Symptoms from swallowing more than a tablespoon of this acid may include: Burning pain in the mouth Chest pain from burns ...

  3. Sodium hydroxide poisoning

    MedlinePlus

    Agency for Toxic Substances and Disease Registry (ATSDR). Medical Management Guidelines for Sodium Hydroxide (NaOH) . Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. Available at: www.atsdr.cdc. ...

  4. Sodium Polystyrene Sulfonate

    MedlinePlus

    ... comes as a suspension and as an oral powder for suspension to take by mouth. The suspension ... evenly.If you are taking sodium polystyrene sulfonate powder by mouth, mix the powder with 20 to ...

  5. Effect of abomasal butyrate infusion on net nutrient flux across the portal-drained viscera and liver of growing lambs.

    PubMed

    Foote, A P; Freetly, H C

    2016-07-01

    The purpose of this experiment was to determine if supplying butyrate to the postruminal gastrointestinal tract of growing lambs alters blood flow and nutrient flux across the portal-drained viscera (PDV) and hepatic tissues. Polled Dorset wether lambs ( = 10; initial BW = 55 ± 3.3 kg) had catheters surgically implanted into the portal vein, a branch of the hepatic vein, a mesenteric vein, and the abdominal aorta. A cannula was placed in the abomasum to deliver the treatment. Lambs were fed a pelleted ration once daily consisting of 69.7% dehydrated alfalfa, 30.0% ground corn, and 0.3% salt at 1.3 × NE requirement. The experimental design was a crossover balanced in time, so that each lamb received both treatments. Treatments consisted of either a pulse dose infusion of butyrate (buffered solution) to supply butyrate (10 mg/kg BW) or a buffered saline solution (1 mL/kg BW) once daily at the time of feeding. On d 14 of the treatment period, nutrient fluxes were measured using para-aminohippuric acid as a blood flow marker. Blood samples were collected from the aorta, portal vein, and hepatic vein every hour for 9 h beginning at 30 min prior to treatment/feeding. There was a tendency for a treatment × time interaction ( = 0.05) for portal vein blood flow, indicating that blood flow began to decrease earlier postprandial in lambs receiving butyrate. The butyrate treatment tended to increase the uptake of O ( = 0.07) and increased the uptake of glucose ( = 0.002), glutamate ( = 0.04), and glutamine ( = 0.02) by the PDV. There was a treatment × time interaction ( < 0.01) for flux of acetate, propionate, butyrate, isobutyrate, and valerate across the PDV. The interaction was mainly due to an earlier postprandial peak and associated decrease in the flux rate of the VFA. The alteration in timing of the postprandial peak of VFA flux was also observed in hepatic fluxes of VFA. It appears that supplying butyrate to the postruminal tissues through an abomasal cannula

  6. Sodium hypochlorite dental accidents.

    PubMed

    Goswami, Mridula; Chhabra, Nidhi; Kumar, Gyanendra; Verma, Mahesh; Chhabra, Anuj

    2014-02-01

    Sodium hypochlorite is widely used in dentistry as an intra-canal irrigant, for debridement and to disinfect root canals. Although it is considered to be safe, serious mishap can result from its inappropriate use, and this has been reported infrequently in the literature. Two unusual cases of sodium hypochlorite toxicity and their successful non-surgical management are described in a 14-year-old girl and a 13-year-old boy. PMID:24090808

  7. Autophagy inhibitors.

    PubMed

    Pasquier, Benoit

    2016-03-01

    Autophagy is a lysosome-dependent mechanism of intracellular degradation. The cellular and molecular mechanisms underlying this process are highly complex and involve multiple proteins, including the kinases ULK1 and Vps34. The main function of autophagy is the maintenance of cell survival when modifications occur in the cellular environment. During the past decade, extensive studies have greatly improved our knowledge and autophagy has exploded as a research field. This process is now widely implicated in pathophysiological processes such as cancer, metabolic, and neurodegenerative disorders, making it an attractive target for drug discovery. In this review, we will summarize the different types of inhibitors that affect the autophagy machinery and provide some potential therapeutic perspectives. PMID:26658914

  8. Voltage gated sodium channels as drug discovery targets

    PubMed Central

    Bagal, Sharan K; Marron, Brian E; Owen, Robert M; Storer, R Ian; Swain, Nigel A

    2015-01-01

    Voltage-gated sodium (NaV) channels are a family of transmembrane ion channel proteins. They function by forming a gated, water-filled pore to help establish and control cell membrane potential via control of the flow of ions between the intracellular and the extracellular environments. Blockade of NaVs has been successfully accomplished in the clinic to enable control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias. First generation sodium channel modulator drugs, despite low inherent subtype selectivity, preferentially act on over-excited cells which reduces undesirable side effects in the clinic. However, the limited therapeutic indices observed with the first generation demanded a new generation of sodium channel inhibitors. The structure, function and the state of the art in sodium channel modulator drug discovery are discussed in this chapter. PMID:26646477

  9. Corrosion inhibition by inorganic cationic inhibitors on the high strength alumunium alloy, 2024-T3

    NASA Astrophysics Data System (ADS)

    Chilukuri, Anusha

    alkaline is retarded in the absence of oxygen. As a result precipitation of Zn oxides and hydroxides was suppressed. Impedance in decarbonated chloride solutions showed that the absence of CO 2 reduces inhibition by Zn2+ at pH 4. The carbonate protective layer formed in aerated solutions is essential for providing better protection of the substrate at pH 4. Inhibitor cations were exchanged into insoluble ion-exchanging sodium bentonites and incorporated as pigments in organic coatings applied to AA 2024-T3 substrates. XRD of the pigments ensured ion exchange and UV-visible spectroscopy was used to characterize inhibitor ion release from the bentonites. Salt spray exposure tests on scribed panels were preformed and results were compared to those from SrCrO4 pigmented coatings. Zn-exchanged bentonite pigmented coatings showed better performance compared to the other exchanged bentonites when incorporated into epoxy coatings with total impedance magnitude in the same order as SrCrO4. PVB (Polyvinyl Butyral) coatings containing Zn bentonite, however, did not show superior behaviour in the impedance response due to less or no water uptake. Salt spray exposures for a period of 336 h, showed that Zn bentonite incorporated into PVB suppressed blistering compared to the neat PVB and other pigmented bentonites.

  10. Dose-dependent stimulatory and inhibitory effects of luminal and serosal n-butyric acid on epithelial cell proliferation of pig distal colonic mucosa.

    PubMed

    Inagaki, Akiko; Sakata, Takashi

    2005-06-01

    Large bowel bacteria convert various carbohydrates into short-chain fatty acids (SCFA). SCFA stimulate epithelial cell proliferation of the large intestine in vivo and inhibit that of various cells in vitro. Supposing that too high concentration of SCFA on the serosal side is responsible for their inhibitory effect in vitro, we studied effects of luminal and serosal n-butyric acid (0, 0.1, 1, or 10 mmol/L, adjusted to neutral pH) on the epithelial cell proliferation rate of pig colonic mucosa in organ culture taking crypt cell production rate (CCPR) as the measure of proliferative activity. With 0 or 0.1 mmol/L n-butyric acid on the serosal side, luminal n-butyric acid increased CCPR at 1.0 mmol/L, and decreased CCPR at 10 mmol/L when compared to the luminal 0 mmol/L control. With 1.0 or 10 mmol/L serosal n-butyric acid, luminal n-butyric acid depressed CCPR dose-dependently. The above results indicated that n-butyric acid stimulated colonic epithelial cell proliferation at low concentration and inhibit it at high concentration with interaction effect to enhance the inhibitory action. The stimulatory effect of a low dose of serosal n-butyric acid may be responsible for the distant trophic effect of SCFA. PMID:16161765

  11. Comparative Analysis of Dibutyric cAMP and Butyric Acid on the Differentiation of Human Eosinophilic Leukemia EoL-1 Cells

    PubMed Central

    2015-01-01

    Purification of enough numbers of circulating eosinophils is difficult because eosinophils account for less than 5% peripheral blood leukocytes. Human eosinophilic leukemia EoL-1 cells have been considered an in vitro source of eosinophils as they can differentiate into mature eosinophil-like cells when incubated with dibutyryl cAMP (dbcAMP) or butyric acid. In this study, the viability and phenotypic maturation of EoL-1 cells stimulated by either dbcAMP or butyric acid were comparatively analyzed. After treatment with 100 µM dbcAMP or 0.5 µM butyric acid, EoL-1 cells showed morphological signs of differentiation, although the number of nonviable EoL-1 cells was significantly increased following butyric acid treatment. Stimulation of EoL-1 cells with 0.5 µM butyric acid more effectively induced the expression of mature eosinophil markers than stimulation with dbcAMP. These results suggest that treatment of EoL-1 cells with 0.5 µM butyric acid for limited duration could be an effective strategy for inducing their differentiation. Considering that expression of CCR3 was not sufficient in EoL-1 cells stimulated with 0.5 µM butyric acid, treatment of the chemically stimulated EoL-1 cells with cytokines, which primarily support eosinophil maturation, would help to obtain differentiated EoL-1 cells with greater functional maturity. PMID:26770185

  12. Sodium intake, RAAS-blockade and progressive renal disease.

    PubMed

    de Borst, Martin H; Navis, Gerjan

    2016-05-01

    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the renal protective effect of RAAS-blockade is incomplete. Short-term clinical studies have demonstrated that dietary sodium restriction potentiates the antiproteinuric effect of RAAS-blockade. More recently, it was shown that this effect is accompanied by a lower risk of end-stage renal disease and adverse cardiovascular outcomes. The modulation of RAAS-blockade efficacy by sodium intake is likely multifactorial, and is mediated by effects of sodium on local tissue RAAS in kidney, vasculature and brain, and by effects on the immune system. Despite the evidence showing the beneficial effects of even a moderate sodium restriction (∼2.5g/d), it remains difficult to realize in clinical practice. In an analysis based on 24-h urinary sodium excretion data from more than 10,000 CKD patients and renal transplant recipients, we found that sodium intake in these patients is on average 3.8g/d, closely resembling the global general population (3.95g/d). Behavioral approaches including the use of online dietary coaching (ehealth) and feedback using data from 24-h urine collections may be useful to successfully lower dietary sodium intake, aiming to improve cardio-renal outcomes in patients with CKD. PMID:27041482

  13. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes.

    PubMed

    Mali, Prashant; Chou, Bin-Kuan; Yen, Jonathan; Ye, Zhaohui; Zou, Jizhong; Dowey, Sarah; Brodsky, Robert A; Ohm, Joyce E; Yu, Wayne; Baylin, Stephen B; Yusa, Kosuke; Bradley, Allan; Meyers, David J; Mukherjee, Chandrani; Cole, Philip A; Cheng, Linzhao

    2010-04-01

    We report here that butyrate, a naturally occurring fatty acid commonly used as a nutritional supplement and differentiation agent, greatly enhances the efficiency of induced pluripotent stem (iPS) cell derivation from human adult or fetal fibroblasts. After transient butyrate treatment, the iPS cell derivation efficiency is enhanced by 15- to 51-fold using either retroviral or piggyBac transposon vectors expressing 4 to 5 reprogramming genes. Butyrate stimulation is more remarkable (>100- to 200-fold) on reprogramming in the absence of either KLF4 or MYC transgene. Butyrate treatment did not negatively affect properties of iPS cell lines established by either 3 or 4 retroviral vectors or a single piggyBac DNA transposon vector. These characterized iPS cell lines, including those derived from an adult patient with sickle cell disease by either the piggyBac or retroviral vectors, show normal karyotypes and pluripotency. To gain insights into the underlying mechanisms of butyrate stimulation, we conducted genome-wide gene expression and promoter DNA methylation microarrays and other epigenetic analyses on established iPS cells and cells from intermediate stages of the reprogramming process. By days 6 to 12 during reprogramming, butyrate treatment enhanced histone H3 acetylation, promoter DNA demethylation, and the expression of endogenous pluripotency-associated genes, including DPPA2, whose overexpression partially substitutes for butyrate stimulation. Thus, butyrate as a cell permeable small molecule provides a simple tool to further investigate molecular mechanisms of cellular reprogramming. Moreover, butyrate stimulation provides an efficient method for reprogramming various human adult somatic cells, including cells from patients that are more refractory to reprogramming. PMID:20201064

  14. SGLT2 Inhibitors and the Diabetic Kidney.

    PubMed

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experime