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Sample records for acid significantly suppressed

  1. Suppression of sourness: a comparative study involving mixtures of organic acids and sugars.

    PubMed

    Savant, Lotika; McDaniel, Mina R

    2004-05-01

    The degree of sourness suppression of perceptually equisour levels of citric, lactic, and malic acids by equal molar and weight amounts of sucrose, fructose, and glucose was determined in binary mixtures. Equisour acid levels were obtained by magnitude estimation. Mixture intensity ratings were collected on a categorical scale, using trained panelists. In general, equal sugar molarities and weights did not effect equivalent suppression. Instead, the perceived intensity of the sugars appeared to suppress sourness more systematically, implying that dominantly central neural mechanisms underlie suppression. This was confirmed when no significant differences were found between the suppressive abilities of sweetness-matched levels of sucrose, fructose, and an equiratio mixture of the two on citric acid sourness. The possibility of a separate receptor site/mechanism for glucose and a small peripheral component to suppression is also suggested.

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

    PubMed

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

    2015-02-01

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

  3. 5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets.

    PubMed

    Park, Jae B

    2009-10-01

    Caffeic acid and 5-caffeoylquinic acid are naturally occurring phenolic acid and its quinic acid ester found in plants. In this article, potential effects of 5-caffeoylquinic acid and caffeic acid on P-selectin expression were investigated due to its significant involvement in platelet activation. First, the effects of 5-caffeoylquinic acid and caffeic acid on cyclooxygenase (COX) enzymes were determined due to their profound involvement in regulating P-selectin expression on platelets. At the concentration of 0.05 microM, 5-caffeoylquinic acid and caffeic acid were both able to inhibit COX-I enzyme activity by 60% (P<.013) and 57% (P<.017), respectively. At the same concentration, 5-caffeoylquinic acid and caffeic acid were also able to inhibit COX-II enzyme activity by 59% (P<.012) and 56% (P<.015), respectively. As expected, 5-caffeoylquinic acid and caffeic acid were correspondingly able to inhibit P-selectin expression on the platelets by 33% (P<.011) and 35% (P<.018), at the concentration of 0.05 microM. In animal studies, 5-caffeoylquinic acid and caffeic acid orally administered to mice were detected as intact forms in the plasma. Also, P-selectin expression was respectively reduced by 21% (P<.016) and 44% (P<.019) in the plasma samples from mice orally administered 5-caffeoylquinic acid (400 microg per 30 g body weight) and caffeic acid (50 microg per 30 g body weight). These data suggest that both 5-caffeoylquinic acid and caffeic acid orally administered can be absorbed and suppress P-selectin expression on mouse platelets.

  4. Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

    PubMed

    Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

    2013-05-01

    Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

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

    PubMed Central

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

    2014-01-01

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

  6. The effectiveness of different sweeteners in suppressing citric acid sourness.

    PubMed

    Schifferstein, H N; Frijters, J E

    1991-01-01

    The exact mechanism that causes taste suppression in a perceptually heterogeneous mixture, and the locus of that mechanism, are as yet unknown. The present study was designed to explore the idea that mixture suppression is a perceptual phenomenon and not the result of physical, chemical, or receptor-substance interactions. An investigation was carried out as to whether perceptually similar taste stimuli give rise to the same sensory interactions when mixed with a substance of a different taste quality. In the first study, five different sweeteners (sucrose, fructose, aspartame, saccharin, and sorbitol) were matched in perceived sweetness intensity, in order to obtain five perceptually similar stimuli. Every equisweet sweetener concentration was mixed with each of four citric acid concentrations. In a second study, the sourness-suppressing effects of two sweeteners, sucrose and aspartame, were compared at four different concentration levels. Sourness scale values of unmixed citric acid, the unmixed sweeteners, and the citric acid/sweetener mixtures were assessed with a functional measurement approach in combination with a two-stimulus procedure. The equisweet sweeteners were equally effective in suppressing the perceived sourness intensity of citric acid over the concentration range used. The side tastes of the sweeteners, if present, did not have a substantial effect on the degree of sourness suppression.

  7. Perfluorooctanoic Acid Exposure Suppresses T-independent Antibody Responses

    EPA Science Inventory

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

  8. [Significance of hydrocyanic acid formation during fires].

    PubMed

    von Meyer, L; Drasch, G; Kauert, G

    1979-01-01

    Cyanide concentrations of blood samples from fire victims autopsied in the Institute of Legal Medicine, Munich, have been determined. In 25% of 48 analyzed cases cyanide concentrations from 0.52 microgram to 6.24 microgram Cyanide/ml blood have been detected. These results are compared to former studies and the higher mean level in our collective is emphasized. The importance of hydrocyanid acid in the toxicity of fire gases is evidently greater, than assumed. Hydrocyanic acid may be produced from nitrogen continaing polymers during combustion. The quote of these polymers in clothing, furniture, and also in equipment of cars is increasing. Therefore, it is necessary to take more notice of the formation of hydrocyanic acid during combustion, even though carbon monoxide is in general the main toxic agent in fire gases.

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

    PubMed Central

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

    2016-01-01

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

  10. Lipoic acid nanoparticles: effect of polymeric stabilizer on appetite suppression.

    PubMed

    Park, Chul Ho; Lee, Ki-Up; Park, Joong-Yeol; Koh, Eun-Hee; Kim, Hyoun-Sik; Lee, Jonghwi

    2010-08-01

    Alpha-lipoic acid (ALA), which is common in the human body, is efficacious in appetite suppression. However, its typical formulations of salt or micronized crystals cannot satisfy the desired bioavailability requirements for appetite suppression due to low absorption and a short plasma half-life. Herein, we describe a new ALA nanoparticulate formulation produced by nano-comminution using polymeric stabilizers, such as hydroxypropyl cellulose, Pluronic F127, and polyvinylpyrrolidone. Nanoparticles of similar sizes did not show any remarkable differences in the in vitro release profiles. However, the in vivo results from food intake studies in mice demonstrated that the hydroxypropyl cellulose case had the largest improved efficacy among the three polymeric stabilizer cases. Compared to the nanosuspension formulations, the powder formulations of nanoparticles had improved efficacy in reducing food intake for six hours, possibly because of the delayed release kinetics. Therefore, the ALA powder formulation of nanoparticles is a candidate to replace the current formulations to achieve proper appetite suppression.

  11. Risk of Spontaneous Bacterial Peritonitis Associated With Gastric Acid Suppression

    PubMed Central

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

    2015-01-01

    Abstract The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case–control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30–90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95%CI: 1.90–4.04) and H2RAs was 2.62 (95%CI: 2.00–3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60–3.02) or H2RAs (aRR: 1.72, 95%CI: 1.25–2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95%CI: 2.08–5.05) and H2RAs (aRR 2.43; 95%CI 1.71–3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers. PMID:26039135

  12. Amino acid suppression of taurine-sensitive chemosensory neurons.

    PubMed

    Gleeson, R A; Ache, B W

    1985-05-27

    Single unit recordings from chemoreceptors on the antennule of the spiny lobster revealed a population of taurine-sensitive cells whose response is suppressed when taurine is presented in mixture with certain amino acids. A synthetic mixture of 21 amino acids plus betaine, which mimics the composition of a natural food stimulus (crab muscle tissue) and itself contains taurine, totally and reversibly blocked the taurine response of this group of receptor cells. An analysis of the contribution to this suppression by the six major components (based on concentration) in the mixture revealed partial or complete inhibitory activity by five of the compounds. In a sample group of the inhibited cells, mean percent suppression of the taurine response was 99% for glycine and L-arginine, 98% for L-glutamine, 60% for L-alanine and 43% for L-proline. Both glycine and alanine in binary mixture with taurine caused a right-shift in the concentration-response function for taurine, suggesting a competitive mechanism of suppression. pA2 values determined from these data yielded 4.17 for glycine and 3.55 for alanine. These results suggest that the processing of chemical information in quality and/or intensity coding of natural stimulus mixtures can be tempered by interactions of the components at the receptor-cell level, and possibly at the receptor-sites themselves.

  13. The use of long-term acid-suppression therapy.

    PubMed

    Rubin, G P; Contractor, B; Bramble, M G

    1995-01-01

    Drug therapy to suppress gastric acid secretion is commonly used in the management of dyspepsia, many patients taking such therapy over long periods of time. An audit of patients on long-term (> 12 months) acid-suppression therapy was carried out in the two practices providing primary healthcare to a town in Northeast England. Patients on continuous therapy (> 10 months' supply in the previous year) and intermittent therapy (6-10 months' supply in the previous year) were identified through computerised prescribing records. Their written and computer records were scrutinised to determine diagnosis, duration of therapy, use of NSAIDs and other features. A total of 365 patients were identified (208 men, 157 women): 132 were on intermittent and 233 on continuous therapy. Of the total, 83% were over 45 years and one-fifth were taking NSAIDs. Of the 310 patients investigated for their dyspepsia, only 250 had a positive diagnosis, of which duodenal ulcer (154) was the most common. PMID:7779658

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

    PubMed

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

    2015-01-01

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

  15. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells

    PubMed Central

    Lu, Yong; Jiang, Feng; Jiang, Hao; Wu, Kalina; Zheng, Xuguang; Cai, Yizhong; Katakowski, Mark; Chopp, Michael; To, Shing-Shun Tony

    2010-01-01

    Gallic acid, an organic acid, also known as 3,4,5-trihydroxybenzoic acid, is cytotoxic against certain cancer cells, without harming normal cells. The objective of this study is to evaluate whether gallic acid can inhibit glioma cell viability, proliferation, invasion and reduce glioma cell mediated angiogenesis. Treatment of U87 and U251n glioma cells with gallic acid inhibited cell viability in a dose- and time-dependent manner. BrdU and tube formation assays indicated that gallic acid significantly decreased glioma cell proliferation and tube formation in mouse brain endothelial cells, respectively. In addition, gallic acid decreased U87 cell invasion in vitro. Western blot analysis showed that expression of ADAM17, p-Akt and p-Erk was suppressed by gallic acid in both U87 and U251n cell lines. These data suggest that suppression of ADAM17 and downregulation of PI3K/Akt and Ras/MAPK signaling pathways may contribute to gallic acid-induced decrease of invasiveness. Gallic acid may be a valuable candidate for treatment of brain tumor. PMID:20553913

  16. Significant intensity noise suppression of single-frequency fiber laser via cascading semiconductor optical amplifier

    NASA Astrophysics Data System (ADS)

    Feng, Zhouming; Li, Can; Xu, Shanhui; Huang, Xiang; Yang, Changsheng; Zhou, Kaijun; Gan, Jiulin; Deng, Huaqiu; Yang, Zhongmin

    2015-09-01

    Significant suppression of the intensity noise of single-frequency fiber laser is demonstrated with a cascading semiconductor optical amplifier (SOA). Based on the nonlinear amplification dynamics of the SOA, intensity noise reduction would take place in every transmission of the laser signal. By cascading two SOAs, a maximum noise suppression of 30 dB at around the resonant relaxation oscillation (RRO) frequency as well as a suppression bandwidth of up to 50 MHz is realized. Moreover, the RRO peak is restricted to a significant narrow frequency band, outside of which the laser noise approaches the noise floor of the measurement. The remarkable amplified spontaneous emission (ASE) introduced by the SOA is entirely filtered out with a fiber Bragg grating (FBG). Furthermore, no noticeable degradation of laser frequency noise has been observed.

  17. Effect of gastric acid suppressants on human gastric motility

    PubMed Central

    Parkman, H; Urbain, J; Knight, L; Brown, K; Trate, D; Miller, M; Maurer, A; Fisher, R

    1998-01-01

    Background—The effect of histamine H2 receptor antagonists on gastric emptying is controversial. 
Aims—To determine the effects of ranitidine, famotidine, and omeprazole on gastric motility and emptying. 
Patients and methods—Fifteen normal subjects underwent simultaneous antroduodenal manometry, electrogastrography (EGG), and gastric emptying with dynamic antral scintigraphy (DAS). After 30 minutes of fasting manometry and EGG recording, subjects received either intravenous saline, ranitidine, or famotidine, followed by another 30 minutes recording and then three hours of postprandial recording after ingestion of a radiolabelled meal. Images were obtained every 10-15 minutes for three hours to measure gastric emptying and assess antral contractility. Similar testing was performed after omeprazole 20 mg daily for one week. 
Results—Fasting antral phase III migrating motor complexes (MMCs) were more common after ranitidine (9/15 subjects, 60%), famotidine (12/15, 80%), and omeprazole (8/12, 67%) compared with placebo (4/14, 29%; p<0.05). Postprandially, ranitidine, famotidine, and omeprazole slowed gastric emptying, increased the amplitude of DAS contractions, increased the EGG power, and increased the antral manometric motility index. 
Conclusions—Suppression of gastric acid secretion with therapeutic doses of gastric acid suppressants is associated with delayed gastric emptying but increased antral motility. 

 Keywords: gastric motility; gastric emptying; histamine H2 receptor antagonists; proton pump inhibitors; gastric acid secretion; scintigraphy PMID:9536950

  18. Epidermal urocanic acid and suppression of contact hypersensitivity by ultraviolet radiation in Monodelphis domestica.

    PubMed

    Reeve, V E; Ley, R D; Reilly, W G; Bosnic, M

    1996-03-01

    A single specific epidermal photoreceptor for the immunosuppressive action of UV radiation has not been defined, although separate evidence is accruing in favour of each of two candidates, trans-urocanic acid and DNA. In Monodelphis domestica, specific photoreactivation repair of UV radiation-induced pyrimidine dimers has been shown to abrogate the suppression of contact hypersensitivity (CHS), thus suggesting that DNA is the target for this impairment. However, the both haired and hairless mice, immunosuppressive effects of UV radiation have been reproduced by the exogenous administration of the UV photoproduct of urocanic acid, cis-urocanic acid. We show here that the epidermis of M. domestica contains urocanic acid, that UV irradiation of the shaved dorsal skin has resulted in an increase in epidermal cis-urocanic acid and that the topical application of a cis-urocanic acid-containing lotion significantly depressed the capacity of Monodelphis to respond to contact sensitisers, in a manner analogous to these responses in the hairless mouse. Therefore in Monodelphis, suppression of CHS by UV irradiation appears to involve both urocanic acid photo-isomerisation and epidermal DNA damage.

  19. Characterization of bacteria that suppress rhizoctonia damping-off in bark compost media by analysis of Fatty Acid biomarkers.

    PubMed

    Tunlid, A; Hoitink, H A; Low, C; White, D C

    1989-06-01

    Examination of cucumber roots (Cucumis sativus L.) grown in bark compost media and of the surrounding edaphic substrate showed profiles of polar lipid fatty acids commonly found in bacteria. The composition of fatty acids in these profiles differed significantly between roots grown in a medium naturally suppressive to Rhizoctonia damping-off and roots from a conducive medium. Cucumber roots from the suppressive medium had higher proportions of cis-vaccenic acid (18:1 omega 7c) and the iso-branched monoenoic fatty acid i17:1 omega 8 but lower proportions of several iso- and anteiso-branched fatty acids compared with roots from the conducive medium. The concentrations of the bacterial fatty acids were significantly lower in the surrounding media. However, the suppressive and conducive growth substrates had differences in the composition of the bacterial fatty acids similar to those found between the cucumber roots proper. These results suggest major differences in bacterial community composition between suppressive and conducive systems. Fatty acid analyses were also utilized to examine the effects on bacterial community composition of root colonization by Flavobacterium balustinum 299, a biocontrol agent. The concentration of the most prominent fatty acid in this bacterium, i17:1 omega 8, was increased on roots produced from inoculated seeds in a medium rendered suppressive by the treatment. This change was concomitant with a significant increase in the concentration of 18:1 omega 7c, not present in the lipids of the antagonist, indicating a shift in the microflora from a conducive to a suppressive bacterial community.

  20. Dietary histidine increases mouse skin urocanic acid levels and enhances UVB-induced immune suppression of contact hypersensitivity.

    PubMed

    Reilly, S K; De Fabo, E C

    1991-04-01

    Urocanic Acid (UCA) exists in mammalian skin primarily as the trans isomer and is photoisomerized to cis UCA upon UVB absorption. Our previous studies indicated that the photoisomerization of UCA is the initiating event in UBV-induced suppression of cell-mediated immunity (tUCA----cUCA----immune suppression). The purpose of this study was to verify the role of UCA in UV-induced immune suppression of contact hypersensitivity (CHS) in BALB/c mice. Since UCA is a metabolite of the amino acid L-histidine, we reasoned that increased dietary levels of histidine should raise skin tUCA levels. If skin tUCA is the UVB photoreceptor for immune suppression, this increase should enhance UV-induced suppression of CHS. HPLC analysis of skin from BALB/c mice given a histidine-rich diet (10%) showed that the total amount of UCA is significantly higher in these animals than in mice fed a normal diet. Further, levels of suppression of CHS of 3% and 49% in control fed mice, induced by 4.8 and 7.2 kJ/m2 UVB were significantly increased to 21% and 71% respectively in histidine-fed animals at these same UVB doses. These findings provide additional support for the UCA model for immune suppression, and provide the first evidence that UV-induced immune suppression can be enhanced by a dietary component, L-histidine. PMID:1857737

  1. The physiological significance of phenylacetic Acid in abscising cotton cotyledons.

    PubMed

    Suttle, J C; Mansager, E R

    1986-06-01

    The physiological role of phenylacetic acid (PAA) as an endogenous regulator of cotyledon abscission was examined using cotton (Gossypium hirsutum L. cv LG 102) seedlings. Application of 100 micromolar or more PAA to leafless cotyledon abscission-zone explants resulted in the retardation of petiole abscission and a decrease in the rise of ethylene evolution that normally accompanies aging of these explants in vitro. The partial inhibition of ethylene evolution in these explants by PAA was indirect since application of this compound stimulated short-term (<24 hours) ethylene production. PAA treatment partially suppressed the stimulation of petiole abscission elicited by either ethylene or abscisic acid. Both free and an acid-labile, bound form of PAA were identified in extracts prepared from cotyledons. No discernible pattern of changes in free or bound PAA was found during the course of ethylene-induced cotyledon abscission. Unlike indole-3-acetic acid, transport of PAA in isolated petiole segments was limited and exhibited little polarity. On the whole, these results are not consistent with the direct participation of PAA in the endogenous regulation of cotyledon abscission.

  2. Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver.

    PubMed

    Kurtz, C Lisa; Fannin, Emily E; Toth, Cynthia L; Pearson, Daniel S; Vickers, Kasey C; Sethupathy, Praveen

    2015-01-01

    MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia. PMID:26246194

  3. Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver

    PubMed Central

    Kurtz, C. Lisa; Fannin, Emily E.; Toth, Cynthia L.; Pearson, Daniel S.; Vickers, Kasey C.; Sethupathy, Praveen

    2015-01-01

    MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia. PMID:26246194

  4. Acid-suppressive medications and risk of fracture: an updated meta-analysis

    PubMed Central

    Cai, Dawei; Feng, Wan; Jiang, Qing

    2015-01-01

    Background: Acid-suppressive medications are widely used for the management of acid-related disorders. It has been reported that acid-suppressive medication users were at increased risk of fracture, but such an association was inconsistent among observational studies. The purpose of our analysis was to assess the relationship between use of antacid drugs and fracture risk. Methods: We systematically searched electronic database and manually examined the reference lists of previous reviews for potentially eligible studies. Given the heterogeneity across studies, random effects models were used to calculate summary estimates. Subgroup analysis and sensitivity analysis were conducted to explore the potential heterogeneity. Results: 18 studies met our inclusion criteria. PPI and H2RA were associated with increased risk of hip fracture, with substantial heterogeneity (PPI: 1.216, 1.134-1.304, I2=71.3%; H2RA: 1.128, 1.022-1.245, I2=72.1%). High risk of spine fracture was observed in PPI users (1.216, 95% CI: 1.134-1.304) but not H2RA users. When considering 5 studies conducted among postmenopausal women, the RR was 1.376, (95% CI: 1.043-1.816) with modest heterogeneity (I2=57.7%). Subgroup analysis and sensitivity analysis found consistent association between hip fracture risk and PPI use but not H2RA use. Positive association for H2RA use lost its significance when considering case-control studies and European studies. Conclusion: Results of this updated meta-analysis provided evidence to support that acid-suppressive medications were associated with increased risk of fracture, especially hip fracture. PMID:26309543

  5. Immune suppressive virus-like particles in a Drosophila parasitoid: significance of their intraspecific morphological variations.

    PubMed

    Dupas, S; Brehelin, M; Frey, F; Carton, Y

    1996-09-01

    The Eucoilid parasitoid Leptopilina boulardi is able to suppress its host Drosophila melanogaster immune reaction. Some strains, however, are non-immune suppressive to that host. Virus-like particles (VLPs) responsible for the immune suppressive ability were investigated in different strains of L. boulardi with histochemical and ultrastructural techniques. Membrane-bound particles containing vesicles were observed in the reservoir of the long gland and also in the egg canal of the ovipositor. These particles are homologous with the immune suppressive VLPs already described in the reservoir of L. heterotoma. Similarities were also observed with the L2 particles described previously around the chorion of the parasitoid egg after infestation. A weak positive DNA specific histochemical reaction was observed inside the reservoir and at the ultrastructural level. Feulgen-derived techniques demonstrated that the reaction was localized inside the particles. The morphology of the particles as well as the immune suppressive ability varied between strains. Two morphotypes of VLPs are described; the 'Is' morphotype (always observed in immune suppressive or Is strains) and the 'NIs' morphotype (observed in the non-immune suppressive or NIs strain). The hybrids between Is and NIs strains produce a third type of particle, the 'HIs' morphotype with half-immune suppressive ability and intermediate morphology. The origin of the particles' immune suppressive activity against D. melanogaster is discussed within the scope of host specificity. PMID:8811846

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

    PubMed

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

    2015-12-01

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

  7. Suppression of Spermatogenesis by Bisdichloroacetyldiamines Is Mediated by Inhibition of Testicular Retinoic Acid Biosynthesis

    PubMed Central

    Amory, John K.; Muller, Charles H.; Shimshoni, Jakob A.; Isoherranen, Nina; Paik, Jisun; Moreb, Jan S.; Amory, David W.; Evanoff, Ryan; Goldstein, Alex S.; Griswold, Michael D.

    2012-01-01

    The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC50 of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive. PMID:20705791

  8. Degrees of acid suppression and ulcer healing: dosage considerations.

    PubMed

    Pounder, R E

    1991-01-01

    The human stomach has a normal circadian rhythm of intragastric acidity characterized by increasing acidity during the day and peaks in the early hours of the morning. Eating causes a transient decrease of intragastric acidity. Acid appears to be the permissive factor in peptic ulcer disease and to be responsible for symptoms; the patient with duodenal ulcer may secrete too much acid. Pharmacological control of gastric acid secretion will speed ulcer healing. Modern regimens, which typically use a bedtime dose of an H2-receptor antagonist, produce a pulse of decreased acidity. Intragastric acidity is decreased during the night and early morning, leaving a normal profile of acidity during the day and early evening. Higher or more frequent doses of an antisecretory agent can produce a more profound decrease of 24-h intragastric acidity. Theoretical problems associated with a sustained or profound decrease of 24-h intragastric acidity include the threat of enteric infection and infestation, potential bacterial overgrowth with possible N-nitrosamine formation, and drug-induced hypergastrinaemia. In light of these potential problems, for the management of simple peptic ulceration, it appears sensible to use the minimum intervention required. Bedtime H2-receptor blockade is one such regimen. The more potent antisecretory regimens can be used for difficult clinical problems such as the Zollinger-Ellison syndrome, intractable duodenal ulceration, and severe oesophagitis.

  9. Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

    PubMed Central

    Berry, Daniel C.; DeSantis, David; Soltanian, Hooman; Croniger, Colleen M.; Noy, Noa

    2012-01-01

    Retinoic acid (RA) protects mice from diet-induced obesity. The activity is mediated in part through activation of the nuclear receptors RA receptors (RARs) and peroxisome proliferator–activated receptor β/δ and their associated binding proteins cellular RA binding protein type II (CRABP-II) and fatty acid binding protein type 5 in adipocytes and skeletal muscle, leading to enhanced lipid oxidation and energy dissipation. It was also reported that RA inhibits differentiation of cultured preadipocytes. However, whether the hormone suppresses adipogenesis in vivo and how the activity is propagated remained unknown. In this study, we show that RA inhibits adipocyte differentiation by activating the CRABP-II/RARγ path in preadipose cells, thereby upregulating the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2). In turn, KLF2 induces the expression of CRABP-II and RARγ, further potentiating inhibition of adipocyte differentiation by RA. The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity. PMID:22396202

  10. Inhibition of acidic mammalian chitinase by RNA interference suppresses ovalbumin-sensitized allergic asthma.

    PubMed

    Yang, Ching-Jen; Liu, Yu-Kuo; Liu, Chao-Lin; Shen, Chia-Ning; Kuo, Ming-Ling; Su, Chien-Chang; Tseng, Ching-Ping; Yen, Tzu-Chen; Shen, Chia-Rui

    2009-12-01

    Asthma, a chronic helper T cell type 2-mediated inflammatory disease, is characterized by airway hyperresponsiveness and inflammation. Growing evidence suggests that increased expression of acidic mammalian chitinase (AMCase) may play a role in the pathogenesis of asthma. In the present study, we sought to develop an RNA interference approach to suppress allergic asthma in mice through silencing of AMCase expression. Mice sensitized with ovalbumin (OVA) were intratracheally administered a recombinant adeno-associated virus expressing short hairpin RNA (rAAV-shRNA) against AMCase. In OVA-sensitized mice, the development of allergic symptoms was significantly associated with elevated AMCase expression. After administration of rAAV-shRNA, there was a significant reduction of AMCase expression in the lung and in bronchoalveolar lavage fluid (BALF) cells of sensitized mice. Sensitized mice receiving rAAV-shRNA showed a significant improvement in allergic symptoms, including airway hyperresponsiveness (AHR), eosinophil infiltration, eotaxin, interleukin-13 secretion in BALF, and serum OVA-specific IgE level. Our data suggest the hyperexpression of AMCase in asthma can be suppressed by rAAV-mediated shRNA. Silencing AMCase expression by shRNA may be a promising therapeutic strategy in asthma.

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

    PubMed

    Obata, Toshio; Nakashima, Michiko

    2016-03-01

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

  12. Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women

    PubMed Central

    Scharl, A.; Salterberg, A.

    2016-01-01

    Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post-menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

    Japan has been known as a healthy country since its life expectancy became among the highest in the world in the 1980s. The influence of the Japanese diet is one of the factors explaining Japan's high life expectancy. Our recent study that fed representative freeze-dried and powdered Japanese diets from 1960, 1975, 1990, and 2005 based on National Health and Nutrition Research to mice showed the 1975 Japanese diet exhibited the strongest visceral fat accumulation suppression and overall health benefits. However, it is unclear why. We investigated the effects of the fatty acid composition in Japanese diets on visceral fat accumulation in mice. ICR mice were fed diets replicating the fatty acid composition and macronutrient ratios of Japanese diets from 1960, 1975, 1990, and 2005 for four weeks. The 1975 diet suppressed visceral fat accumulation and adipocyte hypertrophy. DNA microarray analysis showed the 1975 diet suppressed Acyl-CoA synthetase and prostaglandin D2 synthase mRNA expressions in white adipose tissue. As the effects of the 1975 diet are likely due to differences in fatty acid intake and/or composition, we investigated test diets that replicated only the fatty acid composition of Japanese diets. There were no significant differences in visceral fat mass. Therefore, both the quality and quantity of fatty acids are involved in the anti-obesity effects of the 1975 Japanese diet. PMID:26743670

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

    PubMed

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

    1997-04-01

    Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsule containing enteric-coated granules that release the drug in alkaline medium. In clinical situations where patients are unable to take the capsule orally, the optimum means of administration is uncertain. Eleven normal volunteers were given omeprazole 20 mg every day for one week before breakfast in random order as either a 20-mg capsule with water or free enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzer antacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hr intragastric pH study was performed following omeprazole 20 mg and standard breakfast. The median percentage of time of gastric acid pH > 4 after an omeprazole capsule was 68.5 (25-100); after granules with orange juice 59 (43-100); after granules in Alka-Seltzer solution 63 (31-100), and after granules in apple sauce 65 (30-99), with no significant differences (ANOVA). The time for the gastric pH to reach <4' after having been above was also similar for all four regimens (ANOVA). Omeprazole granules administered orally in a variety of ways achieve gastric acid suppression as effectively as the intact capsule. PMID:9125637

  16. Biologic significance of polyunsaturated fatty acids in the skin.

    PubMed

    Ziboh, V A; Chapkin, R S

    1987-12-01

    Deficiency of essential fatty acid (EFA) containing linoleic acid (18:2n-6) in humans or animals induces morphologic changes characterized by severe scaly dermatosis, extensive percutaneous water loss, and hyperproliferation of the epidermis. Microscopically, the epidermis is characterized by hyperkeratosis and acanthosis. The refeeding of safflower oil containing linoleic acid or primrose oil (containing linoleic acid [18:2n-6] and gamma-linolenic acid [18:3n-6]) acids to EFA-deficient guinea pigs reverses the EFA-deficiency symptoms. In contrast, replacement of safflower oil with menhaden fish oil, (containing eicosapentaenoic acid [20:5n-3] and docosahexaenoic acid [22:6n-3]) did not reverse the symptoms of EFA deficiency. These results indicate: (1) that an understanding of the roles of vegetable or fish oil in skin must evolve from an understanding of the roles of each constituent n-6 or n-3 fatty acid, and (2) that the n-3 fatty acids may function to modulate the metabolism and function of the n-6 fatty acids in vivo.

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

    PubMed

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

    2016-04-01

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

  18. The significance of folic acid for epilepsy patients.

    PubMed

    Moore, James Layne

    2005-09-01

    The following is a comprehensive review of the current understanding of the many important roles of folic acid in the health of patients with epilepsy. A review of past and current literature reveals that folic acid plays important roles in the areas of hematology, neurology, development, and reproduction. Also highlighted are new areas for exploration.

  19. Limited significance of asymmetric adrenal visualization on dexamethasone-suppression scintigraphy

    SciTech Connect

    Gross, M.D.; Shapiro, B.; Freitas, J.E.

    1985-01-01

    To access whether a single measurement of the adrenal uptake of 6..beta..-(/sup 131/I)-iodomethylnorocholesterol (NP-59) on constant dexamethasone suppression would allow discrimination of adenoma from normal and bilateral hyperplasia, the adrenal uptake of 6..beta..-(/sup 131/I)-iodomethylnorocholesterol (NP-59) was determined in 50 patients with primary aldosteronism (30 adenoma, 20 hyperplasia) and in 13 with hyperandrogenism (six adenoma, seven hyperplasia). Bilateral adrenal NP-59 activity at 5 days was seen in 14 of 36 patients with adenoma whereas marked asymmetric uptake of NP-59 was seen in six of 27 patients with hyperplasia. Thus the level of adrenal NP-59 uptake does not alone serve to distinguish either adenoma from the normal, contralateral adrenal or the adrenal glands in bilateral hyperplasia in all cases. It appears that the pattern of adrenal imaging best serves to separate adrenal adenoma from bilateral hyperplasia.

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

    PubMed Central

    Feldman, Rebecca; Martinez, Jesse D.

    2009-01-01

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

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

    EPA Science Inventory

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

  2. Myristoleic acid inhibits osteoclast formation and bone resorption by suppressing the RANKL activation of Src and Pyk2.

    PubMed

    Kwon, Jun-Oh; Jin, Won Jong; Kim, Bongjun; Kim, Hong-Hee; Lee, Zang Hee

    2015-12-01

    Cytoskeletal changes in osteoclasts such as formation of actin ring is required for bone-resorbing activity. The tyrosine kinase Src is a key player in massive cytoskeletal change of osteoclasts, thereby in bone destruction. In order for Src to be activated, trafficking to the inner plasma membrane via myristoylation is of importance. A previous study reported that myristoleic acid derived from myristic acid, inhibited N-myristoyl-transferase, an essential enzyme for myristoylation process. This prompted us to investigate whether myristoleic acid could affect osteoclastogenesis. Indeed, we observed that myristoleic acid inhibited RANKL-induced osteoclast formation in vitro, especially, at later stages of differentiation. Myristoleic acid attenuated the tyrosine phosphorylation of c-Src and Pyk2, which associates with Src, by RANKL. When myristoleic acid was co-administered with soluble RANKL into mice, RANKL-induced bone loss was substantially prevented. Bone dissection clearly revealed that the number of multinucleated osteoclasts was significantly diminished by myristoleic acid. On the other hand, myristoleic acid treatment had little or no influence on early osteoclast differentiation markers, such as c-Fos and NFATc1, and proteins related to cytoskeletal rearrangement, including DC-STAMP, integrin αv and integrin β3 in vitro. Taken together, our data suggest that myristoleic acid is capable of blocking the formation of large multinucleated osteoclasts and bone resorption likely through suppressing activation of Src and Pyk2.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  4. Significance of classifying antiarrhythmic actions since the cardiac arrhythmia suppression trial.

    PubMed

    Vaughan Williams, E M

    1991-02-01

    The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS. H-V and J-T intervals and of effective refractory period (ERP) as follows: 1--(QRS) wide, 2--(HV) long, 3--(ERP) unchanged, 4--(JT) unchanged. In vitro electrophysiology helped to explain the clinical findings. Flecainide and encainide rendered Na channels as nonconducting, but F and E were only slowly released from the channels after repolarization. At any given drug concentration, a proportion of total channels were eliminated, and the steady-state proportion increased at rising heart rate. It is not proven that the properties that lead to classification of a drug as 1C were those that caused excess deaths in the CAST. The proarrhythmic tendency of 1C drugs can be reduced by beta-blockade, and the mechanisms of adrenergic arrhythmogenicity are discussed. Propafenone is both a 1C drug and a beta-blocker, and its pharmacologic profile is reviewed to illustrate how it resembles and differs from flecainide and encainide. Some features of the CAST are assessed with particular reference to the extent to which conclusions drawn from the results may be justifiably extrapolated to other drugs classified as 1C.

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

    PubMed

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

    2015-01-01

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

  6. 5-Caffeoylquinic acid and caffeic acid orally administered suppresses P-selectin expression on mouse platelets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Caffeic acid and 5-caffeoylquinic acid are a naturally occurring phenolic acid and its ester found in human diets. In this paper, potential effects of caffeic acid and 5-caffeoylquinic acid found in coffee and other plant sources on platelet activation were studied via investigating P-selectin expre...

  7. Zoledronic acid suppresses transforming growth factor-β-induced fibrogenesis by human gingival fibroblasts

    PubMed Central

    KOMATSU, YUKO; IBI, MIHO; CHOSA, NAOYUKI; KYAKUMOTO, SEIKO; KAMO, MASAHARU; SHIBATA, TOSHIYUKI; SUGIYAMA, YOSHIKI; ISHISAKI, AKIRA

    2016-01-01

    Bisphosphonates (BPs) are analogues of pyro-phosphate that are known to prevent bone resorption by inhibiting osteoclast activity. Nitrogen-containing BPs, such as zoledronic acid (ZA), are widely used in the treatment of osteoporosis and bone metastasis. However, despite having benefits, ZA has been reported to induce BP-related osteonecrosis of the jaw (BRONJ) in cancer patients. The molecular pathological mechanisms responsible for the development of BRONJ, including necrotic bone exposure after tooth extraction, remain to be elucidated. In this study, we examined the effects of ZA on the transforming growth factor-β (TGF-β)-induced myofibroblast (MF) differentiation of human gingival fibroblasts (hGFs) and the migratory activity of hGFs, which are important for wound closure by fibrous tissue formation. The ZA maximum concentration in serum (Cmax) was found to be approximately 1.47 µM, which clinically, is found after the intravenous administration of 4 mg ZA, and ZA at this dose is considered appropriate for the treatment of cancer bone metastasis or bone diseases, such as Erdheim-Chester disease. At Cmax, ZA significantly suppressed i) the TGF-β-induced promotion of cell viability, ii) the TGF-β-induced expression of MF markers such as α-smooth muscle actin (α-SMA) and type I collagen, iii) the TGF-β-induced migratory activity of hGFs and iv) the expression level of TGF-β type I receptor on the surfaces of hGFs, as well as the TGF-β-induced phosphorylation of Smad2/3. Thus, ZA suppresses TGF-β-induced fibrous tissue formation by hGFs, possibly through the inhibition of Smad-dependent signal transduction. Our findings partly elucidate the molecular mechanisms underlying BRONJ and may prove to be beneficial to the identification of drug targets for the treatment of this symptom at the molecular level. PMID:27176567

  8. Gallic acid suppresses inflammation in dextran sodium sulfate-induced colitis in mice: Possible mechanisms.

    PubMed

    Pandurangan, Ashok Kumar; Mohebali, Nooshin; Esa, Norhaizan Mohd; Looi, Chung Yeng; Ismail, Salmiah; Saadatdoust, Zeinab

    2015-10-01

    Inflammatory bowel diseases (IBD) encompass at least two forms of intestinal inflammation: Crohn's disease and ulcerative colitis (UC). Both conditions are chronic and inflammatory disorders in the gastrointestinal tract, with an increasing prevalence being associated with the industrialization of nations and in developing countries. Patients with these disorders are 10 to 20 times more likely to develop cancer of the colon. The aim of this study was to characterize the effects of a naturally occurring polyphenol, gallic acid (GA), in an experimental murine model of UC. A significant blunting of weight loss and clinical symptoms was observed in dextran sodium sulfate (DSS)-exposed, GA-treated mice compared with control mice. This effect was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in the expression of inflammatory mediators, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and pro-inflammatory cytokines. In addition, GA reduced the activation and nuclear accumulation of p-STAT3(Y705), preventing the degradation of the inhibitory protein IκB and inhibiting of the nuclear translocation of p65-NF-κB in colonic mucosa. These findings suggest that GA exerts potentially clinically useful anti-inflammatory effects mediated through the suppression of p65-NF-κB and IL-6/p-STAT3(Y705) activation.

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

    PubMed

    Goso, Yukinobu

    2016-03-01

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

  10. Mechanism and Physiologic Significance of the Suppression of Cholesterol Esterification in Human Interstitial Fluid

    PubMed Central

    Miller, Norman E.; Olszewski, Waldemar L.; Miller, Irina P.; Nanjee, Mahmud N.

    2016-01-01

    Cholesterol esterification in high density lipoproteins (HDLs) by lecithin:cholesterol acyltransferase (LCAT) promotes unesterified cholesterol (UC) transfer from red cell membranes to plasma in vitro. However, it does not explain the transfer of UC from most peripheral cells to interstitial fluid in vivo, as HDLs in afferent peripheral lymph are enriched in UC. Having already reported that the endogenous cholesterol esterification rate (ECER) in lymph is only 5% of that in plasma, we have now explored the underlying mechanism. In peripheral lymph from 20 healthy men, LCAT concentration, LCAT activity (assayed using an optimized substrate), and LCAT specific activity averaged, respectively, 11.8, 10.3, and 84.9% of plasma values. When recombinant human LCAT was added to lymph, the increments in enzyme activity were similar to those when LCAT was added to plasma. Addition of apolipoprotein AI (apo AI), fatty acid-free albumin, Intralipid, or the d < 1.006 g/ml plasma fraction had no effect on ECER. During incubation of lymph plus plasma, the ECER was similar to that observed with buffer plus plasma. When lymph was added to heat-inactivated plasma, the ECER was 11-fold greater than with lymph plus buffer. Addition of discoidal proteoliposomes of apo AI and phosphatidycholine (PC) to lymph increased ECER 10-fold, while addition of apo AI/PC/UC disks did so by only six-fold. We conclude that the low ECER in lymph is due to a property of the HDLs, seemingly substrate inhibition of LCAT by excess cell-derived UC. This is reversed when lymph enters plasma, consequent upon redistribution of UC from lymph HDLs to plasma lipoproteins. PMID:27471469

  11. Mechanism and Physiologic Significance of the Suppression of Cholesterol Esterification in Human Interstitial Fluid.

    PubMed

    Miller, Norman E; Olszewski, Waldemar L; Miller, Irina P; Nanjee, Mahmud N

    2016-01-01

    Cholesterol esterification in high density lipoproteins (HDLs) by lecithin:cholesterol acyltransferase (LCAT) promotes unesterified cholesterol (UC) transfer from red cell membranes to plasma in vitro. However, it does not explain the transfer of UC from most peripheral cells to interstitial fluid in vivo, as HDLs in afferent peripheral lymph are enriched in UC. Having already reported that the endogenous cholesterol esterification rate (ECER) in lymph is only 5% of that in plasma, we have now explored the underlying mechanism. In peripheral lymph from 20 healthy men, LCAT concentration, LCAT activity (assayed using an optimized substrate), and LCAT specific activity averaged, respectively, 11.8, 10.3, and 84.9% of plasma values. When recombinant human LCAT was added to lymph, the increments in enzyme activity were similar to those when LCAT was added to plasma. Addition of apolipoprotein AI (apo AI), fatty acid-free albumin, Intralipid, or the d < 1.006 g/ml plasma fraction had no effect on ECER. During incubation of lymph plus plasma, the ECER was similar to that observed with buffer plus plasma. When lymph was added to heat-inactivated plasma, the ECER was 11-fold greater than with lymph plus buffer. Addition of discoidal proteoliposomes of apo AI and phosphatidycholine (PC) to lymph increased ECER 10-fold, while addition of apo AI/PC/UC disks did so by only six-fold. We conclude that the low ECER in lymph is due to a property of the HDLs, seemingly substrate inhibition of LCAT by excess cell-derived UC. This is reversed when lymph enters plasma, consequent upon redistribution of UC from lymph HDLs to plasma lipoproteins. PMID:27471469

  12. DNA/polyethyleneimine/hyaluronic acid small complex particles and tumor suppression in mice.

    PubMed

    Ito, Tomoko; Yoshihara, Chieko; Hamada, Katsuyuki; Koyama, Yoshiyuki

    2010-04-01

    The highest barriers for non-viral vectors to an efficient in vivo gene transfection would be (1) non-specific interaction with biological molecules, and (2) large size of the DNA complex particles. Protective coating of the DNA/polyethyleneimine (PEI) complexes by hyaluronic acid (HA) effectively diminished the adverse interactions with biological molecules. Here we found HA also protected the DNA/PEI complexes against aggregation and inactivation through lyophilization-and-rehydration procedures. It allows us to prepare the concentrated very small DNA complex particles (<70 nm) suspension by preparing the complexes at highly diluted conditions, followed by lyophilized-and-rehydrated to a small volume. In vivo gene expression efficiency of the small complex was examined with mice subcutaneously inoculated with B16 melanoma cells. These formulations showed high reporter-gene expression level in tumor after intravenous injection into tumor-bearing mice. Small complex was then made of the plasmid encoding GM-CSF gene, and injected into the mice bearing subcutaneous solid B16 tumor. After intravenous injection, it induced apparent tumor growth suppression in 50% of the mice. Notably, significant therapeutic effect was detected in the mice that received intratumoral injection, and 75% of the mice were completely cured with disappearance of tumor. PMID:20047759

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

    PubMed Central

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

    2016-01-01

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

  14. Oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling

    PubMed Central

    Mu, Da-Wei; Guo, He-Qing; Zhou, Gao-Biao; Li, Jian-Ye; Su, Bin

    2015-01-01

    Oleanolic acid has significant pharmacological activities, such as anti-tumor, regulating blood sugar level and liver protection, which are more effective compared with free aglyconeoleanolic acid. However, it is still unknown if oleanolic acid affects the proliferation of human bladder cancer. We utilized T24 cells to study the effect of oleanolic acid on the proliferation and apoptosis of human bladder cancer. In this study, we found that the anti-cancer effect of oleanolic acid significantly suppressed cell proliferation and increased apoptosis and caspase-3 activity of T24 cells. Furthermore, Akt, mTOR and S6K protein expression was greatly inhibited in T24 cells under oleanolic acid treatment. Meanwhile, ERK1/2 of phosphorylation protein expression was significantly promoted by oleanolic acid treatment. Taken together, we provided evidences that oleanolic acid was Akt/mTOR/S6K and ERK1/2 signaling-targeting anti-tumor agent. These findings represent new evidences that oleanolic acid suppresses the proliferation of human bladder cancer by Akt/mTOR/S6K and ERK1/2 signaling, and oleanolic acid may be used to prevent human bladder cancer. PMID:26823699

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

    Yang, Yue; Wu, Haitao; Zhou, Jian

    2016-01-01

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

  17. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2

    PubMed Central

    Ye, Jiangbin; Palm, Wilhelm; Peng, Min; King, Bryan; Lindsten, Tullia; Li, Ming O.; Koumenis, Constantinos; Thompson, Craig B.

    2015-01-01

    Mammalian cells possess two amino acid-sensing kinases: general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1). Their combined effects orchestrate cellular adaptation to amino acid levels, but how their activities are coordinated remains poorly understood. Here, we demonstrate an important link between GCN2 and mTORC1 signaling. Upon deprivation of various amino acids, activated GCN2 up-regulates ATF4 to induce expression of the stress response protein Sestrin2, which is required to sustain repression of mTORC1 by blocking its lysosomal localization. Moreover, Sestrin2 induction is necessary for cell survival during glutamine deprivation, indicating that Sestrin2 is a critical effector of GCN2 signaling that regulates amino acid homeostasis through mTORC1 suppression. PMID:26543160

  18. Dose-dependent food allergy induction against ovalbumin under acid-suppression: A murine food allergy model

    PubMed Central

    Diesner, S.C.; Knittelfelder, R.; Krishnamurthy, D.; Pali-Schöll, I.; Gajdzik, L.; Jensen-Jarolim, E.; Untersmayr, E.

    2010-01-01

    Background Animal models are essential for analyzing the allergenic potential of food proteins and for investigating mechanisms underlying food allergy. Based on previous studies revealing acid-suppression medication as risk factor for food allergy induction, we aimed to establish a mouse model mimicking the natural route of sensitization in patients. Methods The effect of acid-suppressing medication on murine gastric pH was assessed by intragastric pH measurements after two injections of a proton pump inhibitor (PPI). To investigate dose-dependency, mice were fed different concentrations of ovalbumin (OVA; 0.2, 0.5, 1.0, 2.5 or 5.0 mg) either with or without anti-ulcer medication. Additionally, different routes of exposure (i.p. vs. oral) were compared in a second immunization experiment. Sera were screened for OVA-specific antibody titers (IgG1, IgG2a and IgE) in ELISA and RBL assay. Clinical reactivity was evaluated by measuring rectal temperature after oral challenge and by type I skin tests. Results Two intravenous injections of PPI significantly elevated the gastric pH from 2.97 to 5.3. Only oral immunization with 0.2 mg OVA under anti-acid medication rendered elevated IgG1, IgG2a and IgE titers compared to all other concentrations. Protein feeding alone altered antibody titers only marginally. Even though also i.p. immunizations induced high levels of specific IgE, only oral immunizations under anti-acids induced anaphylactic reactions evidenced by a significant decrease of body temperature. Conclusion Only low-dosage ovalbumin feedings under anti-acid medication resulted in IgE mediated food allergy. Based on this knowledge we have established a suitable food allergy model for further investigations of food adverse reactions. PMID:18824031

  19. Prognostic Significance of Uric Acid Levels in Ischemic Stroke Patients.

    PubMed

    Zhang, Xia; Huang, Zhi-Chao; Lu, Tao-Sheng; You, Shou-Jiang; Cao, Yong-Jun; Liu, Chun-Feng

    2016-01-01

    The importance and function of serum uric acid (UA) levels in patients with cardiovascular disease or stroke are unclear. We sought to evaluate the appropriate UA levels for stroke patients and the association between endogenous UA levels and clinical outcomes in acute ischemic stroke (AIS) patients, particularly regarding the possible interaction between gender and UA levels with respect to AIS prognosis. We examined 303 patients who had an onset of ischemic stroke within 48 h. Of those, 101 patients received thrombolytic treatment. Serum UA (μmol/L) levels were measured the second morning after admission. Patient prognosis was evaluated 90 days after clinical onset by modified Rankin Scale. Patients were divided into four groups according to serum UA quartiles. A binary multivariate logistic regression model was used to assess clinical relevance in regard to functional outcome and endogenous UA levels. Analysis of subgroups by gender and normal glomerular filtration rate were also been done. Poor functional outcome was associated with older age, history of atrial fibrillation, or higher baseline National Institutes of Health Stroke Scale scores. After adjustment for potential confounders, patients with higher UA levels (>380 μmol/L) or lower UA levels (≤250 μmol/L) were 2-3 times more likely to have a poor outcome (OR 2.95, 95% CI 1.14-7.61; OR 2.78, 95% CI 1.02-7.58, respectively) compared to the baseline group (UA level 316-380 μmol/L). The same results were observed in thrombolyzed patients. Patients with high and low UA levels were 9-18 times more likely to having poor outcomes compared to the baseline group (UA level: 316-380 μmol/L; OR 18.50, 95% CI: 2.041-167.67; OR 9.66, 95% CI 1.42-65.88, respectively). In men, patients with high UA levels were 6 times more likely to have poor outcomes compared to the baseline group (UA level: 279-334 μmol/L; OR 6.10, 95% CI 1.62-22.93). However, female patients with UA level 271-337 μmol/L were seven times more

  20. TGA Transcription Factors Activate the Salicylic Acid-Suppressible Branch of the Ethylene-Induced Defense Program by Regulating ORA59 Expression.

    PubMed

    Zander, Mark; Thurow, Corinna; Gatz, Christiane

    2014-07-01

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

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

    PubMed Central

    Zander, Mark; Thurow, Corinna; Gatz, Christiane

    2014-01-01

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

  2. 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

    PubMed

    Zhou, Jieru; Cai, Wei; Jin, Min; Xu, Jingwei; Wang, Yanan; Xiao, Yichuan; Hao, Li; Wang, Bei; Zhang, Yanyun; Han, Jie; Huang, Rui

    2015-01-01

    Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.

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

    PubMed

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

    2015-05-01

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

  4. Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation

    PubMed Central

    Batumalaie, Kalaivani; Amin, Muhammad Arif; Murugan, Dharmani Devi; Sattar, Munavvar Zubaid Abdul; Abdullah, Nor Azizan

    2016-01-01

    Activation of inflammatory pathways via reactive oxygen species (ROS) by free fatty acids (FFA) in obesity gives rise to insulin resistance and endothelial dysfunction. Withaferin A (WA), possesses both antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress palmitic acid (PA)-induced oxidative stress and inflammation and hence, insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and IL-6 production in endothelial cells by specifically suppressing IKKβ/NF-κβ phosphorylation. WA inhibited inflammation-stimulated IRS-1 serine phosphorylation and improved the impaired insulin PI3-K signaling, and restored the decreased nitric oxide (NO) production triggered by PA. WA also decreased endothelin-1 and plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and inflammation to restore impaired insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings. PMID:27250532

  5. Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation.

    PubMed

    Batumalaie, Kalaivani; Amin, Muhammad Arif; Murugan, Dharmani Devi; Sattar, Munavvar Zubaid Abdul; Abdullah, Nor Azizan

    2016-01-01

    Activation of inflammatory pathways via reactive oxygen species (ROS) by free fatty acids (FFA) in obesity gives rise to insulin resistance and endothelial dysfunction. Withaferin A (WA), possesses both antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress palmitic acid (PA)-induced oxidative stress and inflammation and hence, insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and IL-6 production in endothelial cells by specifically suppressing IKKβ/NF-κβ phosphorylation. WA inhibited inflammation-stimulated IRS-1 serine phosphorylation and improved the impaired insulin PI3-K signaling, and restored the decreased nitric oxide (NO) production triggered by PA. WA also decreased endothelin-1 and plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and inflammation to restore impaired insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings. PMID:27250532

  6. Climate dependency of tree growth suppressed by acid deposition effects on soils in northwest Russia.

    PubMed

    Lawrence, Gregory B; Lapenis, Andrei G; Berggren, Dan; Aparin, Boris F; Smith, Kevin T; Shortle, Walter C; Bailey, Scott W; Varlyguin, Dmitry L; Babikov, Boris

    2005-04-01

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

  7. Acute hypothalamic suppression significantly affects trabecular bone but not cortical bone following recovery and ovariectomy surgery in a rat model

    PubMed Central

    Mitchell, Kathryn A.; Lunny, Megan

    2016-01-01

    RH-a group compared to C, a similar deficit in BV/TV was also measured following recovery and post-OVX. The trabecular number and thickness were lower in the GnRH-a group compared to control. Conclusion. These data suggest that following a transient delay in pubertal onset, trabecular bone volume was significantly lower and no restoration of bone volume occurred following recovery or post-OVX surgery. However, cortical bone strength was maintained through architectural adaptations in the cortical bone envelope. An increase in the polar moment of inertia offset increased bone resorption. The current data are the first to suppress trabecular bone during growth, and then add an OVX protocol at maturity. Trabecular bone and cortical bone differed in their response to hypothalamic suppression during development; trabecular bone was more sensitive to the negative effects of hypothalamic suppression. PMID:26793427

  8. Acute hypothalamic suppression significantly affects trabecular bone but not cortical bone following recovery and ovariectomy surgery in a rat model.

    PubMed

    Yingling, Vanessa R; Mitchell, Kathryn A; Lunny, Megan

    2016-01-01

    RH-a group compared to C, a similar deficit in BV/TV was also measured following recovery and post-OVX. The trabecular number and thickness were lower in the GnRH-a group compared to control. Conclusion. These data suggest that following a transient delay in pubertal onset, trabecular bone volume was significantly lower and no restoration of bone volume occurred following recovery or post-OVX surgery. However, cortical bone strength was maintained through architectural adaptations in the cortical bone envelope. An increase in the polar moment of inertia offset increased bone resorption. The current data are the first to suppress trabecular bone during growth, and then add an OVX protocol at maturity. Trabecular bone and cortical bone differed in their response to hypothalamic suppression during development; trabecular bone was more sensitive to the negative effects of hypothalamic suppression. PMID:26793427

  9. Docosahexaenoic acid reduces suppressive and migratory functions of CD4CD25 regulatory T-cells

    PubMed Central

    Yessoufou, Akadiri; Plé, Aude; Moutairou, Kabirou; Hichami, Aziz; Khan, Naim Akhtar

    2009-01-01

    Immunological tolerance is one of the fundamental aspects of the immune system. The CD4+CD25+ regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4+CD25− effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-β, and IL-10; nonetheless, this fatty acid increased the expression of p27KIP1 mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease. PMID:19561360

  10. Docosahexaenoic acid reduces suppressive and migratory functions of CD4+CD25+ regulatory T-cells.

    PubMed

    Yessoufou, Akadiri; Plé, Aude; Moutairou, Kabirou; Hichami, Aziz; Khan, Naim Akhtar

    2009-12-01

    Immunological tolerance is one of the fundamental aspects of the immune system. The CD4(+)CD25(+) regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4(+)CD25(-) effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-beta, and IL-10; nonetheless, this fatty acid increased the expression of p27(KIP1) mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease.

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

    SciTech Connect

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

    2013-11-01

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

  12. Endogenous released ascorbic acid suppresses ethanol-induced hydroxyl radical production in rat striatum.

    PubMed

    Huang, Mei; Liu, Wen; Li, Qiang; Wu, Chun Fu

    2002-07-19

    Previous studies have shown that acute systemic administration of ethanol induced ascorbic acid release in the striatum. However, the pharmacological implications of ethanol-induced striatal ascorbic acid release are unclear. In the present study, ethanol-induced extracellular changes of ascorbic acid and hydroxyl radical levels were detected in rat striatum by using brain microdialysis coupled to high-performance liquid chromatography with electrochemical detection. It was found that both in male and female rats, ethanol (3.0 g/kg, i.p.) increased striatal ascorbic acid release in the first 60 min after ethanol administration. Meanwhile, the extracellular hydroxyl radical levels, detected as 2,3- and 2,5-DHBA, were significantly decreased. However, when the ascorbic acid levels returned to the baseline, hydroxyl radical levels rebounded. Administration of DL-fenfluramine (20 mg/kg, i.p.) had no effect on the basal levels of ascorbic acid and hydroxyl radical, but significantly blocked ethanol-induced ascorbic acid release and increased hydroxyl radical levels significantly. Exogenous administration of ascorbic acid (20 mg/kg, s.c.) increased the extracellular levels of ascorbic acid in the striatum, and inhibited the increase of 2,3- and 2,5-DHBA in DL-fenfluramine plus ethanol group. These results provide first evidence that release of endogenous ascorbic acid in the striatum plays an important role in preventing oxidative stress by trapping hydroxyl radical in the central nervous system.

  13. Suppressed blinking behavior of thioglycolic acid capped CdTe quantum dot by amine functionalization

    NASA Astrophysics Data System (ADS)

    Mandal, Abhijit; Tamai, Naoto

    2011-12-01

    Prepared water soluble thioglycolic acid capped CdTe quantum dots (QDs) were further surface functionalized by ethylene diamine (EDA). Amine functionalized CdTe QDs demonstrate enhanced luminescence intensity at ensemble measurements and suppressed luminescence intermittency behavior at the single molecule level. A clear decrease in the power law exponent for "on" time behavior is observed in amine modified CdTe QDs. Our results show that surface of CdTe QDs modified by EDA can lead to an important physical mechanism to enhance fluorescence intensity, reduce blinking, and increase photostability.

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-09-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  19. Heavy metal extraction from an artificially contaminated sandy soil under EDDS deficiency: significance of humic acid and chelant mixture.

    PubMed

    Yip, Theo C M; Yan, Dickson Y S; Yui, Matthew M T; Tsang, Daniel C W; Lo, Irene M C

    2010-06-01

    Biodegradable EDDS ([S,S]-ethylenediaminedisuccinic acid) has been suggested for enhancing heavy metal extraction from contaminated soils. Recent studies showed that Zn and Pb are less effectively extracted due to metal exchange and re-adsorption onto the soil surfaces, especially for EDDS-deficiency conditions. This study therefore investigated the influence of dissolved organic matter and the co-presence of EDTA (ethylene-diamine-tetraacetic acid) on metal extraction from an artificially contaminated sandy soil under deficient amount of chelants in batch kinetics experiments. The addition of 10 and 20mgL(-1) of humic acid as dissolved organic matter (DOC) suppressed metal extraction by EDDS, probably resulting from the competition of adsorbed humic acid for heavy metals and adsorption of metal-humate complexes onto the soil surfaces. The effects were most significant for Pb because of greater extent of metal exchange of PbEDDS and high affinity towards organic matter. Thus, one should be cautious when there is a high content of organic matter in soils or groundwater. On the other hand, compared to individual additions of EDDS or EDTA, the equimolar EDDS and EDTA mixture exhibited significantly higher Pb extraction without notable Pb re-adsorption. The synergistic performance of the EDDS and EDTA mixture probably resulted from the change of chemical speciation and thus less competition among Cu, Zn and Pb for each chelant. These findings suggest further investigation into an optimum chemistry of the chelant mixture taking into account the effectiveness and associated environmental impact.

  20. The combination effect of L-arginine and NaCl on bitterness suppression of amino acid solutions.

    PubMed

    Ogawa, Tazuko; Nakamura, Tomoko; Tsuji, Eriko; Miyanaga, Yohko; Nakagawa, Hiroyo; Hirabayashi, Hitomi; Uchida, Takahiro

    2004-02-01

    The purpose of the present study was to quantify the degree of suppression of the bitterness of two amino acids (L-isoleucine (L-Ile), and L-phenylalanine (L-Phe)) which could be achieved by the addition of various test chemicals, and to examine the mechanism of this bitterness suppression. The test chemicals used were two sweeteners (sucrose, aspartame), NaCl, various acidic (L-aspartic acid, L-glutamic acid), or basic (L-histidine, L-lysine and L-arginine) amino acids, tannic acid and phosphatidic acid. The combination of L-arginine (L-Arg) and NaCl together was the most effective in reducing the bitterness of 100 mM L-Ile and L-Phe solutions in human gustatory sensation tests. Even in bitterness of 0.1 mM quinine solution, L-Arg was also successful in reducing the bitterness. This bitterness-suppression effect was specific to L-Arg and not to the other basic amino acids. No comparable taste-masking effect was observed for the acidic amino acids. The artificial taste sensor failed to predict completely the bitterness-suppressing effect of L-Arg. It seems likely that the bitterness-suppressing effect of L-Arg is mediated not only by binding at the receptor site, but also elsewhere in the process of bitterness perception, such as a direct effect on the sodium channel. It is conjectured that the guanidinium group of L-Arg may interact with sodium channels in taste bud membranes.

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

    PubMed Central

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

    2016-01-01

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

  2. gamma-Hydroxybutyric acid (GHB) suppresses alcohol's motivational properties in alcohol-preferring rats.

    PubMed

    Maccioni, Paola; Pes, Daniela; Fantini, Noemi; Carai, Mauro A M; Gessa, Gian Luigi; Colombo, Giancarlo

    2008-03-01

    gamma-Hydroxybutyric acid (GHB) reduces alcohol drinking, promotes abstinence from alcohol, suppresses craving for alcohol, and ameliorates alcohol withdrawal syndrome in alcoholics. At preclinical level, GHB suppresses alcohol withdrawal signs and alcohol intake in rats. The present study was designed to investigate whether GHB administration was capable of affecting alcohol's motivational properties (the possible animal correlate of human craving for alcohol) in selectively bred Sardinian alcohol-preferring rats. To this aim, rats were initially trained to lever press for alcohol (15%, vol/vol) under a procedure of operant, oral alcohol self-administration (fixed ratio 4 in 30-min daily sessions). Once responding for alcohol had stabilized, rats were divided into two groups and allocated to two independent experiments. Experiment 1 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on breakpoint for alcohol, defined as the lowest response requirement not achieved by each rat when exposed to a single-session progressive ratio schedule of reinforcement. Experiment 2 assessed the effect of GHB (0, 25, 50, and 100mg/kg, i.p.) on single-session extinction responding for alcohol (alcohol was absent and unreinforced responding was recorded). Breakpoint and extinction responding for alcohol are reliable indexes of alcohol's motivational strength. In Experiment 1, all doses of GHB reduced--by approximately 20% in comparison to saline-treated rats--breakpoint for alcohol. In Experiment 2, administration of 25, 50, and 100mg/kg GHB reduced--by approximately 25%, 40%, and 50%, respectively, in comparison to saline-treated rats--extinction responding for alcohol. Conversely, no dose of GHB altered breakpoint and extinction responding for sucrose (3%, wt/vol) in two independent subsets of Sardinian alcohol-preferring rats. Together, these data suggest that GHB administration specifically suppressed alcohol's motivational properties in Sardinian alcohol-preferring rats

  3. β-alanine suppresses malignant breast epithelial cell aggressiveness through alterations in metabolism and cellular acidity in vitro

    PubMed Central

    2014-01-01

    Background Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. β-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of β-alanine on the metabolic cancerous phenotype. Methods Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with β-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified by measuring extracellular acidification rate (ECAR) and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR). mRNA of metabolism-related genes was quantified by qRT-PCR with corresponding protein expression quantified by immunoblotting, or by flow cytometry which was verified by confocal microscopy. Mitochondrial content was quantified using a mitochondria-specific dye and measured by flow cytometry. Results Cells treated with β-alanine displayed significantly suppressed basal and peak ECAR (aerobic glycolysis), with simultaneous increase in glucose transporter 1 (GLUT1). Additionally, cells treated with β-alanine exhibited significantly reduced basal and peak OCR (oxidative metabolism), which was accompanied by reduction in mitochondrial content with subsequent suppression of genes which promote mitochondrial biosynthesis. Suppression of glycolytic and oxidative metabolism by β-alanine resulted in the reduction of total metabolic rate, although cell viability was not affected. Because β-alanine treatment reduces extracellular acidity, a constituent of the invasive microenvironment that promotes progression, we investigated the effect of β-alanine on breast cell viability and migration. β-alanine was shown to reduce both cell migration and proliferation

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

    USGS Publications Warehouse

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

    2005-01-01

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

  5. Gallic acid-grafted chitooligosaccharides suppress antigen-induced allergic reactions in RBL-2H3 mast cells.

    PubMed

    Vo, Thanh-Sang; Ngo, Dai-Hung; Kim, Se-Kwon

    2012-09-29

    In this study, a bioactive derivative of chitooligosaccharides (3-5 kDa) was synthesized via grafting of gallic acid onto chitooligosaccharides (G-COS) to enhance anti-allergic activity. Hence, G-COS was evaluated for its capabilities against allergic reactions in RBL-2H3 mast cells sensitized with dinitrophenyl-specific immunoglobulin E antibody and stimulated by antigen dinitrophenyl-bovine serum albumin. It was revealed that G-COS exhibited significant inhibition on histamine release and production as well as intracellular Ca(2+) elevation at the concentration of 200μg/ml. Likewise, the suppressive effects of G-COS on expression and production of interleukin (IL)-4 and tumor necrosis factor (TNF)-α were evidenced. Moreover, G-COS treatment caused a remarkable blockade on degradation of inhibitory κB-α (IκB-α) protein, translocation of nuclear factor (NF)-κB, and phosphorylation of mitogen-activated protein kinases (MAPKs). Notably, the inhibitory activities of G-COS on allergic reactions were found as a consequence of suppression of FcεRI expression in antigen-stimulated cells. Accordingly, G-COS was suggested to be a promising candidate of novel inhibitors against allergic reactions.

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

    PubMed

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

    2013-04-01

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

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

    PubMed

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

    2012-06-07

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

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

    PubMed Central

    2012-01-01

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

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

    PubMed

    Yoshikawa, Kenji; Soda, Yuko; Sakuragawa, Akio

    2009-12-01

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

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

    PubMed

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

    2006-12-01

    We previously demonstrated that arachidonic acid (AA) inhibits epithelial Na channels (ENaC) through the cytochrome P-450 (CYP) epoxygenase-dependent pathway (34). In the present study, we tested the hypothesis that low Na intake suppresses the expression of CYP2C23, which is mainly responsible for converting AA to epoxyeicosatrienoic acid (EET) in the kidney (11) and attenuates the AA-induced inhibition of ENaC. Immunostaining showed that CYP2C23 is expressed in the Tamm-Horsfall protein (THP)-positive and aquaporin 2 (AQP2)-positive tubules. This suggests that CYP2C23 is expressed in the thick ascending limb (TAL) and collecting duct (CD). Na restriction significantly suppressed the expression of CYP2C23 in the TAL and CD. Western blot also demonstrated that the expression of CYP2C23 in renal cortex and outer medulla diminished in rats on Na-deficient diet (Na-D) but increased in those on high-Na diet (4%). Moreover, the content of 11,12-epoxyeicosatrienoic acid (EET) decreased in the isolated cortical CD from rats on Na-D compared with those on a normal-Na diet (0.5%). Patch-clamp study showed that application of 15 microM AA inhibited the activity of ENaC by 77% in the CCD of rats on a Na-D for 3 days. However, the inhibitory effect of AA on ENaC was significantly attenuated in rats on Na-D for 14 days. Furthermore, inhibition of CYP epoxygenase with MS-PPOH increased the ENaC activity in the CCD of rats on a control Na diet. We also used microperfusion technique to examine the effect of MS-PPOH on Na transport in the distal nephron. Application of MS-PPOH significantly increased Na absorption in the distal nephron of control rats but had no significant effect on Na absorption in rats on Na-D for 14 days. We conclude that low Na intake downregulates the activity and expression of CYP2C23 and attenuates the inhibitory effect of AA on Na transport. PMID:16849695

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  16. Abscisic acid suppresses hypocotyl elongation by dephosphorylating plasma membrane H(+)-ATPase in Arabidopsis thaliana.

    PubMed

    Hayashi, Yuki; Takahashi, Koji; Inoue, Shin-Ichiro; Kinoshita, Toshinori

    2014-04-01

    Plasma membrane H(+)-ATPase is thought to mediate hypocotyl elongation, which is induced by the phytohormone auxin through the phosphorylation of the penultimate threonine of H(+)-ATPase. However, regulation of the H(+)-ATPase during hypocotyl elongation by other signals has not been elucidated. Hypocotyl elongation in etiolated seedlings of Arabidopsis thaliana was suppressed by the H(+)-ATPase inhibitors vanadate and erythrosine B, and was significantly reduced in aha2-5, which is a knockout mutant of the major H(+)-ATPase isoform in etiolated seedlings. Application of the phytohormone ABA to etiolated seedlings suppressed hypocotyl elongation within 30 min at the half-inhibitory concentration (4.2 µM), and induced dephosphorylation of the penultimate threonine of H(+)-ATPase without affecting the amount of H(+)-ATPase. Interestingly, an ABA-insensitive mutant, abi1-1, did not show ABA inhibition of hypocotyl elongation or ABA-induced dephosphorylation of H(+)-ATPase. This indicates that ABI1, which is an early ABA signaling component through the ABA receptor PYR/PYL/RCARs (pyrabactin resistance/pyrabactin resistance 1-like/regulatory component of ABA receptor), is involved in these responses. In addition, we found that the fungal toxin fusiccocin (FC), an H(+)-ATPase activator, induced hypocotyl elongation and phosphorylation of the penultimate threonine of H(+)-ATPase, and that FC-induced hypocotyl elongation and phosphorylation of H(+)-ATPase were significantly suppressed by ABA. Taken together, these results indicate that ABA has an antagonistic effect on hypocotyl elongation through, at least in part, dephosphorylation of H(+)-ATPase in etiolated seedlings.

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

    SciTech Connect

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

    1989-12-01

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

  18. Salicylic acid alleviates aluminum toxicity in rice seedlings better than magnesium and calcium by reducing aluminum uptake, suppressing oxidative damage and increasing antioxidative defense.

    PubMed

    Pandey, Poonam; Srivastava, Rajneesh Kumar; Dubey, R S

    2013-05-01

    Aluminum toxicity is a major constraint to crop production in acid soils. The present study was undertaken to examine the comparative ameliorating effects of salicylic acid, Ca and Mg on Al toxicity in rice (Oryza sativa L.) seedlings grown in hydroponics. Al treatment (0.5 mM AlCl3) caused decrease in plant vigour, loss of root plasma membrane integrity, increased contents of O 2 (∙-) , H2O2, lipid peroxidation, protein carbonyls and decline in the level of protein thiol. Al treatment caused significant changes in activity of antioxidative enzymes in rice seedlings. Exogenously added salicylic acid (60 μM), Ca (1 mM) and Mg (0.25 mM) significantly alleviated Al toxicity effects in the seedlings marked by restoration of growth, suppression of Al uptake, restoration of root plasma membrane integrity and decline in O 2 (∙-) , H2O2, lipid peroxidation and protein carbonyl contents. Salicylic acid, Ca and Mg suppressed Al-induced increase in SOD, GPX and APX activities while it elevated Al-induced decline in CAT activity. By histochemical staining of O 2 (∙-) using NBT and H2O2 using DAB, it was further confirmed that added salicylic acid, Ca or Mg decreased Al-induced accumulation of O 2 (∙-) and H2O2 in the leaf tissues. Results indicate that exogenously added salicylic acid, Ca or Mg alleviates Al toxicity in rice seedlings by suppressing Al uptake, restoring root membrane integrity, reducing ROS level and ROS induced oxidative damage and regulating the level of antioxidative enzyme activities. Further salicylic appears to be superior to Mg and Ca in alleviating Al toxicity effects in rice plants.

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

    PubMed

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

    2016-10-01

    Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TGF-β-activated kinase-1, JNK, ERK, and NF-κB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to hypoxia-inducible factor (HIF)-1α, which was enhanced in bone marrow-derived mast cells treated with LA. Because HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and miR-155-3p species were measured. In fact, LA selectively suppressed miR-155-5p in an HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, because LA injected i.p. into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation. PMID:27559047

  20. Hypertension induces tissue-specific gene suppression of a fatty acid binding protein in rat aorta.

    PubMed Central

    Sarzani, R; Claffey, K P; Chobanian, A V; Brecher, P

    1988-01-01

    The effect of hypertension on the expression of a fatty acid binding protein localized in the rat aorta was studied. The presence of rat heart fatty acid binding protein (hFABP) was documented in aortic tissue by using a cDNA probe and polyclonal antibodies. Hypertension was induced in groups of rats by implantation of deoxycorticosterone acetate in conjunction with 1% salt in the drinking water (deoxycorticosterone/salt). By the third week of this treatment a marked reduction (by a factor of 20) in the expression of hFABP mRNA in aorta was found, concomitant with a reduction in immunologically detectable protein, suggesting transcriptional regulation. This effect was tissue specific, since no change in the normal amounts of hFABP mRNA in heart, skeletal muscle, or kidney was found. This reduction in aortic hFABP mRNA was also found in mildly hypertensive uninephrectomized rats given salt but no deoxycorticosterone and in normotensive rats given deoxycorticosterone but no excess salt intake. A marked decrease in aortic hFABP mRNA also was observed in the Goldblatt two kidney-one clip hypertensive model, and administration of angiotensin II for 6 days by osmotic minipump also caused a reduction. These findings suggest that hFABP is under complex regulation in aortic tissue and is suppressed by arterial hypertension. Images PMID:3174661

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

    PubMed

    Brzeziński, Tomasz; von Elert, Eric

    2015-11-01

    Herbivorous zooplankton avoid size-selective predation by vertical migration to a deep, cold water refuge. Adaptation to low temperatures in planktonic poikilotherms depends on essential dietary lipids; the availability of these lipids often limits growth and reproduction of zooplankton. We hypothesized that limitation by essential lipids may affect habitat preferences and predator avoidance behavior in planktonic poikilotherms. We used a liposome supplementation technique to enrich the green alga Scenedesmus obliquus and the cyanobacterium Synecchococcus elongatus with the essential lipids, cholesterol and eicosapentaenoic acid (EPA), and an indoor system with a stratified water-column (plankton organ) to test whether the absence of these selected dietary lipids constrains predator avoidance (habitat preferences) in four species of the key-stone pelagic freshwater grazer Daphnia. We found that the capability of avoiding fish predation through habitat shift to the deeper and colder environment was suppressed in Daphnia unless the diet was supplemented with EPA; however, the availability of cholesterol did not affect habitat preferences of the tested taxa. Thus, their ability to access a predator-free refuge and the outcome of predator-prey interactions depends upon food quality (i.e. the availability of an essential fatty acid). Our results suggest that biochemical food quality limitation, a bottom-up factor, may affect the top-down control of herbivorous zooplankton. PMID:26232092

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

    PubMed Central

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

    2015-01-01

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

  3. A Drug-Repositioning Screening Identifies Pentetic Acid as a Potential Therapeutic Agent for Suppressing the Elastase-Mediated Virulence of Pseudomonas aeruginosa

    PubMed Central

    Gi, Mia; Jeong, Junhui; Lee, Keehoon; Lee, Kang-Mu; Toyofuku, Masanori; Yong, Dong Eun

    2014-01-01

    Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 μM DTPA. Supplementation with Zn2+ or Mn2+ ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection. PMID:25246397

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

    PubMed

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

    2010-07-01

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

  5. Liquid human milk fortifier significantly improves docosahexaenoic and arachidonic acid status in preterm infants.

    PubMed

    Berseth, C L; Harris, C L; Wampler, J L; Hoffman, D R; Diersen-Schade, D A

    2014-09-01

    We report the fatty acid composition of mother׳s own human milk from one of the largest US cohorts of lactating mothers of preterm infants. Milk fatty acid data were used as a proxy for intake at enrollment in infants (n=150) who received human milk with a powder human milk fortifier (HMF; Control) or liquid HMF [LHMF; provided additional 12mg docosahexaenoic acid (DHA), 20mg arachidonic acid (ARA)/100mL human milk]. Mothers provided milk samples (n=129) and reported maternal DHA consumption (n=128). Infant blood samples were drawn at study completion (Study Day 28). Human milk and infant PPL fatty acids were analyzed using capillary column gas chromatography. DHA and ARA were within ranges previously published for US term and preterm human milk. Compared to Control HMF (providing no DHA or ARA), human milk fortified with LHMF significantly increased infant PPL DHA and ARA and improved preterm infant DHA and ARA status.

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

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  8. Docosahexaenoic acid content is significantly higher in ghrita prepared by traditional Ayurvedic method

    PubMed Central

    Joshi, Kalpana S.

    2014-01-01

    Background: Ghee (clarified butter) also known as ghrita, has been utilized for thousands of years in Ayurveda. Ghee is mostly prepared by traditional method in Indian households or by direct cream method at industry level. Ayurvedic classics mention that ghrita made from cow milk is superior. However, there is no scientific comparison available on preparation methods and essential fatty acids content of ghrita. Objective: To investigate fatty acid composition of ghrita prepared by traditional/Ayurvedic method and commercial method (direct cream method). Materials and Methods: Fatty Acid Methyl Esters (FAME) extracted from ghrita samples were analysed on Gas Chromatography (GC) Shimadzu B using capillary column BPX70 (0.32 mm*60 m, ID of 0.25 mm). The fatty acids in the samples were identified by comparing peaks with the external standard 68A (Nu-Chek-Prep, Inc.USA). Significant differences between the experimental groups were assessed by analysis of variance. Results: Distribution of fatty acids was compared in ghrita samples prepared by traditional method and direct cream method which is commercially used. Saturated fatty acids were predominant in both the groups. Mono unsaturated fatty acids and poly unsaturated fatty acids were in the range of 17-18% and 3-6% respectively. DHA content was significantly higher in ghee prepared by traditional method using curd starter fermentation. Conclusion: The findings suggested that ghrita prepared by traditional ayurvedic methods contains higher amount of DHA; Omega-3 long-chain polyunsaturated fatty acids, which is a major component of retinal and brain tissues and remains important in prevention of various diseases. PMID:24948858

  9. Limonium sinense and gallic acid suppress hepatitis C virus infection by blocking early viral entry.

    PubMed

    Hsu, Wen-Chan; Chang, Shun-Pang; Lin, Lie-Chwen; Li, Chia-Lin; Richardson, Christopher D; Lin, Chun-Ching; Lin, Liang-Tzung

    2015-06-01

    A preventive vaccine against hepatitis C virus (HCV) infection remains unavailable and newly developed drugs against viral replication are complicated by potential drug-resistance and high cost. These issues justify the need to develop alternative antiviral agents and expand the scope of strategies for the treatment of hepatitis C, such as targeting viral entry. In this study, we explore the bioactivity of Limonium sinense (L. sinense) and its purified constituents against HCV life cycle using subgenomic replicon and infectious HCV culture systems. Data indicated that the water extract from the underground part of L. sinense (LS-UW) exhibited potent inhibitory activity against HCV at non-cytotoxic concentrations. LS-UW targeted early HCV infection without affecting viral replication, translation, and cell-to-cell transmission, and blocked viral attachment and post-attachment entry/fusion steps. Bioactivity analysis of major constituents from LS-UW through viral infectivity/entry assays revealed that gallic acid (GA) also inhibits HCV entry. Furthermore, both LS-UW and GA could suppress HCV infection of primary human hepatocytes. Due to their potency and ability to target HCV early viral entry, LS-UW and GA may be of value for further development as prospective antivirals against HCV.

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

    PubMed

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

    2014-02-15

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

  11. Limonium sinense and gallic acid suppress hepatitis C virus infection by blocking early viral entry.

    PubMed

    Hsu, Wen-Chan; Chang, Shun-Pang; Lin, Lie-Chwen; Li, Chia-Lin; Richardson, Christopher D; Lin, Chun-Ching; Lin, Liang-Tzung

    2015-06-01

    A preventive vaccine against hepatitis C virus (HCV) infection remains unavailable and newly developed drugs against viral replication are complicated by potential drug-resistance and high cost. These issues justify the need to develop alternative antiviral agents and expand the scope of strategies for the treatment of hepatitis C, such as targeting viral entry. In this study, we explore the bioactivity of Limonium sinense (L. sinense) and its purified constituents against HCV life cycle using subgenomic replicon and infectious HCV culture systems. Data indicated that the water extract from the underground part of L. sinense (LS-UW) exhibited potent inhibitory activity against HCV at non-cytotoxic concentrations. LS-UW targeted early HCV infection without affecting viral replication, translation, and cell-to-cell transmission, and blocked viral attachment and post-attachment entry/fusion steps. Bioactivity analysis of major constituents from LS-UW through viral infectivity/entry assays revealed that gallic acid (GA) also inhibits HCV entry. Furthermore, both LS-UW and GA could suppress HCV infection of primary human hepatocytes. Due to their potency and ability to target HCV early viral entry, LS-UW and GA may be of value for further development as prospective antivirals against HCV. PMID:25865056

  12. Omega-3 Free Fatty Acids Suppress Macrophage Inflammasome Activation by Inhibiting NF-κB Activation and Enhancing Autophagy

    PubMed Central

    Williams-Bey, Yolanda; Boularan, Cedric; Vural, Ali; Huang, Ning-Na; Hwang, Il-Young; Shan-Shi, Chong; Kehrl, John H.

    2014-01-01

    The omega-3 (ω3) fatty acid docosahexaenoic acid (DHA) can suppress inflammation, specifically IL-1β production through poorly understood molecular mechanisms. Here, we show that DHA reduces macrophage IL-1β production by limiting inflammasome activation. Exposure to DHA reduced IL-1β production by ligands that stimulate the NLRP3, AIM2, and NAIP5/NLRC4 inflammasomes. The inhibition required Free Fatty Acid Receptor (FFAR) 4 (also known as GPR120), a G-protein coupled receptor (GPR) known to bind DHA. The exposure of cells to DHA recruited the adapter protein β-arrestin1/2 to FFAR4, but not to a related lipid receptor. DHA treatment reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB. DHA also reduced IL-1β levels by enhancing autophagy in the cells. As a consequence macrophages derived from mice lacking the essential autophagy protein ATG7 were partially resistant to suppressive effects of DHA. Thus, DHA suppresses inflammasome activation by two distinct mechanisms, inhibiting the initial priming step and by augmenting autophagy, which limits inflammasome activity. PMID:24911523

  13. Molecular mechanism and functional significance of acid generation in the Drosophila midgut

    PubMed Central

    Overend, Gayle; Luo, Yuan; Henderson, Louise; Douglas, Angela E.; Davies, Shireen A.; Dow, Julian A. T.

    2016-01-01

    The gut of Drosophila melanogaster includes a proximal acidic region (~pH 2), however the genome lacks the H+/K+ ATPase characteristic of the mammalian gastric parietal cell, and the molecular mechanisms of acid generation are poorly understood. Here, we show that maintenance of the low pH of the acidic region is dependent on H+ V-ATPase, together with carbonic anhydrase and five further transporters or channels that mediate K+, Cl− and HCO3− transport. Abrogation of the low pH did not influence larval survival under standard laboratory conditions, but was deleterious for insects subjected to high Na+ or K+ load. Insects with elevated pH in the acidic region displayed increased susceptibility to Pseudomonas pathogens and increased abundance of key members of the gut microbiota (Acetobacter and Lactobacillus), suggesting that the acidic region has bacteriostatic or bacteriocidal activity. Conversely, the pH of the acidic region was significantly reduced in germ-free Drosophila, indicative of a role of the gut bacteria in shaping the pH conditions of the gut. These results demonstrate that the acidic gut region protects the insect and gut microbiome from pathological disruption, and shed light on the mechanisms by which low pH can be maintained in the absence of H+, K+ ATPase. PMID:27250760

  14. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I

    PubMed Central

    Park, Seung Bum; Seronello, Scott; Mayer, Wasima; Ojcius, David M.

    2016-01-01

    Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain) were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity. PMID:27404108

  15. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.

    PubMed

    Park, Seung Bum; Seronello, Scott; Mayer, Wasima; Ojcius, David M

    2016-01-01

    Hepatitis C virus (HCV) actively evades host interferon (IFN) responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I)-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP) from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP) and poly(IC). The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain) were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity. PMID:27404108

  16. Corosolic acid suppresses the expression of inflammatory marker genes in CCL4-induced-hepatotoxic rats.

    PubMed

    Balakrishnan, Aristatile; Al-Assaf, Abdullah Hassan

    2016-07-01

    The aim of the study was to asses the anti-inflammatory effects of corosolic acid on the carbon tetrachloride (CCL4) toxicity in rats. Liver toxicity was induced by administered CCL4 (single dose (1:1 in liquid paraffin) orally at 1.25 ml/kg. Rats were pretreated with CRA for 7 days before made CCL(4) toxicity at 20 mg/kg BW. The mRNA levels of TNF-α, IL-6, iNOS, COX-2 and NF-kB were assayed by reverse transcriptase PCR analysis. The mRNA levels of proinflammatory cytokines such as TNF-α, IL-6, and the inflammatory markers such as iNOS, COX-2 and NF-kB were significantly up regulated in CCl(4) induced rats and treatment with corosolic acid significantly reduced the expression of the above indicators. Our results suggest that the inhibition of TNF-α, IL-6, iNOS, COX-2 and NF-κB by corosolic acid, a potential candidate could possess anti-inflammatory activity besides its hepatoprotective effect in CCl4 liver toxicity in rats. PMID:27393448

  17. Caffeic acid phenethyl ester suppresses monocyte adhesion to the endothelium by inhibiting NF-κB/NOX2-derived ROS signaling.

    PubMed

    Nakahara, Risa; Makino, Junya; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

    2016-05-01

    Caffeic acid phenethyl ester (CAPE), one of the major polyphenols, exhibits anti-oxidative, anti-bacterial, and anti-cancer properties. Atherosclerosis is a chronic inflammatory disease, the progression of which is closely related to the accumulated adhesion of inflammatory monocytes/macrophages to the endothelium. We herein determined whether CAPE and its derivatives suppressed THP-1 cell adhesion to human umbilical vein endothelial cells (HUVEC). Of the four polyphenols tested, CAPE significantly suppressed the 12-O-tetradecanoylphorbol 13-acetate (TPA)-elicited expression of cluster for differentiation (CD) 11b, 14, and 36, and this was accompanied by the inhibition of THP-1 cell adhesion to HUVEC. CAPE also suppressed the activation of TPA-elicited nuclear factor-κB (NF-κB) and accumulation of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS), but did not affect extracellular signal-regulated kinase (ERK) phosphorylation. Taken together, these results demonstrated that CAPE suppressed THP-1 cell adhesion to HUVEC through, at least in part, the NF-κB, NOX2, and ROS-derived signaling axis. PMID:27257341

  18. Caffeic acid phenethyl ester suppresses monocyte adhesion to the endothelium by inhibiting NF-κB/NOX2-derived ROS signaling

    PubMed Central

    Nakahara, Risa; Makino, Junya; Kamiya, Tetsuro; Hara, Hirokazu; Adachi, Tetsuo

    2016-01-01

    Caffeic acid phenethyl ester (CAPE), one of the major polyphenols, exhibits anti-oxidative, anti-bacterial, and anti-cancer properties. Atherosclerosis is a chronic inflammatory disease, the progression of which is closely related to the accumulated adhesion of inflammatory monocytes/macrophages to the endothelium. We herein determined whether CAPE and its derivatives suppressed THP-1 cell adhesion to human umbilical vein endothelial cells (HUVEC). Of the four polyphenols tested, CAPE significantly suppressed the 12-O-tetradecanoylphorbol 13-acetate (TPA)-elicited expression of cluster for differentiation (CD) 11b, 14, and 36, and this was accompanied by the inhibition of THP-1 cell adhesion to HUVEC. CAPE also suppressed the activation of TPA-elicited nuclear factor-κB (NF-κB) and accumulation of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS), but did not affect extracellular signal-regulated kinase (ERK) phosphorylation. Taken together, these results demonstrated that CAPE suppressed THP-1 cell adhesion to HUVEC through, at least in part, the NF-κB, NOX2, and ROS-derived signaling axis. PMID:27257341

  19. Ferulic Acid Suppresses Glutamate Release Through Inhibition of Voltage-Dependent Calcium Entry in Rat Cerebrocortical Nerve Terminals

    PubMed Central

    Lin, Tzu Yu; Lu, Cheng Wei; Huang, Shu-Kuei

    2013-01-01

    Abstract This study investigated the effects and possible mechanism of ferulic acid, a naturally occurring phenolic compound, on endogenous glutamate release in the nerve terminals of the cerebral cortex in rats. Results show that ferulic acid inhibited the release of glutamate evoked by the K+ channel blocker 4-aminopyridine (4-AP). The effect of ferulic acid on the evoked glutamate release was prevented by chelating the extracellular Ca2+ ions, but was insensitive to the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate. Ferulic acid suppressed the depolarization-induced increase in a cytosolic-free Ca2+ concentration, but did not alter 4-AP–mediated depolarization. Furthermore, the effect of ferulic acid on evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking ryanodine receptors or mitochondrial Na+/Ca2+ exchange. These results show that ferulic acid inhibits glutamate release from cortical synaptosomes in rats through the suppression of presynaptic voltage-dependent Ca2+ entry. PMID:23342970

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

    PubMed Central

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

    2011-01-01

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

  1. Apoptotic effect of gambogic acid in esophageal squamous cell carcinoma cells via suppression of the NF-κB pathway

    PubMed Central

    LIU, WEN-YUE; WU, XU; LIAO, CHENG-QUAN; SHEN, JIE; LI, JUN

    2016-01-01

    Despite extensive investigations of therapeutic improvements for surgical techniques, chemotherapy and chemoradiotherapy, esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive forms of cancer, and the prognosis for patients with advanced ESCC remains poor. Therefore, effective therapies are urgently required in order to improve the prognosis of patients with ESCC. TE-1 cells were treated with gambogic acid (GA), and then subjected to western blot analysis, TUNEL assay and caspase activity analysis. GA significantly induced apoptosis in ESCC TE-1 cells. In addition, the antitumor activity of GA was accompanied by the decreased expression of phosphorylated-protein kinase B (p-AKT) and nuclear factor of κ light polypeptide gene enhancer in B-cells 1 (NF-κB). The inhibition of protein kinase B (AKT) and NF-κB activation by chemical inhibitors augmented the apoptotic effect responses to GA in the TE-1 cells. The pan-caspase inhibitor z-VAD-fmk (zVAD) decreased GA-induced apoptosis. Furthermore, zVAD attenuated GA-induced growth inhibition in TE-1 cells. GA induced apoptosis in ESCC TE-1 via suppression of NF-κB pathway. The findings of the present study may provide a novel insight into ESCC treatment. PMID:27284372

  2. Suppression of Jasmonic Acid-Mediated Defense by Viral-Inducible MicroRNA319 Facilitates Virus Infection in Rice.

    PubMed

    Zhang, Chao; Ding, Zuomei; Wu, Kangcheng; Yang, Liang; Li, Yang; Yang, Zhen; Shi, Shan; Liu, Xiaojuan; Zhao, Shanshan; Yang, Zhirui; Wang, Yu; Zheng, Luping; Wei, Juan; Du, Zhenguo; Zhang, Aihong; Miao, Hongqin; Li, Yi; Wu, Zujian; Wu, Jianguo

    2016-09-01

    MicroRNAs (miRNAs) are pivotal modulators of plant development and host-virus interactions. However, the roles and action modes of specific miRNAs involved in viral infection and host susceptibility remain largely unclear. In this study, we show that Rice ragged stunt virus (RRSV) infection caused increased accumulation of miR319 but decreased expression of miR319-regulated TCP (TEOSINTE BRANCHED/CYCLOIDEA/PCF) genes, especially TCP21, in rice plants. Transgenic rice plants overexpressing miR319 or downregulating TCP21 exhibited disease-like phenotypes and showed significantly higher susceptibility to RRSV in comparison with the wild-type plants. In contrast, only mild disease symptoms were observed in RRSV-infected lines overexpressing TCP21 and especially in the transgenic plants overexpressing miR319-resistant TCP21. Both RRSV infection and overexpression of miR319 caused the decreased endogenous jasmonic acid (JA) levels along with downregulated expression of JA biosynthesis and signaling-related genes in rice. However, treatment of rice plants with methyl jasmonate alleviated disease symptoms caused by RRSV and reduced virus accumulation. Taken together, our results suggest that the induction of miR319 by RRSV infection in rice suppresses JA-mediated defense to facilitate virus infection and symptom development. PMID:27381440

  3. Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice.

    PubMed

    Su, Jin; Sherman, Alexandra; Doerfler, Phillip A; Byrne, Barry J; Herzog, Roland W; Daniell, Henry

    2015-10-01

    Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 μg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 μg rhGAA per dose, with several-fold lower titre of GAA-specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30-fold (up to 190 μg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation.

  4. Suppression of heparine-induced increment of rat free fatty acids by oxprenolol.

    PubMed

    Bartsokas, S K; Trichopoulou-Polychronopoulou, A D; Charissiadou, A; Valsamakis, S; Kalaitjidou, C

    1975-05-01

    Injection of heparin i.v. into rats increased significantly free fatty acids (FFAs) plasma levels. When 20 min before the heparin injection 1-(o-allyloxy-phenoxy)-3-isopropylamino-propane-2-ol-hydrochloride (oxprenolol, Trasicor) was administered i.p., FFAs increment was prevented. Isoproterenol-induced plasma FFAs rise was also inhibited by the administration of this beta-adrenergic receptor blocking agent. Treatment by beta-adrenergic receptor blockade for prevention of heparine-induced FFAs increase, which possibly contributes to the appearance of heart arrhythmias, must be considered. PMID:1242320

  5. alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis.

    PubMed

    Ha, Hyunil; Lee, Jong-Ho; Kim, Ha-Neui; Kim, Hyun-Man; Kwak, Han Bok; Lee, Seungbok; Kim, Hong-Hee; Lee, Zang Hee

    2006-01-01

    alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several pathological conditions, including diabetic polyneuropathy. In the present study, we examined the effects of LA on osteoclastic bone loss associated with inflammation. LA significantly inhibited IL-1-induced osteoclast formation in cocultures of mouse osteoblasts and bone marrow cells, but LA had only a marginal effect on osteoclastogenesis from bone marrow macrophages induced by receptor activator of NF-kappaB ligand (RANKL). LA inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts. In addition, treatment with either prostaglandin E2 (PGE2) or RANKL rescued IL-1-induced osteoclast formation inhibited by LA or NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, in cocultures. LA blocked IL-1-induced PGE2 production even in the presence of arachidonic acid, without affecting the expression of COX-2 and membrane-bound PGE2 synthase. Dihydrolipoic acid (the reduced form of LA), but not LA, attenuated recombinant COX-2 activity in vitro. LA also inhibited osteoclast formation and bone loss induced by IL-1 and LPS in mice. Our results suggest that the reduced form of LA inhibits COX-2 activity, PGE2 production, and sustained RANKL expression, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.

  6. Dietary Omega-3 Polyunsaturated Fatty Acids Suppress NHE-1 Upregulation in a Rabbit Model of Volume- and Pressure-Overload

    PubMed Central

    van Borren, Marcel M. G. J.; den Ruijter, Hester M.; Baartscheer, Antonius; Ravesloot, Jan H.; Coronel, Ruben; Verkerk, Arie O.

    2012-01-01

    Background: Increased consumption of omega-3 polyunsaturated fatty acids (ω3-PUFAs) from fish oil (FO) may have cardioprotective effects during ischemia/reperfusion, hypertrophy, and heart failure (HF). The cardiac Na+/H+-exchanger (NHE-1) is a key mediator for these detrimental cardiac conditions. Consequently, chronic NHE-1 inhibition appears to be a promising pharmacological tool for prevention and treatment. Acute application of the FO ω3-PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) inhibit the NHE-1 in isolated cardiomyocytes. We studied the effects of a diet enriched with ω3-PUFAs on the NHE-1 activity in healthy rabbits and in a rabbit model of HF induced by volume- and pressure-overload. Methods: Rabbits were allocated to four groups. The first two groups consisted of healthy rabbits, which were fed either a diet containing 1.25% (w/w) FO (ω3-PUFAs), or 1.25% high-oleic sunflower oil (ω9-MUFAs) as control. The second two groups were also allocated to either a diet containing ω3-PUFAs or ω9-MUFAs, but underwent volume- and pressure-overload to induce HF. Ventricular myocytes were isolated by enzymatic dissociation and used for intracellular pH (pHi) and patch-clamp measurements. NHE-1 activity was measured in HEPES-buffered conditions as recovery rate from acidosis due to ammonium prepulses. Results: In healthy rabbits, NHE-1 activity in ω9-MUFAs and ω3-PUFAs myocytes was not significantly different. Volume- and pressure-overload in rabbits increased the NHE-1 activity in ω9-MUFAs myocytes, but not in ω3-PUFAs myocytes, resulting in a significantly lower NHE-1 activity in myocytes of ω3-PUFA fed HF rabbits. The susceptibility to induced delayed afterdepolarizations (DADs), a cellular mechanism of arrhythmias, was lower in myocytes of HF animals fed ω3-PUFAs compared to myocytes of HF animals fed ω9-MUFAs. In our rabbit HF model, the degree of hypertrophy was similar in the ω3-PUFAs group compared to the ω9-MUFAs group

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

    SciTech Connect

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

    2015-09-10

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

  8. Intravenous anesthetic propofol suppresses prostaglandin E2 and cysteinyl leukotriene production and reduces edema formation in arachidonic acid-induced ear inflammation.

    PubMed

    Inada, Takefumi; Hirota, Kiichi; Shingu, Koh

    2015-01-01

    Propofol is an intravenous drug widely used for anesthesia and sedation. Previously, propofol was shown to inhibit cyclo-oxygenase (COX) and 5-lipoxygenase (5-LOX) activities. Because these enzyme-inhibiting effects have only been demonstrated in vitro, this study sought to ascertain whether similar effects might also be observed in vivo. In the current studies, effects of propofol were tested in a murine model of arachidonic acid-induced ear inflammation. Specifically, propofol - as a pre-treatment -- was intraperitoneally and then topical application of arachidonic acid was performed. After 1 h, tissue biopsies were collected and tested for the presence of edema and for levels of inflammatory mediators. The results indicated that the administration of propofol significantly suppressed ear edema formation, tissue myeloperoxidase activity, and tissue production of both prostaglandin E2 and cysteinyl leukotrienes. From the data, it can be concluded that propofol could exert anti-COX and anti-5-LOX activities in an in vivo model and that these activities in turn could have, at least in part, suppressed arachidonic acid-induced edema formation in the ear.

  9. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    SciTech Connect

    Chien, Chia-Wen; Yao, Ju-Hsien; Chang, Shih-Yu; Lee, Pei-Chih; Lee, Te-Chang

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivo in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.

  10. Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPAR{sub β/δ} in HepG2 cells

    SciTech Connect

    Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua; Berggren-Söderlund, Maria; Nilsson-Ehle, Peter; Zhang, Xiaoying; Xu, Ning

    2014-02-28

    Highlights: • Palmitic acid significantly inhibited APOM gene expression in HepG2 cells. • Palmitic acid could obviously increase PPARB/D mRNA levels in HepG2 cells. • PPAR{sub β/δ} antagonist, GSK3787, had no effect on APOM expression. • GSK3787 could reverse the palmitic acid-induced down-regulation of APOM expression. • Palmitic acid induced suppression of APOM expression is mediated via the PPAR{sub β/δ} pathway. - Abstract: It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPAR{sub β/δ}) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPAR{sub β/δ} pathway.

  11. Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

    PubMed Central

    Yang, Qiao-ling; Yang, Fan; Gong, Jun-ting; Tang, Xiao-wen; Wang, Guang-yun; Wang, Zheng-tao; Yang, Li

    2016-01-01

    Aim: Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice. Methods: Mice received sweroside (120 mg·kg−1·d−1, ig) or a positive control INT-747 (12 mg·kg−1·d−1, ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined. Results: Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT-induced elevation of individual hepatic bile acids, such as β-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability. Conclusion: Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses. PMID:27498779

  12. Identification of significant medium components that affect docosahexaenoic acid production by Schizochytrium sp. SW1

    NASA Astrophysics Data System (ADS)

    Manikan, Vidyah; Hamid, Aidil A.

    2013-11-01

    Central composite design (CCD) was employed to investigate the significance of glucose, yeast extract, MSG and sea salt in affecting the amount of docosahexaenoic acid (DHA) accumulated by a locally isolated strain of Schizochytrium. Design Expert software was used to construct a set of experiments where each medium component mentioned above was varied over three levels. Cultivation was carried out in 250mL flasks containing 50mL of medium, incubated at 30°C with 200 rpm agitation for 96 hours. ANOVA was conducted to identify the influential factors and the level of their significance where factors that scored a probability value of less than 0.05 were considered significant. The level of influence for each independent variable was also interpreted using perturbation whereas pattern of interaction between the factors were interpreted using interaction plots. This experiment revealed that yeast extract and monosodium glutamate have significant influence on DHA accumulation process by Schizochytrium sp. SW1.

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

    EPA Science Inventory

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

  14. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.

    PubMed

    Holt, Jason A; Luo, Guizhen; Billin, Andrew N; Bisi, John; McNeill, Y Yvette; Kozarsky, Karen F; Donahee, Mary; Wang, Da Yuan; Mansfield, Traci A; Kliewer, Steven A; Goodwin, Bryan; Jones, Stacey A

    2003-07-01

    The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.

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

    PubMed Central

    Kang, Jaeseung; Kim, Eunjoon

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-08-01

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

  18. Surfactants, aromatic and isoprenoid compounds, and fatty acid biosynthesis inhibitors suppress Staphylococcus aureus production of toxic shock syndrome toxin 1.

    PubMed

    McNamara, Peter J; Syverson, Rae Ellen; Milligan-Myhre, Kathy; Frolova, Olga; Schroeder, Sarah; Kidder, Joshua; Hoang, Thanh; Proctor, Richard A

    2009-05-01

    Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1.

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

    PubMed

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

    2015-03-01

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

  20. The chemotaxonomic significance of two bioactive caffeic acid esters, nepetoidins A and B, in the Lamiaceae.

    PubMed

    Grayer, Renée J; Eckert, Maria R; Veitch, Nigel C; Kite, Geoffrey C; Marin, Petar D; Kokubun, Tetsuo; Simmonds, Monique S J; Paton, Alan J

    2003-09-01

    A survey of leaf surface constituents in the family Lamiaceae using HPLC with diode array detection revealed the presence of two characteristic phenolic compounds in many species. The distribution of these phenolics in the Lamiaceae was found to be of taxonomic significance, as they were present in the great majority of species investigated for the subfamily Nepetoideae, including representatives of the well-known genera of culinary herbs, mint, rosemary, sage, thyme and basil. In contrast, they were absent from species of the other subfamilies of Lamiaceae studied and from the related families Verbenaceae, Scrophulariaceae, Acanthaceae and Buddlejaceae. The compounds were isolated from Plectranthus crassus and identified by NMR spectroscopy as the known caffeic acid esters (Z,E)-[2-(3,5-dihydroxyphenyl)ethenyl] 3-(3,4-dihydroxyphenyl)-2-propenoate and (Z,E)-[2-(3,4-dihydroxyphenyl)ethenyl] 3-(3,4-dihydroxyphenyl)-2-propenoate, for which the trivial names nepetoidins A and B are proposed. The presence of this pair of caffeic acid esters adds another character to the chemical, palynological and embryological features distinguishing the Nepetoideae from the other subfamilies of Lamiaceae and related families, and supports the view that the Nepetoideae are a specialised and monophyletic group within the family. Nepetoidin B was shown to have a greater antioxidant activity than gallic, rosmarinic and caffeic acids, and showed activity as an insect phagostimulant. Both compounds were antifungal.

  1. Gastric ulcer treatment: cure of Helicobacter pylori infection without subsequent acid-suppressive therapy: is it effective?

    PubMed

    van Zanten, Sander Veldhuyzen; van der Knoop, Bloeme

    2008-06-01

    Whether it is a requirement to continue with anti-secretory therapy following anti-Helicobacter therapy in H. pylori positive gastric ulcers is an important question. As gastric ulcers tend to heal more slowly than duodenal ulcers, may be asymptomatic or only causing mild symptoms and success at curing H. pylori with current fist line therapies is 80% at best, clinicians will likely err on the side of caution and continue acid suppressive therapy to ensure healing of gastric ulcers. This is certainly recommended when dealing with bleeding ulcers.

  2. Acid-base titrations for polyacids: Significance of the pK sub a and parameters in the Kern equation

    NASA Technical Reports Server (NTRS)

    Meites, L.

    1978-01-01

    A new method is suggested for calculating the dissociation constants of polyvalent acids, especially polymeric acids. In qualitative form the most significant characteristics of the titration curves are demonstrated and identified which are obtained when titrating the solutions of such acids with a standard base potentiometrically.

  3. Combined dermal exposure to permethrin and cis-urocanic acid suppresses the contact hypersensitivity response in C57BL/6N mice in an additive manner.

    PubMed

    Prater, M R; Blaylock, B L; Holladay, S D

    2005-01-14

    Cutaneous exposure to the pyrethroid insecticide permethrin significantly suppresses contact hypersensitivity (CH) response to oxazolone in C57BL/6N mice. Additionally, cis-urocanic acid (cUCA), an endogenous cutaneous chromophore isomerized to its active form following exposure to ultraviolet radiation, modulates cell-mediated cutaneous immune responses. This study describes cutaneous immune alterations following combined topical permethrin and intradermal cUCA exposure. Female C57BL/6N mice were administered 5, 50 or 100 microg cUCA daily for 5 consecutive days. CH was then evaluated by the mouse ear swelling test (MEST) response to oxazolone. Decreased responses of 52.3%, 76.3% and 76.3%, respectively, as compared to controls were observed. Then, mice were co-exposed to 5 microg cUCA daily for 5 days and 1.5, 5, 15, or 25 microL permethrin, on either day 1, 3 or 5 of the cUCA treatment to evaluate combined immunomodulatory effects of the two chemicals, or cUCA daily for 5 days followed by permethrin on day 3, 5, or 7 after the last cUCA injection to demonstrate prolonged immunosuppressive effects. Two days after final treatment, mice were sensitized with oxazolone and MEST was performed. Mice receiving five cUCA injections and permethrin topically on cUCA injection day 1 showed up to 93.3% suppression of MEST compared to vehicle control. CH was suppressed by 87.5%, 86.6% and 74.2% in mice treated with 25 muL permethrin on days 3, 5 and 7 after cUCA, respectively, compared to vehicle control. Taken together, these data indicate co-exposure to cUCA and permethrin profoundly suppresses cell-mediated cutaneous immunity. PMID:15629246

  4. Significance of acid-mucin-positive nongoblet columnar cells in the distal esophagus and gastroesophageal junction.

    PubMed

    Chen, Y Y; Wang, H H; Antonioli, D A; Spechler, S J; Zeroogian, J M; Goyal, R; Shahsafaei, A; Odze, R D

    1999-12-01

    Acidic mucin-positive nongoblet columnar cells (NGCC) have recently been observed in the surface epithelium of the gastroesophageal junction (GEJ) and distal esophagus in resections from patients with traditional long segment (>3 cm) Barrett's esophagus (BE). However, the significance of finding acidic mucin-positive NGCC in the surface epithelium of biopsy specimens from the distal esophagus/GEJ region in the absence of goblet cells (GC) remains unknown. Therefore, to determine the significance of mucin histochemical changes in the distal esophagus/GEJ region, we analyzed and compared the types, prevalence, and distribution of neutral and acidic mucins in biopsy specimens obtained from 2 groups of patients: those with (32 patients) and those without (107 patients) GC identified in this area. Various mucin histochemical stains (PAS-Ab pH 2.5, HID-Ab pH 2.5, PB/KOH/PAS) were used to identify neutral mucins, acidic mucins (sialomucins and sulphomucins), and o-acetylated sialomucins. The results were compared between the 2 patient groups and correlated with the clinical, endoscopic, and pathologic features. Compared with patients without GC, patients with GC had a significantly higher male/female ratio and a higher proportion of patients with greater than 3 cm of columnar epithelium within the esophagus. Acidic mucin (sialomucin and sulphomucin)-positive NGCC in the surface, foveolar, and glandular epithelium did not show any correlation with any of the clinical, endoscopic, or pathologic features, such as esophagitis, carditis, antritis, Helicobacter pylori infection, or length of columnar epithelium in the distal esophagus. However, acidic mucin-positive NGCC correlated strongly with the presence of GC (P < .001). For example, sialomucin-positive NGCC were present in 28 of 32 (88%) patients with GC compared with 31 of 107 (29%) patients without GC (P < .001). Similarly, sulphomucin-positive NGCC were present in 20 of 32 (62%) patients with GC, compared with 11 of

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

    PubMed

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

    2015-07-01

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

  6. Epigenetic suppression of the antitumor cytotoxicity of NK cells by histone deacetylase inhibitor valproic acid

    PubMed Central

    Shi, Xiumin; Li, Min; Cui, Meizi; Niu, Chao; Xu, Jianting; Zhou, Lei; Li, Wei; Gao, Yushun; Kong, Weisheng; Cui, Jiuwei; Hu, Jifan; Jin, Haofan

    2016-01-01

    Natural killer (NK) cells play an essential role in the fight against tumor development. The therapeutic use of autologous NK cells has been exploited to treat human malignancies, yet only limited antitumor activity is observed in cancer patients. In this study, we sought to augment the antitumor activity of NK cells using epigenetic approaches. Four small molecules that have been known to promote epigenetic reprogramming were tested for their ability to enhance the activity of NK cells. Using a tumor cell lysis assay, we found that the DNA demethylating agent 5-azacytidine and vitamin C did not significantly affect the tumor killing ability of NK cells. The thyroid hormone triiodothyronine (T3) slightly increased the activity of NK cells. The histone deacetylase inhibitor valproic acid (VPA), however, inhibited NK cell lytic activity against leukemic cells in a dose-dependent manner. Pretreatment using VPA reduced IFNγ secretion, impaired CD107a degranulation, and induced apoptosis by activating the PD-1/PD-L1 pathway. VPA downregulated the expression of the activating receptor NKG2D (natural-killer group 2, member D) by inducing histone K9 hypermethylation and DNA methylation in the gene promoter. Histone deacetylase inhibitors have been developed as anticancer agents for use as monotherapies or in combination with other anticancer therapies. Our data suggest that the activity of histone deacetylase inhibitors on NK cell activity should be considered in drug development. PMID:27152238

  7. Fasting-induced suppression of hypothalamic-pituitary-gonadal axis in the adult rhesus monkey: evidence for involvement of excitatory amino acid neurotransmitters.

    PubMed

    Shahab, M; Zaman, W; Bashir, K; Arslan, M

    1997-01-01

    The present study was designed to examine whether acute food-restriction in non-human primates, suppresses hypothalamic-pituitary-testicular (HPT) axis via alterations in the excitatory amino acid (EAA) neurotransmitter-utilizing drive to the GnRH neuron. This was achieved indirectly by comparing the plasma testosterone (T) responses to administration of an excitatory amino acid analogue, N-methyl-D,L-aspartic acid (NMA), in acutely fasted and normal fed monkeys. A set of 4 chair-restrained adult male rhesus monkeys, was assigned to the following treatments: a) normal feeding, b) one-day fasting (omission of morning and afternoon meals), c) normal feeding+NMA (15 mg/kg BW) and d) one-day fasting+NMA (15 mg/kg BW). Starting 1 h after the provision or omission of the afternoon meal, frequent blood sampling was initiated at 15-min intervals for a period of 3-h. NMA was administered as an iv bolus 1 h after start of the sampling. Secretion of T was affected (P<0.005) by the treatments. A peak in T was evident during the first h of the sampling in fed but not fasted monkeys. Mean 3-h T concentrations were suppressed (P<0.001) by the fasting. Administration of NMA in fasting conditions resulted into an acute stimulation of T secretion in 2 of the 4 monkeys. However, mean 60-min post-NMA T concentrations were greater (P<0.05) than those prevailing during the same period in fasted animals not given NMA. In contrast, all 4 fed-monkeys showed significant T elevations in plasma immediately following the NMA challenge and mean T levels during the 60-min post-NMA period were higher (P<0.05) than those in fed animals not injected with NMA, at a comparable time. Testosterone area under the curve for the 2-h post-NMA period was greater (P<0.05) in fed- than in fasted-monkeys. These results indicate that although NMA can stimulate GnRH release both in fed and short-term fasting conditions, the response appears to be suppressed in the later situation suggesting that fasting

  8. Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester.

    PubMed

    Lim, Kyung-Min; Bae, SeungJin; Koo, Jung Eun; Kim, Eun-Sun; Bae, Ok-Nam; Lee, Joo Young

    2015-04-01

    Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-α-induced NF-κB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-α, cyclooxygenase-2 and inducible NO synthase in TPA-stimulated skin. TPA-induced phosphorylation of IκB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-κB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans-epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases.

  9. Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester.

    PubMed

    Lim, Kyung-Min; Bae, SeungJin; Koo, Jung Eun; Kim, Eun-Sun; Bae, Ok-Nam; Lee, Joo Young

    2015-04-01

    Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-α-induced NF-κB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-α, cyclooxygenase-2 and inducible NO synthase in TPA-stimulated skin. TPA-induced phosphorylation of IκB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-κB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans-epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases. PMID:25501505

  10. Suppression of the allogeneic response by the anti-allergy drug N-(3,4-dimethoxycinnamonyl) anthranilic acid results from T-cell cycle arrest

    PubMed Central

    Zaher, Sarah S; Coe, David; Chai, Jian-Guo; Larkin, Daniel FP; George, Andrew JT

    2013-01-01

    Previously we have shown that indoleamine 2,3-dioxygenase (IDO) and the tryptophan metabolite, 3-hydroxykynurenine (3HK) can prolong corneal allograft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan by breakdown to kynurenines, which themselves act directly on T lymphocytes. The tryptophan metabolite analogue N-(3,4-dimethoxycinnamonyl) anthranilic acid (DAA, ‘Tranilast’) shares the anthranilic acid core with 3HK. Systemic administration of DAA to mice receiving a fully MHC-mismatched allograft of cornea or skin resulted in significant delay in rejection (median survival of controls 12 days, 13 days for cornea and skin grafts, respectively, and of treated mice 24 days (P < 0·0001) and 17 days (P < 0·03), respectively). We provide evidence that DAA-induced suppression of the allogeneic response, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T-cell death. Cell cycle arrest was mediated by up-regulation of the cell cycle-specific inhibitors p21 and p15, and associated with a significant reduction in interleukin-2 production, allowing us to characterize a novel mechanism for DAA-induced T-cell anergy. Currently licensed as an anti-allergy drug, the oral bioavailability and safe therapeutic profile of DAA make it a candidate for the prevention of rejection of transplanted cornea and other tissues. PMID:23121382

  11. Nitric acid photolysis on surfaces in low-NOx environments: Significant atmospheric implications

    NASA Astrophysics Data System (ADS)

    Zhou, Xianliang; Gao, Honglian; He, Yi; Huang, Gu; Bertman, Steven B.; Civerolo, Kevin; Schwab, James

    2003-12-01

    Nitric acid (HNO3) is the dominant end product of NOx (= NO + NO2) oxidation in the troposphere, and its dry deposition is considered to be a major removal pathway for the atmospheric reactive nitrogen. Here we present both field and laboratory results to demonstrate that HNO3 deposited on ground and vegetation surfaces may undergo effective photolysis to form HONO and NOx, 1-2 orders of magnitude faster than in the gas phase and aqueous phase. With this enhanced rate, HNO3 photolysis on surfaces may significantly impact the chemistry of the overlying atmospheric boundary layer in remote low-NOx regions via the emission of HONO as a radical precursor and the recycling of HNO3 deposited on ground surfaces back to NOx.

  12. Influence of disease-suppressive strains of Streptomyces on the native Streptomyces community in soil as determined by the analysis of cellular fatty acids.

    PubMed

    Bowers, J H; Kinkel, L L; Jones, R K

    1996-01-01

    Analysis of cellular fatty acid profiles was used to distinguish among introduced pathogen- suppressive strains and indigenous strains of Streptomyces spp. isolated from soil of field plots established to test the efficacy of Streptomyces strains PonSSII and PonR in the biological control of potato scab. Reference libraries of fatty acid profiles were developed for a collection of known pathogenic strains and the introduced suppressive strains. Population densities of pathogen-related, suppressive, and saprophytic Streptomyces strains were determined from the relationship of field isolates to mean library profiles using cluster analysis and the unweighted pair-group method using arithmetic averages. Community diversity was similarly determined. Streptomyces strains PonSSII and PonR were distinguished from each other and from the pathogen group (which clustered together) based on fatty acid profiles. The introduced, suppressive strains successfully colonized the soil and represented 2-19% of the isolates sampled over 2 years. The introduction of the suppressive strains inhibited the population of strains related to the pathogen library at each sample date; the pathogen population was substantially lower in soil from treatments where the suppressive strains were introduced compared with the nonamended control. At harvest, the pathogen-related population was suppressed 85-93 and 36-44% in 1991 and 1992, respectively, in treatments with the suppressive strains compared with the nonamended control. Diversity of the community was not affected by the introduced strains, and diversity and equitability indices were similar among treatments at any sample time. The inhibition of the pathogen-related population was correlated with a reduction of scab symptoms observed in the field plots into which the suppressive strains were introduced. Implications of a fundamental shift in the pathogen-related population in response to the introduction of the suppressive strains for long

  13. A novel primary bile acid in the Shoebill stork and herons and its phylogenetic significance.

    PubMed

    Hagey, L R; Schteingart, C D; Ton-Nu, H-T; Hofmann, A F

    2002-05-01

    The Shoebill stork, an enigma phylogenetically, was found to contain as its dominant biliary bile acid 16alpha-hydroxychenodeoxycholic acid, a heretofore undescribed bile acid. The bile acid occurred as its taurine N-acyl amidate; structure was established by nuclear magnetic resonance (NMR) and mass spectrometry (MS). A search for this novel bile acid in other Ciconiiformes showed that it constituted >92% of biliary bile acids in five of nine herons in the Ardidae, but was absent in all other families (Ciconiidae, Threskiornithidae, Scopidae, Phoenicopteridae). The presence of this biochemical trait in the Shoebill stork and certain herons suggests that these birds are closely related.

  14. Potent Anti-Inflammatory Activity of Ursolic Acid, a Triterpenoid Antioxidant, Is Mediated through Suppression of NF-κB, AP-1 and NF-AT

    PubMed Central

    Checker, Rahul; Sandur, Santosh K.; Sharma, Deepak; Patwardhan, Raghavendra S.; Jayakumar, S.; Kohli, Vineet; Sethi, Gautam; Aggarwal, Bharat B.; Sainis, Krishna B.

    2012-01-01

    Background Ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, is the major component of many plants including apples, basil, cranberries, peppermint, rosemary, oregano and prunes and has been reported to possess antioxidant and anti-tumor properties. These properties of UA have been attributed to its ability to suppress NF-κB (nuclear factor kappa B) activation. Since NF-κB, in co-ordination with NF-AT (nuclear factor of activated T cells) and AP-1(activator protein-1), is known to regulate inflammatory genes, we hypothesized that UA might exhibit potent anti-inflammatory effects. Methodology/Principal Findings The anti-inflammatory effects of UA were assessed in activated T cells, B cells and macrophages. Effects of UA on ERK, JNK, NF-κB, AP-1 and NF-AT were studied to elucidate its mechanism of action. In vivo efficacy of UA was studied using mouse model of graft-versus-host disease. UA inhibited activation, proliferation and cytokine secretion in T cells, B cells and macrophages. UA inhibited mitogen-induced up-regulation of activation markers and co-stimulatory molecules in T and B cells. It inhibited mitogen-induced phosphorylation of ERK and JNK and suppressed the activation of immunoregulatory transcription factors NF-κB, NF-AT and AP-1 in lymphocytes. Treatment of cells with UA prior to allogenic transplantation significantly delayed induction of acute graft-versus-host disease in mice and also significantly reduced the serum levels of pro-inflammatory cytokines IL-6 and IFN-γ. UA treatment inhibited T cell activation even when added post-mitogenic stimulation demonstrating its therapeutic utility as an anti-inflammatory agent. Conclusions/Significance The present study describes the detailed mechanism of anti-inflammatory activity of UA. Further, UA may find application in the treatment of inflammatory disorders. PMID:22363615

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

    PubMed Central

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

    2016-01-01

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

  16. Fasciola hepatica fatty acid binding protein inhibits TLR4 activation and suppresses the inflammatory cytokines induced by LPS in vitro and in vivo

    PubMed Central

    Martin, Ivelisse; Cabán-Hernández, Kimberly; Figueroa-Santiago, Olgary; Espino, Ana M.

    2015-01-01

    Toll-like receptor 4 (TLR4), the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial lipopolysaccharide (LPS), which is a major cause of the high mortality associated with bacterial sepsis. We report here that a single intraperitoneal injection of 15μg Fasciola hepatica fatty acid binding protein (Fh12) 1 hour before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Because macrophages are good source of IL12p70 and TNFα, and critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow derived macrophages (bmMΦs). Whereas Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL12, TNFα, IL6 and IL1β cytokines as well as iNOS2 in bmMΦs, and also impaired the phagocytic capacity of bmMΦs. Fh12 had a limited effect on the expression of inflammatory cytokines induced in response to other TLR-ligands. One mechanism used by Fh12 to exert its anti-inflammatory effect is binding to the CD14 co-receptor. Moreover, it suppresses phosphorylation of ERK, p38 and JNK. The potent anti-inflammatory properties of Fh12 demonstrated here open doors to further studies directed at exploring the potential of this molecule as a new class of drug against septic shock or other inflammatory diseases. PMID:25780044

  17. Suppression of VLDL secretion by cultured hepatocytes incubated with chylomicron remnants enriched in n-3 polyunsaturated fatty acids is regulated by hepatic nuclear factor-4alpha.

    PubMed

    López-Soldado, Iliana; Avella, Michael; Botham, Kathleen M

    2009-12-01

    Dietary n-3 polyunsaturated fatty acids (PUFA) suppress the secretion of very low density lipoprotein (VLDL) directly when delivered to the liver in chylomicron remnants (CMR). The role of sterol regulatory element-binding proteins (SREBPs) and hepatic nuclear factor-4alpha (HNF-4alpha) in the regulation of this effect was investigated. Chylomicron remnant-like particles (CRLPs) containing triacylglycerol (TG) from palm (rich in saturated fatty acids (SFA)) or fish (rich in n-3 PUFA) oil were incubated with cultured rat hepatocytes (24h) and the expression of protein and mRNA for SREBP-1, SREBP-2 and HNF-4alpha, and levels of mRNA for their target genes were determined. SREBP-1 and -2 protein expression in the membrane and nuclear fractions was unaffected by either type of CRLPs. mRNA abundance for SREBP-1c and -2 was also unchanged by CRLP-treatment, as were levels of mRNA for target genes of SREBP-1, including steroyl CoA desaturase, acetyl CoA carboxylase, fatty acid synthase and ATP citrate lyase, and SREBP-2 (3-hydroxy-3-methylglutaryl CoA reductase). In contrast, HNF-4alpha protein and mRNA levels were significantly decreased by CRLPs enriched in n-3 PUFA, but not SFA, and the expression of mRNA for HNF-4alpha target genes, including HNF-1alpha, apolipoprotein B and the microsomal TG transfer protein, was also lowered by n-3 PUFA-, but not SFA-enriched CRLPs. These findings suggest that the direct suppression of VLDL secretion by dietary n-3 PUFA delivered to the liver in CMR is mediated via decreased expression of HNF-4alpha.

  18. Antisense suppression of phospholipase D alpha retards abscisic acid- and ethylene-promoted senescence of postharvest Arabidopsis leaves.

    PubMed

    Fan, L; Zheng, S; Wang, X

    1997-12-01

    Membrane disruption has been proposed to be a key event in plant senescence, and phospholipase D (PLD; EC 3.1.4.4) has been thought to play an important role in membrane deterioration. We recently cloned and biochemically characterized three different PLDs from Arabidopsis. In this study, we investigated the role of the most prevalent phospholipid-hydrolyzing enzyme, PLD alpha, in membrane degradation and senescence in Arabidopsis. The expression of PLD alpha was suppressed by introducing a PLD alpha antisense cDNA fragment into Arabidopsis. When incubated with abscisic acid and ethylene, leaves detached from the PLD alpha-deficient transgenic plants showed a slower rate of senescence than did those from wild-type and transgenic control plants. The retardation of senescence was demonstrated by delayed leaf yellowing, lower ion leakage, greater photosynthetic activity, and higher content of chlorophyll and phospholipids in the PLD alpha antisense leaves than in those of the wild type. Treatment of detached leaves with abscisic acid and ethylene stimulated PLD alpha expression, as indicated by increases in PLD alpha mRNA, protein, and activity. In the absence of abscisic acid and ethylene, however, detached leaves from the PLD alpha-deficient and wild-type plants showed a similar rate of senescence. In addition, the suppression of PLD alpha did not alter natural plant growth and development. These data suggest that PLD alpha is an important mediator in phytohormone-promoted senescence in detached leaves but is not a direct promoter of natural senescence. The physiological relevance of these findings is discussed.

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

    PubMed Central

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

    1990-01-01

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

  20. Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet.

    PubMed

    Huang, Hsiu-Chen; Lin, Jen-Kun

    2012-02-01

    Although green tea extract has been reported to suppress hyperlipidemia, it is unclear how tea extracts prepared from green, oolong, black and pu-erh teas modulate fatty acid synthase expression in rats fed on a high-fructose diet. In this animal study, we evaluated the hypolipidemic and hypoleptinemia effect of these four different tea leaves fed to male Wistar rats for 12 weeks. The results showed that a fructose-rich diet significantly elevated serum triacylglycerols, cholesterol, insulin, and leptin concentrations, as compared with those in the control group. Interestingly, consuming tea leaves for 12 weeks almost normalized the serum triacylglycerols concentrations. Again, rats fed with fructose/green tea and fructose/pu-erh tea showed the greatest reduction in serum TG, cholesterol, insulin and leptin levels. In contrast, serum cholesterol and insulin concentrations of the fructose/oolong tea-fed rats did not normalize. The relative epididymal adipose tissue weight was lower in all rats supplemented with tea leaves than those fed with fructose alone. There was molecular evidence of improved lipid homeostasis according to fatty acid synthase (FAS) protein expression. Furthermore, supplementation of green, black, and pu-erh tea leaves significantly decreased hepatic FAS mRNA and protein levels, and increased AMPK phosphorylation, compared with those of rats fed with fructose only. These findings suggest that the intake of green, black, and pu-erh tea leaves ameliorated the fructose-induced hyperlipidemia and hyperleptinemia state in part through the suppression of FAS protein levels and increased AMPK phosphorylation.

  1. Overexpression of PAD1 and FDC1 results in significant cinnamic acid decarboxylase activity in Saccharomyces cerevisiae.

    PubMed

    Richard, Peter; Viljanen, Kaarina; Penttilä, Merja

    2015-01-01

    The S. cerevisiae PAD1 gene had been suggested to code for a cinnamic acid decarboxylase, converting trans-cinnamic acid to styrene. This was suggested for the reason that the over-expression of PAD1 resulted in increased tolerance toward cinnamic acid, up to 0.6 mM. We show that by over-expression of the PAD1 together with the FDC1 the cinnamic acid decarboxylase activity can be increased significantly. The strain over-expressing PAD1 and FDC1 tolerated cinnamic acid concentrations up to 10 mM. The cooperation of Pad1p and Fdc1p is surprising since the PAD1 has a mitochondrial targeting sequence and the FDC1 codes for a cytosolic protein. The cinnamic acid decarboxylase activity was also seen in the cell free extract. The activity was 0.019 μmol per minute and mg of extracted protein. The overexpression of PAD1 and FDC1 resulted also in increased activity with the hydroxycinnamic acids ferulic acid, p-coumaric acid and caffeinic acid. This activity was not seen when FDC1 was overexpressed alone. An efficient cinnamic acid decarboxylase is valuable for the genetic engineering of yeast strains producing styrene. Styrene can be produced from endogenously produced L-phenylalanine which is converted by a phenylalanine ammonia lyase to cinnamic acid and then by a decarboxylase to styrene.

  2. Arachidonic acid and docosahexaenoic acid suppress osteoclast formation and activity in human CD14+ monocytes, in vitro.

    PubMed

    Kasonga, Abe E; Deepak, Vishwa; Kruger, Marlena C; Coetzee, Magdalena

    2015-01-01

    An unbalanced diet can have adverse effects on health. Long chain polyunsaturated fatty acids (LCPUFAs) have been the focus of research owing to their necessity of inclusion in a healthy diet. However, the effects of LCPUFAs on human osteoclast formation and function have not been explored before. A human CD14+ monocyte differentiation model was used to elucidate the effects of an ω-3 LCPUFA, docosahexaenoic acid (DHA), and an ω-6 LCPUFA, arachidonic acid (AA), on osteoclast formation and activity. CD14+ monocytes were isolated from peripheral blood of healthy donors and stimulated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand to generate osteoclasts. Data from this study revealed that both the LCPUFAs decreased osteoclast formation potential of CD14+ monocytes in a dose-dependent manner when treated at an early stage of differentiation. Moreover, when exposed at a late stage of osteoclast differentiation AA and DHA impaired the bone resorptive potential of mature osteoclasts without affecting osteoclast numbers. AA and DHA abrogated vitronectin receptor expression in differentiating as well as mature osteoclasts. In contrast, the degree of inhibition for calcitonin receptor expression varied between the LCPUFAs with only AA causing inhibition during osteoclast differentiation. Furthermore, AA and DHA down regulated the expression of key osteoclast-specific genes in differentiating as well as mature osteoclasts. This study demonstrates for the first time that LCPUFAs can modulate osteoclast formation and function in a human primary osteoclast cell line.

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

    PubMed Central

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

    2013-01-01

    The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis. PMID:23652017

  4. Neuroprotective effect of suppression of astrocytic activation by arundic acid on brain injuries in rats with acute subdural hematomas.

    PubMed

    Wajima, Daisuke; Nakagawa, Ichiro; Nakase, Hiroyuki; Yonezawa, Taiji

    2013-06-26

    Acute subdural hematoma (ASDH) can cause massive ischemic cerebral blood flow (CBF) underneath the hematoma, but early surgical evacuation of the mass reduces mortality. The aim of this study was to evaluate whether arundic acid improves the secondary ischemic damage induced by ASDH. Our results confirmed that arundic acid decreases the expression of S100 protein produced by activated astrocytes around ischemic lesions due to cytotoxic edema after ASDH as well as reducing infarction volumes and numbers of apoptotic cells around the ischemic lesions. In this study, we also evaluate the relationship of brain edema and the expression of Aquaporin 4 (AQP4) in an ASDH model. The expression of AQP4 was decreased in the acute phase after ASDH. Cytotoxic edema, assumed to be the main cause of ASDH, could also cause ischemic lesions around the edema area. Arundic acid decreased the infarction volume and number of apoptotic cells via suppression of S100 protein expression in ischemic lesions without changing the expression of AQP4.

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

    PubMed Central

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

    2016-01-01

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

  6. Gamma-irradiation of malic acid in aqueous solutions. [prebiotic significance

    NASA Technical Reports Server (NTRS)

    Negron-Mendoza, A.; Graff, R. L.; Ponnamperuma, C.

    1980-01-01

    The gamma-irradiation of malic acid in aqueous solutions was studied under initially oxygenated and oxygen-free conditions in an attempt to determine the possible interconversion of malic acid into other carboxylic acids, specifically those associated with Krebs cycle. The effect of dose on product formation of the system was investigated. Gas-liquid chromatography combined with mass spectrometry was used as the principal means of identification of the nonvolatile products. Thin layer chromatography and direct probe mass spectroscopy were also employed. The findings show that a variety of carboxylic acids are formed, with malonic and succinic acids in greatest abundance. These products have all been identified as being formed in the gamma-irradiation of acetic acid, suggesting a common intermediary. Since these molecules fit into a metabolic cycle, it is strongly suggestive that prebiotic pathways provided the basis for biological systems.

  7. The BH3-mimetic gossypol and noncytotoxic doses of valproic acid induce apoptosis by suppressing cyclin-A2/Akt/FOXO3a signaling

    PubMed Central

    Pan, Hao; Lin, Qiu-Ru; Huang, Mei-Yun; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2015-01-01

    Previously we reported that valproic acid (VPA) acts in synergy with GOS to enhance cell death in human DU145 cells. However, the underlying mechanism remains elusive. In this study, we observed that such synergistic cytotoxicity of GOS and VPA could be extended to human A375, HeLa, and PC-3 cancer cells. GOS and VPA co-treatment induced robust apoptosis as evidenced by caspase-8/-9/-3 activation, PARP cleavage, and nuclear fragmentation. GOS and VPA also markedly decreased cyclin A2 protein expression. Owing to the reduction of cyclin A2, Akt signaling was suppressed, leading to dephosphorylation of FOXO3a. Consequently, FOXO3a was activated and the expression of its target genes, including pro-apoptotic FasL and Bim, was upregulated. Supporting this, FOXO3a knockdown attenuated FasL and Bim upregulation and apoptosis induction in GOS+VPA-treated cells. Furthermore, blocking proteasome activity by MG132 prevented the downregulation of cyclin A2, dephosphorylation of Akt and FOXO3a, and induction of apoptosis in cells co-treated with GOS and VPA. In mouse model, GOS and VPA combination significantly inhibited the growth of A375 melanoma xenografts. Our findings indicate that GOS and VPA co-treatment induces apoptosis in human cancer cells by suppressing the cyclin-A2/Akt/FOXO3a pathway. PMID:26517515

  8. Gambogic acid sensitizes resistant breast cancer cells to doxorubicin through inhibiting P-glycoprotein and suppressing survivin expression.

    PubMed

    Wang, Shengpeng; Wang, Lu; Chen, Meiwan; Wang, Yitao

    2015-06-25

    The development of resistance to chemotherapeutic agents remains a major challenge to breast cancer chemotherapy. Overexpression of drug efflux transporters like P-glycoprotein (P-gp) and resistance to apoptosis are the two key factors that confer cancer drug resistance. Gambogic acid (GA), a major component of Gamboge resin, has potent anticancer effects and can inhibit the growth of several types of human cancers. However, the potential and underlying mechanisms of GA in reversing cancer resistance remain poorly understood. In the present study, we found that GA can markedly sensitize doxorubicin (DOX)-resistant breast cancer cells to DOX-mediated cell death. GA increased the intracellular accumulation of DOX by inhibiting both P-gp expression and activity. Meanwhile, the combination effect was associated with the generation of intracellular reactive oxygen species (ROS) and the suppression of anti-apoptotic protein survivin. Scavenging intracellular ROS or overexpression of survivin blocked the sensitizing effects of GA in DOX-induced apoptosis. Furthermore, ROS-mediated activation of p38 MAPK was revealed in GA-mediated suppression of survivin expression. This study gives rise to the possibility of applying GA as an anticancer agent for the purpose of combating DOX-resistant breast cancer.

  9. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours.

    PubMed

    Harvey, Philip W; Everett, David J

    2004-01-01

    This issue of Journal of Applied Toxicology publishes the paper Concentrations of Parabens in Human Breast Tumours by Darbre et al. (2004), which reports that esters of p-hydroxybenzoic acid (parabens) can be detected in samples of tissue from human breast tumours. Breast tumour samples were supplied from 20 patients, in collaboration with the Edinburgh Breast Unit Research Group, and analysed by high-pressure liquid chromatography and tandem mass spectrometry. The parabens are used as antimicrobial preservatives in underarm deodorants and antiperspirants and in a wide range of other consumer products. The parabens also have inherent oestrogenic and other hormone related activity (increased progesterone receptor gene expression). As oestrogen is a major aetiological factor in the growth and development of the majority of human breast cancers, it has been previously suggested by Darbre that parabens and other chemicals in underarm cosmetics may contribute to the rising incidence of breast cancer. The significance of the finding of parabens in tumour samples is discussed here in terms of 1). Darbre et al's study design, 2). what can be inferred from this type of data (and what can not, such as the cause of these tumours), 3). the toxicology of these compounds and 4). the limitations of the existing toxicology database and the need to consider data that is appropriate to human exposures.

  10. Control of ACTH secretion by excitatory amino acids: functional significance and clinical implications.

    PubMed

    Jezova, Daniela

    2005-12-01

    The involvement of excitatory amino acids in the control of ACTH release is well established. Activation of ionotropic glutamate receptors has a stimulatory effect on ACTH release, while the role of metabotropic receptors is not yet understood in detail. Glutamatergic regulation of ACTH release has a clear significance for the stress response and neuroendocrine functions during development. A dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis has been reported in several psychiatric and neurological disorders. So far, only fractional indices on the clinical importance of the interaction between glutamate and ACTH secretion have been obtained in both preclinical and clinical studies. Some antidepressant drugs, such as tianeptine, which were found to modulate ACTH release, appear to interfere with brain glutamatergic system. Changes in ACTH and cortisol release may be of importance for mood stabilizing effects of antiepileptic drugs modulating glutamate release, such as lamotrigine. Brain glutamate and HPA axis interaction seems to be of importance in alcohol and drug abuse. Little information is available on ACTH release in response to glutamate-modulating drugs used in the treatment of schizophrenia and Alzheimer disease. Nevertheless, pharmacological interventions influencing interaction between glutamate and the HPA axis are promising treatment possibilities in psychiatry and neurology.

  11. Significant effect of Ca2+ on improving the heat resistance of lactic acid bacteria.

    PubMed

    Huang, Song; Chen, Xiao Dong

    2013-07-01

    The heat resistance of lactic acid bacteria (LAB) has been extensively investigated due to its highly practical significance. Reconstituted skim milk (RSM) has been found to be one of the most effective protectant wall materials for microencapsulating microorganisms during convective drying, such as spray drying. In addition to proteins and carbohydrate, RSM is rich in calcium. It is not clear which component is critical in the RSM protection mechanism. This study investigated the independent effect of calcium. Ca(2+) was added to lactose solution to examine its influence on the heat resistance of Lactobacillus rhamnosus ZY, Lactobacillus casei Zhang, Lactobacillus plantarum P8 and Streptococcus thermophilus ND03. The results showed that certain Ca(2+) concentrations enhanced the heat resistance of the LAB strains to different extents, that is produced higher survival and shorter regrowth lag times of the bacterial cells. In some cases, the improvements were dramatic. More scientifically insightful and more intensive instrumental study of the Ca(2+) behavior around and in the cells should be carried out in the near future. In the meantime, this work may lead to the development of more cost-effective wall materials with Ca(2+) added as a prime factor. PMID:23617813

  12. Significance of the C-terminal amino acid residue in mengovirus RNA-dependent RNA polymerase.

    PubMed

    Dmitrieva, Tatiana M; Alexeevski, Andrei V; Shatskaya, Galina S; Tolskaya, Elena A; Gmyl, Anatoly P; Khitrina, Elena V; Agol, Vadim I

    2007-08-15

    Replication of picornavirus genomes is accomplished by the virally encoded RNA-dependent RNA polymerase (RdRP). Although the primary structure of this enzyme exhibits a high level of conservation, there are several significant differences among different picornavirus genera. In particular, a comparative alignment indicates that the C-terminal sequences of cardiovirus RdRP (known also as 3D(pol)), are 1-amino-acid residue (arginine or tryptophan) longer than that of the enterovirus or rhinovirus enzymes. Here, it is shown that alterations of the last codon of the RdRP-encoding sequence of mengovirus RNA leading to deletion of the C-terminal Trp460 or its replacement by Ala or Phe dramatically impaired viral RNA replication and, in the former case, resulted in a quasi-infectious phenotype (i.e., the mutant RNA might generate a low yield of pseudorevertants acquiring a Tyr residue in place of the deleted Trp460). The replacement of Trp460 by His or Tyr did not appreciably alter the viral growth potential. Homology modeling of three-dimensional structure of mengovirus RdRP suggested that Trp460 may be involved in interaction between the thumb and palm domains of the enzyme. Specifically, Trp460 of the thumb may form a hydrogen bond with Thr219 and hydrophobically interact with Val216 of the palm. The proposed interactions were consistent with the results of in vivo SELEX experiment, which demonstrated that infectious virus could contain Ser or Thr at position 219 and hydrophobic Val, Leu, Ile, as well as Arg (whose side chain has a nonpolar part) at position 216. A similar thumb-palm domain interaction may be a general feature of several RdRPs and its possible functional significance is discussed. PMID:17467026

  13. Dietary polyunsaturated fatty acids suppress acute hepatitis, alter gene expression and prolong survival of female Long-Evans Cinnamon rats, a model of Wilson disease.

    PubMed

    Du, Chunyan; Fujii, Yoichi; Ito, Masafumi; Harada, Manabu; Moriyama, Emiko; Shimada, Ryo; Ikemoto, Atsushi; Okuyama, Harumi

    2004-05-01

    In the Long-Evans Cinnamon rat, copper accumulates in the liver because of a mutation in the copper-transporting ATPase gene, and peroxidative stresses are supposed to be augmented. We examined the effects of dietary fatty acids on hepatitis, hepatic gene expression, and survival. Rats were fed a conventional, low-fat diet (CE2), a CE2 diet supplemented with 10 wt% of lard (Lar), high-linoleic soybean oil (Soy), or a mixture of docosahexaenoic acid (DHA)-rich fish oil and soybean oil (DHA/Soy). Among female rats, the mean survival times of the DHA/Soy and the Soy groups were longer by 17 approximately 20% than in the Lar and the CE2 groups. Among male rats, the survival times were much longer than in the females, but no significant difference in survival was observed among the dietary groups. Serum ceruloplasmin levels in female and male rats of all of the dietary groups were similar. Serum transaminase levels of the DHA/Soy group tended to be lower than in the CE2 group. Histological examinations revealed a marked degeneration in hepatic tissue integrity in the Lar and CE2 groups but not in the DHA/Soy group. Hepatic levels of metal-related genes, transferrin and ceruloplasmin, as well as those related to bile acid synthesis were up-regulated, and an inflammation-related gene (cyclooxygenase [COX]-2) was down-regulated in the DHA/Soy group. Some proliferation-related genes were also affected by the dietary fatty acids. These results indicate that polyunsaturated fatty acids suppress the development of acute hepatitis and prolong survival in females, regardless of whether they are of the n-6 or n-3 type, which are associated with altered gene expressions.

  14. Prenatal folic acid treatment suppresses acrania and meroanencephaly in mice mutant for the Cart1 homeobox gene.

    PubMed

    Zhao, Q; Behringer, R R; de Crombrugghe, B

    1996-07-01

    The paired-class homeobox-containing gene, Cart1, is expressed in forebrain mesenchyme, branchial arches, limb buds and cartilages during embryogenesis. Here, we show that Cart1-homozygous mutant mice are born alive with acrania and meroanencephaly but die soon after birth-a phenotype that strikingly resembles a corresponding human syndrome caused by a neural tube closure defect. Developmental studies suggest that Cart1 is required for forebrain mesenchyme survival and that its absence disrupts cranial neural tube morphogenesis by blocking the initiation of closure in the midbrain region that ultimately leads to the generation of lethal craniofacial defects. Prenatal treatment of Cart1 homozygous mutants with folic acid suppresses the development of the acrania/meroanencephaly phenotype. PMID:8673125

  15. Gambogic acid inhibits osteoclast formation and ovariectomy-induced osteoporosis by suppressing the JNK, p38 and Akt signalling pathways.

    PubMed

    Ma, Jianjun; Ma, Yan; Liu, Xuqiang; Chen, Shuai; Liu, Chao; Qin, An; Fan, Shunwu

    2015-08-01

    Excessive osteoclast formation and bone resorption are key causes of osteoporosis. Natural compounds can serve as alternative therapeutic agents for the prevention and treatment of osteoporosis, and some natural compounds may have advantages over traditional drugs. In the present paper, we report that the natural compound GBA (gambogic acid), which is bioavailable, effective and less toxic, inhibits osteoclast formation, thereby attenuating osteoclastic bone resorption in vitro. Further in vivo studies demonstrated that GBA prevented ovariectomy-induced bone loss in a dose-dependent manner. Moreover, we demonstrated that GBA suppressed RANKL (receptor activator of nuclear factor κB ligand)-induced JNK (c-Jun N-terminal kinase), p38 and Akt phosphorylation. Taken together, our results demonstrate that GBA inhibits osteoclast formation in vitro and in vivo, suggesting that it is of potential value in the treatment of osteoclast-related diseases.

  16. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis

    PubMed Central

    Eom, Chun-Sick; Jeon, Christie Y.; Lim, Ju-Won; Cho, Eun-Geol; Park, Sang Min; Lee, Kang-Sook

    2011-01-01

    Background Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association. Methods We searched three electronic databases (MEDLINE [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used random-effects meta-analysis to obtain pooled estimates of effect. Results We identified 31 studies: five case–control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11–1.46, I2 90.5%) and histamine2 receptor antagonists (adjusted OR 1.22, 95% CI 1.09–1.36, I2 0.0%). In the randomized controlled trials, use of histamine2 receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01–1.48, I2 30.6%). Interpretation Use of a proton pump inhibitor or histamine2 receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk. PMID:21173070

  17. Suppression of AMF/PGI-mediated tumorigenic activities by ursolic acid in cultured hepatoma cells and in a mouse model.

    PubMed

    Shih, Wen-Ling; Yu, Feng-Ling; Chang, Ching-Dong; Liao, Ming-Huei; Wu, Hung-Yi; Lin, Ping-Yuan

    2013-10-01

    Our previous studies demonstrated that autocrine motility factor/phosphoglucose isomerase (AMF/PGI) possesses tumorigenic activities through the modulation of intracellular signaling. We then investigated the effects of ursolic acid (UA), oleanolic acid (OA), tangeretin, and nobiletin against AMF/PGI-mediated oncogenesis in cultured stable Huh7 and Hep3B cells expressing wild-type or mutated AMF/PGI and in a mouse model in this study. The working concentrations of the tested compounds were lower than their IC10 , which was determined by Brdu incorporation and colony formation assay. Only UA efficiently suppressed the AMF/PGI-induced Huh7 cell migration and MMP-3 secretion. Additionally, UA inhibited the AMF/PGI-mediated protection against TGF-β-induced apoptosis in Hep3B cells, whereas OA, tangeretin, and nobiletin had no effect. In Huh7 cells and tumor tissues, UA disrupted the Src/RhoA/PI 3-kinase signaling and complex formation induced by AMF/PGI. In the Hep3B system, UA dramatically suppressed AMF/PGI-induced anti-apoptotic signaling transmission, including Akt, p85, Bad, and Stat3 phosphorylation. AMF/PGI enhances tumor growth, angiogenesis, and pulmonary metastasis in mice, which is correlated with its enzymatic activity, and critically, UA intraperitoneal injection reduces the tumorigenesis in vivo, enhances apoptosis in tumor tissues and also prolongs mouse survival. Combination of sub-optimal dose of UA and cisplatin, a synergistic tumor cell-killing effects was found. Thus, UA modulates intracellular signaling and might serve as a functional natural compound for preventing or alleviating hepatocellular carcinoma.

  18. Alpha-tocopherol acetate significantly suppressed the increase in heart interstitial 8-hydroxydeoxyguanosine following myocardial ischemia and reperfusion in anesthetized rats.

    PubMed

    Yang, C S; Chen, W Y; Tsai, P J; Kuo, J S

    1999-07-01

    The effect of alpha-tocopherol acetate, an aqueous form of alpha-tocopherol, on the increase in heart interstitial 8-hydroxydeoxyguanosine (8-OH-dG) levels following myocardial ischemia/reperfusion was investigated. A microdialysis probe was implanted in the left ventricular interstitial space of anesthetized rat hearts. Myocardial ischemia was induced by ligating the left anterior descending coronary artery. Levels of 8-OH-dG in microdialysates were analyzed via an on-line high-performance liquid chromatography system equipped with an electrochemical detector. The 8-OH-dG levels significantly increased (maximum 3.6-fold of increase relative to basal value) during the 60-min reperfusion stage following a 20 min ischemia. Administration of alpha-tocopherol acetate (20 mg/kg, intravenous, bolus) at 3 min prior to onset of reperfusion, significantly suppressed the reperfusion-induced increase in 8-OH-dG levels. These results suggested that one of the possible protective effect of alpha-tocopherol acetate was to reduce oxidative DNA damage during in myocardial ischemia and reperfusion.

  19. HIV-1 p24 antigen is a significant inverse correlate of CD4 T-cell change in patients with suppressed viremia under long-term antiretroviral therapy.

    PubMed

    Schüpbach, Jörg; Böni, Jürg; Bisset, Leslie R; Tomasik, Zuzana; Fischer, Marek; Günthard, Huldrych F; Ledergerber, Bruno; Opravil, Milos

    2003-07-01

    An HIV-1 p24 antigen test involving signal amplification-boosted ELISA of heat-denatured plasma was evaluated prospectively in 55 patients whose viral RNA in plasma had previously been suppressed for at least 6 months under antiretroviral combination therapy. During a median follow-up of 504 days, CD4 counts increased by a median of 62 cells per year. By univariate and multivariate linear regression analysis, the level of p24 antigen as expressed by the absorbance/cutoff ratio was a significant inverse correlate of both the CD4 count in a sample (p =.013) and its annual change in a patient (p <.0001). The p24 antigen retained significance even among 48 individuals whose HIV-1 RNA, apart from occasional blips, remained below 400 copies/mL. Batch-wise retesting of 70 samples from 5 such patients with a further improved procedure showed measurable p24 antigen in all but 1 sample and an inverse correlation with both the CD4 count (p =.0331) and percentage (p <.0001), thus confirming the prospectively generated data. Comparison of p24 antigen and HIV-1 RNA concentrations indicate that the p24 antigen detected in these samples is not associated with viral RNA-containing particles and may originate from other compartments of virus expression.

  20. Tauroursodeoxycholic acid suppresses endoplasmic reticulum stress in the chondrocytes of patients with osteoarthritis.

    PubMed

    Liu, Chao; Cao, Yongping; Yang, Xin; Shan, Pengcheng; Liu, Heng

    2015-10-01

    The main pathogenic events in osteoarthritis (OA) include loss and abnormal remodeling of cartilage extracellular matrix. The present study aimed to evaluate the protective effect of tauroursodeoxycholic acid on chondrocyte apoptosis induced by endoplasmic reticulum (ER) stress. Articular cartilage tissues were collected from 18 patients who underwent total knee arthroplasty and were analyzed histologically. Subsequently, chondrocyte apoptosis was assessed by TUNEL. Quantitative polymerase chain reaction and western blot analysis were employed to evaluate gene and protein expression, respectively, of ER stress markers, including glucose‑regulated protein 78 (GRP78), growth arrest and DNA‑damage‑inducible gene 153 (GADD153) and caspase‑12 along with type II collagen. Chondrocytes obtained from osteoarthritis patients at different stages were cultured in three conditions including: No treatment (CON group), tunicamycin treatment to induce ER stress (ERS group) and tauroursodeoxycholic acid treatment after 4 h of tunicamycin (TDA group); and cell proliferation, apoptosis, function and ER stress level were assessed. Degradation of cartilage resulted in histological damage with more apoptotic cartilage cells observed. Of note, GRP78, GADD153 and caspase‑12 mRNA and protein expression increased gradually from grade I to III cartilage tissue, while type II collagen expression decreased. Tunicamycin induced ER stress, as shown by a high expression of ER stress markers, reduced cell proliferation, increased apoptosis and decreased synthesis of type II collagen. Notably, tauroursodeoxycholic acid treatment resulted in the improvement of tunicamycin‑induced ER stress. These results indicated that ER stress is highly involved in the tunicamycin‑induced apoptosis in chondrocytes, which can be prevented by tauroursodeoxycholic acid. PMID:26238983

  1. Abiogenic Syntheses of Lipoamino Acids and Lipopeptides and their Prebiotic Significance

    NASA Astrophysics Data System (ADS)

    Sproul, Gordon

    2015-12-01

    Researchers have formed peptide bonds under a variety of presumed prebiotic conditions. Here it is proposed that these same conditions would have also formed amide bonds between fatty acids and amino acids, producing phosphate-free amphipathic lipoamino acids and lipopeptides. These compounds are known to form vesicles and are ubiquitous in living organisms. They could represent molecules that provided protection by membranes as well as possibilities for proto-life metabolism . It is here demonstrated that when a fatty acid is heated with various amino acids, optimally in the presence of suitable salts or minerals, lipoamino acids are formed. Magnesium and potassium carbonates as well as iron (II) sulfide are found to be particularly useful in these reactions. In this manner N-lauroylglycine, N-lauroylalanine, N-stearoylalanine and several other lipoamino acids have been synthesized. Similarly, when glycylglycine was heated with lauric acid in the presence of magnesium carbonate, the lipopeptide N-lauroylglycylglycine was formed. Such compounds are proposed to have been critical precursors to the development of life.

  2. Abiogenic Syntheses of Lipoamino Acids and Lipopeptides and their Prebiotic Significance.

    PubMed

    Sproul, Gordon

    2015-12-01

    Researchers have formed peptide bonds under a variety of presumed prebiotic conditions. Here it is proposed that these same conditions would have also formed amide bonds between fatty acids and amino acids, producing phosphate-free amphipathic lipoamino acids and lipopeptides. These compounds are known to form vesicles and are ubiquitous in living organisms. They could represent molecules that provided protection by membranes as well as possibilities for proto-life metabolism . It is here demonstrated that when a fatty acid is heated with various amino acids, optimally in the presence of suitable salts or minerals, lipoamino acids are formed. Magnesium and potassium carbonates as well as iron (II) sulfide are found to be particularly useful in these reactions. In this manner N-lauroylglycine, N-lauroylalanine, N-stearoylalanine and several other lipoamino acids have been synthesized. Similarly, when glycylglycine was heated with lauric acid in the presence of magnesium carbonate, the lipopeptide N-lauroylglycylglycine was formed. Such compounds are proposed to have been critical precursors to the development of life. PMID:26248658

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

    PubMed

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

    2014-11-01

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

  4. Suppression of leukotriene B4 generation by ex-vivo neutrophils isolated from asthma patients on dietary supplementation with gammalinolenic acid-containing borage oil: possible implication in asthma.

    PubMed

    Ziboh, Vincent A; Naguwa, Stanley; Vang, Kao; Wineinger, Julie; Morrissey, Brian M; Watnik, Mitchell; Gershwin, M Eric

    2004-03-01

    Dietary gammalinolenic acid (GLA), a potent inhibitor of 5-lipoxygenase (5-LOX) and suppressor of leukotriene B4 (LTB4), can attenuate the clinical course of rheumatoid arthritics, with negligible side effects. Since Zileuton, also an inhibitor of 5-LOX, attenuates asthma but with an undesirable side effect, we investigated whether dietary GLA would suppress biosynthesis of PMN-LTB4 isolated from asthma patients and attenuate asthma. Twenty-four mild-moderate asthma patients (16-75 years) were randomized to receive either 2.0 g daily GLA (borage oil) or corn oil (placebo) for 12 months. Blood drawn at 3 months intervals was used to prepare sera for fatty acid analysis, PMNs for determining phospholipid fatty acids and for LTB4 generation. Patients were monitored by daily asthma scores, pulmonary function, and exhaled NO. Ingestion of daily GLA (i) increased DGLA (GLA metabolite) in PMN-phospholipids; (ii) increased generation of PMN-15-HETrE (5-LOX metabolite of DGLA). Increased PMN-DGLA/15-HETrE paralleled the decreased PMN generation of proinflammatory LTB4. However, the suppression of PMN-LTB4 did not reveal statistically significant suppression of the asthma scores evaluated. Nonetheless, the study demonstrated dietary fatty acid modulation of endogenous inflammatory mediators without side effects and thus warrant further explorations into the roles of GLA at higher doses, leukotrienes and asthma. PMID:15154607

  5. Suppression of leukotriene B4 generation by ex-vivo neutrophils isolated from asthma patients on dietary supplementation with gammalinolenic acid-containing borage oil: possible implication in asthma.

    PubMed

    Ziboh, Vincent A; Naguwa, Stanley; Vang, Kao; Wineinger, Julie; Morrissey, Brian M; Watnik, Mitchell; Gershwin, M Eric

    2004-03-01

    Dietary gammalinolenic acid (GLA), a potent inhibitor of 5-lipoxygenase (5-LOX) and suppressor of leukotriene B4 (LTB4), can attenuate the clinical course of rheumatoid arthritics, with negligible side effects. Since Zileuton, also an inhibitor of 5-LOX, attenuates asthma but with an undesirable side effect, we investigated whether dietary GLA would suppress biosynthesis of PMN-LTB4 isolated from asthma patients and attenuate asthma. Twenty-four mild-moderate asthma patients (16-75 years) were randomized to receive either 2.0 g daily GLA (borage oil) or corn oil (placebo) for 12 months. Blood drawn at 3 months intervals was used to prepare sera for fatty acid analysis, PMNs for determining phospholipid fatty acids and for LTB4 generation. Patients were monitored by daily asthma scores, pulmonary function, and exhaled NO. Ingestion of daily GLA (i) increased DGLA (GLA metabolite) in PMN-phospholipids; (ii) increased generation of PMN-15-HETrE (5-LOX metabolite of DGLA). Increased PMN-DGLA/15-HETrE paralleled the decreased PMN generation of proinflammatory LTB4. However, the suppression of PMN-LTB4 did not reveal statistically significant suppression of the asthma scores evaluated. Nonetheless, the study demonstrated dietary fatty acid modulation of endogenous inflammatory mediators without side effects and thus warrant further explorations into the roles of GLA at higher doses, leukotrienes and asthma.

  6. Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats

    PubMed Central

    2009-01-01

    Background Breast cancer is a major problem in the United States leading to tens of thousands of deaths each year. Although citrus auraptene suppresses cancer in numerous rodent models, its role in breast cancer prevention previously has not been reported. Thus, our goal was to determine the anticarcinogenic effects of auraptene against breast cancer. Methods The effects of auraptene on cell proliferation of MCF-7 and MDA-MB-231 human breast carcinoma cells in culture was assessed by measuring metabolism of a substrate to a formazan dye. Dietary effects of auraptene on tumor incidence, multiplicity and latency were studied in the N-methyl nitrosourea (MNU) induced mammary carcinogenesis model in female Sprague Dawley rats. The concentration of auraptene in rat tissues was analyzed by reverse phase HPLC. Cyclin D1 expression in MCF-7 cells and rat tumors was measured by western blot. Results Auraptene (500 ppm) significantly delayed median time to tumor by 39 days compared to the MNU only group (p < 0.05, n = 24–26). Auraptene (10 μM) reduced Insulin like Growth Factor-1 (IGF-1, 10 ng/mL)-induced cyclin D1 expression by 40% in MCF-7 cells. In comparison, western blot analysis of rat mammary tumors (n = 10 per group) confirmed that auraptene (500 ppm) significantly reduced (p < 0.05) cyclin D1 expression by 49% compared to the MNU only group. Analysis of rat mammary tissue extract by HPLC with fluorescence detection indicated an average concentration (means ± S.E.) of 1.4 ± 0.5 μM and 1.8 ± 0.3 μM in the normal mammary glands of the auraptene 200 ppm and 500 ppm groups, respectively. The concentration (means ± S.E.) of auraptene in the mammary tumors of the auraptene 200 ppm group was 0.31 ± 0.98 μM. Conclusion Overall, these observations suggest that the predominant effect of auraptene was to delay the development of tumors possibly through the suppression of cyclin D1 expression. These results point to the potential chemopreventive effects of auraptene

  7. Activation of lytic cycle of Epstein-Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma.

    PubMed

    Hui, K F; Ho, Dona N; Tsang, C M; Middeldorp, Jaap M; Tsao, George S W; Chiang, Alan K S

    2012-10-15

    Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV). We reported that suberoylanilide hydroxamic acid (SAHA) induced EBV lytic cycle in EBV-positive gastric carcinoma cells and mediated enhanced cell death. However, expression of EBV lytic proteins was thought to exert antiapoptotic effect in EBV-infected cells. Here, we examined the in vitro and in vivo effects of SAHA on EBV lytic cycle induction in NPC cells and investigated the cellular consequences. Micromolar concentrations of SAHA significantly induced EBV lytic cycle in EBV-positive NPC cells. Increased apoptosis and proteolytic cleavage of poly(ADP-ribose) polymerase and caspase-3, -7 and -9 in EBV-positive versus EBV-negative NPC cells were observed. More than 85% of NPC cells expressing immediate-early (Zta), early (BMRF1) or late (gp350/220) lytic proteins coexpressed cleaved caspase-3. Tracking of expression of EBV lytic proteins and cleaved caspase-3 over time demonstrated that NPC cells proceeded to apoptosis following EBV lytic cycle induction. Inhibition of EBV DNA replication and late lytic protein expression by phosphonoformic acid did not impact on SAHA's induced cell death in NPC, indicating that early rather than late phase of EBV lytic cycle contributed to the apoptotic effect. In vivo effects of SAHA on EBV lytic cycle induction and tumor growth suppression were also observed in NPC xenografts in nude mice. Taken together, our data indicated that activation of lytic cycle from latent cycle of EBV by SAHA leads to apoptosis and tumor growth suppression of NPC thereby providing experimental evidence for virus-targeted therapy against EBV-positive cancer.

  8. The antagonistic regulation of abscisic acid-inhibited root growth by brassinosteroids is partially mediated via direct suppression of ABSCISIC ACID INSENSITIVE 5 expression by BRASSINAZOLE RESISTANT 1.

    PubMed

    Yang, Xiaorui; Bai, Yang; Shang, Jianxiu; Xin, Ruijiao; Tang, Wenqiang

    2016-09-01

    Brassinosteroids (BRs) and abscisic acid (ABA) are plant hormones that antagonistically regulate many aspects of plant growth and development; however, the mechanisms that regulate the crosstalk of these two hormones are still not well understood. BRs regulate plant growth and development by activating BRASSINAZOLE RESISTANT 1 (BZR1) family transcription factors. Here we show that the crosstalk between BRs and ABA signalling is partially mediated by BZR1 regulated gene expression. bzr1-1D is a dominant mutant with enhanced BR signalling; our results showed that bzr1-1D mutant is less sensitive to ABA-inhibited primary root growth. By RNA sequencing, a subset of BZR1 regulated ABA-responsive root genes were identified. Of these genes, the expression of a major ABA signalling component ABA INSENSITIVE 5 (ABI5) was found to be suppressed by BR and by BZR1. Additional evidences showed that BZR1 could bind strongly with several G-box cis-elements in the promoter of ABI5, suppress the expression of ABI5 and make plants less sensitive to ABA. Our study demonstrated that ABI5 is a direct target gene of BZR1, and modulating the expression of ABI5 by BZR1 plays important roles in regulating the crosstalk between the BR and ABA signalling pathways.

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

    PubMed

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

    2015-01-01

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

  10. The Apollo program and amino acids. [precursors significance in molecular evolution

    NASA Technical Reports Server (NTRS)

    Fox, S. W.

    1973-01-01

    Apollo lunar sample analyses designed to detect the presence of organic compounds are reviewed, and the results are discussed from the viewpoint of relevance to laboratory experiments on the synthesis of amino acids and to theoretical models of cosmochemical processes resulting in the formation of organic compounds. Glycine, alanine, glutamic acid, aspartic acid, serine, and threonine have been found repeatedly in the hydrolyzates of hot aqueous extracts of lunar dust. These compounds represent an early step in the sequence of events leading to the rise of living material and were probably deposited by the solar wind. The results of the Apollo program so far suggest that the pathway from cosmic organic matter to life as it evolved on earth could have been pursued on the moon to the stage of amino acid precursors and then may have been terminated for lack of sufficient water.

  11. Occurrence of 3-hydroxy acids in microalgae and cyanobacteria and their geochemical significance

    NASA Astrophysics Data System (ADS)

    Matsumoto, Genki I.; Nagashima, Hideyuki

    1984-08-01

    3-Hydroxy acids were detected in pure cultured microalgae: Chlorophyta— Chlamydomonas reinhardtii and Chlorella pyrenoidosa and Rhodophyta— Cyanidium caldarium (two strains), and cyanobacteria (Cyanophyta)— Anacystis nidulans, Phormidium foveolarum, Anabaena variabilis and Oscillatoria sp. Normal and branched (iso and anteiso) 3-hydroxy acids in the ranges of C 8-C 26 were found in all the samples studied at concentrations ranging from 0.036 to 2.3 and 0.000 to 0.12 mg g -1 of dry sample, respectively. The major constituents were generally even-carbon numbered normal acids with carbon chain lengths below C 20. Microalgae and cyanobacteria may be the important sources of 3-hydroxy acids in natural environments.

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

    PubMed

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

    2012-08-22

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

  13. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats

    SciTech Connect

    Sato, Keiichiro; Awasaki, Yasuyuki; Kandori, Hitoshi; Tanakamaru, Zen-yo; Nagai, Hirofumi; Baron, David; Yamamoto, Masaki

    2011-03-15

    Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manual counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats.

  14. Improved amber and opal suppressor tRNAs for incorporation of unnatural amino acids in vivo. Part 2: Evaluating suppression efficiency

    PubMed Central

    Rodriguez, Erik A.; Lester, Henry A.; Dougherty, Dennis A.

    2007-01-01

    The incorporation of unnatural amino acids into proteins is a valuable tool for addition of biophysical probes, bio-orthogonal functionalities, and photoreactive cross-linking agents, although these approaches often require quantities of protein that are difficult to access with chemically aminoacylated tRNAs. THG73 is an amber suppressor tRNA that has been used extensively, incorporating over 100 residues in 20 proteins. In vitro studies have shown that the Escherichia coli Asn amber suppressor (ENAS) suppresses better than THG73. However, we report here that ENAS suppresses with <26% of the efficiency of THG73 in Xenopus oocytes. We then tested the newly developed Tetrahymena thermophila Gln amber suppressor (TQAS) tRNA library, which contains mutations in the second to fourth positions of the acceptor stem. The acceptor stem mutations have no adverse effect on suppression efficiency and, in fact, can increase the suppression efficiency. Combining mutations causes an averaging of suppression efficiency, and increased suppression efficiency does not correlate with increased ΔG of the acceptor stem. We created a T. thermophila opal suppressor, TQOpS′, which shows ∼50% suppression efficiency relative to THG73. The TQAS tRNA library, composed of functional suppressor tRNAs, has been created and will allow for screening in eukaryotic cells, where rapid analysis of large libraries is not feasible. PMID:17698637

  15. Blueberry diet derived 3-(3-hydroxyphenyl) propionic acid (PPA) suppresses osteoblastic cell senescence to promote bone accretion in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A blueberry (BB) supplemented diet has been previously shown to significantly stimulate bone formation in rapidly growing male and female rodents. Phenolic acids (PAs) are metabolites derived from polyphenols found in fruits and vegetables as a result of the actions of gut bacteria, and the levels o...

  16. Significance of CO2 donor on the production of succinic acid by Actinobacillus succinogenes ATCC 55618

    PubMed Central

    2011-01-01

    Background Succinic acid is a building-block chemical which could be used as the precursor of many industrial products. The dissolved CO2 concentration in the fermentation broth could strongly regulate the metabolic flux of carbon and the activity of phosphoenolpyruvate (PEP) carboxykinase, which are the important committed steps for the biosynthesis of succinic acid by Actinobacillus succinogenes. Previous reports showed that succinic acid production could be promoted by regulating the supply of CO2 donor in the fermentation broth. Therefore, the effects of dissolved CO2 concentration and MgCO3 on the fermentation process should be investigated. In this article, we studied the impacts of gaseous CO2 partial pressure, dissolved CO2 concentration, and the addition amount of MgCO3 on succinic acid production by Actinobacillus succinogenes ATCC 55618. We also demonstrated that gaseous CO2 could be removed when MgCO3 was fully supplied. Results An effective CO2 quantitative mathematical model was developed to calculate the dissolved CO2 concentration in the fermentation broth. The highest succinic acid production of 61.92 g/L was obtained at 159.22 mM dissolved CO2 concentration, which was supplied by 40 g/L MgCO3 at the CO2 partial pressure of 101.33 kPa. When MgCO3 was used as the only CO2 donor, a maximal succinic acid production of 56.1 g/L was obtained, which was just decreased by 7.03% compared with that obtained under the supply of gaseous CO2 and MgCO3. Conclusions Besides the high dissolved CO2 concentration, the excessive addition of MgCO3 was beneficial to promote the succinic acid synthesis. This was the first report investigating the replaceable of gaseous CO2 in the fermentation of succinic acid. The results obtained in this study may be useful for reducing the cost of succinic acid fermentation process. PMID:22040346

  17. Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

    PubMed Central

    Kato, Junko; Kanematsu, Masako; Gaowa, Siqin; Mori, Ryutaro; Tanahashi, Toshiyuki; Matsuhashi, Nobuhisa; Yoshida, Kazuhiro

    2016-01-01

    Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status. PMID:26437179

  18. The Histone Deacetylase Inhibitor Vaproic Acid Induces Cell Growth Arrest in Hepatocellular Carcinoma Cells via Suppressing Notch Signaling

    PubMed Central

    Sun, Guangchun; Mackey, Lily V.; Coy, David H.; Yu, Cui-Yun; Sun, Lichun

    2015-01-01

    Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents. PMID:26366213

  19. Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells.

    PubMed

    Timiri Shanmugam, Prakash Srinivasan; Nair, Renjith Parameshwaran; De Benedetti, Arrigo; Caldito, Gloria; Abreo, Fleurette; Sunavala-Dossabhoy, Gulshan

    2016-04-01

    Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS-SV-AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS-SV-AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells.

  20. Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids

    PubMed Central

    Chang, Perng-Kuang; Hua, Sui Sheng T.; Sarreal, Siov Bouy L.; Li, Robert W.

    2015-01-01

    The saprophytic soil fungus Aspergillus flavus infects crops and produces aflatoxin. Pichia anomala, which is a biocontrol yeast and produces the major volatile 2-phenylethanol (2-PE), is able to reduce growth of A. flavus and aflatoxin production when applied onto pistachio trees. High levels of 2-PE are lethal to A. flavus and other fungi. However, at low levels, the underlying mechanism of 2-PE to inhibit aflatoxin production remains unclear. In this study, we characterized the temporal transcriptome response of A. flavus to 2-PE at a subinhibitory level (1 µL/mL) using RNA-Seq technology and bioinformatics tools. The treatment during the entire 72 h experimental period resulted in 131 of the total A. flavus 13,485 genes to be significantly impacted, of which 82 genes exhibited decreased expression. They included those encoding conidiation proteins and involved in cyclopiazonic acid biosynthesis. All genes in the aflatoxin gene cluster were also significantly decreased during the first 48 h treatment. Gene Ontology (GO) analyses showed that biological processes with GO terms related to catabolism of propionate and branched-chain amino acids (valine, leucine and isoleucine) were significantly enriched in the down-regulated gene group, while those associated with ribosome biogenesis, translation, and biosynthesis of α-amino acids were over-represented among the up-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways negatively impacted among the down-regulated genes parallel to those active at 30 °C, a condition conducive to aflatoxin biosynthesis. In contrast, metabolic pathways positively related to the up-regulated gene group resembled those at 37 °C, which favors rapid fungal growth and is inhibitory to aflatoxin biosynthesis. The results showed that 2-PE at a low level stimulated active growth of A. flavus but concomitantly rendered decreased activities in branched-chain amino acid degradation

  1. Suppression of Aflatoxin Biosynthesis in Aspergillus flavus by 2-Phenylethanol Is Associated with Stimulated Growth and Decreased Degradation of Branched-Chain Amino Acids.

    PubMed

    Chang, Perng-Kuang; Hua, Sui Sheng T; Sarreal, Siov Bouy L; Li, Robert W

    2015-10-01

    The saprophytic soil fungus Aspergillus flavus infects crops and produces aflatoxin. Pichia anomala, which is a biocontrol yeast and produces the major volatile 2-phenylethanol (2-PE), is able to reduce growth of A. flavus and aflatoxin production when applied onto pistachio trees. High levels of 2-PE are lethal to A. flavus and other fungi. However, at low levels, the underlying mechanism of 2-PE to inhibit aflatoxin production remains unclear. In this study, we characterized the temporal transcriptome response of A. flavus to 2-PE at a subinhibitory level (1 μL/mL) using RNA-Seq technology and bioinformatics tools. The treatment during the entire 72 h experimental period resulted in 131 of the total A. flavus 13,485 genes to be significantly impacted, of which 82 genes exhibited decreased expression. They included those encoding conidiation proteins and involved in cyclopiazonic acid biosynthesis. All genes in the aflatoxin gene cluster were also significantly decreased during the first 48 h treatment. Gene Ontology (GO) analyses showed that biological processes with GO terms related to catabolism of propionate and branched-chain amino acids (valine, leucine and isoleucine) were significantly enriched in the down-regulated gene group, while those associated with ribosome biogenesis, translation, and biosynthesis of α-amino acids OPEN ACCESS Toxins 2015, 7 3888 were over-represented among the up-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that metabolic pathways negatively impacted among the down-regulated genes parallel to those active at 30 °C, a condition conducive to aflatoxin biosynthesis. In contrast, metabolic pathways positively related to the up-regulated gene group resembled those at 37 °C, which favors rapid fungal growth and is inhibitory to aflatoxin biosynthesis. The results showed that 2-PE at a low level stimulated active growth of A. flavus but concomitantly rendered decreased activities in

  2. Isolation, characterization, and systematic significance of 2-pyrone-4,6-dicarboxylic acid in Rosaceae.

    PubMed

    Wilkes, S; Glasl, H

    2001-10-01

    2-Pyrone-4,6-dicarboxylic acid was isolated from Potentilla anserina. Until now this substance was only found in bacteria and not in higher plants. By sterile cultivation it was verified that this compound is genuine also in plants. In addition the systematic relevance of 2-pyrone-4,6-dicarboxylic acid within the Rosaceae was tested. The compound seems to be a chemotaxonomic marker for the Rosoideae sensu stricto proposed by Morgan et al. (Morgan, D.R., Soltis, D.E., Robertson, K.R., 1994. Systematic and evolutionary implications of rbcL sequence variation in Rosaceae. American Journal of Botany 81, 890-903).

  3. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway

    PubMed Central

    Yin, Guojian; Fan, Yuting; Wu, Deqing; Qiu, Lei; Yu, Ge; Xing, Miao; Hu, Guoyong; Wang, Xingpeng; Wan, Rong

    2015-01-01

    Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice. PMID:26556479

  4. Suppression of 9-cis-Epoxycarotenoid Dioxygenase, Which Encodes a Key Enzyme in Abscisic Acid Biosynthesis, Alters Fruit Texture in Transgenic Tomato1[W][OA

    PubMed Central

    Sun, Liang; Sun, Yufei; Zhang, Mei; Wang, Ling; Ren, Jie; Cui, Mengmeng; Wang, Yanping; Ji, Kai; Li, Ping; Li, Qian; Chen, Pei; Dai, Shengjie; Duan, Chaorui; Wu, Yan; Leng, Ping

    2012-01-01

    Cell wall catabolism during fruit ripening is under complex control and is key for fruit quality and shelf life. To examine the role of abscisic acid (ABA) in tomato (Solanum lycopersicum) fruit ripening, we suppressed SlNCED1, which encodes 9-cis-epoxycarotenoid dioxygenase (NCED), a key enzyme in the biosynthesis of ABA. To suppress SlNCED1 specifically in tomato fruits, and thus avoid the pleiotropic phenotypes associated with ABA deficiency, we used an RNA interference construct driven by the fruit-specific E8 promoter. ABA accumulation and SlNCED1 transcript levels in the transgenic fruit were down-regulated to between 20% and 50% of the levels measured in the control fruit. This significant reduction in NCED activity led to a down-regulation in the transcription of genes encoding major cell wall catabolic enzymes, specifically polygalacturonase (SlPG), pectin methyl esterase (SlPME), β-galactosidase precursor mRNA (SlTBG), xyloglucan endotransglycosylase (SlXET), endo-1,4-β-cellulose (SlCels), and expansin (SlExp). This resulted in an increased accumulation of pectin during ripening. In turn, this led to a significant extension of the shelf life to 15 to 29 d compared with a shelf life of only 7 d for the control fruit and an enhancement of fruit firmness at the mature stage by 30% to 45%. In conclusion, ABA affects cell wall catabolism during tomato fruit ripening via down-regulation of the expression of major catabolic genes (SlPG, SlPME, SlTBG, SlXET, SlCels, and SlExp). PMID:22108525

  5. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway.

    PubMed

    Xiao, Wenqin; Jiang, Weiliang; Shen, Jie; Yin, Guojian; Fan, Yuting; Wu, Deqing; Qiu, Lei; Yu, Ge; Xing, Miao; Hu, Guoyong; Wang, Xingpeng; Wan, Rong

    2015-01-01

    Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice. PMID:26556479

  6. Boswellic Acid Suppresses Growth and Metastasis of Human Pancreatic Tumors in an Orthotopic Nude Mouse Model through Modulation of Multiple Targets

    PubMed Central

    Park, Byoungduck; Prasad, Sahdeo; Yadav, Vivek; Sung, Bokyung; Aggarwal, Bharat B.

    2011-01-01

    Pancreatic cancer (PaCa) is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA), an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation). These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg) significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets. PMID:22066019

  7. Interactive suppression of aberrant crypt foci induced by azoxymethane in rat colon by phytic acid and green tea.

    PubMed

    Challa, A; Rao, D R; Reddy, B S

    1997-10-01

    Several epidemiological studies point to a strong correlation between nutrient composition of the diet and cancer of the colon. Phytic acid, present in grains, has been credited with reducing the risk of cancer of the colon. A number of reports are available indicating the benefits of green tea consumption in reducing the risk of stomach, lung and skin cancer, but little data are available on the effect of green tea in reducing the risk of colon cancer. Also, there are no studies on the combined effect of these compounds on colon tumorigenesis. Thus the primary objective of this investigation was to elucidate the combined effects of green tea and phytic acid on colonic preneoplastic lesions and the Phase II enzyme glutathione S-transferase. Fisher 344 male weanling rats were divided into nine groups of 15 rats each and fed the experimental diet for 13 weeks. Rats received two s.c. injections of azoxymethane in saline at 16 mg/kg body wt at 7 and 8 weeks of age. Rats received three levels (0, 1 and 2%) of phytic acid with three levels (0, 1 and 2%) of green tea within each phytic acid level in a 3 x 3 factorial experiment. Results indicate that while green tea had a marginal effect (P < 0.14), phytic acid significantly reduced the incidence of aberrant crypt foci (P < 0.008). The interaction between green tea and phytic acid was significant (P < 0.029 for distal and < 0.0168 for entire colon) and positive, pointing to a synergistic effect of green tea and phytic acid.

  8. DISRUPTION IN RAT ESTROUS CYCLICITY BY THE DRINKING WATER DISINFECTANT BY-PRODUCT DIBROMOACETIC ACID: RELATIONSHIP TO A SUPPRESSION ON ESTRADIOL METABOLISM?

    EPA Science Inventory

    Disruption in Rat Estrous Cyclicity by the Drinking Water Disinfectant By-Product Dibromoacetic Acid: Relationship to A Suppression on Estradiol Metabolism?

    Ashley S. Murr and Jerome M. Goldman, Endocrinology Branch, Reproductive Toxicology Division National Health and En...

  9. MODERATING INFLUENCE OF THE DRINKING WATER DISINFECTION BY-PRODUCT DIBROMOACETIC ACID ON A DITHIOCARBAMATE-INDUCED SUPPRESSION OF THE LUTEINIZING HORMONE SURGE IN FEMALE RATS.

    EPA Science Inventory

    The disinfection by-product dibromoacetic acid (DBA) has been found in female rats to increase circulating concentrations of both estradiol (E2) and estrone (E1). This effect is apparently due, at least in part, to a suppression in hepatic catabolism. The present study investigat...

  10. Exogenous abscisic acid significantly affects proteome in tea plant (Camellia sinensis) exposed to drought stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tea [Camellia sinensis (L.) O. Kuntze] is an important economic crop, and drought is the most important abiotic stress affecting yield and quality. Abscisic acid (ABA) is an important phytohormone responsible for activating drought resistance. Increased understanding of ABA effects on tea plant unde...

  11. The significance of linoleic acid in food sources for detritivorous benthic invertebrates

    PubMed Central

    Vonk, J. Arie; van Kuijk, Bernd F.; van Beusekom, Mick; Hunting, Ellard R.; Kraak, Michiel H. S.

    2016-01-01

    Chemical composition of organic matter (OM) is a key driver for detritus consumption by macroinvertebrates and polyunsaturated fatty acid (PUFA) content is considered a candidate indicator of food palatability. Since traditionally used complex natural OM covaries in many quality attributes, it remains uncertain whether benthic invertebrates developed an actual preference for PUFA-rich food. Therefore we aimed to test the influence of the PUFA linoleic acid on OM consumption by aquatic macroinvertebrates using standardized surrogate substrates (decomposition and consumption tablet, DECOTAB) with added linoleic acid (PUFA) in comparison to consumption of DECOTAB containing only cellulose (Standard) or ground macrophytes (Plant). In microcosms, we observed a higher consumption rate of PUFA DECOTAB in comparison to Standard DECOTAB in two functionally distinct invertebrate species (Lumbriculus variegatus and Asellus aquaticus). This effect appeared to be overruled in the field due to unknown sources of natural variation. Although we observed higher consumption rates in species-rich ditches compared to species-poor ditches, consumption rates were comparable for all three types of DECOTAB deployed. Upon reduced food quality and palatability, results presented here hint that PUFA like linoleic acid may be a key OM attribute driving the performance of benthic macroinvertebrates and inherent functioning of aquatic ecosystems. PMID:27767068

  12. Methods for evaluating the biological significance of acidic episodes in streams

    SciTech Connect

    Christensen, S.W.; Sale, M.J.; Beauchamp, J.J.

    1987-01-01

    During storms or periods of snowmelt, the levels of acidity and aluminum in streams can increase greatly. An approach is presented for designing and analyzing laboratory experiments that investigate the relationship between episodic changes in water chemistry and survival of fish. (ACR)

  13. The Significance of Acid Alteration in the Los Humeros High-Temperature Geothermal Field, Puebla, Mexico.

    NASA Astrophysics Data System (ADS)

    Elders, W. A.; Izquierdo, G.

    2014-12-01

    The Los Humeros geothermal field is a high-enthalpy hydrothermal system with more than 40 drilled deep wells, mostly producing high steam fractions at > 300oC. However, although it has a large resource potential, low permeability and corrosive acid fluids have hampered development so that it currently has an installed electrical generating capacity of only 40 MWe. The widespread production of low pH fluids from the reservoir is inconsistent with the marked absence in the reservoir rocks of hydrothermal minerals typical of acid alteration. Instead the hydrothermal alteration observed is typical of that due to neutral to alkaline pH waters reacting with the volcanic rocks of the production zones. Thus it appears that since the reservoir has recently suffered a marked drop in fluid pressure and is in process of transitioning from being water-dominated to being vapor-dominated. However sparse examples of acid leaching are observed locally at depths of about 2 km in the form of bleached, intensely silicified zones, in low permeability and very hot (>350oC) parts of reservoir. Although these leached rocks retain their primary volcanic and pyroclastic textures, they are altered almost entirely to microcrystalline quartz, with some relict pseudomorphs of plagioclase phenocrysts and traces of earlier-formed hydrothermal chlorite and pyrite. These acid-altered zones are usually only some tens of meters thick and deeper rocks lack such silicification. The acid fluids responsible for their formation could either be magmatic volatiles, or could be formed during production (e.g. reaction of water and salts forming hydrogen chloride by hydrolysis at high temperatures). The very high boron content of the fluids produced by the Los Humeros wells suggests that their ultimate source is most likely magmatic gases. However, these acid gases did not react widely with the rocks. We suggest that the silicified zones are forming locally where colder descending waters are encountering

  14. Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation.

    PubMed

    Hill, Shauna; Lamberson, Connor R; Xu, Libin; To, Randy; Tsui, Hui S; Shmanai, Vadim V; Bekish, Andrei V; Awad, Agape M; Marbois, Beth N; Cantor, Charles R; Porter, Ned A; Clarke, Catherine F; Shchepinov, Mikhail S

    2012-08-15

    Polyunsaturated fatty acids (PUFAs) undergo autoxidation and generate reactive carbonyl compounds that are toxic to cells and associated with apoptotic cell death, age-related neurodegenerative diseases, and atherosclerosis. PUFA autoxidation is initiated by the abstraction of bis-allylic hydrogen atoms. Replacement of the bis-allylic hydrogen atoms with deuterium atoms (termed site-specific isotope-reinforcement) arrests PUFA autoxidation due to the isotope effect. Kinetic competition experiments show that the kinetic isotope effect for the propagation rate constant of Lin autoxidation compared to that of 11,11-D(2)-Lin is 12.8 ± 0.6. We investigate the effects of different isotope-reinforced PUFAs and natural PUFAs on the viability of coenzyme Q-deficient Saccharomyces cerevisiae coq mutants and wild-type yeast subjected to copper stress. Cells treated with a C11-BODIPY fluorescent probe to monitor lipid oxidation products show that lipid peroxidation precedes the loss of viability due to H-PUFA toxicity. We show that replacement of just one bis-allylic hydrogen atom with deuterium is sufficient to arrest lipid autoxidation. In contrast, PUFAs reinforced with two deuterium atoms at mono-allylic sites remain susceptible to autoxidation. Surprisingly, yeast treated with a mixture of approximately 20%:80% isotope-reinforced D-PUFA:natural H-PUFA are protected from lipid autoxidation-mediated cell killing. The findings reported here show that inclusion of only a small fraction of PUFAs deuterated at the bis-allylic sites is sufficient to profoundly inhibit the chain reaction of nondeuterated PUFAs in yeast.

  15. Tumor-targeted delivery of a C-terminally truncated FADD (N-FADD) significantly suppresses the B16F10 melanoma via enhancing apoptosis

    PubMed Central

    Yang, Yun-Wen; Zhang, Chun-Mei; Huang, Xian-Jie; Zhang, Xiao-Xin; Zhang, Lin-Kai; Li, Jia-Huang; Hua, Zi-Chun

    2016-01-01

    Fas-associated protein with death domain (FADD), a pivotal adaptor protein transmitting apoptotic signals, is indispensable for the induction of extrinsic apoptosis. However, overexpression of FADD can form large, filamentous aggregates, termed death effector filaments (DEFs) by self-association and initiate apoptosis independent of receptor cross-linking. A mutant of FADD, which is truncated of the C-terminal tail (m-FADD, 182–205 aa) named N-FADD (m-FADD, 1–181 aa), can dramatically up-regulate the strength of FADD self-association and increase apoptosis. In this study, it was found that over-expression of FADD or N-FADD caused apoptosis of B16F10 cells in vitro, even more, N-FADD showed a more potent apoptotic effect than FADD. Meanwhile, Attenuated Salmonella Typhimurium strain VNP20009 was engineered to express FADD or N-FADD under the control of a hypoxia-induced NirB promoter and each named VNP-pN-FADD and VNP-pN-N-FADD. The results showed both VNP-pN-FADD and VNP-pN-N-FADD delayed tumor growth in B16F10 mice model, while VNP-pN-N-FADD suppressed melanoma growth more significantly than VNP-pN-FADD. Additionally, VNP-pN-FADD and VNP-pN-N-FADD induced apoptosis of tumor cells by activating caspase-dependent apoptotic pathway. Our results show that N-FADD is a more potent apoptotic inducer and VNP20009-mediated targeted expression of N-FADD provides a possible cancer gene therapeutic approach for the treatment of melanoma. PMID:27767039

  16. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX).

    PubMed

    Ohia, Sunny E; Opere, Catherine A; LeDay, Angela M; Bagchi, Manashi; Bagchi, Debasis; Stohs, Sidney J

    2002-09-01

    A growing body of evidence demonstrates the efficacy of Garcinia cambogia-derived natural (-)-hydroxycitric acid (HCA) in weight management by curbing appetite and inhibiting body fat biosynthesis. However, the exact mechanism of action of this novel phytopharmaceutical has yet to be fully understood. In a previous study, we showed that in the rat brain cortex a novel HCA extract (HCA-SX, Super CitriMax) increases the release/availability of radiolabeled 5-hydroxytryptamine or serotonin ([3H]-5-HT), a neurotransmitter implicated in the regulation of eating behavior and appetite control. The aim of the present study was 2-fold: (a) to determine the effect of HCA-SX on 5-HT uptake in rat brain cortex in vitro; and (b) to evaluate the safety of HCA-SX in vivo. Isolated rat brain cortex slices were incubated in oxygenated Krebs solution for 20 min and transferred to buffer solutions containing [3H]-5-HT for different time intervals. In some experiments, tissues were exposed to HCA-SX (10 microM - 1 mM) and the serotonin receptor reuptake inhibitors (SRRI) fluoxetine (100 microM) plus clomipramine (10 microM). Uptake of [3H]-5-HT was expressed as d.p.m./mg wet weight. A time-dependent uptake of [3H]-5-HT occurred in cortical slices reaching a maximum at 60 min. HCA-SX, and fluoxetine plus clomipramine inhibited the time-dependent uptake of [3H]-5-HT. At 90 min, HCA-SX (300 microM) caused a 20% decrease, whereas fluoxetine plus clomipramine inhibited [3H]-5-HT uptake by 30%. In safety studies, acute oral toxicity, acute dermal toxicity, primary dermal irritation and primary eye irritation, were conducted in animals using various doses of HCA-SX. Results indicate that the LD50 of HCA-SX is greater than 5,000 mg/kg when administered once orally via gastric intubation to fasted male and female Albino rats. No gross toxicological findings were observed under the experimental conditions. Taken together, these in vivo toxicological studies demonstrate that HCA-SX is a safe

  17. Cilostazol suppresses β-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-β.

    PubMed

    Lee, Hye Rin; Shin, Hwa Kyoung; Park, So Youn; Kim, Hye Young; Lee, Won Suk; Rhim, Byung Yong; Hong, Ki Whan; Kim, Chi Dae

    2014-11-01

    The accumulation of plaques of β-amyloid (Aβ) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of β- and γ-secretases. However, the production of Aβ can be avoided by alternate cleavage of APP by α-and γ-secretases. We hypothesized that cilostazol attenuates Aβ production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α-secretase activity via SIRT1-coupled retinoic acid receptor-β (RARβ) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aβ overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3∼24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full-length APP (FL-APP) and Aβ in a time-dependent manner (3-24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10-30 μM), FL-APP and Aβ levels were significantly reduced, and ADAM10 and α-secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp-cAMPS and sirtinol and by SIRT1-gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all-trans retinoic acid, cilostazol enhanced the protein expressions of RARβ and ADAM10, and the cilostazol-stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARβ inhibitor), sirtinol, and RARβ-gene silencing. In conclusion, cilostazol suppresses the accumulations of FL-APP and Aβ by activating ADAM10 via the upregulation of SIRT1-coupled RARβ.

  18. The Escherichia coli Acid Stress Response and Its Significance for Pathogenesis.

    PubMed

    De Biase, Daniela; Lund, Peter A

    2015-01-01

    Escherichia coli has a remarkable ability to survive low pH and possesses a number of different genetic systems that enable it to do this. These may be expressed constitutively, typically in stationary phase, or induced by growth under a variety of conditions. The activities of these systems have been implicated in the ability of E. coli to pass the acidic barrier of the stomach and to become established in the gastrointestinal tract, something causing serious infections. However, much of the work characterizing these systems has been done on standard laboratory strains of E. coli and under conditions which do not closely resemble those found in the human gut. Here we review what is known about acid resistance in E. coli as a model laboratory organism and in the context of its lifestyle as an inhabitant-sometimes an unwelcome one-of the human gut.

  19. Ecophysiological Significance of CO2-Recycling via Crassulacean Acid Metabolism in Talinum calycinum Engelm. (Portulacaceae) 1

    PubMed Central

    Martin, Craig E.; Higley, Michael; Wang, Wei-Zhong

    1988-01-01

    High levels of variability in gas exchange characteristics and degree of CAM-cycling were found in the same and different individuals of Talinum calycinum Engelm. collected from rock outcrops in Missouri. Differences in CO2 assimilation were mostly correlated with differences in shoot conductance to CO2 not shoot internal CO2 concentration. As found previously, CAM acid fluctuations were evident in well-watered plants exhibiting C3 gas exchange patterns (CAM-cycling) and also in drought-stressed plants with stomata closed, or nearly so, day and night (CAM-idling). Drought stress also resulted in rapid stomatal closure, conserving water during droughts. Maximal CO2 uptake rates occurred below 35°C; higher temperatures induced decreases in CO2 assimilation and conductance while shoot internal CO2 concentrations remained similar. Plant water-use-efficiency was severely curtailed at temperatures above 30°C. Tissue acid fluctuations were the result of changes in malic acid concentrations. Calculations of the amount of water potentially conserved by CAM-cycling yielded values of approximately 5 to 44% of daytime water loss. Thus, CAM-cycling may be an important adaptation minimizing water loss by perennial succulents growing in shallow soil on rock outcrops. PMID:16665946

  20. Ecophysiological Significance of CO(2)-Recycling via Crassulacean Acid Metabolism in Talinum calycinum Engelm. (Portulacaceae).

    PubMed

    Martin, C E; Higley, M; Wang, W Z

    1988-02-01

    High levels of variability in gas exchange characteristics and degree of CAM-cycling were found in the same and different individuals of Talinum calycinum Engelm. collected from rock outcrops in Missouri. Differences in CO(2) assimilation were mostly correlated with differences in shoot conductance to CO(2) not shoot internal CO(2) concentration. As found previously, CAM acid fluctuations were evident in well-watered plants exhibiting C(3) gas exchange patterns (CAM-cycling) and also in drought-stressed plants with stomata closed, or nearly so, day and night (CAM-idling). Drought stress also resulted in rapid stomatal closure, conserving water during droughts. Maximal CO(2) uptake rates occurred below 35 degrees C; higher temperatures induced decreases in CO(2) assimilation and conductance while shoot internal CO(2) concentrations remained similar. Plant water-use-efficiency was severely curtailed at temperatures above 30 degrees C. Tissue acid fluctuations were the result of changes in malic acid concentrations. Calculations of the amount of water potentially conserved by CAM-cycling yielded values of approximately 5 to 44% of daytime water loss. Thus, CAM-cycling may be an important adaptation minimizing water loss by perennial succulents growing in shallow soil on rock outcrops.

  1. Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age.

    PubMed

    Colapinto, Cynthia K; O'Connor, Deborah L; Dubois, Lise; Tremblay, Mark S

    2012-04-01

    One-fifth of Canadian women of childbearing age (WCBA) have red blood cell (RBC) folate concentrations below those considered optimal for neural tube defect risk reduction (≥906 nmol·L(-1)). Determinants of optimal concentrations have not been examined in a nationally representative sample of Canadian WCBA since food fortification with folic acid was implemented. This study explored correlates of optimal RBC folate concentrations and characteristics of folic acid supplement users in a sample of Canadian WCBA. RBC folate concentrations from the 2007-2009 Canadian Health Measures Survey were assessed in women aged 15 to 45 years (n = 1162). Sociodemographic, behavioural, and clinical determinants of RBC folate ≥906 nmol·L(-1) were examined using univariate and separate multiple logistic regression models that controlled for age and household income. t tests were used to study differences between folic acid supplement users and nonusers. WCBA not taking folic acid supplements were less likely to achieve a RBC folate concentration ≥906 nmol·L(-1) compared with folic acid supplement users (odds ratio, 0.47; 95% confidence interval, 0.24, 0.92). Twenty-five percent of WCBA reported folic acid supplement use, and there was a higher percentage of folic acid supplement users in the highest income group. Folic acid supplement users were also more frequent consumers of supplemental vitamin B(12) and of fruit and vegetables (>3 times per day). Folic acid supplement use was the most significant predictor of WCBA achieving optimal RBC folate concentrations. These results indicate a need for targeted strategies to improve compliance with folic acid supplement recommendations among WCBA.

  2. Suppression of TNF-α induced NFκB activity by gallic acid and its semi-synthetic esters: possible role in cancer chemoprevention.

    PubMed

    Morais, Mauro C C; Luqman, Suaib; Kondratyuk, Tamara P; Petronio, Maicon S; Regasini, Luis O; Silva, Dulce H S; Bolzani, Vanderlan S; Soares, Christiane P; Pezzuto, John M

    2010-11-01

    Gallic acid (3,4,5-trihydroxybenzoic acid), found in many plants either in free-form or part of tannins, is known to possess anti-microbial, antioxidant and cytotoxic properties. NFκB regulates the expression of several genes involved in carcinogenesis. These include anti-apoptotic, cytokines and cell cycle-regulatory genes. It is well established that the transcriptional factor NFκB is deregulated in many forms of cancer. Thus, agents that can suppress NFκB activation have the potential of suppressing carcinogenesis. In the present investigation, gallic acid was isolated from Alchornea glandulosa (Euphorbiaceae) and eight esters were synthesised. These compounds were evaluated against TNF-α-induced NFκB activation with stably transfected 293/NFκB-Luc human embryonic kidney cells. Gallates with IC(50) values in a range of 10-56 µM mediated inhibitory activity higher than gallic acid (IC(50) 76.0 ± 4.9 µM). In addition to inhibiting NFκB activation, gallic acid mediated a modest cytotoxic effect, and some of the gallates affected cell viability at the tested concentrations. Based on these results, suppression of NFκB activation by gallate esters could play a chemopreventive role in carcinogenesis.

  3. Pseudolaric acid B exerts antitumor activity via suppression of the Akt signaling pathway in HeLa cervical cancer cells.

    PubMed

    Li, Mingqun; Hong, Li

    2015-08-01

    Pseudolaric acid B (PAB) is a diterpene acid isolated from the bark of the root and trunk of Pseudolarix kaempferi Gordon (Pinaceae), which has demonstrated cytotoxic effects against various types of cancer. However, the mechanisms underlying the anticancer effects of PAB have remained to be elucidated. In the present study, the effects of PAB on the viability and apoptosis of HeLa cells were investigated by MTT assay, flow cytometric analysis of Annexin V-fluorescein isothiocyanate/propidium iodide staining, Rhodamine 123 staining and western blot analysis. The results demonstrated that PAB had antiproliferative and apoptosis-inducing effects on HeLa cells. PAB markedly inhibited HeLa cell viability in a time- and concentration-dependent manner. Flow cytometric analysis indicated that PAB induced apoptosis in HeLa cells in a dose-dependent manner. Treatment with PAB suppressed the expression of anti-apoptotic factor B cell lymphoma-2, and promoted the expression of pro-apoptotic factor Bcl-2-associated X protein. In addition, PAB induced an increase in Caspase-3 activity and loss of mitochondrial membrane potential, suggesting that this apoptosis may be mediated by mitochondrial pathways. Furthermore, the results of western blot analysis indicated that PAB was able to reduce Akt phosphorylation, thereby inhibiting the Akt pathway. These results suggested that PAB inhibited cell proliferation and induced apoptosis in HeLa cells, and that the anti-tumor effects of PAB were associated with inhibition of the Akt pathway. In conclusion, the results of the present study suggested that PAB may represent a novel therapeutic strategy for the treatment of human cervical cancer. However, additional studies are required to investigate the underlying apoptotic mechanisms.

  4. Purification and partial amino acid sequence of suppressive lymphokine from a CD8+ CD57+ human T hybridoma.

    PubMed Central

    Quan, C P; Watanabe, S; Vuillier, F; Pires, R; Matsuo, T; Stanislawski, M; Pillot, J; Bouvet, J P

    1993-01-01

    A T-suppressor (TS) lymphokine was purified from the supernatant of a T hybridoma established from CD3+ CD8+ CD57+ lymphocytes of a healthy bone marrow transplant patient. Using polyclonal rabbit antibodies, raised against a TS-enriched preparation, a specific protein of 47,000 MW was identified, which was used to prepare monoclonal antibodies. The screening of hybridomas was carried out by strip-ELISA, in which the 47,000 MW band, transferred on a membrane, served as antigen. One of these monoclonal antibodies (IgM kappa) was selected for purification of the native TS molecule, which exhibited the high suppressive activity on the phytohaemagglutinin (PHA) and alloantigen responses of peripheral blood lymphocytes. The establishment of amino acid sequences of five trypsinized cleavage peptides confirmed that this protein has not been previously identified. This lymphokine--also detected in the supernatant of normal CD8+ CD57+ lymphocytes--is likely involved in bone marrow transplantation tolerance. Images Figure 1 Figure 3 PMID:7682534

  5. Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration.

    PubMed

    Anderson, Ethan J; Yamazaki, Hanae; Neufer, P Darrell

    2007-10-26

    Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal muscle under metabolic states associated with elevated lipid metabolism, yet the function of UCP3 in a physiological context remains controversial. Here, in situ mitochondrial H(2)O(2) emission and respiration were measured in permeabilized fiber bundles prepared from both rat and mouse (wild-type) gastrocnemius muscle after a single bout of exercise plus 18 h of recovery (Ex/R) that induced a approximately 2-4-fold increase in UCP3 protein. Elevated uncoupling activity (i.e. GDP inhibitable) was evident in Ex/R fibers only upon the addition of palmitate (known activator of UCP3) or under substrate conditions eliciting substantial rates of H(2)O(2) production (i.e. respiration supported by succinate or palmitoyl-L-carnitine/malate but not pyruvate/malate), indicative of UCP3 activation by endogenous reactive oxygen species. In mice completely lacking UCP3 (ucp3(-/-)), Ex/R failed to induce uncoupling activity. Surprisingly, when UCP3 activity was inhibited by GDP (rats) or in the absence of UCP3 (ucp3(-/-)), H(2)O(2) emission was significantly (p < 0.05) higher in Ex/R versus non-exercised control fibers. Collectively, these findings demonstrate that the oxidant emitting potential of mitochondria is increased in skeletal muscle during recovery from exercise, possibly as a consequence of prolonged reliance on lipid metabolism and/or altered mitochondrial biochemistry/morphology and that induction of UCP3 in vivo mediates an increase in uncoupling activity that restores mitochondrial H(2)O(2) emission to non-exercised, control levels.

  6. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: A mechanistic approach

    SciTech Connect

    Abhilash, P.A.; Harikrishnan, R.; Indira, M.

    2014-01-15

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4 g/kg b.wt for 90 days. After 90 days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250 mg/kg b.wt) and AA (250 mg/kg b.wt) supplemented groups and maintained for 30 days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β{sub 1} and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α{sub 1} (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. - Highlights: • Alcohol increases intestinal bacterial overgrowth and permeability of endotoxin. • Endotoxin mediated inflammation plays a major role in alcoholic liver fibrosis. • Ascorbic acid reduces endotoxemia, NF-κB activation and proinflammatory cytokines. • AA's action is by inhibition of SIBO, IKKβ and alteration of

  7. A medium-chain fatty acid, capric acid, inhibits RANKL-induced osteoclast differentiation via the suppression of NF-κB signaling and blocks cytoskeletal organization and survival in mature osteoclasts.

    PubMed

    Kim, Hyun-Ju; Yoon, Hye-Jin; Kim, Shin-Yoon; Yoon, Young-Ran

    2014-08-01

    Fatty acids, important components of a normal diet, have been reported to play a role in bone metabolism. Osteoclasts are bone-resorbing cells that are responsible for many bone-destructive diseases such as osteoporosis. In this study, we investigated the impact of a medium-chain fatty acid, capric acid, on the osteoclast differentiation, function, and survival induced by receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (MCSF). Capric acid inhibited RANKL-mediated osteoclastogenesis in bone marrow-derived macrophages and suppressed RANKL-induced IκBα phosphorylation, p65 nuclear translocation, and NF-κB transcriptional activity. Capric acid further blocked the RANKL-stimulated activation of ERK without affecting JNK or p38. The induction of NFATc1 in response to RANKL was also attenuated by capric acid. In addition, capric acid abrogated M-CSF and RANKL-mediated cytoskeleton reorganization, which is crucial for the efficient bone resorption of osteoclasts. Capric acid also increased apoptosis in mature osteoclasts through the induction of Bim expression and the suppression of ERK activation by M-CSF. Together, our results reveal that capric acid has inhibitory effects on osteoclast development. We therefore suggest that capric acid may have potential therapeutic implications for the treatment of bone resorption-associated disorders.

  8. Chimeric HBcAg virus-like particles presenting a HPV 16 E7 epitope significantly suppressed tumor progression through preventive or therapeutic immunization in a TC-1-grafted mouse model

    PubMed Central

    Chu, Xiaojie; Li, Yang; Long, Qiong; Xia, Ye; Yao, Yufeng; Sun, Wenjia; Huang, Weiwei; Yang, Xu; Liu, Cunbao; Ma, Yanbing

    2016-01-01

    Background Therapeutic human papillomavirus (HPV) vaccines are currently being developed. However, no therapeutic efficacy has been achieved in clinical trials for the treatment of cervical intraepithelial neoplasia or cancer. One of the important issues in increasing vaccine efficacy is determining the best way to enhance tumor antigen-specific cellular immune responses. This study aimed to explore the virus-like particles (VLPs) of hepatitis B core antigen (HBcAg) as potential therapeutic vaccine carriers and to assess its immunological characteristics. Methods Chimeric VLPs presenting a HPV 16 cytotoxic T lymphocytes epitope E749–57 (amino acid 49–57 of the E7 protein) were prepared using recombinant genes. C57BL/6 mice were immunized with VLPs and grafted with tumor cells TC-1 which is an E7-expressing tumorigenic cell line. The dynamic tumor growth was monitored and anti-tumor immune responses were investigated. Results Using a preventive strategy, immunization with VLPs resulted in nearly complete suppression of tumor growth. In treatment studies, VLP immunization significantly suppressed the tumor progression in mice carrying 2–3 mm tumors and in those bearing even larger tumors with diameters up to 8–9 mm. The VLP structure was shown to be important to induce vigorous antitumor immunity and effects. In immunized mice, enhanced E749–57-specific cellular immune responses were evidenced by increased interferon (IFN)-γ expression and decreased interleukin (IL)-4 expression in splenic lymphocytes, as well as an elevated number of effector cells expressing IFN-γ in response to the in vitro stimulation of the specific peptide E749–57. In addition, effective immune memory after VLP immunization was maintained for at least 16 weeks, preventing significant tumor growth after subsequent TC-1 challenge. Conclusion While VLPs were highly immunogenic in stimulating humoral immunity, our results strongly indicated that VLPs, such as HBcAg particles, might

  9. Significance of pH on the Cytotoxic Potential of the Water Disinfection By-Product Iodoacetic Acid

    EPA Science Inventory

    Significance of pH on the Cytotoxic Potential of the Water Disinfection By-Product Iodoacetic Acid Vicki Richardson1, Susan D. Richardson2, Mary Moyer3, Jane Ellen Simmons1, and Anthony DeAngelo1, 1U.S. Environmental Protection Agency, Research Triangle Park, NC, 2University of...

  10. Allicin alleviates inflammation of trinitrobenzenesulfonic acid-induced rats and suppresses P38 and JNK pathways in Caco-2 cells.

    PubMed

    Li, Chen; Lun, Weijian; Zhao, Xinmei; Lei, Shan; Guo, Yandong; Ma, Jiayi; Zhi, Fachao

    2015-01-01

    Background. Allicin has anti-inflammatory, antioxidative and proapoptotic properties. Aims. To evaluate the effects and investigate the mechanism of allicin on trinitrobenzenesulfonic acid-induced colitis, specifically with mesalazine or sulfasalazine. Methods. 80 rats were divided equally into 8 groups: control; trinitrobenzenesulfonic acid; allicin prevention; allicin; mesalazine; sulfasalazine; allicin + sulfasalazine, and mesalazine + allicin. Systemic and colonic inflammation parameters were analysed. In addition, protein and culture medium of Caco-2 cells treated with various concentrations of IL-1β or allicin were collected for investigation of IL-8, NF-κB p65 P38, ERK, and JNK. One-way ANOVA and Kruskal-Wallis H test were used for parametric and nonparametric tests, respectively. Results. Allicin reduced the body weight loss of trinitrobenzenesulfonic acid-induced rats, histological score, serum TNF-α and IL-1β levels, and colon IL-1β mRNA level and induced serum IL-4 level, particularly in combination with mesalazine. In addition, 1 ng/mL IL-1β stimulated the P38, ERK, and JNK pathways, whereas pretreatment with allicin depressed this phenomenon, except for the ERK pathway. Conclusions. The inflammation induced by trinitrobenzenesulfonic acid is mitigated significantly by allicin treatment, particularly combined with mesalazine. Allicin inhibits the P38 and JNK pathways and the expression of NF-κB which explained the potential anti-inflammatory mechanisms of allicin. PMID:25729217

  11. Antisense suppression of an acid invertase gene (MAI1) in muskmelon alters plant growth and fruit development.

    PubMed

    Yu, Xiyan; Wang, Xiufeng; Zhang, Wenqian; Qian, Tingting; Tang, Guimin; Guo, Yankui; Zheng, Chengchao

    2008-01-01

    To unravel the roles of soluble acid invertase in muskmelon (Cucumis melo L.), its activity in transgenic muskmelon plants was reduced by an antisense approach. For this purpose, a 1038 bp cDNA fragment of muskmelon soluble acid invertase was expressed in antisense orientation behind the 35S promoter of the cauliflower mosaic virus. The phenotype of the antisense plants clearly differed from that of control plants. The transgenic plant leaves were markedly smaller, and the stems were obviously thinner. Transmission electron microscopy revealed that degradation of the chloroplast membrane occurred in transgenic leaves and the number of grana in the chloroplast was significantly reduced, suggesting that the slow growth and weaker phenotype of the transgenic plants may be due to damage to the chloroplast ultrastructure, which in turn resulted in a decrease in net photosynthetic rate. The sucrose concentration increased and levels of acid invertase decreased in transgenic fruit, and the fruit size was 60% smaller than that of the control. In addition, transgenic fruit reached full-slip at 25 d after pollination (DAP), approximately 5 d before the control fruit (full-slip at 30 DAP), and this accelerated maturity correlated with a dramatic elevation of ethylene production at the later stages of fruit development. Together, these results suggest that soluble acid invertase not only plays an important role during muskmelon plant and fruit development but also controls the sucrose content in muskmelon fruit.

  12. Carnosine (beta-alanylhistidine) protects from the suppression of contact hypersensitivity by ultraviolet B (280-320 nm) radiation or by cis urocanic acid.

    PubMed

    Reeve, V E; Bosnic, M; Rozinova, E

    1993-01-01

    Carnosine is a naturally occurring histidine-containing dipeptide in mammalian tissues for which a physiological role has not been defined. It has antioxidant properties, but has also been shown to be related metabolically to histidine and histamine, and to have immunopotentiating properties in vivo. It is shown here that carnosine presented topically or in the diet, potentiated the contact hypersensitivity reaction in hairless mice. Carnosine also prevented the systemic suppression of this reaction following exposure of the dorsal skin to ultraviolet B (UVB) radiation. Furthermore, carnosine prevented the systemic suppression caused by a topically applied lotion containing cis urocanic acid, indicating that it may act in competition with this UVB photoproduct which is believed to initiate many of the suppressive effects of UVB radiation.

  13. Dietary walnut suppression of colorectal cancer in mice: Mediation by miRNA patterns and fatty acid incorporation.

    PubMed

    Tsoukas, Michael A; Ko, Byung-Joon; Witte, Theodore R; Dincer, Fadime; Hardman, W Elaine; Mantzoros, Christos S

    2015-07-01

    Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets.

  14. Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far

    PubMed Central

    Espín, Juan Carlos; Larrosa, Mar; García-Conesa, María Teresa; Tomás-Barberán, Francisco

    2013-01-01

    The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2–20 μM. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo. PMID:23781257

  15. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far.

    PubMed

    Espín, Juan Carlos; Larrosa, Mar; García-Conesa, María Teresa; Tomás-Barberán, Francisco

    2013-01-01

    The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2-20  μ M. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo.

  16. Staphylococcus epidermidis Polysaccharide Intercellular Adhesin Production Significantly Increases during Tricarboxylic Acid Cycle Stress

    PubMed Central

    Vuong, Cuong; Kidder, Joshua B.; Jacobson, Erik R.; Otto, Michael; Proctor, Richard A.; Somerville, Greg A.

    2005-01-01

    Staphylococcal polysaccharide intercellular adhesin (PIA) is important for the development of a mature biofilm. PIA production is increased during growth in a nutrient-replete or iron-limited medium and under conditions of low oxygen availability. Additionally, stress-inducing stimuli such as heat, ethanol, and high concentrations of salt increase the production of PIA. These same environmental conditions are known to repress tricarboxylic acid (TCA) cycle activity, leading us to hypothesize that altering TCA cycle activity would affect PIA production. Culturing Staphylococcus epidermidis with a low concentration of the TCA cycle inhibitor fluorocitrate dramatically increased PIA production without impairing glucose catabolism, the growth rate, or the growth yields. These data lead us to speculate that one mechanism by which staphylococci perceive external environmental change is through alterations in TCA cycle activity leading to changes in the intracellular levels of biosynthetic intermediates, ATP, or the redox status of the cell. These changes in the metabolic status of the bacteria result in the attenuation or augmentation of PIA production. PMID:15838022

  17. Enterococcus faecalis lipoteichoic acid suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced IL-8 expression in human periodontal ligament cells.

    PubMed

    Im, Jintaek; Baik, Jung Eun; Kim, Kyoung Whun; Kang, Seok-Seong; Jeon, Jun Ho; Park, Ok-Jin; Kim, Hyun Young; Kum, Kee-Yeon; Yun, Cheol-Heui; Han, Seung Hyun

    2015-08-01

    Periodontitis is caused by multi-bacterial infection and Aggregatibacter actinomycetemcomitans and Enterococcus faecalis are closely associated with inflammatory periodontal diseases. Although lipopolysaccharide (LPS) of A. actinomycetemcomitans (Aa.LPS) and lipoteichoic acid of E. faecalis (Ef.LTA) are considered to be major virulence factors evoking inflammatory responses, their combinatorial effect on the induction of chemokines has not been investigated. In this study, we investigated the interaction between Aa.LPS and Ef.LTA on IL-8 expression in human periodontal ligament (PDL) cells. Aa.LPS, but not Ef.LTA, substantially induced IL-8 expression at the protein and mRNA levels. Interestingly, Ef.LTA suppressed Aa.LPS-induced IL-8 expression without affecting the binding of Aa.LPS to Toll-like receptor (TLR) 4. Ef.LTA reduced Aa.LPS-induced phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38 kinase. Furthermore, Ef.LTA inhibited the Aa.LPS-induced transcriptional activities of the activating protein 1, CCAAT/enhancer-binding protein and nuclear factor-kappa B transcription factors, all of which are known to regulate IL-8 gene expression. Ef.LTA augmented the expression of IL-1 receptor-associated kinase-M (IRAK-M), a negative regulator of TLR intracellular signaling pathways, in the presence of Aa.LPS at both the mRNA and protein levels. Small interfering RNA silencing IRAK-M reversed the attenuation of Aa.LPS-induced IL-8 expression by Ef.LTA. Collectively, these results suggest that Ef.LTA down-regulates Aa.LPS-induced IL-8 expression in human PDL cells through up-regulation of the negative regulator IRAK-M.

  18. Terpenes and sterols from the fruits of Prunus mume and their inhibitory effects on osteoclast differentiation by suppressing tartrate-resistant acid phosphatase activity.

    PubMed

    Yan, Xi-Tao; Lee, Sang-Hyun; Li, Wei; Jang, Hae-Dong; Kim, Young-Ho

    2015-02-01

    The fruits of Prunus mume are a common commercial product and a valuable source of food and medicinal material in Eastern Asian countries. Our phytochemical investigation of the P. mume fruit led to the isolation of nine terpenes, including three ursane-type triterpenes (1-3), two cycloartane-type triterpenes (4 and 5), and four tocopherols (10-13), as well as four sterols (6-9). Their structures were elucidated based on extensive spectroscopic analysis, including 1D and 2D NMR and ESI-MS, and the majority of these compounds were isolated from this plant for the first time. The anti-osteoporosis activities of 1-13 were evaluated by measuring their inhibitory effects on tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor κB ligand-induced osteoclastic RAW 264.7 macrophage cells. Compounds 2-7 and 9-12 significantly suppressed TRAP activity down to 47.96 ± 2.45-86.45 ± 3.07 % relative to the control at a concentration of 1 μM. These results suggest that the fruits of P. mume could be an excellent source of anti-osteoporosis phytochemicals that may be developed as natural nutraceuticals and functional foods.

  19. Inappropriate Use of Gastric Acid Suppression Therapy in Hospitalized Patients with Clostridium difficile—Associated Diarrhea: A Ten-Year Retrospective Analysis

    PubMed Central

    Rashid, Sadat; Rajan, Dhyan; Iqbal, Javed; Lipka, Seth; Jacob, Robin; Zilberman, Valeria; Shah, Mitanshu; Mustacchia, Paul

    2012-01-01

    Purpose. The incidence of Clostridium difficile-associated diarrhea (CDAD) has steadily increased over the past decade. A multitude of factors for this rise in incidence of CDAD have been postulated, including the increased use of gastric acid suppression therapy (GAST). Despite the presence of practice guidelines for use of GAST, studies have demonstrated widespread inappropriate use of GAST in hospitalized patients. We performed a retrospective analysis of inpatients with CDAD, with special emphasis placed on determining the appropriateness of GAST. Methods. A retrospective analysis was conducted at a multidisciplinary teaching hospital on inpatients with CDAD over a 10-year period. We assessed the use of GAST in the cases of CDAD. Data collection focused on the appropriate administration of GAST as defined by standard practice guidelines. Results. An inappropriate indication for GAST was not apparent in a majority (69.4%) of patients with CDAD. The inappropriate use of GAST was more prevalent in medical (86.1%) than on surgical services (13.9%) (P < 0.001). There were more cases (67.6%) of inappropriate use of GAST in noncritical care than in critical care areas (37.4%) (P < 0.001). Conclusion. Our study found that an inappropriate use of inpatient GAST in patients with CDAD was nearly 70 percent. Reduction of inappropriate use of GAST may be an additional approach to reduce the risk of CDAD and significantly decrease patient morbidity and healthcare costs. PMID:22701180

  20. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells

    PubMed Central

    Gruber, Sabrina; Hendrikx, Tim; Tsiantoulas, Dimitrios; Ozsvar-Kozma, Maria; Göderle, Laura; Mallat, Ziad; Witztum, Joseph L.; Shiri-Sverdlov, Ronit; Nitschke, Lars; Binder, Christoph J.

    2016-01-01

    Summary Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL) and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G-deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells. PMID:26947073

  1. The neuroactive steroid allopregnanolone suppresses hypothalamic gonadotropin-releasing hormone release through a mechanism mediated by the gamma-aminobutyric acidA receptor.

    PubMed

    Calogero, A E; Palumbo, M A; Bosboom, A M; Burrello, N; Ferrara, E; Palumbo, G; Petraglia, F; D'Agata, R

    1998-07-01

    The central nervous system (CNS) is able to synthesize and/or metabolize steroid hormones. These neuroactive steroids are capable of modulating several brain functions and, among these, they seem to regulate the hypothalamic-pituitary-gonadal (HPG) axis. Indeed, recent observations have shown that 5 alpha-pregnane-3 alpha-ol-20-one (allopregnanolone), one of the most abundant naturally occurring neuroactive steroids, suppresses ovulation and sexual behaviour when administered within the CNS. The present study was undertaken to evaluate the effects of allopregnanolone and its inactive stereoisomer, 5 alpha-pregnane-3 beta-ol-20-one, upon the release of gonadotropin-releasing hormone (GnRH) from individually-incubated hemihypothalami. Allopregnanolone suppressed GnRH release in a concentration-dependent manner with maximal activity in the nanomolar range, a range at which this neurosteroid is capable of playing a biological action. The specificity of allopregnanolone suppression of GnRH release was provided by the lack of effect of its known inactive stereoisomer. To evaluate the involvement of gamma-aminobutyric acidA (GABAA) receptor, we examined the effects of two neurosteroids with GABA-antagonistic properties, pregnanolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEAS), and of bicuculline, a selective antagonist of the GABA binding site on the GABAA receptor, on allopregnanolone (10 nM)-suppressed GnRH release. Both PREG-S and bicuculline overcame the inhibitory effects of allopregnanolone on GnRH release, whereas DHEAS did not. To substantiate the involvement of the GABAA receptor further, we tested the effects of muscimol, a selective agonist for this receptor, which suppressed GnRH release. In conclusion, allopregnanolone suppressed hypothalamic GnRH release in vitro and this effect appeared to be mediated by an interaction with the GABAA receptor. We speculate that the inhibitory effect of allopregnanolone on the HPG axis may also be caused by

  2. Identification of the domains of cauliflower mosaic virus protein P6 responsible for suppression of RNA silencing and salicylic acid signalling

    PubMed Central

    Laird, Janet; McInally, Carol; Carr, Craig; Doddiah, Sowjanya; Yates, Gary; Chrysanthou, Elina; Khattab, Ahmed; Love, Andrew J.; Geri, Chiara; Sadanandom, Ari; Smith, Brian O.; Kobayashi, Kappei

    2013-01-01

    Cauliflower mosaic virus (CaMV) encodes a 520 aa polypeptide, P6, which participates in several essential activities in the virus life cycle including suppressing RNA silencing and salicylic acid-responsive defence signalling. We infected Arabidopsis with CaMV mutants containing short in-frame deletions within the P6 ORF. A deletion in the distal end of domain D-I (the N-terminal 112 aa) of P6 did not affect virus replication but compromised symptom development and curtailed the ability to restore GFP fluorescence in a GFP-silenced transgenic Arabidopsis line. A deletion in the minimum transactivator domain was defective in virus replication but retained the capacity to suppress RNA silencing locally. Symptom expression in CaMV-infected plants is apparently linked to the ability to suppress RNA silencing. When transiently co-expressed with tomato bushy stunt virus P19, an elicitor of programmed cell death in Nicotiana tabacum, WT P6 suppressed the hypersensitive response, but three mutants, two with deletions within the distal end of domain D-I and one involving the N-terminal nuclear export signal (NES), were unable to do so. Deleting the N-terminal 20 aa also abolished the suppression of pathogen-associated molecular pattern-dependent PR1a expression following agroinfiltration. However, the two other deletions in domain D-I retained this activity, evidence that the mechanisms underlying these functions are not identical. The D-I domain of P6 when expressed alone failed to suppress either cell death or PR1a expression and is therefore necessary but not sufficient for all three defence suppression activities. Consequently, concerns about the biosafety of genetically modified crops carrying truncated ORFVI sequences appear unfounded. PMID:24088344

  3. Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes.

    PubMed

    Crown, Scott B; Marze, Nicholas; Antoniewicz, Maciek R

    2015-01-01

    The branched chain amino acids (BCAA) valine, leucine and isoleucine have been implicated in a number of diseases including obesity, insulin resistance, and type 2 diabetes mellitus, although the mechanisms are still poorly understood. Adipose tissue plays an important role in BCAA homeostasis by actively metabolizing circulating BCAA. In this work, we have investigated the link between BCAA catabolism and fatty acid synthesis in 3T3-L1 adipocytes using parallel 13C-labeling experiments, mass spectrometry and model-based isotopomer data analysis. Specifically, we performed parallel labeling experiments with four fully 13C-labeled tracers, [U-13C]valine, [U-13C]leucine, [U-13C]isoleucine and [U-13C]glutamine. We measured mass isotopomer distributions of fatty acids and intracellular metabolites by GC-MS and analyzed the data using the isotopomer spectral analysis (ISA) framework. We demonstrate that 3T3-L1 adipocytes accumulate significant amounts of even chain length (C14:0, C16:0 and C18:0) and odd chain length (C15:0 and C17:0) fatty acids under standard cell culture conditions. Using a novel GC-MS method, we demonstrate that propionyl-CoA acts as the primer on fatty acid synthase for the production of odd chain fatty acids. BCAA contributed significantly to the production of all fatty acids. Leucine and isoleucine contributed at least 25% to lipogenic acetyl-CoA pool, and valine and isoleucine contributed 100% to lipogenic propionyl-CoA pool. Our results further suggest that low activity of methylmalonyl-CoA mutase and mass action kinetics of propionyl-CoA on fatty acid synthase result in high rates of odd chain fatty acid synthesis in 3T3-L1 cells. Overall, this work provides important new insights into the connection between BCAA catabolism and fatty acid synthesis in adipocytes and underscores the high capacity of adipocytes for metabolizing BCAA.

  4. Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes.

    PubMed

    Crown, Scott B; Marze, Nicholas; Antoniewicz, Maciek R

    2015-01-01

    The branched chain amino acids (BCAA) valine, leucine and isoleucine have been implicated in a number of diseases including obesity, insulin resistance, and type 2 diabetes mellitus, although the mechanisms are still poorly understood. Adipose tissue plays an important role in BCAA homeostasis by actively metabolizing circulating BCAA. In this work, we have investigated the link between BCAA catabolism and fatty acid synthesis in 3T3-L1 adipocytes using parallel 13C-labeling experiments, mass spectrometry and model-based isotopomer data analysis. Specifically, we performed parallel labeling experiments with four fully 13C-labeled tracers, [U-13C]valine, [U-13C]leucine, [U-13C]isoleucine and [U-13C]glutamine. We measured mass isotopomer distributions of fatty acids and intracellular metabolites by GC-MS and analyzed the data using the isotopomer spectral analysis (ISA) framework. We demonstrate that 3T3-L1 adipocytes accumulate significant amounts of even chain length (C14:0, C16:0 and C18:0) and odd chain length (C15:0 and C17:0) fatty acids under standard cell culture conditions. Using a novel GC-MS method, we demonstrate that propionyl-CoA acts as the primer on fatty acid synthase for the production of odd chain fatty acids. BCAA contributed significantly to the production of all fatty acids. Leucine and isoleucine contributed at least 25% to lipogenic acetyl-CoA pool, and valine and isoleucine contributed 100% to lipogenic propionyl-CoA pool. Our results further suggest that low activity of methylmalonyl-CoA mutase and mass action kinetics of propionyl-CoA on fatty acid synthase result in high rates of odd chain fatty acid synthesis in 3T3-L1 cells. Overall, this work provides important new insights into the connection between BCAA catabolism and fatty acid synthesis in adipocytes and underscores the high capacity of adipocytes for metabolizing BCAA. PMID:26710334

  5. Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes

    PubMed Central

    Crown, Scott B.; Marze, Nicholas; Antoniewicz, Maciek R.

    2015-01-01

    The branched chain amino acids (BCAA) valine, leucine and isoleucine have been implicated in a number of diseases including obesity, insulin resistance, and type 2 diabetes mellitus, although the mechanisms are still poorly understood. Adipose tissue plays an important role in BCAA homeostasis by actively metabolizing circulating BCAA. In this work, we have investigated the link between BCAA catabolism and fatty acid synthesis in 3T3-L1 adipocytes using parallel 13C-labeling experiments, mass spectrometry and model-based isotopomer data analysis. Specifically, we performed parallel labeling experiments with four fully 13C-labeled tracers, [U-13C]valine, [U-13C]leucine, [U-13C]isoleucine and [U-13C]glutamine. We measured mass isotopomer distributions of fatty acids and intracellular metabolites by GC-MS and analyzed the data using the isotopomer spectral analysis (ISA) framework. We demonstrate that 3T3-L1 adipocytes accumulate significant amounts of even chain length (C14:0, C16:0 and C18:0) and odd chain length (C15:0 and C17:0) fatty acids under standard cell culture conditions. Using a novel GC-MS method, we demonstrate that propionyl-CoA acts as the primer on fatty acid synthase for the production of odd chain fatty acids. BCAA contributed significantly to the production of all fatty acids. Leucine and isoleucine contributed at least 25% to lipogenic acetyl-CoA pool, and valine and isoleucine contributed 100% to lipogenic propionyl-CoA pool. Our results further suggest that low activity of methylmalonyl-CoA mutase and mass action kinetics of propionyl-CoA on fatty acid synthase result in high rates of odd chain fatty acid synthesis in 3T3-L1 cells. Overall, this work provides important new insights into the connection between BCAA catabolism and fatty acid synthesis in adipocytes and underscores the high capacity of adipocytes for metabolizing BCAA. PMID:26710334

  6. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage

    PubMed Central

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-01-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4 (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.—Sasso, O., Migliore, M., Habrant, D., Armirotti, A., Albani, C., Summa, M., Moreno-Sanz, G., Scarpelli, R., Piomelli, D. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. PMID:25757568

  7. RNAi targeting putative genes in phosphatidylcholine turnover results in significant change in fatty acid composition in Crambe abyssinica seed oil.

    PubMed

    Guan, Rui; Li, Xueyuan; Hofvander, Per; Zhou, Xue-Rong; Wang, Danni; Stymne, Sten; Zhu, Li-Hua

    2015-04-01

    The aim of this study was to evaluate the importance of three enzymes, LPCAT, PDCT and PDAT, involved in acyl turnover in phosphatidylcholine in order to explore the possibility of further increasing erucic acid (22:1) content in Crambe seed oil. The complete coding sequences of LPCAT1-1 and LPCAT1-2 encoding lysophosphatidylcholine acyltransferase (LPCAT), PDCT1 and PDCT2 encoding phosphatidylcholine:diacylglycerol cholinephosphotransferase (PDCT), and PDAT encoding phospholipid:diacylglycerol acyltransferase (PDAT) were cloned from developing Crambe seeds. The alignment of deduced amino acid sequences displayed a high similarity to the Arabidopsis homologs. Transgenic lines expressing RNA interference (RNAi) targeting either single or double genes showed significant changes in the fatty acid composition of seed oil. An increase in oleic acid (18:1) was observed, to varying degrees, in all of the transgenic lines, and a cumulative effect of increased 18:1 was shown in the LPCAT-PDCT double-gene RNAi. However, LPCAT single-gene RNAi led to a decrease in 22:1 accumulation, while PDCT or PDAT single-gene RNAi had no obvious effect on the level of 22:1. In agreement with the abovementioned oil phenotypes, the transcript levels of the target genes in these transgenic lines were generally reduced compared to wild-type levels. In this paper, we discuss the potential to further increase the 22:1 content in Crambe seed oil through downregulation of these genes in combination with fatty acid elongase and desaturases.

  8. Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain.

    PubMed

    Nakamoto, Kazuo; Nishinaka, Takashi; Sato, Naoya; Mankura, Mitsumasa; Koyama, Yutaka; Kasuya, Fumiyo; Tokuyama, Shogo

    2013-01-01

    GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty

  9. Hypothalamic GPR40 Signaling Activated by Free Long Chain Fatty Acids Suppresses CFA-Induced Inflammatory Chronic Pain

    PubMed Central

    Nakamoto, Kazuo; Nishinaka, Takashi; Sato, Naoya; Mankura, Mitsumasa; Koyama, Yutaka; Kasuya, Fumiyo; Tokuyama, Shogo

    2013-01-01

    GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty

  10. Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates

    PubMed Central

    Vaidyanathan, Vidya; Bastarrachea, Raul A.; Higgins, Paul B.; Voruganti, V. Saroja; Kamath, Subhash; DiPatrizio, Nicholas V.; Piomelli, Daniele; Comuzzie, Anthony G.

    2012-01-01

    The goal of this study was to determine whether administration of the CB1 cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d31-tripalmitin) and intravenously (13C4-palmitate, 13C1-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg−1·h−1, P = 0.03). These data support the potential for a strong effect of CB1 receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis. PMID:22761159

  11. Omega-3 fatty acid inhibition of prostate cancer progression to hormone independence is associated with suppression of mTOR signaling and androgen receptor expression.

    PubMed

    Friedrichs, William; Ruparel, Shivani B; Marciniak, Robert A; deGraffenried, Linda

    2011-01-01

    Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as preclinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents; however, their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. We used an in vitro model of androgen ablation to determine the effect of treatment with omega-3 fatty acids on the progression to an androgen-independent state. The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were able to prevent progression of LNCaP cells while the omega-6 fatty acid arachidonic acid (AA) actually promoted cell growth under conditions of hormone depletion. These results correlated with a decrease in the expression of the androgen receptor as well as suppression of the Akt/mTOR signaling pathway. Connecting the mechanisms by which omega-3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival.

  12. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment.

    PubMed

    Prasad, Sahdeo; Yadav, Vivek R; Sung, Bokyung; Gupta, Subash C; Tyagi, Amit K; Aggarwal, Bharat B

    2016-03-15

    The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis.

  13. Inhibitory effect of α-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats.

    PubMed

    Fujii, Yuta; Segawa, Risa; Kimura, Masayuki; Wang, Liyun; Ishii, Yuji; Yamamoto, Ryuichi; Morita, Reiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2013-09-25

    To investigate the protective effect of α-lipoic acid (a-LA) on the hepatocarcinogenic process promoted by thioacetamide (TAA), we used a two-stage liver carcinogenesis model in N-diethylnitrosamine (DEN)-initiated and TAA-promoted rats. We examined the modifying effect of co-administered a-LA on the liver tissue environment surrounding preneoplastic hepatocellular lesions, with particular focus on hepatic macrophages and the mechanism behind the decrease in apoptosis of cells surrounding preneoplastic hepatocellular lesions during the early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in the liver. Co-administration with a-LA suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) hepatic macrophages as well as the number of CD3(+) lymphocytes. These effects were also suppressed by a-LA. Transcript levels of some inflammation-related genes were upregulated by TAA and downregulated by a-LA in real-time RT-PCR analysis. Outside the GST-P(+) foci, a-LA reduced the numbers of apoptotic cells, active caspase-8(+) cells and death receptor (DR)-5(+) cells. These results suggest that hepatic macrophages producing proinflammatory factors may be activated in TAA-induced tumor promotion. a-LA may suppress tumor-promoting activity by suppressing the activation of these macrophages and the subsequent inflammatory responses. Furthermore, a-LA may suppress tumor-promoting activity by suppressing the DR5-mediated extrinsic pathway of apoptosis and the subsequent regeneration of liver cells outside GST-P(+) foci.

  14. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment

    PubMed Central

    Prasad, Sahdeo; Yadav, Vivek R.; Sung, Bokyung; Gupta, Subash C.; Tyagi, Amit K.; Aggarwal, Bharat B.

    2016-01-01

    The development of chemoresistance in human pancreatic cancer is one reason for the poor survival rate for patients with this cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of ursolic acid (UA) to sensitize pancreatic cancer cells to gemcitabine, a standard drug used for the treatment of pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and angiogenic proteins. UA (20 μM) also enhanced gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated proteins. In the nude mouse model, oral administration of UA (250 mg/kg) suppressed tumor growth and enhanced the effect of gemcitabine (25 mg/kg). Furthermore, the combination of UA and gemcitabine suppressed the metastasis of cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic proteins regulated by these inflammatory transcription factors in tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with tumorigenesis, in the tumor tissue. UA was found to be bioavailable in animal serum and tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing inflammatory biomarkers linked to proliferation, invasion, angiogenesis, and metastasis. PMID:26909608

  15. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach.

    PubMed

    Abhilash, P A; Harikrishnan, R; Indira, M

    2014-01-15

    Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4g/kg b.wt for 90days. After 90days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250mg/kg b.wt) and AA (250mg/kg b.wt) supplemented groups and maintained for 30days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β1 and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α1 (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis. PMID:24239723

  16. 4-O-Acetyl-sialic acid (Neu4,5Ac2) in acidic milk oligosaccharides of the platypus (Ornithorhynchus anatinus) and its evolutionary significance.

    PubMed

    Urashima, Tadasu; Inamori, Hiroaki; Fukuda, Kenji; Saito, Tadao; Messer, Michael; Oftedal, Olav T

    2015-06-01

    Monotremes (echidnas and platypus) retain an ancestral form of reproduction: egg-laying followed by secretion of milk onto skin and hair in a mammary patch, in the absence of nipples. Offspring are highly immature at hatching and depend on oligosaccharide-rich milk for many months. The primary saccharide in long-beaked echidna milk is an acidic trisaccharide Neu4,5Ac2(α2-3)Gal(β1-4)Glc (4-O-acetyl 3'-sialyllactose), but acidic oligosaccharides have not been characterized in platypus milk. In this study, acidic oligosaccharides purified from the carbohydrate fraction of platypus milk were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and (1)H-nuclear magnetic resonance spectroscopy. All identified structures, except Neu5Ac(α2-3)Gal(β1-4)Glc (3'-sialyllactose) contained Neu4,5Ac2 (4-O-acetyl-sialic acid). These include the trisaccharide 4-O-acetyl 3'-sialyllactose, the pentasaccharide Neu4,5Ac2(α2-3)Gal(β1-4)GlcNAc(β1-3)Gal(β1-4)Glc (4-O-acetyl-3'-sialyllacto-N-tetraose d) and the hexasaccharide Neu4,5Ac2(α2-3)Gal(β1-4)[Fuc(α1-3)]GlcNAc(β1-3)Gal(β1-4)Glc (4-O-acetyl-3'-sialyllacto-N-fucopentaose III). At least seven different octa- to deca-oligosaccharides each contained a lacto-N-neohexaose core (LNnH) and one or two Neu4,5Ac2 and one to three fucose residues. We conclude that platypus milk contains a diverse (≥ 20) array of neutral and acidic oligosaccharides based primarily on lactose, lacto-N-neotetraose (LNnT) and LNnH structural cores and shares with echidna milk the unique feature that all identified acidic oligosaccharides (other than 3'-sialyllactose) contain the 4-O-acetyl-sialic acid moiety. We propose that 4-O-acetylation of sialic acid moieties protects acidic milk oligosaccharides secreted onto integumental surfaces from bacterial hydrolysis via steric interference with bacterial sialidases. This may be of evolutionary significance since taxa ancestral to monotremes and other mammals are

  17. 4-O-Acetyl-sialic acid (Neu4,5Ac2) in acidic milk oligosaccharides of the platypus (Ornithorhynchus anatinus) and its evolutionary significance.

    PubMed

    Urashima, Tadasu; Inamori, Hiroaki; Fukuda, Kenji; Saito, Tadao; Messer, Michael; Oftedal, Olav T

    2015-06-01

    Monotremes (echidnas and platypus) retain an ancestral form of reproduction: egg-laying followed by secretion of milk onto skin and hair in a mammary patch, in the absence of nipples. Offspring are highly immature at hatching and depend on oligosaccharide-rich milk for many months. The primary saccharide in long-beaked echidna milk is an acidic trisaccharide Neu4,5Ac2(α2-3)Gal(β1-4)Glc (4-O-acetyl 3'-sialyllactose), but acidic oligosaccharides have not been characterized in platypus milk. In this study, acidic oligosaccharides purified from the carbohydrate fraction of platypus milk were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and (1)H-nuclear magnetic resonance spectroscopy. All identified structures, except Neu5Ac(α2-3)Gal(β1-4)Glc (3'-sialyllactose) contained Neu4,5Ac2 (4-O-acetyl-sialic acid). These include the trisaccharide 4-O-acetyl 3'-sialyllactose, the pentasaccharide Neu4,5Ac2(α2-3)Gal(β1-4)GlcNAc(β1-3)Gal(β1-4)Glc (4-O-acetyl-3'-sialyllacto-N-tetraose d) and the hexasaccharide Neu4,5Ac2(α2-3)Gal(β1-4)[Fuc(α1-3)]GlcNAc(β1-3)Gal(β1-4)Glc (4-O-acetyl-3'-sialyllacto-N-fucopentaose III). At least seven different octa- to deca-oligosaccharides each contained a lacto-N-neohexaose core (LNnH) and one or two Neu4,5Ac2 and one to three fucose residues. We conclude that platypus milk contains a diverse (≥ 20) array of neutral and acidic oligosaccharides based primarily on lactose, lacto-N-neotetraose (LNnT) and LNnH structural cores and shares with echidna milk the unique feature that all identified acidic oligosaccharides (other than 3'-sialyllactose) contain the 4-O-acetyl-sialic acid moiety. We propose that 4-O-acetylation of sialic acid moieties protects acidic milk oligosaccharides secreted onto integumental surfaces from bacterial hydrolysis via steric interference with bacterial sialidases. This may be of evolutionary significance since taxa ancestral to monotremes and other mammals are

  18. Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum.

    PubMed

    Zaja-Milatovic, Snjezana; Gupta, Ramesh C; Aschner, Michael; Montine, Thomas J; Milatovic, Dejan

    2008-07-01

    Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 microl) was injected intracerebroventricularly to C57Bl/6 mice. F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p<0.001) increase in F2-IsoPs, F4-NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p<0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F2-IsoP, F4-NeuroPs and citrulline levels were found in mice pretreated with vitamin E (alpha-tocopherol, 100mg/kg, i.p.) for 3 days, or with N-tert-butyl-alpha-phenylnitrone (PBN, 200mg/kg, i.p.) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 microg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F2-IsoPs and F4-NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders.

  19. In vitro and in vivo studies on adlay-derived seed extracts: phenolic profiles, antioxidant activities, serum uric acid suppression, and xanthine oxidase inhibitory effects.

    PubMed

    Zhao, Mouming; Zhu, Dashuai; Sun-Waterhouse, Dongxiao; Su, Guowan; Lin, Lianzhu; Wang, Xiao; Dong, Yi

    2014-08-01

    This study aimed to explore the potential of polished adlay, brown adlay, adlay bran, and adlay hull to prevent and treat hyperuricemia. Brown adlay extract effectively decreased the serum uric acid levels of oxonate-induced hyperuricemic rats. Free and bound phenolic extracts from these materials contained significant amounts of phenolics, with free phenolics dominated by chlorogenic acid and p-coumaric acid while bound phenolics dominated by p-coumaric acid and ferulic acid. Free and bound phenolics of adlay bran exhibited significant xanthine oxidase inhibition activities, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities, oxygen radical absorbance capacities, and superoxide radical scavenging activities. Adlay bran phenolics could be effective xanthine oxidase inhibitors and radical scavengers. p-Coumaric acid is a xanthine oxidase inhibitor with strong superoxide radical scavenging activity. However, ferulic acid is a xanthine oxidase inhibitor with weak superoxide radical scavenging activity. Chlorogenic acid is a superoxide radical scavenger with weak xanthine oxidase inhibitory activity.

  20. Human β-D-3 Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid

    PubMed Central

    Semple, Fiona; MacPherson, Heather; Webb, Sheila; Kilanowski, Fiona; Lettice, Laura; McGlasson, Sarah L.; Wheeler, Ann P.; Chen, Valerie; Millhauser, Glenn L.; Melrose, Lauren; Davidson, Donald J.; Dorin, Julia R.

    2015-01-01

    Human β-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six β-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-β in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-β. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-β, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans. PMID:26646717

  1. Human β-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.

    PubMed

    Semple, Fiona; MacPherson, Heather; Webb, Sheila; Kilanowski, Fiona; Lettice, Laura; McGlasson, Sarah L; Wheeler, Ann P; Chen, Valerie; Millhauser, Glenn L; Melrose, Lauren; Davidson, Donald J; Dorin, Julia R

    2015-12-01

    Human β-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six β-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-β in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-β. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-β, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans. PMID:26646717

  2. Human β-Defensin 3 [corrected] Exacerbates MDA5 but Suppresses TLR3 Responses to the Viral Molecular Pattern Mimic Polyinosinic:Polycytidylic Acid.

    PubMed

    Semple, Fiona; MacPherson, Heather; Webb, Sheila; Kilanowski, Fiona; Lettice, Laura; McGlasson, Sarah L; Wheeler, Ann P; Chen, Valerie; Millhauser, Glenn L; Melrose, Lauren; Davidson, Donald J; Dorin, Julia R

    2015-12-01

    Human β-defensin 3 (hBD3) is a cationic host defence peptide and is part of the innate immune response. HBD3 is present on a highly copy number variable block of six β-defensin genes, and increased copy number is associated with the autoimmune disease psoriasis. It is not known how this increase influences disease development, but psoriasis is a T cell-mediated disease and activation of the innate immune system is required for the initial trigger that leads to the amplification stage. We investigated the effect of hBD3 on the response of primary macrophages to various TLR agonists. HBD3 exacerbated the production of type I Interferon-β in response to the viral ligand mimic polyinosinic:polycytidylic acid (polyI:C) in both human and mouse primary cells, although production of the chemokine CXCL10 was suppressed. Compared to polyI:C alone, mice injected with both hBD3 peptide and polyI:C also showed an enhanced increase in Interferon-β. Mice expressing a transgene encoding hBD3 had elevated basal levels of Interferon-β, and challenge with polyI:C further increased this response. HBD3 peptide increased uptake of polyI:C by macrophages, however the cellular response and localisation of polyI:C in cells treated contemporaneously with hBD3 or cationic liposome differed. Immunohistochemistry showed that hBD3 and polyI:C do not co-localise, but in the presence of hBD3 less polyI:C localises to the early endosome. Using bone marrow derived macrophages from knockout mice we demonstrate that hBD3 suppresses the polyI:C-induced TLR3 response mediated by TICAM1 (TRIF), while exacerbating the cytoplasmic response through MDA5 (IFIH1) and MAVS (IPS1/CARDIF). Thus, hBD3, a highly copy number variable gene in human, influences cellular responses to the viral mimic polyI:C implying that copy number may have a significant phenotypic effect on the response to viral infection and development of autoimmunity in humans.

  3. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    SciTech Connect

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  4. On-line cation exchange for suppression of adduct formation in negative-ion electrospray mass spectrometry of nucleic acids.

    PubMed

    Huber, C G; Buchmeiser, M R

    1998-12-15

    One major difficulty in the analysis of nucleic acids by electrospray mass spectrometry is represented by the affinity of the polyanionic sugar-phosphate backbone for nonvolatile cations, especially ubiquitous sodium and potassium ions. A simple on-line sample preparation system comprising a microflow pumping system and 45 x 0.8-mm-i.d. microcolumns packed with weak or strong cation-exchange resins is described for the efficient removal of cations from nucleic acid samples. Samples were analyzed by flow injection analysis at a 3-5 microL/min flow of 10 mM triethylamine in 50% water-50% acetonitrile. After on-line desalting, mass spectra of oligonucleotides revealed no significant sodium adduct peaks. Moreover, signal-to-noise ratios were greatly enhanced compared to direct injection of the samples. Electrospray mass spectrometry with on-line sample preparation allowed accurate molecular mass determinations of picomole amounts of crude oligonucleotide preparations ranging in size from 8 to 80 nucleotides within a few minutes. The good linearity of the calibration plot (R2 = 0.9988) over at least 2 orders of magnitude and a relative standard deviation in peak areas of less than 9% permitted the sensitive quantitative measurement of oligonucleotides in a concentration range of 0.2-20 microM with selected-ion monitoring. Finally, the on-line sample preparation system was evaluated for the mass spectrometric analysis of complex oligonucleotide mixtures. PMID:9868919

  5. Elicidation by a H-2-receptor antagonist of the significance of mucosal histamine mobilization in exciting acid secretion.

    PubMed Central

    Lundell, L

    1975-01-01

    1. The consequence of H-2-receptor blockade for the secretory responses of the gastric mucosa to hormonal or cholinergic stimulation was studied in conscious rats with Heindenhain pouches or Pavlov pouches with the antrum retained or resected. 2. Metiamide almost completely abolished acid secretion induced by pentagastrin without altering significantly the amount of histamine excreted in the urine. Histamine mobilization on pentagastrin infusion determined in vitro, seemed to be larger during H-2-receptor blockade than with pentagastrin alone. 3. CCK-PZ mobilized mucosal histamine to a considerable extent; the secretory response to this hormone was completely abolished by H-2-receptor blockade. 4. Acid secretion in response to 2-deoxy-D-glucose was inhibited by H-2-receptor blockade in the presence or absence of the antrum; however the inhibition was less complete than with hormone-induced secretion. 5. The acid secretory response to 100 mg/kg of 2-deoxy-D-glucose appeared to be less susceptible to H-2-receptor blockade than that of 50-mg/kg of 2-deoxy-D-glucose. 6. Feeding induced a secretory response in the Pavlov pouch which initially was more effectively inhibited by H-2-receptor blockade than the response to 2-deoxy-D-glucose. In the absence of antral gastrin secretion by either stimulus was equally inhibited. 7. Methacholine-induced acid secretion was inhibited by infusion of the H-2-receptor antagonist, an inhibition that was absent when pentagastrin was concomitantly infused. 8. Although acid secretion induced by cholinergic stimuli was readily inhibited by the H-2-receptor antagonist, slight or nor inhibition was noted on pepsin secretion. 9. The role of histamine as a physiological stimulus for the parietal cell is discussed in view of the fact that the secretory effect of natural stimuli, known or demonstrated to mobilize mucosal histamine, is restrained by H-2-receptor blockade. PMID:49418

  6. Autotaxin and Its Product Lysophosphatidic Acid Suppress Brown Adipose Differentiation and Promote Diet-Induced Obesity in Mice

    PubMed Central

    Federico, Lorenzo; Ren, Hongmei; Mueller, Paul A.; Wu, Tao; Liu, Shuying; Popovic, Jelena; Blalock, Eric M.; Sunkara, Manjula; Ovaa, Huib; Albers, Harald M.; Mills, Gordon B.; Morris, Andrew J.

    2012-01-01

    Brown adipose tissue is a thermogenic organ that dissipates stored energy as heat to maintain body temperature. This process may also provide protection from development of diet-induced obesity. We report that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, whereas potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibit reduced expression of brown adipose tissue-related genes in peripheral white adipose tissue and accumulate significantly more fat than wild-type controls when fed a high-fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and are consistent with a model in which a decrease in mature peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice. PMID:22474126

  7. Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA suppressed endometriotic lesion formation

    PubMed Central

    Zhao, Meng-Dan; Cheng, Jin-Lin; Yan, Jing-Jing; Chen, Feng-Ying; Sheng, Jian-Zhong; Sun, Dong-Li; Chen, Jian; Miao, Jing; Zhang, Run-Ju; Zheng, Cai-Hong; Huang, He-Feng

    2016-01-01

    To identify a new drug candidate for treating endometriosis which has fewer side effects, a new polymeric nanoparticle gene delivery system consisting of polyethylenimine-grafted chitosan oligosaccharide (CSO-PEI) with hyaluronic acid (HA) and small interfering RNA (siRNA) was designed. There was no obvious difference in sizes observed between (CSO-PEI/siRNA)HA and CSO-PEI/siRNA, but the fluorescence accumulation in the endometriotic lesion was more significant for (CSO-PEI/siRNA)HA compared with CSO-PEI/siRNA due to the specific binding of HA to CD44. In addition, the (CSO-PEI/siRNA)HA nanoparticle gene therapy significantly decreased the endometriotic lesion sizes with atrophy and degeneration of the ectopic endometrium. The epithelial cells of ectopic endometrium from rat models of endometriosis showed a significantly lower CD44 expression than control after treatment with (CSO-PEI/siRNA)HA. Furthermore, observation under an electron microscope showed no obvious toxic effect on the reproductive organs. Therefore, (CSO-PEI/siRNA)HA gene delivery system can be used as an effective method for the treatment of endometriosis. PMID:27099493

  8. Effective suppression of efficiency droop in GaN-based light-emitting diodes: role of significant reduction of carrier density and built-in field

    PubMed Central

    Yoo, Yang-Seok; Na, Jong-Ho; Son, Sung Jin; Cho, Yong-Hoon

    2016-01-01

    A critical issue in GaN-based high power light-emitting diodes (LEDs) is how to suppress the efficiency droop problem occurred at high current injection while improving overall quantum efficiency, especially in conventional c-plane InGaN/GaN quantum well (QW), without using complicated bandgap engineering or unconventional materials and structures. Although increasing thickness of each QW may decrease carrier density in QWs, formation of additional strain and defects as well as increased built-in field effect due to enlarged QW thickness are unavoidable. Here, we propose a facile and effective method for not only reducing efficiency droop but also improving quantum efficiency by utilizing c-plane InGaN/GaN QWs having thinner barriers and increased QW number while keeping the same single well thickness and total active layer thickness. As the barrier thickness decreases and the QW number increases, both internal electric field and carrier density within QWs are simultaneously reduced without degradation of material quality. Furthermore, we found overall improved efficiency and reduced efficiency droop, which was attributed to the decrease of the built-in field and to less influence by non-radiative recombination processes at high carrier density. This simple and effective approach can be extended further for high power ultraviolet, green, and red LEDs. PMID:27756916

  9. Does the eradication of Helicobacter pylori cure duodenal ulcer disease in communities with a high prevalence rate? Comparison with long-term acid suppression.

    PubMed

    Kepekci, Y; Kadayifci, A

    1999-01-01

    The long-term effect of Helicobacter pylori eradication on the natural history of duodenal ulcer has been investigated and compared with long-term acid suppression treatment in an endemic community for infection. Seventy-three patients with endoscopically verified H. pylori positive active duodenal ulcer disease were included in this prospective study. Patients were divided into two groups. Group A patients (n = 39) were given an omeprazole-based triple eradication regimen, while group B patients (n = 34) were given omeprazole alone followed by long-term famotidine 20 mg daily as maintenance treatment. A control endoscopy was performed at the third month of treatment. The bacterium was eradicated in 32 (82%) of group A patients. All patients were followed up for two years and an endoscopy performed at the end of each year. H. pylori recurred in 13 patients and the reinfection rate was 44.8% over two years. Duodenal ulcer recurred in seven of these patients at two years (24.1%). There was a close association between H. pylori reinfection and ulcer relapse. Group B patients remained H. pylori positive during the study and the ulcer recurred in five of these patients (6.6%) despite continuous famotidine treatment. There was no statistically significant difference in ulcer relapse rate between the groups. These results suggested that H. pylori eradication is not an absolute solution for duodenal ulcer disease in high endemic regions and continuous maintenance treatment with H2-receptor antagonists is still an alternative approach in some chronic recurrent cases.

  10. Omega-3 fatty acids do not improve endothelial function in virologically suppressed HIV-infected men: a randomized placebo-controlled trial.

    PubMed

    Hileman, Corrilynn O; Carman, Teresa L; Storer, Norma J; Labbato, Danielle E; White, Cynthia A; McComsey, Grace A

    2012-07-01

    Omega-3 fatty acids decrease cardiovascular disease (CVD) mortality possibly due to antiinflammatory effect. Inflammation and endothelial dysfunction likely play a role in the heightened CVD risk in HIV. Our goal was to evaluate the effect of omega-3 fatty acids primarily on endothelial function and inflammation in HIV-infected adults with moderate CVD risk on stable antiretroviral therapy. We conducted a 24-week, randomized, double-blind, placebo-controlled study to evaluate the effect of omega-3-acid ethyl esters 1 g twice a day. Flow-mediated dilation (FMD) of the brachial artery, lipoproteins and markers of inflammation, endothelial activation, coagulation, and insulin resistance were measured at entry and week 24. There were no within- or between-group differences in change in FMD over 24 weeks (mean change in FMD -0.13% vs. 1.5% for treatment vs. placebo; p=0.21). There were no between-group differences in changes in lipoprotein levels or biomarkers tested, except soluble tumor necrosis factor receptor-I, which favored omega-3-acid ethyl esters. Omega-3 fatty acids did not improve endothelial function or activation, coagulation, or insulin resistance in virologically suppressed, HIV-infected men with moderate CVD risk; however, inflammation tended to improve. This suggests that omega-3 fatty acids may not be potent enough to counteract the enhanced inflammation and endothelial dysfunction due to HIV and antiretrovirals.

  11. Down-regulation of crambe fatty acid desaturase and elongase in Arabidopsis and crambe resulted in significantly increased oleic acid content in seed oil.

    PubMed

    Li, Xueyuan; Mei, Desheng; Liu, Qing; Fan, Jing; Singh, Surinder; Green, Allan; Zhou, Xue-Rong; Zhu, Li-Hua

    2016-01-01

    High oleic oil is an important industrial feedstock that has been one of the main targets for oil improvement in a number of oil crops. Crambe (Crambe abyssinica) is a dedicated oilseed crop, suitable for industrial oil production. In this study, we down-regulated the crambe fatty acid desaturase (FAD) and fatty acid elongase (FAE) genes for creating high oleic seed oil. We first cloned the crambe CaFAD2, CaFAD3 and CaFAE1 genes. Multiple copies of each of these genes were isolated, and the highly homologous sequences were used to make RNAi constructs. These constructs were first tested in Arabidopsis, which led to the elevated oleic or linoleic levels depending on the genes targeted, indicating that the RNAi constructs were effective in regulating the expression of the target genes in nonidentical but closely related species. Furthermore, down-regulation of CaFAD2 and CaFAE1 in crambe with the FAD2-FAE1 RNAi vector resulted in even more significant increase in oleic acid level in the seed oil with up to 80% compared to 13% for wild type. The high oleic trait has been stable in subsequent five generations and the GM line grew normally in greenhouse. This work has demonstrated the great potential of producing high oleic oil in crambe, thus contributing to its development into an oil crop platform for industrial oil production.

  12. Prolonged Exposure of Primary Human Muscle Cells to Plasma Fatty Acids Associated with Obese Phenotype Induces Persistent Suppression of Muscle Mitochondrial ATP Synthase β Subunit.

    PubMed

    Tran, Lee; Hanavan, Paul D; Campbell, Latoya E; De Filippis, Elena; Lake, Douglas F; Coletta, Dawn K; Roust, Lori R; Mandarino, Lawrence J; Carroll, Chad C; Katsanos, Christos S

    2016-01-01

    Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m2) and lean (BMI, 22±1 kg/m2) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = - 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish

  13. Prolonged Exposure of Primary Human Muscle Cells to Plasma Fatty Acids Associated with Obese Phenotype Induces Persistent Suppression of Muscle Mitochondrial ATP Synthase β Subunit

    PubMed Central

    Tran, Lee; Hanavan, Paul D.; Campbell, Latoya E.; De Filippis, Elena; Lake, Douglas F.; Coletta, Dawn K.; Roust, Lori R.; Mandarino, Lawrence J.; Carroll, Chad C.; Katsanos, Christos S.

    2016-01-01

    Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m2) and lean (BMI, 22±1 kg/m2) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = – 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish

  14. 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.

  15. Suppression of interleukin 2-dependent human T cell growth in vitro by prostaglandin E (PGE) and their precursor fatty acids. Evidence for a PGE-independent mechanism of inhibition by the fatty acids.

    PubMed Central

    Santoli, D; Phillips, P D; Colt, T L; Zurier, R B

    1990-01-01

    PGE represent oxygenation products of polyunsaturated essential fatty acids and are important regulators of cell-mediated immune responses. Because oils enriched in such fatty acids reduce inflammation and tissue injury in vivo, we examined the effects of these PGE precursors on IL-2-driven growth of human T lymphocytes. Dihomogamma linoleic acid (DGLA), AA, and their metabolites (PGE1 and PGE2, respectively) strongly inhibited short- and long-term growth of IL-2-dependent T cell cultures; EPA was much less inhibitory and its product, PGE3, failed to suppress IL-2 responses. Short-term pretreatment of the cells with DGLA or AA and removal of the fatty acids before the proliferation assay resulted in a smaller reduction in [3H]TdR incorporation. PGE and fatty acids did not alter the number of high affinity IL-2 binding sites on the T cell cultures but reduced the percentage of cells expressing CD25 and HLA class II molecules. No PGE was detected in supernatants from the fatty acid-treated cultures. Moreover, indomethacin, a cyclooxygenase inhibitor, did not reverse the antiproliferative effects of the fatty acids. Together, these findings indicate that fatty acids can inhibit IL-2-driven T cell growth via a PGE-independent mechanism and might be relevant to inflammatory diseases associated with persistent T cell activation. Images PMID:2298918

  16. Carnosic acid nanoparticles suppress liver ischemia/reperfusion injury by inhibition of ROS, Caspases and NF-κB signaling pathway in mice.

    PubMed

    Li, Hui; Sun, Jian-Jun; Chen, Guo-Yong; Wang, Wei-Wei; Xie, Zhan-Tao; Tang, Gao-Feng; Wei, Si-Dong

    2016-08-01

    Living donor liver transplantation (LDLT) requires ischemia/reperfusion (I/R), which can lead to early graft injury. However, the detailed molecular mechanism of I/R injury remains unclear. Carnosic acid, as a phenolic diterpene with function of anti-inflammation, anti-cancer, anti-bacterial, anti-diabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. Administration of carnosic acid nanoparticles was thought to be sufficient to lead to considerable inhibition of liver injury progression induced by ischemia/reperfusion. In our study, liver ischemia/reperfusion injury was established successfully with C57BL/6 animal model. 10 and 20mg/kg carnosic acid nanoparticles were injected to mice for five days prior to ischemia. After liver ischemia/reperfusion, the levels of serum AST, ALT and APL were increased, which was attenuated by pre-treatment with carnosic acid nanoparticles. In addition, carnosic acid nanoparticles inhibited ROS production via its related signals regulation. And carnosic acid nanoparticles also suppressed the ischemia/reperfusion-induced up-regulation in the pro-apoptotic protein and mRNA levels of Bax, Cyto-c, Apaf-1 and Caspase-9/3 while increased ischemia/reperfusion-induced decrease of anti-apoptotic factor of Bcl-2. Further, ischemia/reperfusion-induced inflammation was also inhibited for carnosic acid nanoparticles administration via inactivating NF-κB signaling pathway, leading to down-regulation of pro-inflammatory cytokines releasing. In conclusion, our study suggested that carnosic acid nanoparticles protected against liver ischemia/reperfusion injury via its role of anti-oxidative, anti-apoptotic and anti-inflammatory bioactivity. PMID:27470360

  17. Curcumin protects against gallic acid-induced oxidative stress, suppression of glutathione antioxidant defenses, hepatic and renal damage in rats.

    PubMed

    Abarikwu, Sunny O; Durojaiye, Mojisola; Alabi, Adenike; Asonye, Bede; Akiri, Oghenetega

    2016-01-01

    Curcumin (Cur) and gallic acid (Gal) are major food additives. Cur has well-known antioxidant properties, whereas Gal has both antioxidant and pro-oxidant effects. The present study investigated the effects of oral administration of Gal with or without Cur on antioxidant enzymes activities, glutathione (GSH) and the enzymes in its metabolism in rat liver in vivo and markers of tissue damage in the serum. Results showed that the increase in serum creatinine level, alkaline phosphatase and lactate dehydrogenase activities by Gal treatment were inhibited by combined administration of Gal and Cur. The decrease in GSH-peroxidase, GSH-S-transferase, superoxide dismutase and GSH-reductase activities by Gal treatment were inhibited when both Gal and Cur were administered together. The malondialdehyde concentration and catalase activity were significantly increased following administration of Gal but not when the administration of Gal was combined with Cur. Finally, the increase in GSH level was seen following administration of Cur alone or in combination with Gal but not with Gal alone. These results suggest that Gal might induce oxidative stress in the rat liver and affect renal function that can be inhibited by the combined administration of Gal and Cur. PMID:26707166

  18. Chlorogenic acid attenuates lipopolysaccharide-induced mice mastitis by suppressing TLR4-mediated NF-κB signaling pathway.

    PubMed

    Ruifeng, Gao; Yunhe, Fu; Zhengkai, Wei; Ershun, Zhou; Yimeng, Li; Minjun, Yao; Xiaojing, Song; Zhengtao, Yang; Naisheng, Zhang

    2014-04-15

    Chlorogenic acid (CGA), one of the most abundant polyphenols in the diet, has been reported to have potent anti-inflammatory properties. However, the effect of CGA on lipopolysaccharide (LPS)-induced mice mastitis has not been investigated. The purpose of the present study was to elucidate whether CGA could ameliorate the inflammation response in LPS-induced mice mastitis and to clarify the possible mechanism. The mouse model of mastitis was induced by injection of LPS through the duct of mammary gland. CGA was administered intraperitoneally with the dose of 12.5, 25, and 50mg/kg respectively 1h before and 12h after induction of LPS. In this study, the effect of CGA on LPS-induced mice mastitis was assessed through histopathological examination, ELISA assay, and western blot analysis. The results showed that CGA significantly reduced TNF-α, IL-1β, and IL-6 production compared with LPS group. Besides, western blot analysis showed that CGA could inhibit the expression of TLR4 and the phosphorylation of NF-κB and IκB induced by LPS. These results suggested that anti-inflammatory effects of CGA against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-κB signaling pathway. Therefore, CGA may be a potent therapeutic reagent for the prevention of the immunopathology encountered during Escherichia coli elicited mastitis.

  19. 3,4,5-Tricaffeoylquinic Acid Attenuates TRAIL-induced Apoptosis in Human Keratinocytes by Suppressing Apoptosis-related Protein Activation.

    PubMed

    Lee, Da Hee; Nam, Yoon Jeong; Lee, Min Sung; Sohn, Dong Suep; Shin, Yong Kyoo; Lee, Chung Soo

    2015-10-01

    Caffeoyl derivatives exhibit antiinflammatory and antioxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in keratinocytes that may be involved in skin diseases has not been studied. In this respect, we investigated the effect of 3,4,5-tricaffeoylquinic acid on TRAIL-induced apoptosis in human keratinocytes. 3,4,5-Tricaffeoylquinic acid and oxidant scavengers attenuated the decrease in the cytosolic levels of Bid, Bcl-2, and survivin proteins; the increase in the levels of cytosolic Bax, p53, and phosphorylated p53; the increase in the levels of phosphorylated p38; the increase in the mitochondrial levels of the voltage-dependent anion channel; loss of the mitochondrial transmembrane potential; the release of cytochrome c; activation of caspases (8, 9, and 3); cleavage of poly [ADP-ribose] polymerase-1; production of reactive oxygen species; the depletion of glutathione (GSH); nuclear damage; and cell death in keratinocytes treated with TRAIL. These results suggest that 3,4,5-tricaffeoylquinic acid may reduce TRAIL-induced apoptosis in human keratinocytes by suppressing the activation of the caspase-8 and Bid pathways and the mitochondria-mediated cell death pathway. The effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. 3,4,5-Tricaffeoylquinic acid appears to be effective in the prevention of TRAIL-induced apoptosis-mediated skin diseases.

  20. Studies on Synthesis of Electrochemically Exfoliated Functionalized Graphene and Polylactic Acid/Ferric Phytate Functionalized Graphene Nanocomposites as New Fire Hazard Suppression Materials.

    PubMed

    Feng, Xiaming; Wang, Xin; Cai, Wei; Qiu, Shuilai; Hu, Yuan; Liew, Kim Meow

    2016-09-28

    Practical application of functionalized graphene in polymeric nanocomposites is hampered by the lack of cost-effective and eco-friendly methods for its production. Here, we reported a facile and green electrochemical approach for preparing ferric phytate functionalized graphene (f-GNS) by simultaneously utilizing biobased phytic acid as electrolyte and modifier for the first time. Due to the presence of phytic acid, electrochemical exfoliation leads to low oxidized graphene sheets (a C/O ratio of 14.8) that are tens of micrometers large. Successful functionalization of graphene was confirmed by the appearance of phosphorus and iron peaks in the X-ray photoelectron spectrum. Further, high-performance polylactic acid/f-GNS nanocomposites are readily fabricated by a convenient masterbatch strategy. Notably, inclusion of well-dispersed f-GNS resulted in dramatic suppression on fire hazards of polylactic acid in terms of reduced peak heat-release rate (decreased by 40%), low CO yield, and formation of a high graphitized protective char layer. Moreover, obviously improvements in crystallization rate and thermal conductivities of polylactic acid nanocomposites were observed, highlighting its promising potential in practical application. This novel strategy toward the simultaneous exfoliation and functionalization for graphene demonstrates a simple yet very effective approach for fabricating graphene-based flame retardants.

  1. Studies on Synthesis of Electrochemically Exfoliated Functionalized Graphene and Polylactic Acid/Ferric Phytate Functionalized Graphene Nanocomposites as New Fire Hazard Suppression Materials.

    PubMed

    Feng, Xiaming; Wang, Xin; Cai, Wei; Qiu, Shuilai; Hu, Yuan; Liew, Kim Meow

    2016-09-28

    Practical application of functionalized graphene in polymeric nanocomposites is hampered by the lack of cost-effective and eco-friendly methods for its production. Here, we reported a facile and green electrochemical approach for preparing ferric phytate functionalized graphene (f-GNS) by simultaneously utilizing biobased phytic acid as electrolyte and modifier for the first time. Due to the presence of phytic acid, electrochemical exfoliation leads to low oxidized graphene sheets (a C/O ratio of 14.8) that are tens of micrometers large. Successful functionalization of graphene was confirmed by the appearance of phosphorus and iron peaks in the X-ray photoelectron spectrum. Further, high-performance polylactic acid/f-GNS nanocomposites are readily fabricated by a convenient masterbatch strategy. Notably, inclusion of well-dispersed f-GNS resulted in dramatic suppression on fire hazards of polylactic acid in terms of reduced peak heat-release rate (decreased by 40%), low CO yield, and formation of a high graphitized protective char layer. Moreover, obviously improvements in crystallization rate and thermal conductivities of polylactic acid nanocomposites were observed, highlighting its promising potential in practical application. This novel strategy toward the simultaneous exfoliation and functionalization for graphene demonstrates a simple yet very effective approach for fabricating graphene-based flame retardants. PMID:27588582

  2. Clinical significance of elevated serum A-FABP and free fatty acid in neonates with hypoxic ischemic brain damage

    PubMed Central

    Li, Mei; Jiang, Lian; Zhang, Huifen; Wang, Dandan; Zhang, Min; Zhang, Lianshan

    2016-01-01

    The main function of adipocyte fatty acid-binding protein (A-FABP) is to regulate fatty acid metabolism as its molecular chaperone. The clinical significance of A-FABP in hypoxic-ischemic brain damage (HIBD) neonates is not yet clear. Free fatty acid (FFA) in cerebral cortex increases along with hypoxia ischemia degree. Thus, we aimed to investigate whether FFA can induce A-FABP expression and elevate the serum A-FABP level in HIBD neonates. In the present study, 42 HIBD neonates were selected including 11 cases as mild, 16 cases as moderate and 15 cases as severe. The serum was collected from peripheral vein at 72 h after the first visit (acute stage) and 7 days after birth (recovery stage), and the serum from 10 normal neonates was used as the control. The serum level of A-FABP and FFA in 42 neonates with acute phase and recovery phase HIBD were detected using ELISA and copper colorimetric method. The overall serum A-FABP content in HIBD neonates at the acute stage was significantly higher compared to the normal neonates (P<0.05). The serum A-FABP level in severe HIBD neonates was significantly higher than that in mild HIBD, moderate HIBD and normal neonates (P<0.05). The serum FFA level in HIBD neonates at the acute stage was 1,521.57±605.63 µmol/l, which was significantly higher than that in the normal neonates 838.24±294.22 µmol/l. The serum FFA levels in mild, moderate and severe HIBD neonates were significantly higher than those in the normal neonates. The overall A-FABP level in HIBD neonates at the recovery stage was significantly lower compared to the acute stage, which was significant in severe HIBD neonates. A-FABP levels in mild and moderate HIBD neonates at recovery stage were decreased compared with the acute stage, although there was no statistical difference. There was a positive correlation between serum A-FABP and FFA in HIBD neonates at acute stage (r=0.369, P<0.05). In conclusion, serum A-FABP and FFA levels were signifcantly increased in

  3. Controlling for sugar and ascorbic acid, a mixture of flavonoids matching navel oranges significantly increases human postprandial serum antioxidant capacity.

    PubMed

    Snyder, Shannon M; Reber, Josh D; Freeman, Brenner L; Orgad, Kfir; Eggett, Dennis L; Parker, Tory L

    2011-07-01

    Fruit and vegetable consumption reduces the risk for cardiovascular disease development. The postprandial state is an important contributor to chronic disease development. Orange flavonoids may reduce postprandial oxidation. It was hypothesized that a mixture of orange flavonoids would reduce postprandial oxidation better than a single orange flavonoid or orange sugar and ascorbic acid, but not as well as orange juice, when consumed with a typical breakfast. A placebo-controlled crossover trial (16 male and female participants, 4 treatments, 4 visits) was carried out. Treatments were placebo (ascorbic acid and sugar equivalent to orange juice); placebo plus hesperidin; placebo plus hesperidin, luteolin, and naringenin (mixture; found to have synergistic antioxidant properties in vitro in previous work); and orange juice (positive control). Serum oxygen radical absorbance capacity (ORAC), total plasma phenolics (TP), and serum lipoprotein oxidation (LO) were measured after a 12-hour baseline fast and at 1, 2, and 3 hours after sample consumption. The placebo plus mixture and orange juice groups were significantly increased in ORAC and LO lag time. Data for TP were inconsistent with ORAC and LO. Contrary to previous studies attributing the protective postprandial effect to fructose and ascorbate in other fruit trials, orange phenolic compounds contribute directly to the postprandial oxidative protection of serum, despite an inconsistent change in serum TP.

  4. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2.

    PubMed

    Yue, Wen; Zheng, Xi; Lin, Yong; Yang, Chung S; Xu, Qing; Carpizo, Darren; Huang, Huarong; DiPaola, Robert S; Tan, Xiang-Lin

    2015-08-28

    Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer.

  5. Suppression of the ELO-2 FA elongation activity results in alterations of the fatty acid composition and multiple physiological defects, including abnormal ultradian rhythms, in Caenorhabditis elegans.

    PubMed Central

    Kniazeva, Marina; Sieber, Matt; McCauley, Scott; Zhang, Kang; Watts, Jennifer L; Han, Min

    2003-01-01

    While the general steps of fatty acid (FA) biosynthesis are well understood, the individual enzymes involved in the elongation of long chain saturated and polyunsaturated FA (PUFA) are largely unknown. Recent research indicates that these enzymes might be of considerable physiological importance for human health. We use Caenorhabditis elegans to study FA elongation activities and associated abnormal phenotypes. In this article we report that the predicted C. elegans F11E6.5/ELO-2 is a functional enzyme with the FA elongation activity. It is responsible for the elongation of palmitic acid and is involved in PUFA biosynthesis. RNAi-mediated suppression of ELO-2 causes an accumulation of palmitate and an associated decrease in the PUFA fraction in triacylglycerides and phospholipid classes. This imbalance in the FA composition results in multiple phenotypic defects such as slow growth, small body size, reproductive defects, and changes in rhythmic behavior. ELO-2 cooperates with the previously reported ELO-1 in 20-carbon PUFA production, and at least one of the enzymes must function to provide normal growth and development in C. elegans. The presented data indicate that suppression of a single enzyme of the FA elongation machinery is enough to affect various organs and systems in worms. This effect resembles syndromic disorders in humans. PMID:12586704

  6. An early methamphetamine challenge suppresses the maturation of dopamine fibres in the nucleus accumbens of gerbils: on the significance of rearing conditions.

    PubMed

    Neddens, J; Lesting, J; Dawirs, R R; Teuchert-Noodt, G

    2002-02-01

    The effect of a single early methamphetamine (MA) challenge on postnatal maturation of the nucleus accumbens (NAC) was studied. Therefore, male gerbils received a single dose of MA (50 mg/kg, i.p.) on postnatal day 14. At the age of postnatal day 90, dopamine fibres were stained immunocytochemically and innervation density was determined in several test fields along the rostrocaudal extent of both core and shell of the NAC. Since we already know that the differential environment can alter ontogeny of dopamine innervation in the prefrontal cortex of gerbils, in the present study we investigated whether probable drug effects may be influenced by rearing conditions. For that purpose, animals were bred and reared either isolated in standard laboratory cages or grouped in an object-filled environment. The results showed that a single early MA challenge significantly alters maturation of dopamine fibre innervation in both subregions of the NAC. In seminaturally reared gerbils the drug challenge caused dopamine fibre densities which were about 54% below those of saline-treated controls in both the shell and core. However, in animals from restricted rearing this MA-induced effect was more pronounced in the core (-43%) but not significant in the shell (-14%). In conclusion, an early MA challenge caused a significant restraint of adult dopamine fibre density developing in the NAC postnatally. Additionally, rearing conditions significantly interfered with drug-induced alterations in maturation of dopaminergic innervation pattern of the NAC. The present results are discussed with recent findings on MA-induced impairment of prefrontal dopamine innervation and further reactive morphogenetic effects caused by the drug. In this respect, functional interactions between the prefrontal cortex and NAC are specifically considered.

  7. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity

    PubMed Central

    Labonté, Eric D.; Pfluger, Paul T.; Cash, James G.; Kuhel, David G.; Roja, Juan C.; Magness, Daniel P.; Jandacek, Ronald J.; Tschöp, Matthias H.; Hui, David Y.

    2010-01-01

    Decrease in fat catabolic rate on consuming a high-fat diet contributes to diet-induced obesity. This study used group 1B phospholipase A2 (Pla2g1b)-deficient mice, which are resistant to hyperglycemia, to test the hypothesis that Pla2g1b and its lipolytic product lysophospholipid suppress hepatic fat utilization and energy metabolism in promoting diet-induced obesity. The metabolic consequences of hypercaloric diet, including body weight gain, energy expenditure, and fatty acid oxidation, were compared between Pla2g1b+/+ and Pla2g1b−/− mice. The Pla2g1b−/− mice displayed normal energy balance when fed chow, but were resistant to obesity when challenged with a hypercaloric diet. Obesity resistance in Pla2g1b−/− mice is due to their ability to maintain elevated energy expenditure and core body temperature when subjected to hypercaloric diet, which was not observed in Pla2g1b+/+ mice. The Pla2g1b−/− mice also displayed increased postprandial hepatic fat utilization due to increased expression of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-δ, PPAR-γ, cd36/Fat, and Ucp2, which coincided with reduced postprandial plasma lysophospholipid levels. Lysophospholipids produced by Pla2g1b hydrolysis suppress hepatic fat utilization and down-regulate energy expenditure, thereby preventing metabolically beneficial adaptation to a high-fat diet exposure in promoting diet-induced obesity and type 2 diabetes.—Labonté, E. D., Pfluger, P. T., Cash, J. G., Kuhel, D. G., Rojas, J. C., Magness, D. P., Jandacek, R. J., Tschöp, M. H., Hui, D. Y. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity. PMID:20215528

  8. Preparation of Oxaliplatin-Deoxycholic Acid Derivative Nanocomplexes and In Vivo Evaluation of Their Oral Absorption and Tumor Growth Suppression.

    PubMed

    Jeon, Ok-Cheol; Byun, Youngro; Park, Jin Woo

    2016-02-01

    To prepare orally available oxaliplatin (OXA), nanocomplexes were formed by ionic conjugation of OXA with the deoxycholic acid derivative, Nalpha-deoxycholy-L-lysyl-methylester (DCK), as an oral absorption enhancer. We characterized the DCK-conjugated OXA nanocomplexes by differential scanning calorimetry, particle size determination, and morphological analysis. To evaluate the effects of DCK on the intestinal permeability of OXA, we assessed the solubilities and partition coefficients of OXA and the OXA/DCK nanocomplex, and then conducted in vitro artificial intestinal membrane and Caco-2 cell permeability studies. Finally, bioavailability in rats and tumor growth inhibition in the squamous cell carcinoma (SCC7) model after oral administration of the OXA/DCK nanocomplex were investigated compared to pure OXA. Analysis of the ionic complex formation of OXA with DCK revealed that OXA existed in an amorphous form within the complex, resulting in for- mation of nanocomp;exes (35.05 +/- 4.48 nm in diameter). The solubility of OXA in water was approximately 7.07 mg/mL, whereas the water solubility of OXA/DCK was approximately 2.04 mg/mL and its partition coefficient was approximately 1.2-fold higher than that of OXA. The in vitro intestinal membrane permeability of OXA was significantly enhanced by complex formation with DCK. An in vivo pharmacokinetic study revealed that the Cm value of the OXA/DCK nanocomplex was 3.18-fold higher than that of OXA (32.22 +/- 10.24 ng/mL), and the resulting oral bioavailability of the OXA/DCK nanocomplex was 39.3-fold more than that of OXA. Furthermore, the oral administration of OXA/DCK significantly inhibited tumor growth in SCC7-bearing mice, and maximally inhibited tumor volume by 54% compared to the control. These findings demonstrate the therapeutic potential of the OXA/DCK nanocomplex as an oral anti-cancer therapy because it improves the oral absorption of OXA, which may improve patient compliance and expand the therapeutic

  9. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner.

    PubMed

    Moghei, Mahshid; Tavajohi-Fini, Pegah; Beatty, Brendan; Adegoke, Olasunkanmi A J

    2016-09-01

    Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that α-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (-34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae. PMID:27488662

  10. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells

    PubMed Central

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 106 MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm3, sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44+/CD24- or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an innovative

  11. Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

    PubMed

    Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

    2014-01-01

    The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10(6) MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm(3), sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44(+)/CD24(-) or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an

  12. Suppression of Growth Rate of Colony-Associated Fungi by High Fructose Corn Syrup Feeding Supplement, Formic Acid, and Oxalic Acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Select colony-associated fungi (bee isolates). Absidia sp., Ascosphaera apis, Aspergillus flavus, Fusarium sp., Penicillium glabrum, Mucor sp., showed a 40% reduction in radial growth rate with formic acid, a 28% reduction with oxalic acid, and a 15% reduction with fructose and high fructose corn sy...

  13. Dietary supplementation of omega-3 fatty acid-containing fish oil suppresses F2-isoprostanes but enhances inflammatory cytokine response in a mouse model of ovalbumin-induced allergic lung inflammation.

    PubMed

    Yin, Huiyong; Liu, Wei; Goleniewska, Kasia; Porter, Ned A; Morrow, Jason D; Peebles, R Stokes

    2009-09-01

    Epidemiological and clinical evidence has suggested that increased dietary intake of fish oil containing omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be associated with a reduced risk of asthma. However, interventional studies on these effects have been equivocal and controversial. Free radical oxidation products of lipids and cyclooxygenases-derived prostaglandins are believed to play an important role in asthma, and fish oil supplementation may modulate the levels of these critical lipid mediators. We employed a murine model of allergic inflammation produced by sensitization to ovalbumin (OVA) to study the effects of fish oil supplementation on airway inflammation. Our studies demonstrated that omega-3 fatty acids were dose dependently incorporated into mouse lung tissue after dietary supplementation. We examined the oxidative stress status by measuring the levels of isoprostanes (IsoPs), the gold standard for oxidative stress in vivo. OVA challenge caused significant increase of F(2)-IsoPs in mouse lung, suggesting an elevated level of oxidative stress. Compared to the control group, fish oil supplementation led to a significant reduction of F(2)-IsoP (from arachidonic acid) with a concomitant increase of F(3)-IsoPs (from EPA) and F(4)-IsoPs (from DHA). Surprisingly, however, fish oil supplementation enhanced production of proinflammatory cytokine IL-5 and IL-13. Furthermore, fish oil supplementation suppressed the production of pulmonary protective PGE(2) in the bronchoalveolar lavage (BAL) while the level of urinary metabolites of the PGE(2) was increased. Our data suggest that augmented lung inflammation after fish oil supplementation may be due to the reduction of PGE(2) production in the lung and these dichotomous results bring into question the role of fish oil supplementation in the treatment of asthma.

  14. Incorporating significant amino acid pairs and protein domains to predict RNA splicing-related proteins with functional roles.

    PubMed

    Hsu, Justin Bo-Kai; Huang, Kai-Yao; Weng, Tzu-Ya; Huang, Chien-Hsun; Lee, Tzong-Yi

    2014-01-01

    Machinery of pre-mRNA splicing is carried out through the interaction of RNA sequence elements and a variety of RNA splicing-related proteins (SRPs) (e.g. spliceosome and splicing factors). Alternative splicing, which is an important post-transcriptional regulation in eukaryotes, gives rise to multiple mature mRNA isoforms, which encodes proteins with functional diversities. However, the regulation of RNA splicing is not yet fully elucidated, partly because SRPs have not yet been exhaustively identified and the experimental identification is labor-intensive. Therefore, we are motivated to design a new method for identifying SRPs with their functional roles in the regulation of RNA splicing. The experimentally verified SRPs were manually curated from research articles. According to the functional annotation of Splicing Related Gene Database, the collected SRPs were further categorized into four functional groups including small nuclear Ribonucleoprotein, Splicing Factor, Splicing Regulation Factor and Novel Spliceosome Protein. The composition of amino acid pairs indicates that there are remarkable differences among four functional groups of SRPs. Then, support vector machines (SVMs) were utilized to learn the predictive models for identifying SRPs as well as their functional roles. The cross-validation evaluation presents that the SVM models trained with significant amino acid pairs and functional domains could provide a better predictive performance. In addition, the independent testing demonstrates that the proposed method could accurately identify SRPs in mammals/plants as well as effectively distinguish between SRPs and RNA-binding proteins. This investigation provides a practical means to identifying potential SRPs and a perspective for exploring the regulation of RNA splicing.

  15. Steam cooking significantly improves in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage.

    PubMed

    Kahlon, Talwinder Singh; Chiu, Mei-Chen M; Chapman, Mary H

    2008-06-01

    Bile acid binding capacity has been related to the cholesterol-lowering potential of foods and food fractions. Lowered recirculation of bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increased risk of cancer. Bile acid binding potential has been related to lowering the risk of heart disease and that of cancer. Previously, we have reported bile acid binding by several uncooked vegetables. However, most vegetables are consumed after cooking. How cooking would influence in vitro bile acid binding of various vegetables was investigated using a mixture of bile acids secreted in human bile under physiological conditions. Eight replicate incubations were conducted for each treatment simulating gastric and intestinal digestion, which included a substrate only, a bile acid mixture only, and 6 with substrate and bile acid mixture. Cholestyramine (a cholesterol-lowering, bile acid binding drug) was the positive control treatment and cellulose was the negative control. Relative to cholestyramine, in vitro bile acid binding on dry matter basis was for the collard greens, kale, and mustard greens, 13%; broccoli, 10%; Brussels sprouts and spinach, 8%; green bell pepper, 7%; and cabbage, 5%. These results point to the significantly different (P < or = .05) health-promoting potential of collard greens = kale = mustard greens > broccoli > Brussels sprouts = spinach = green bell pepper > cabbage as indicated by their bile acid binding on dry matter basis. Steam cooking significantly improved the in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage compared with previously observed bile acid binding values for these vegetables raw (uncooked). Inclusion of steam-cooked collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage in our daily diet as health-promoting vegetables should be emphasized. These green

  16. Steam cooking significantly improves in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage.

    PubMed

    Kahlon, Talwinder Singh; Chiu, Mei-Chen M; Chapman, Mary H

    2008-06-01

    Bile acid binding capacity has been related to the cholesterol-lowering potential of foods and food fractions. Lowered recirculation of bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increased risk of cancer. Bile acid binding potential has been related to lowering the risk of heart disease and that of cancer. Previously, we have reported bile acid binding by several uncooked vegetables. However, most vegetables are consumed after cooking. How cooking would influence in vitro bile acid binding of various vegetables was investigated using a mixture of bile acids secreted in human bile under physiological conditions. Eight replicate incubations were conducted for each treatment simulating gastric and intestinal digestion, which included a substrate only, a bile acid mixture only, and 6 with substrate and bile acid mixture. Cholestyramine (a cholesterol-lowering, bile acid binding drug) was the positive control treatment and cellulose was the negative control. Relative to cholestyramine, in vitro bile acid binding on dry matter basis was for the collard greens, kale, and mustard greens, 13%; broccoli, 10%; Brussels sprouts and spinach, 8%; green bell pepper, 7%; and cabbage, 5%. These results point to the significantly different (P < or = .05) health-promoting potential of collard greens = kale = mustard greens > broccoli > Brussels sprouts = spinach = green bell pepper > cabbage as indicated by their bile acid binding on dry matter basis. Steam cooking significantly improved the in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage compared with previously observed bile acid binding values for these vegetables raw (uncooked). Inclusion of steam-cooked collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage in our daily diet as health-promoting vegetables should be emphasized. These green

  17. n-3 polyunsaturated fatty acids suppress CD4(+) T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization.

    PubMed

    Hou, Tim Y; Barhoumi, Rola; Fan, Yang-Yi; Rivera, Gonzalo M; Hannoush, Rami N; McMurray, David N; Chapkin, Robert S

    2016-01-01

    The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4(+) T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Förster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4(+) T cells enriched in n-3 PUFA display increased co-clustering of Lck(N10) and LAT(ΔCP), markers of lipid rafts. CD4(+) T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-δ), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4(+) T cells enriched with n-3 PUFA. Furthermore, CD4(+) T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2.

  18. Haplotypes of the D-Amino Acid Oxidase Gene Are Significantly Associated with Schizophrenia and Its Neurocognitive Deficits

    PubMed Central

    Hwu, Hai-Gwo; Fann, Cathy Shen-Jang; Yang, Ueng-Cheng; Yang, Wei-Chih; Hsu, Pei-Chun; Chang, Chien-Ching; Wen, Chun-Chiang; Tsai-Wu, Jyy-Jih; Hwang, Tzung-Jeng; Hsieh, Ming H.; Liu, Chen-Chung; Chien, Yi-Ling; Fang, Chiu-Ping; Faraone, Stephen V.; Tsuang, Ming T.; Chen, Wei J.; Liu, Chih-Min

    2016-01-01

    D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia. PMID:26986737

  19. Availability of Amino Acids Extends Chronological Lifespan by Suppressing Hyper-Acidification of the Environment in Saccharomyces cerevisiae

    PubMed Central

    Maruyama, Yo; Ito, Toshiyuki; Kodama, Hiroaki; Matsuura, Akira

    2016-01-01

    The chronological lifespan of Saccharomyces cerevisiae represents the duration of cell survival in the postdiauxic and stationary phases. Using a prototrophic strain derived from the standard auxotrophic laboratory strain BY4742, we showed that supplementation of non-essential amino acids to a synthetic defined (SD) medium increases maximal cell growth and extends the chronological lifespan. The positive effects of amino acids can be reproduced by modulating the medium pH, indicating that amino acids contribute to chronological longevity in a cell-extrinsic manner by alleviating medium acidification. In addition, we showed that the amino acid-mediated effects on extension of chronological longevity are independent of those achieved through a reduction in the TORC1 pathway, which is mediated in a cell-intrinsic manner. Since previous studies showed that extracellular acidification causes mitochondrial dysfunction and leads to cell death, our results provide a path to premature chronological aging caused by differences in available nitrogen sources. Moreover, acidification of culture medium is generally associated with culture duration and cell density; thus, further studies are required on cell physiology of auxotrophic yeast strains during the stationary phase because an insufficient supply of essential amino acids may cause alterations in environmental conditions. PMID:26991662

  20. Cinnamic-derived acids significantly affect Fusarium graminearum growth and in vitro synthesis of type B trichothecenes.

    PubMed

    Ponts, Nadia; Pinson-Gadais, Laetitia; Boutigny, Anne-Laure; Barreau, Christian; Richard-Forget, Florence

    2011-08-01

    The impact of five phenolic acids (ferulic, coumaric, caffeic, syringic, and p-hydroxybenzoic acids) on fungal growth and type B trichothecene production by four strains of Fusarium graminearum was investigated. All five phenolic acids inhibited growth but the degree of inhibition varied between strains. Our results suggested that the more lipophilic phenolic acids are, the higher is the effect they have on growth. Toxin accumulation in phenolic acid-supplemented liquid glucose, yeast extract, and peptone cultures was enhanced in the presence of ferulic and coumaric acids but was reduced in the presence of p-hydroxybenzoic acid. This modulation was shown to correlate with a regulation of TRI5 transcription. In this study, addition of phenolic acids with greater antioxidant properties resulted in a higher toxin accumulation, indicating that the modulation of toxin accumulation may be linked to the antioxidant properties of the phenolic acids. These data suggest that, in planta, different compositions in phenolic acids of kernels from various cultivars may reflect different degrees of sensitivity to "mycotoxinogenesis."

  1. An evaluation of the significance of mouth and hand contamination for lead absorption in lead-acid battery workers.

    PubMed

    Far, H S; Pin, N T; Kong, C Y; Fong, K S; Kian, C W; Yan, C K

    1993-01-01

    The present study was conducted to evaluate the role of ingestion through hand and mouth contamination in the absorption of lead in 25 lead-acid battery workers. Levels of personal exposure to airborne lead ranged from 0.004 to 2.58 mg/m3 [geometric mean 0.098, with 25% of samples exceeding threshold limit values (ACGIH) of 0.15 mg/m3]; the mean (SD) blood lead level was 48.9 (10.8) micrograms/dl. Mean hand lead contents increased 33-fold from preshift levels on Monday mornings (33.5 micrograms/500 ml) to midshift levels on Thursday afternoons (1121 micrograms/500 ml). Mouth lead contents increased 16-fold from 0.021 micrograms/50 ml on Mondays to 0.345 micrograms/50 ml on Thursdays. The typical Malay racial habit of feeding with bare hands and fingers without utensils (closely associated with mouth and hand lead levels on Mondays) explained the bulk of the variance in blood lead levels (40%), with mouth lead on Thursdays (closely associated with poor personal hygiene) explaining a further 10%. Air lead was not a significant explanatory variable. The implementation of a programme of reinforcing hand-washing and mouth-rinsing practices resulted in a reduction of the blood lead level by 11.5% 6 months later. These results indicate that parenteral intake from hand and mouth contamination is an important cause of lead absorption in lead-exposed workers.

  2. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

    PubMed Central

    Claudel, Thierry; Sturm, Ekkehard; Duez, Hélène; Torra, Inés Pineda; Sirvent, Audrey; Kosykh, Vladimir; Fruchart, Jean-Charles; Dallongeville, Jean; Hum, Dean W.; Kuipers, Folkert; Staels, Bart

    2002-01-01

    Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid–activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells. PMID:11927623

  3. Vaccenic acid suppresses intestinal inflammation by increasing anandamide and related N-acylethanolamines in the JCR:LA-cp rat.

    PubMed

    Jacome-Sosa, Miriam; Vacca, Claudia; Mangat, Rabban; Diane, Abdoulaye; Nelson, Randy C; Reaney, Martin J; Shen, Jianheng; Curtis, Jonathan M; Vine, Donna F; Field, Catherine J; Igarashi, Miki; Piomelli, Daniele; Banni, Sebastiano; Proctor, Spencer D

    2016-04-01

    Vaccenic acid (VA), the predominant ruminant-derivedtransfat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cprats were assigned to a control diet with or without VA (1% w/w),cis-9,trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P< 0.001), but did not change AA in tissue PLs. There was no additive effect of combining VA+CLA on 2-AG relative to VA alone (P> 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P< 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1β (P< 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine.

  4. Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression

    PubMed Central

    Lin, Chun-Kuang; Tseng, Chin-Kai; Chen, Kai-Hsun; Wu, Shih-Hsiung; Liaw, Chih-Chuang; Lee, Jin-Ching

    2015-01-01

    Background and Purpose This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity. Experimental Approach HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement. Key Results BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway. Conclusions and Implications BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients. PMID:26102077

  5. Suppression of γ-aminobutyric acid (GABA) transaminases induces prominent GABA accumulation, dwarfism and infertility in the tomato (Solanum lycopersicum L.).

    PubMed

    Koike, Satoshi; Matsukura, Chiaki; Takayama, Mariko; Asamizu, Erika; Ezura, Hiroshi

    2013-05-01

    Tomatoes accumulate γ-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and α-ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this work, we conducted loss-of-function analyses utilizing RNA interference (RNAi) transgenic plants with suppressed pyruvate- and glyoxylate-dependent GABA-T gene expression to clarify which GABA-T isoforms are essential for its function. The RNAi plants with suppressed SlGABA-T gene expression, particularly SlGABA-T1, showed severe dwarfism and infertility. SlGABA-T1 expression was inversely associated with GABA levels in the fruit at the red ripe stage. The GABA contents in 35S::SlGABA-T1(RNAi) lines were 1.3-2.0 times and 6.8-9.2 times higher in mature green and red ripe fruits, respectively, than the contents in wild-type fruits. In addition, SlGABA-T1 expression was strongly suppressed in the GABA-accumulating lines. These results indicate that pyruvate- and glyoxylate-dependent GABA-T is the essential isoform for GABA metabolism in tomato plants and that GABA-T1 primarily contributes to GABA reduction in the ripening fruits.

  6. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

    PubMed Central

    Dračínská, Helena; Bárta, František; Levová, Kateřina; Hudecová, Alena; Moserová, Michaela; Schmeiser, Heinz H.; Kopka, Klaus; Frei, Eva; Arlt, Volker M.; Stiborová, Marie

    2016-01-01

    Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the 32P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts. PMID:26845733

  7. Steam Cooking Significantly Improves in Vitro Bile Acid Binding of Beets, Eggplant, Asparagus, Carrots, Green Beans and Cauliflower

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The relative healthful potential of cooked beets, okra, eggplant, asparagus, carrots, green beans, cauliflower and turnips was evaluated by determining their in vitro bile acid binding using a mixture of bile acids secreted in human bile at a duodenal physiological pH of 6.3. Six treatments and two...

  8. Mycophenolic acid inhibits inosine 5'-monophosphate dehydrogenase and suppresses production of pro-inflammatory cytokines, nitric oxide, and LDH in macrophages.

    PubMed

    Jonsson, Charlotte A; Carlsten, Hans

    2002-01-01

    Mycophenolic acid (MPA) inhibits reversibly inosine 5(')-monophosphate dehydrogenase, an enzyme involved in the de novo synthesis of guanine nucleotides. Previously, mycophenolate mofetil (MMF), the pro-drug of MPA, was shown to exert beneficial effects on the systemic lupus erythematosus (SLE)-like disease in MRLlpr/lpr mice. In this study MPA's immunomodulating effects in vitro on the murine macrophage cell line IC-21 were investigated. The cells were exposed to MPA together with lipopolysaccharide and IFN-gamma. Cytokine, NO(2)(-), and lactate dehydrogenase levels in supernatants and cell lysates were analysed as well as the proliferation of IC-21 cells. MPA exposure reduced the total levels of all molecules investigated and suppressed the proliferation. All MPA-induced effects were reversed by the addition of guanosine to the cultures. Since macrophages play a role in lupus nephritis, our results indicate that modulation of macrophages may be involved in the ameliorating effects of MMF in SLE. PMID:12381354

  9. Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility.

    PubMed

    Murase, Remi; Sato, Hiroyasu; Yamamoto, Kei; Ushida, Ayako; Nishito, Yasumasa; Ikeda, Kazutaka; Kobayashi, Tetsuyuki; Yamamoto, Toshinori; Taketomi, Yoshitaka; Murakami, Makoto

    2016-03-25

    Within the secreted phospholipase A2(sPLA2) family, group X sPLA2(sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies usingPla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2(cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2 Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizerin vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.

  10. [THE DETECTION OF CONTENT OF DIAGNOSTICALLY SIGNIFICANT FATTY ACIDS AND INDIVIDUAL TRIGLYCERIDES IN BIOLOGICAL MEDIUMS BASED ON INFRARED SPECTROMETRY].

    PubMed

    Kalinin, A V; Krasheninnikov, V N; Sviridov, A P; Titov, V N

    2015-11-01

    The content of clinically important fatty acids and individual triglycerides in food and biological mediums are traditionally detected by gas and fluid chromatography in various methodical modifications. The techniques are hard-to-get in laboratories of clinical biochemistry. The study was carried out to develop procedures and equipment for operative quantitative detection of concentration of fatty acids, primarily palmitic saturated fatty acid and oleic mono unsaturated fatty acid. Also detection was applied to sums ofpolyenoic (eicosapentaenoic and docosahexaenoic acid) fatty acids in biological mediums (cod-liver oil, tissues, blood plasma) using spectrometers of short-range infrared band of different types: with Fourier transform, diffraction and combined scattering. The evidences of reliable and reproducible quantitative detection offatty acids were received on the basis of technique of calibration (regression) by projection on latent structures using standard samples of mixtures of oils and fats. The evaluation is implemented concerning possibility of separate detection of content of palmitic and oleic triglycerides in mediums with presence of water The choice of technical conditions and mode of application of certain types of infrared spectrometers and techniques of their calibration is substantiated PMID:26999859

  11. Incorporating significant amino acid pairs to identify O-linked glycosylation sites on transmembrane proteins and non-transmembrane proteins

    PubMed Central

    2010-01-01

    Background While occurring enzymatically in biological systems, O-linked glycosylation affects protein folding, localization and trafficking, protein solubility, antigenicity, biological activity, as well as cell-cell interactions on membrane proteins. Catalytic enzymes involve glycotransferases, sugar-transferring enzymes and glycosidases which trim specific monosaccharides from precursors to form intermediate structures. Due to the difficulty of experimental identification, several works have used computational methods to identify glycosylation sites. Results By investigating glycosylated sites that contain various motifs between Transmembrane (TM) and non-Transmembrane (non-TM) proteins, this work presents a novel method, GlycoRBF, that implements radial basis function (RBF) networks with significant amino acid pairs (SAAPs) for identifying O-linked glycosylated serine and threonine on TM proteins and non-TM proteins. Additionally, a membrane topology is considered for reducing the false positives on glycosylated TM proteins. Based on an evaluation using five-fold cross-validation, the consideration of a membrane topology can reduce 31.4% of the false positives when identifying O-linked glycosylation sites on TM proteins. Via an independent test, GlycoRBF outperforms previous O-linked glycosylation site prediction schemes. Conclusion A case study of Cyclic AMP-dependent transcription factor ATF-6 alpha was presented to demonstrate the effectiveness of GlycoRBF. Web-based GlycoRBF, which can be accessed at http://GlycoRBF.bioinfo.tw, can identify O-linked glycosylated serine and threonine effectively and efficiently. Moreover, the structural topology of Transmembrane (TM) proteins with glycosylation sites is provided to users. The stand-alone version of GlycoRBF is also available for high throughput data analysis. PMID:21034461

  12. AGPAT9 suppresses cell growth, invasion and metastasis by counteracting acidic tumor microenvironment through KLF4/LASS2/V-ATPase signaling pathway in breast cancer

    PubMed Central

    Wu, Zhi-yong; Zhang, Zi-feng; Lu, Jun; Li, Meng-qiu; Shan, Qun; Wu, Dong-mei; Sun, Chun-hui; Hu, Bin; Zheng, Yuan-lin

    2015-01-01

    Human 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) is the gene identified from adipose tissue in 2007. We found AGPAT9 expression was significantly higher in poorly invasive MCF7 human breast cancer cells than the highly invasive MDA-MB-231 cells. AGPAT9 significantly inhibited the proliferation of breast cancer cells in vitro and in vivo. Live-cell imaging and transwell assays showed that AGPAT9 could significantly inhibit the migration and invasive capacities of breast cancer cells. The inhibitory effect of AGPAT9 on metastasis was also observed in vivo in lung metastasis model. AGPAT9 inhibited breast cancer cell proliferation, migration and invasion through, at least in part, suppressing the V-ATPase activity. In addition, increased AGPAT9 expression in MCF-7/ADR cells could increase the chemosensitivity to doxorubicin (Dox). Our findings suggest that increasing AGPAT9 expression may be a new approach that can be used for breast cancer treatment. PMID:26110566

  13. Cichoric Acid Reverses Insulin Resistance and Suppresses Inflammatory Responses in the Glucosamine-Induced HepG2 Cells.

    PubMed

    Zhu, Di; Wang, Yutang; Du, Qingwei; Liu, Zhigang; Liu, Xuebo

    2015-12-30

    Cichoric acid, a caffeic acid derivative found in Echinacea purpurea, basil, and chicory, has been reported to have bioactive effects, such as anti-inflammatory, antioxidant, and preventing insulin resistance. In this study, to explore the effects of CA on regulating insulin resistance and chronic inflammatory responses, the insulin resistance model was constructed by glucosamine in HepG2 cells. CA stimulated glucosamine-mediated glucose uptake by stimulating translocation of the glucose transporter 2. Moreover, the production of reactive oxygen, the expression of COX-2 and iNOS, and the mRNA levels of TNF-α and IL-6 were attenuated. Furthermore, CA was verified to promote glucosamine-mediated glucose uptake and inhibited inflammation through PI3K/Akt, NF-κB, and MAPK signaling pathways in HepG2 cells. These results implied that CA could increase glucose uptake, improve insulin resistance, and attenuate glucosamine-induced inflammation, suggesting that CA is a potential natural nutraceutical with antidiabetic properties and anti-inflammatory effects. PMID:26592089

  14. Sea Cucumber Saponin Echinoside A (EA) Stimulates Hepatic Fatty Acid β-Oxidation and Suppresses Fatty Acid Biosynthesis Coupling in a Diurnal Pattern.

    PubMed

    Wen, Min; Fu, Xueyuan; Han, Xiuqing; Hu, Xiaoqian; Dong, Ping; Xu, Jie; Xue, Yong; Wang, Jingfeng; Xue, Changhu; Wang, Yuming

    2016-01-01

    Circadian rhythms control aspects of physiological events, including lipid metabolism, showing rhythmic fluctuation over 24 h. Therefore, it is not sufficient to evaluate thoroughly how dietary components regulate lipid metabolism with a single time-point assay. In the present study, a time-course study was performed to analyze the effect of sea cucumber saponin echinoside A (EA) on lipid metabolism over 24 h. Results showed that EA lowered the levels of TC and TG in both serum and liver at most time-points during the 24 h. Activities of hepatic lipogenic enzymes and lipolytic enzymes were inhibited and elevated respectively by EA to varied degrees at different time-points. Meanwhile, parallel variation trends of gene expression involved in fatty acid synthesis and β-oxidation were observed accordingly. The interaction between EA and lipid metabolism showed a time-dependent effect. Overall, EA impaired fatty acid synthesis and enhanced mitochondrial fatty acid β-oxidation in ad libitum feeding over 24 h. PMID:27465723

  15. Significance of technetium-99m human serum albumin diethylenetriamine pentaacetic acid scintigraphy in patients with nephrotic syndrome.

    PubMed

    Takashima, Tsuyoshi; Kishi, Tomoya; Onozawa, Koji; Rikitake, Shuichi; Miyazono, Motoaki; Otsuka, Takateru; Irie, Hiroyuki; Iwakiri, Ryuichi; Fujimoto, Kazuma; Ikeda, Yuji

    2015-01-01

    It is thought that a large amount of albumin leaking from the glomerulus in nephrotic syndrome (NS) is reabsorbed at the proximal tubule and catabolized. Therefore, it is possible the final quantity of urinary protein does not always reflect the amount of leakage of protein from the glomerulus. We experienced two cases without nephrotic range proteinuria thought to involve hypoproteinemia due to the same pathophysiology as NS. On these patients, we performed protein leakage scintigraphy with technetium-99m human serum albumin diethylenetriamine pentaacetic acid (99mTc-HSAD) to exclude a diagnosis of protein-losing gastroenteropathy and observed diffuse positive accumulation in the kidneys with more intense uptake in the kidney than the liver on the anterior view 24 hours after 99mTc-HSAD administration. In healthy adults intravenously given 99mTc-HSAD, the same dynamics are observed as in albumin metabolism, and the organ radioactivity of the liver and kidneys after 24 hours is equal. Therefore, we thought it was possible that the renal uptake 24 hours after 99mTc-HSAD administration was a characteristic finding of NS. In order to confirm it, the subjects were divided into two groups: the NS group (n = 10) and the non-NS group (n = 7). We defined more intense uptake in the kidney than the liver on the anterior view 24 hours after 99mTc-HSAD administration as Dense Kidney (+). Furthermore, we designed regions of interest in the right and left kidneys and liver on anterior and posterior images, then calculated the kidney-liver ratio. Nine of the ten patients had Dense Kidney (+) in the NS group, compared to none in the non-NS group. And the kidney-liver ratio was significantly higher in the NS group than in the non-NS group on each view in the bilateral kidneys. In conclusion, our results suggest that the renal uptake 24 hours after 99mTc-HSAD administration is a characteristic finding of NS.

  16. Significance of Technetium-99m Human Serum Albumin Diethylenetriamine Pentaacetic Acid Scintigraphy in Patients with Nephrotic Syndrome

    PubMed Central

    Takashima, Tsuyoshi; Kishi, Tomoya; Onozawa, Koji; Rikitake, Shuichi; Miyazono, Motoaki; Otsuka, Takateru; Irie, Hiroyuki; Iwakiri, Ryuichi; Fujimoto, Kazuma; Ikeda, Yuji

    2015-01-01

    It is thought that a large amount of albumin leaking from the glomerulus in nephrotic syndrome (NS) is reabsorbed at the proximal tubule and catabolized. Therefore, it is possible the final quantity of urinary protein does not always reflect the amount of leakage of protein from the glomerulus. We experienced two cases without nephrotic range proteinuria thought to involve hypoproteinemia due to the same pathophysiology as NS. On these patients, we performed protein leakage scintigraphy with technetium-99m human serum albumin diethylenetriamine pentaacetic acid (99mTc-HSAD) to exclude a diagnosis of protein-losing gastroenteropathy and observed diffuse positive accumulation in the kidneys with more intense uptake in the kidney than the liver on the anterior view 24 hours after 99mTc-HSAD administration. In healthy adults intravenously given 99mTc-HSAD, the same dynamics are observed as in albumin metabolism, and the organ radioactivity of the liver and kidneys after 24 hours is equal. Therefore, we thought it was possible that the renal uptake 24 hours after 99mTc-HSAD administration was a characteristic finding of NS. In order to confirm it, the subjects were divided into two groups: the NS group (n = 10) and the non-NS group (n = 7). We defined more intense uptake in the kidney than the liver on the anterior view 24 hours after 99mTc-HSAD administration as Dense Kidney (+). Furthermore, we designed regions of interest in the right and left kidneys and liver on anterior and posterior images, then calculated the kidney-liver ratio. Nine of the ten patients had Dense Kidney (+) in the NS group, compared to none in the non-NS group. And the kidney-liver ratio was significantly higher in the NS group than in the non-NS group on each view in the bilateral kidneys. In conclusion, our results suggest that the renal uptake 24 hours after 99mTc-HSAD administration is a characteristic finding of NS. PMID:25859658

  17. Retinoic acid suppresses the canonical Wnt signaling pathway in embryonic stem cells and activates the noncanonical Wnt signaling pathway

    PubMed Central

    Osei-Sarfo, Kwame; Gudas, Lorraine J.

    2014-01-01

    Embryonic stem cells (ESCs) have both the ability to self-renew and to differentiate into various cell lineages. Retinoic acid (RA), a metabolite of Vitamin A, has a critical function in initiating lineage differentiation of ESCs through binding to the retinoic acid receptors (RARs). Additionally, the Wnt signaling pathway plays a role in pluripotency and differentiation, depending on the activation status of the canonical and noncanonical pathways. The activation of the canonical Wnt signaling pathway, which requires the nuclear accumulation of β-catenin and its interaction with Tcf1/Lef at Wnt response elements, is involved in ESC stemness maintenance. The noncanonical Wnt signaling pathway, through actions of Tcf3, can antagonize the canonical pathway. We show that RA activates the noncanonical Wnt signaling pathway, while concomitantly inhibiting the canonical pathway. RA increases the expression of ligands and receptors of the noncanonical Wnt pathway (Wnt 5a, 7a, Fzd2 and Fzd6), downstream signaling, and Tcf3 expression. RA reduces the phosphorylated β-catenin level by 4-fold, though total β-catenin levels don't change. We show that RA signaling increases the dissociation of Tcf1 and the association of Tcf3 at promoters of genes that regulate stemness (e.g. NR5A2,Lrh-1) or differentiation (eg. Cyr61, Zic5). Knockdown of Tcf3 increases Lrh-1 transcript levels in mESCs and prevents the RA-associated, ∼4-fold increase in Zic5, indicating that RA requires Tcf3 to effect changes in Zic5 levels. We demonstrate a novel role for RA in altering the activation of these two Wnt signaling pathways and show that Tcf3 mediates some actions of RA during differentiation. PMID:24648413

  18. [Significance of electron interactions of fatty acids of phospholipid molecules in the organism adaptation to habitation temperature].

    PubMed

    Zabelinskiĭ, S A; Chebotareva, M A; Arakelova, E S; Shukoliukova, E P; Furaev, V V; Kalandarov, A M; Feĭzulaev, B A; Krivchenko, A I

    2009-01-01

    Data in the fatty acid composition of muscle tissue phospholipids of some representatives of gastropod molluscs (Gastropoda) have been presented for the first time. In the lake phytophagues Lymnaea stagnalis and Lymnaea ovata the long-chained C22-acid was not detected, whereas in the predator common whelk Buccinum undatum, C22:6omega3 was present. Comparison of absorption spectra (240-720 nm) of lipid extracts of the studied invertebrates and of rat has been performed. The obtained data are discussed from the point of view of participation of pi-electrons of phospholipid fatty acid molecules in adaptation of membranes to the habitation temperature, which arises owing to interelectron attraction and to the process of formation of Cooper's pairs.

  19. Dietary cholesterol supplementation to a plant-based diet suppresses the complete pathway of cholesterol synthesis and induces bile acid production in Atlantic salmon (Salmo salar L.).

    PubMed

    Kortner, Trond M; Björkhem, Ingemar; Krasnov, Aleksei; Timmerhaus, Gerrit; Krogdahl, Åshild

    2014-06-28

    Plants now supply more than 50 % of protein in Norwegian salmon aquafeeds. The inclusion of plant protein in aquafeeds may be associated with decreased lipid digestibility and cholesterol and bile salt levels, indicating that the replacement of fishmeal with plant protein could result in inadequate supplies of cholesterol in fish. A reduction in feed efficiency, fish growth and pathogen resistance is often observed in parallel to alterations in sterol metabolism. Previous studies have indicated that the negative effects induced by plant components can be attenuated when diets are supplemented with cholesterol. The present study evaluated the effects of dietary cholesterol supplementation (1·5 %) in Atlantic salmon fed a plant-based diet for 77 d. The weights of body, intestines and liver were recorded and blood, tissues, faeces, chyme and bile were sampled for the evaluation of effects on growth, nutrient utilisation and metabolism, and transcriptome and metabolite levels, with particular emphasis on sterol metabolism and organ structure and function. Cholesterol supplementation did not affect the growth or organ weights of Atlantic salmon, but seemed to promote the induction of cholesterol and plant sterol efflux in the intestine while suppressing sterol uptake. Cholesterol biosynthesis decreased correspondingly and conversion into bile acids increased. The marked effect of cholesterol supplementation on bile acid synthesis suggests that dietary cholesterol can be used to increase bile acid synthesis in fish. The present study clearly demonstrated how Atlantic salmon adjusted their metabolic functions in response to the dietary load of cholesterol. It has also expanded our understanding of sterol metabolism and turnover, adding to the existing, rather sparse, knowledge of these processes in fish.

  20. Dietary cholesterol supplementation to a plant-based diet suppresses the complete pathway of cholesterol synthesis and induces bile acid production in Atlantic salmon (Salmo salar L.).

    PubMed

    Kortner, Trond M; Björkhem, Ingemar; Krasnov, Aleksei; Timmerhaus, Gerrit; Krogdahl, Åshild

    2014-06-28

    Plants now supply more than 50 % of protein in Norwegian salmon aquafeeds. The inclusion of plant protein in aquafeeds may be associated with decreased lipid digestibility and cholesterol and bile salt levels, indicating that the replacement of fishmeal with plant protein could result in inadequate supplies of cholesterol in fish. A reduction in feed efficiency, fish growth and pathogen resistance is often observed in parallel to alterations in sterol metabolism. Previous studies have indicated that the negative effects induced by plant components can be attenuated when diets are supplemented with cholesterol. The present study evaluated the effects of dietary cholesterol supplementation (1·5 %) in Atlantic salmon fed a plant-based diet for 77 d. The weights of body, intestines and liver were recorded and blood, tissues, faeces, chyme and bile were sampled for the evaluation of effects on growth, nutrient utilisation and metabolism, and transcriptome and metabolite levels, with particular emphasis on sterol metabolism and organ structure and function. Cholesterol supplementation did not affect the growth or organ weights of Atlantic salmon, but seemed to promote the induction of cholesterol and plant sterol efflux in the intestine while suppressing sterol uptake. Cholesterol biosynthesis decreased correspondingly and conversion into bile acids increased. The marked effect of cholesterol supplementation on bile acid synthesis suggests that dietary cholesterol can be used to increase bile acid synthesis in fish. The present study clearly demonstrated how Atlantic salmon adjusted their metabolic functions in response to the dietary load of cholesterol. It has also expanded our understanding of sterol metabolism and turnover, adding to the existing, rather sparse, knowledge of these processes in fish. PMID:24635969

  1. Suppression of insulin-like growth factor acid-labile subunit expression--a novel mechanism for deoxynivalenol-induced growth retardation.

    PubMed

    Amuzie, Chidozie J; Pestka, James J

    2010-02-01

    Consumption of deoxynivalenol (DON), a trichothecene mycotoxin commonly detected in cereal-based foods, causes impaired growth in many animal species. While growth retardation is used as a basis for regulating DON levels in human food, the underlying mechanisms remain poorly understood. Oral exposure of mice to DON rapidly induces multiorgan expression of proinflammatory cytokines, and this is followed by upregulation of several suppressors of cytokine signaling (SOCS), some of which are capable of impairing growth hormone (GH) signaling. The purpose of this study was to test the hypothesis that impairment of the GH axis precedes DON-induced growth retardation in the mouse. Subchronic dietary exposure of young (4-week old) mice to DON (20 ppm) over a period of 2-8 weeks was found to (1) impair weight gain, (2) result in a steady-state plasma DON concentration (40-60 ng/ml), (3) downregulate hepatic insulin-like growth factor acid-labile subunit (IGFALS) mRNA expression, and (4) reduce circulating insulin-like growth factor 1 (IGF1) and IGFALS levels. Acute oral exposure to DON at 0.5-12.5 mg/kg body weight (bw) markedly suppressed hepatic IGFALS mRNA levels within 2 h in a dose-dependent fashion, whereas 0.1 mg/kg bw was without effect. DON-induced IGFALS mRNA upregulation occurred both with and without exogenous GH treatment. These latter effects co-occurred with robust hepatic suppressors of cytokine signaling 3 upregulation. Taken together, these data suggest that oral DON exposure perturbs GH axis by suppressing two clinically relevant growth-related proteins, IGFALS and IGF1. Both have potential to serve as biomarkers of effect in populations exposed to this common foodborne mycotoxin.

  2. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice.

    PubMed

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D

    2014-12-01

    Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na⁺/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.

  3. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice[S

    PubMed Central

    Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D.

    2014-01-01

    Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na+/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine. PMID:25278499

  4. Regulatory CD8{sup +} T cells induced by exposure to all-trans retinoic acid and TGF-{beta} suppress autoimmune diabetes

    SciTech Connect

    Kishi, Minoru; Yasuda, Hisafumi; Abe, Yasuhisa; Sasaki, Hirotomo; Shimizu, Mami; Arai, Takashi; Okumachi, Yasuyo; Moriyama, Hiroaki; Hara, Kenta; Yokono, Koichi; Nagata, Masao

    2010-03-26

    Antigen-specific regulatory CD4{sup +} T cells have been described but there are few reports on regulatory CD8{sup +} T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8{sup +} T cells from 8.3-NOD transgenic mice. CD8{sup +} T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-{beta}, and all-trans retinoic acid (ATRA) for 5 days. CD8{sup +} T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-{beta} and ATRA had low Foxp3{sup +} expression (1.7 {+-} 0.9% and 3.2 {+-} 4.5%, respectively). In contrast, CD8{sup +} T cells induced by exposure to IGRP, SpDCs, TGF-{beta}, and ATRA showed the highest expression of Foxp3{sup +} in IGRP-reactive CD8{sup +} T cells (36.1 {+-} 10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8{sup +} T cells cultured with IGRP, SpDCs, TGF-{beta}, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8{sup +} T cells suppressed the proliferation of diabetogenic CD8{sup +} T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-{beta} induces CD8{sup +}Foxp3{sup +} T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

  5. Acetyl-11-keto-β-Boswellic Acid Suppresses Invasion of Pancreatic Cancer Cells Through The Downregulation of CXCR4 Chemokine Receptor Expression

    PubMed Central

    Park, Byoungduck; Sung, Bokyung; Yadav, Vivek R.; Cho, Sung-Gook; Liu, Mingyao; Aggarwal, Bharat B.

    2011-01-01

    Ninety percent of cancer-mediated deaths are due to metastasis of the tumor, but the mechanisms controlling metastasis remain poorly understood. Thus, no therapy targeting this process has yet been approved. Chemokines and their receptors are mediators of chronic inflammation and have been linked to the metastasis of numerous cancers. More recently, the CXC chemokine receptor 4 (CXCR4) has emerged as a key mediator of tumor metastasis; therefore, identification of inhibitors of this receptor has the potential to abrogate metastasis. In this report, we demonstrate that acetyl-11-keto-β-boswellic acid (AKBA), a component of the therapeutic plant Boswellia serrata, can downregulate CXCR4 expression in pancreatic cancer cells. The reduction in CXCR4 induced by this terpenoid was found to be cell-type specific, as its expression was also abrogated in leukemia, myeloma, and breast cancer cell lines. Neither proteasome inhibitors nor lysosomal stabilization could prevent the AKBA-induced reduction in CXCR4 expression, and downregulation occurred at the transcriptional level. Suppression of CXCR4 by AKBA was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. AKBA also abolished breast tumor cell invasion, and this effect correlated with the disappearance of both the CXCR4 mRNA and CXCR4 protein. Overall, our results show that AKBA is a novel inhibitor of CXCR4 expression and, thus, has the potential to suppress the invasion and metastasis of cancer cells. PMID:21448932

  6. Suppression of hepatic fat accumulation by highly purified eicosapentaenoic acid prevents the progression of d-galactosamine-induced hepatitis in mice fed with a high-fat/high-sucrose diet.

    PubMed

    Kajikawa, Satoshi; Harada, Tsuyoshi; Kawashima, Akiko; Imada, Kazunori; Mizuguchi, Kiyoshi

    2009-04-01

    The pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis. BALB/cA mice were fed with a standard diet (STD) or a high-fat and high-sucrose diet (HFHSD) for 14 days followed by intraperitoneal injection of d-galactosamine (DGalN) or vehicle. After 20-21 h, plasma and liver tissue were collected and analyzed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma were increased significantly in HFHSD-fed mice treated with DGalN compared to STD-fed mice treated with DGalN. This exacerbation by the HFHSD was also observed in the plasma soluble tumor necrosis factor receptor (sTNFR) levels, and hepatic levels of reactive oxygen species (ROS) and the fibrogenic gene expression, such as tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), connective tissue growth factor (CTGF) and osteopontin (OPN) in HFHSD-fed mice treated with DGalN. The triglyceride contents of the liver were significantly increased by the HFHSD. When eicosapentaenoic acid (EPA), a suppressor of sterol regulatory element binding protein 1 (SREBP-1), was administered to HFHSD-fed mice, the sensitivity of DGalN, as a result of plasma ALT and AST levels, was suppressed accompanied by reduced plasma sTNFR2 level and hepatic levels of triglyceride, ROS, and fibrogenic parameters, and by increased plasma adiponectin levels. These data suggest that the progression of steatotic liver injury closely depends on the accumulation of fat in the liver and is prevented by EPA through the suppression of the fatty liver change. PMID:19416647

  7. Fulgidic Acid Isolated from the Rhizomes of Cyperus rotundus Suppresses LPS-Induced iNOS, COX-2, TNF-α, and IL-6 Expression by AP-1 Inactivation in RAW264.7 Macrophages.

    PubMed

    Shin, Ji-Sun; Hong, Yujin; Lee, Hwi-Ho; Ryu, Byeol; Cho, Young-Wuk; Kim, Nam-Jung; Jang, Dae Sik; Lee, Kyung-Tae

    2015-01-01

    To identify bioactive natural products possessing anti-inflammatory activity, the potential of fulgidic acid from the rhizomes of Cyperus rotundus and the underlying mechanisms involved in its anti-inflammatory activity were evaluated in this study. Fulgidic acid reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Consistent with these findings, fulgidic acid suppressed the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level, as well as iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Fulgidic acid suppressed the LPS-induced transcriptional activity of activator protein-1 (AP-1) as well as the phosphorylation of c-Fos and c-Jun. On the other hand, fulgidic acid did not show any effect on LPS-induced nuclear factor κB (NF-κB) activity. Taken together, these results suggest that the anti-inflammatory effect of fulgidic acid is associated with the suppression of iNOS, COX-2, TNF-α, and IL-6 expression through down-regulating AP-1 activation in LPS-induced RAW264.7 macrophages. PMID:26133719

  8. The parasitic plant Cuscuta australis is highly insensitive to abscisic acid-induced suppression of hypocotyl elongation and seed germination.

    PubMed

    Li, Juan; Hettenhausen, Christian; Sun, Guiling; Zhuang, Huifu; Li, Jian-Hong; Wu, Jianqiang

    2015-01-01

    Around 1% of angiosperms are parasitic plants. Their growth and development solely or partly depend on host plants from which they extract water, nutrients, and other molecules using a parasitic plant-specific organ, the haustorium. Strong depletion of nutrients can result in serious growth retardation and in some cases, death of the hosts. The genus Cuscuta (dodder) comprises about 200 holoparasitic species occurring on all continents. Their seedlings have no roots and cotyledons but are only string-like hypocotyls. When they contact suitable host plants, haustoria are formed and thereafter seedlings rapidly develop into vigorously growing branches without roots and leaves. This highly specialized lifestyle suggests that Cuscuta plants likely have unique physiology in development and stress responses. Using germination and seedling growth assays, we show that C. australis seeds and seedlings are highly insensitive to abscisic acid (ABA). Transcriptome analysis and protein sequence alignment with Arabidopsis, tomato, and rice homologs revealed that C. australis most likely consists of only four functional ABA receptors. Given that Cuscuta plants are no longer severely challenged by drought stress, we hypothesize that the ABA-mediated drought resistance pathway in Cuscuta spp. might have had degenerated over time during evolution. PMID:26258814

  9. The parasitic plant Cuscuta australis is highly insensitive to abscisic acid-induced suppression of hypocotyl elongation and seed germination.

    PubMed

    Li, Juan; Hettenhausen, Christian; Sun, Guiling; Zhuang, Huifu; Li, Jian-Hong; Wu, Jianqiang

    2015-01-01

    Around 1% of angiosperms are parasitic plants. Their growth and development solely or partly depend on host plants from which they extract water, nutrients, and other molecules using a parasitic plant-specific organ, the haustorium. Strong depletion of nutrients can result in serious growth retardation and in some cases, death of the hosts. The genus Cuscuta (dodder) comprises about 200 holoparasitic species occurring on all continents. Their seedlings have no roots and cotyledons but are only string-like hypocotyls. When they contact suitable host plants, haustoria are formed and thereafter seedlings rapidly develop into vigorously growing branches without roots and leaves. This highly specialized lifestyle suggests that Cuscuta plants likely have unique physiology in development and stress responses. Using germination and seedling growth assays, we show that C. australis seeds and seedlings are highly insensitive to abscisic acid (ABA). Transcriptome analysis and protein sequence alignment with Arabidopsis, tomato, and rice homologs revealed that C. australis most likely consists of only four functional ABA receptors. Given that Cuscuta plants are no longer severely challenged by drought stress, we hypothesize that the ABA-mediated drought resistance pathway in Cuscuta spp. might have had degenerated over time during evolution.

  10. The Parasitic Plant Cuscuta australis Is Highly Insensitive to Abscisic Acid-Induced Suppression of Hypocotyl Elongation and Seed Germination

    PubMed Central

    Li, Juan; Hettenhausen, Christian; Sun, Guiling; Zhuang, Huifu; Li, Jian-Hong; Wu, Jianqiang

    2015-01-01

    Around 1% of angiosperms are parasitic plants. Their growth and development solely or partly depend on host plants from which they extract water, nutrients, and other molecules using a parasitic plant-specific organ, the haustorium. Strong depletion of nutrients can result in serious growth retardation and in some cases, death of the hosts. The genus Cuscuta (dodder) comprises about 200 holoparasitic species occurring on all continents. Their seedlings have no roots and cotyledons but are only string-like hypocotyls. When they contact suitable host plants, haustoria are formed and thereafter seedlings rapidly develop into vigorously growing branches without roots and leaves. This highly specialized lifestyle suggests that Cuscuta plants likely have unique physiology in development and stress responses. Using germination and seedling growth assays, we show that C. australis seeds and seedlings are highly insensitive to abscisic acid (ABA). Transcriptome analysis and protein sequence alignment with Arabidopsis, tomato, and rice homologs revealed that C. australis most likely consists of only four functional ABA receptors. Given that Cuscuta plants are no longer severely challenged by drought stress, we hypothesize that the ABA-mediated drought resistance pathway in Cuscuta spp. might have had degenerated over time during evolution. PMID:26258814

  11. Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer

    PubMed Central

    Toyoda, M; Kaira, K; Ohshima, Y; Ishioka, N S; Shino, M; Sakakura, K; Takayasu, Y; Takahashi, K; Tominaga, H; Oriuchi, N; Nagamori, S; Kanai, Y; Oyama, T; Chikamatsu, K

    2014-01-01

    Background: Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer. Methods: Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. Results: L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. Conclusions: L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer. PMID:24762957

  12. Does acid suppression by antacids and H2 receptor antagonists increase the incidence of atrophic gastritis in patients with or without H. pylori gastritis?

    PubMed

    Carter, M; Katz, D L; Haque, S; DeLuca, V A

    1999-09-01

    Currently there is controversial evidence that suggests that the accepted incidence of atrophic gastritis of 1.2 to 3.3% in patients with Helicobacter pylori gastritis may be increased by the long-term suppression of acid by a proton pump inhibitor (omeprazole). The purpose of this study is to show whether lesser forms of acid suppression by antacids or H2 receptor antagonists may have an influence on the development of atrophic gastritis. The authors recently reported a study in which a cohort of 36 patients with symptoms of dyspepsia were followed clinically for a period of 7 to 19 years. In that report all subjects underwent upper endoscopy with two biopsy specimens each from the antrum and fundus, on at least two occasions, 7 to 19 years apart. A diagnosis of atrophic gastritis was based on the interpretation of these biopsies by two gastrointestinal pathologists. The presence of H. pylori colonization was determined by tissue sampling and by a campylobacter-like organisms test of the antrum. Of the 36 patients in the authors' previous report, 33 had adequate baseline and follow-up data on medications consumed throughout the period of the study. In their current report they now present the findings of a retrospective review in which they correlate the presence of atrophic gastritis with the sole use of antacids and H2 receptor antagonists throughout the period of the study. In the cohort of 33 patients evaluated from the previous report, the authors found that atrophic gastritis had developed in all 28 patients positive for H. pylori, and in none of the 5 patients negative for H. pylori (p < 0.0001). A retrospective analysis of this previously studied cohort of 33 patients revealed that the use of antacids and H2 receptor antagonists did not predict the development of atrophic gastritis in either H. pylori-negative or -positive subjects. In a retrospective analysis of a cohort of 33 patients followed for an average of 11.7 years, atrophic gastritis developed in

  13. COX-2, aspirin and metabolism of arachidonic, eicosapentaenoic and docosahexaenoic acids and their physiological and clinical significance.

    PubMed

    Poorani, R; Bhatt, Anant N; Dwarakanath, B S; Das, Undurti N

    2016-08-15

    Polyunsaturated fatty acids (PUFAs) are vital for normal growth and development and physiological function of various tissues in humans. PUFAs have immunomodulatory actions in addition to their ability to modulate inflammation, vascular reactivity, neurotransmission and stem cell biology. PUFAs and their metabolites possess both pro- and anti-inflammatory properties that underlie their actions and involvement in several diseases. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), possesses both cyclo-oxygenase (COX) and lipoxygenase (LOX) inhibitory action and enhances the production of anti-inflammatory lipoxin A4 {(called as epi-lipoxin A4, aspirin-triggered lipoxins (ATLs))}. In addition, at low doses aspirin may not interfere with the production of prostacyclin (PGI2). Both lipoxin A4 and PGI2 have vasodilator, platelet anti-aggregator and anti-inflammatory actions that may underlie the beneficial actions of aspirin. Paradoxically, other NSAIDs may not have the same actions as that of aspirin on PUFA metabolism. Similar anti-inflammatory compounds are formed from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by the action of aspirin termed as resolvins (from EPA and DHA) and protectins and maresins from DHA. PUFAs: arachidonic acid (AA), EPA and DHA and their various products modulate not only inflammation and immune response but also possess actions on various genes, nuclear factors, cyclic AMP and GMP, G-protein coupled receptors (GPRs), hypothalamic neurotransmitters, hormones, cytokines and enzymes, and interact with nitric oxide, carbon monoxide, and hydrogen sulfide to regulate their formation and action and to form new compounds that have several biological actions. These pleiotropic actions of PUFAs and their metabolites may explain their ability to play a role in several physiological actions and diseases. The big challenge is to harness these actions to prevent and manage clinical conditions. PMID:26335394

  14. Investigating the significance of zero-point motion in small molecular clusters of sulphuric acid and water

    SciTech Connect

    Stinson, Jake L. Ford, Ian J.; Kathmann, Shawn M.

    2014-01-14

    The nucleation of particles from trace gases in the atmosphere is an important source of cloud condensation nuclei, and these are vital for the formation of clouds in view of the high supersaturations required for homogeneous water droplet nucleation. The methods of quantum chemistry have increasingly been employed to model nucleation due to their high accuracy and efficiency in calculating configurational energies; and nucleation rates can be obtained from the associated free energies of particle formation. However, even in such advanced approaches, it is typically assumed that the nuclei have a classical nature, which is questionable for some systems. The importance of zero-point motion (also known as quantum nuclear dynamics) in modelling small clusters of sulphuric acid and water is tested here using the path integral molecular dynamics method at the density functional level of theory. The general effect of zero-point motion is to distort the mean structure slightly, and to promote the extent of proton transfer with respect to classical behaviour. In a particular configuration of one sulphuric acid molecule with three waters, the range of positions explored by a proton between a sulphuric acid and a water molecule at 300 K (a broad range in contrast to the confinement suggested by geometry optimisation at 0 K) is clearly affected by the inclusion of zero point motion, and similar effects are observed for other configurations.

  15. Engineered Expression Vectors Significantly Enhanced the Production of 2-Keto-D-gluconic Acid by Gluconobacter oxidans.

    PubMed

    Shi, Yuan-yuan; Li, Ke-fei; Lin, Jin-ping; Yang, Sheng-li; Wei, Dong-zhi

    2015-06-10

    2-Keto-D-gluconic acid (2KGA), a precursor of the important food antioxidant erythorbic acid, can be produced by Gluconobacter oxidans. To genetically engineer G. oxidans for improved 2KGA production, six new expression vectors with increased copy numbers based on pBBR1MCS-5 were constructed via rational mutagenesis. The utility of the mutant vectors was demonstrated by the increased ga2dh mRNA abundance, enzyme activity, and 2KGA production when the ga2dh gene was overexpressed using these vectors. Among the obtained constructs, G. oxidans/pBBR-3510-ga2dh displayed the highest oxidative activity toward gluconic acid (GA). In a batch biotransformation process, the G. oxidans/pBBR-3510-ga2dh strain exhibited 2KGA productivity (0.63 g/g CWW/h) higher than that obtained using strain G. oxidans/pBBR-ga2dh (0.40 g/g CWW/h). When sufficient oxygen was supplied during the biotransformation, up to 480 g/L GA was exhausted in 45 h by the G. oxidans/pBBR-3510-ga2dh strain and approximately 486 g/L 2KGA was produced, generating the productivity of 0.54 g/g CWW/h.

  16. Estimates of Soil Bacterial Ribosome Content and Diversity Are Significantly Affected by the Nucleic Acid Extraction Method Employed

    PubMed Central

    Wüst, Pia K.; Nacke, Heiko; Kaiser, Kristin; Marhan, Sven; Sikorski, Johannes; Kandeler, Ellen; Daniel, Rolf

    2016-01-01

    Modern sequencing technologies allow high-resolution analyses of total and potentially active soil microbial communities based on their DNA and RNA, respectively. In the present study, quantitative PCR and 454 pyrosequencing were used to evaluate the effects of different extraction methods on the abundance and diversity of 16S rRNA genes and transcripts recovered from three different types of soils (leptosol, stagnosol, and gleysol). The quality and yield of nucleic acids varied considerably with respect to both the applied extraction method and the analyzed type of soil. The bacterial ribosome content (calculated as the ratio of 16S rRNA transcripts to 16S rRNA genes) can serve as an indicator of the potential activity of bacterial cells and differed by 2 orders of magnitude between nucleic acid extracts obtained by the various extraction methods. Depending on the extraction method, the relative abundances of dominant soil taxa, in particular Actinobacteria and Proteobacteria, varied by a factor of up to 10. Through this systematic approach, the present study allows guidelines to be deduced for the selection of the appropriate extraction protocol according to the specific soil properties, the nucleic acid of interest, and the target organisms. PMID:26896137

  17. Investigating the significance of zero-point motion in small molecular clusters of sulphuric acid and water.

    PubMed

    Stinson, Jake L; Kathmann, Shawn M; Ford, Ian J

    2014-01-14

    The nucleation of particles from trace gases in the atmosphere is an important source of cloud condensation nuclei, and these are vital for the formation of clouds in view of the high supersaturations required for homogeneous water droplet nucleation. The methods of quantum chemistry have increasingly been employed to model nucleation due to their high accuracy and efficiency in calculating configurational energies; and nucleation rates can be obtained from the associated free energies of particle formation. However, even in such advanced approaches, it is typically assumed that the nuclei have a classical nature, which is questionable for some systems. The importance of zero-point motion (also known as quantum nuclear dynamics) in modelling small clusters of sulphuric acid and water is tested here using the path integral molecular dynamics method at the density functional level of theory. The general effect of zero-point motion is to distort the mean structure slightly, and to promote the extent of proton transfer with respect to classical behaviour. In a particular configuration of one sulphuric acid molecule with three waters, the range of positions explored by a proton between a sulphuric acid and a water molecule at 300 K (a broad range in contrast to the confinement suggested by geometry optimisation at 0 K) is clearly affected by the inclusion of zero point motion, and similar effects are observed for other configurations.

  18. Functional significance of cumulus expansion in the mouse: roles for the preovulatory synthesis of hyaluronic acid within the cumulus mass.

    PubMed

    Chen, L; Russell, P T; Larsen, W J

    1993-01-01

    Gonadotropin-stimulated expansion of the mouse cumulus oocyte complex (COC) in vitro, measured with a quantitative videographic method, is comparable to that observed to occur in vivo when medium is supplemented with porcine follicle stimulating hormone (pFSH), 10% fetal bovine serum (FBS), and 2.5 mM glucosamine or optimal concentrations of glutamine and glucose. In the absence of glucosamine, the volumetric expansion of COCs in vitro is never more than 25% of that occurring in its presence. The addition of 6-diazo-5-oxo-1-norleucine (DON), an inhibitor of glucosamine synthesis to medium supplemented with glutamine and glucose, completely inhibits cumulus expansion in vitro. This system was utilized to examine the relationship between cumulus expansion and fertilization rates, and the maintenance of fertilizability in culture. Successful fertilization (as determined by development to the 2-cell stage) was correlated with the quantity and quality of the expanded cumulus mass, and conversely, the spontaneous loss or mechanical removal of the cumulus was correlated with a loss of fertilizability following additional incubation in culture medium. In addition, the i.p. injection of DON inhibited cumulus expansion within the intact follicle and suppressed ovulation.

  19. 12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid suppresses UV-induced IL-6 synthesis in keratinocytes, exerting an anti-inflammatory activity

    PubMed Central

    Lee, Jin-Wook; Ryu, Ho-Cheol; Ng, Yee Ching; Kim, Cheolmin; Wei, Jun-Dong; Sabaratnam, Vikineswary

    2012-01-01

    12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) is an enzymatic product of prostaglandin H2 (PGH2) derived from cyclooxygenase (COX)-mediated arachidonic acid metabolism. Despite the high level of 12-HHT present in tissues and bodily fluids, its precise function remains largely unknown. In this study, we found that 12-HHT treatment in HaCaT cells remarkably down-regulated the ultraviolet B (UVB) irradiation-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation. In an approach to identify the down-stream signaling mechanism by which 12-HHT down-regulates UVB-induced IL-6 synthesis in keratinocytes, we observed that 12-HHT inhibits the UVB-stimulated activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). In addition, we found that 12-HHT markedly up-regulates MAPK phosphatase-1 (MKP-1), a critical negative regulator of p38 MAPK. When MKP-1 was suppressed by siRNA knock-down, the 12-HHT-mediated inhibitory effects on the UVB-stimulated activation of p38 MAPK and NF-κB, as well as the production of IL-6, were attenuated in HaCaT cells. Taken together, our results suggest that 12-HHT exerts anti-inflammatory effect via up-regulation of MKP-1, which negatively regulates p38 MAPK and NF-κB, thus attenuating IL-6 production in UVB-irradiated HaCaT cells. Considering the critical role of IL-6 in cutaneous inflammation, our findings provide the basis for the application of 12-HHT as a potential anti-inflammatory therapeutic agent in UV-induced skin diseases. PMID:22391335

  20. Mycosporine-like amino acids (MAAs): chemical structure, biosynthesis and significance as UV-absorbing/screening compounds.

    PubMed

    Singh, Shailendra P; Kumari, Sunita; Rastogi, Rajesh P; Singh, Kanchan L; Sinha, Rajeshwar P

    2008-01-01

    Continuous depletion of the stratospheric ozone layer has resulted in an increase in ultraviolet-B (UV-B; 280-315 nm) radiation on the earth's surface which inhibits photochemical and photobiological processes. However, certain photosynthetic organisms have evolved mechanisms to counteract the toxicity of ultraviolet or high photosynthetically active radiation by synthesizing the UV-absorbing/screening compounds, such as mycosporine-like amino acids (MAAs) and scytonemin besides the repair of UV-induced damage of DNA and accumulation of carotenoids and detoxifying enzymes or radical quenchers and antioxidants. Chemical structure of various MAAs, their possible biochemical routes of synthesis and role as photoprotective compounds in various organisms are discussed.

  1. Protection of acute GVHD by all-trans retinoic acid through suppression of T cell expansion and induction of regulatory T cells through IL-2 signaling.

    PubMed

    Yang, Haojun; Gu, Jian; Zhu, Qin; Lu, Hao; Wang, Kunpeng; Ni, Xuhao; Lu, Yunjie; Lu, Ling

    2015-10-01

    All-trans retinoic acid (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. However, the potential use of atRA as a treatment for acute graft-verse-host disease (aGVHD) has not been realized. Here we studied the ability of atRA to prevent and treat acute-GVHD in the B6-to-F1(D2B6F1) murine model. Our results showed that atRA consistently displayed a potent ability to control aGVHD development and reduce mortality by suppressing the expansion of donor T cells and inhibiting cytokine expression from donor CD8 cells. Interestingly, CD4(+)Foxp3(+) regulatory T cells were markedly increased in the spleens of atRA-treated mice. In vitro treatment with atRA inhibited T cell proliferation in a dose-dependent manner. Injection of an anti-IL-2 antibody impaired the protection by atRA in aGVHD. Therefore, these results strongly implicate atRA as a novel therapeutic strategy for controlling aGVHD progression and treating other inflammatory diseases. PMID:25864619

  2. Identification of genes involved in indole-3-butyric acid-induced adventitious root formation in nodal cuttings of Camellia sinensis (L.) by suppression subtractive hybridization.

    PubMed

    Wei, Kang; Wang, Liyuan; Cheng, Hao; Zhang, Chengcai; Ma, Chunlei; Zhang, Liqun; Gong, Wuyun; Wu, Liyun

    2013-02-10

    The plant hormone auxin plays a key role in adventitious rooting. To increase our understanding of genes involved in adventitious root formation, we identified transcripts differentially expressed in single nodal cuttings of Camellia sinensis treated with or without indole-3-butyric acid (IBA) by suppressive subtractive hybridization (SSH). A total of 77 differentially expressed transcripts, including 70 up-regulated and 7 down-regulated sequences, were identified in tea cuttings under IBA treatment. Seven candidate transcripts were selected and analyzed for their response to IBA, and IAA by real time RT-PCR. All these transcripts were up regulated by at least two folds one day after IBA treatment. Meanwhile, IAA showed less positive effects on the expression of candidate transcripts. The full-length cDNA of a F-box/kelch gene was also isolated and found to be similar to a group of At1g23390 like genes. These unigenes provided a new source for mining genes related to adventitious root formation, which facilitate our understanding of relative fundamental metabolism.

  3. Thioesterase superfamily member 1 suppresses cold thermogenesis by limiting the oxidation of lipid droplet-derived fatty acids in brown adipose tissue

    PubMed Central

    Okada, Kosuke; LeClair, Katherine B.; Zhang, Yongzhao; Li, Yingxia; Ozdemir, Cafer; Krisko, Tibor I.; Hagen, Susan J.; Betensky, Rebecca A.; Banks, Alexander S.; Cohen, David E.

    2016-01-01

    Objective Non-shivering thermogenesis in brown adipose tissue (BAT) plays a central role in energy homeostasis. Thioesterase superfamily member 1 (Them1), a BAT-enriched long chain fatty acyl-CoA thioesterase, is upregulated by cold and downregulated by warm ambient temperatures. Them1−/− mice exhibit increased energy expenditure and resistance to diet-induced obesity and diabetes, but the mechanistic contribution of Them1 to the regulation of cold thermogenesis remains unknown. Methods Them1−/− and Them1+/+ mice were subjected to continuous metabolic monitoring to quantify the effects of ambient temperatures ranging from thermoneutrality (30 °C) to cold (4 °C) on energy expenditure, core body temperature, physical activity and food intake. The effects of Them1 expression on O2 consumption rates, thermogenic gene expression and lipolytic protein activation were determined ex vivo in BAT and in primary brown adipocytes. Results Them1 suppressed thermogenesis in mice even in the setting of ongoing cold exposure. Without affecting thermogenic gene transcription, Them1 reduced O2 consumption rates in both isolated BAT and primary brown adipocytes. This was attributable to decreased mitochondrial oxidation of endogenous but not exogenous fatty acids. Conclusions These results show that Them1 may act as a break on uncontrolled heat production and limit the extent of energy expenditure. Pharmacologic inhibition of Them1 could provide a targeted strategy for the management of metabolic disorders via activation of brown fat. PMID:27110486

  4. Identification of genes involved in indole-3-butyric acid-induced adventitious root formation in nodal cuttings of Camellia sinensis (L.) by suppression subtractive hybridization.

    PubMed

    Wei, Kang; Wang, Liyuan; Cheng, Hao; Zhang, Chengcai; Ma, Chunlei; Zhang, Liqun; Gong, Wuyun; Wu, Liyun

    2013-02-10

    The plant hormone auxin plays a key role in adventitious rooting. To increase our understanding of genes involved in adventitious root formation, we identified transcripts differentially expressed in single nodal cuttings of Camellia sinensis treated with or without indole-3-butyric acid (IBA) by suppressive subtractive hybridization (SSH). A total of 77 differentially expressed transcripts, including 70 up-regulated and 7 down-regulated sequences, were identified in tea cuttings under IBA treatment. Seven candidate transcripts were selected and analyzed for their response to IBA, and IAA by real time RT-PCR. All these transcripts were up regulated by at least two folds one day after IBA treatment. Meanwhile, IAA showed less positive effects on the expression of candidate transcripts. The full-length cDNA of a F-box/kelch gene was also isolated and found to be similar to a group of At1g23390 like genes. These unigenes provided a new source for mining genes related to adventitious root formation, which facilitate our understanding of relative fundamental metabolism. PMID:23201417

  5. Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-{kappa}B and MAPK activation in RAW 264.7 macrophages

    SciTech Connect

    Reddy, D. Bharat; Reddanna, Pallu

    2009-03-27

    Chebulagic acid (CA), a natural anti-oxidant, showed potent anti-inflammatory effects in LPS-stimulated RAW 264.7, a mouse macrophage cell line. These effects were exerted via inhibition of NO and PGE{sub 2} production and down-regulation of iNOS, COX-2, 5-LOX, TNF-{alpha} and IL-6. CA inhibited NF-{kappa}B activation by LPS, and this was associated with the abrogation of I{kappa}B-{alpha} phosphorylation and subsequent decreases in nuclear p50 and p65 protein levels. Further, the phosphorylation of p38, ERK 1/2 and JNK in LPS-stimulated RAW 264.7 cells was suppressed by CA in a concentration-dependent manner. LPS-induced generation of reactive oxygen species (ROS) was also effectively inhibited by CA. These results suggest that CA exerts anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages by inhibition of NF-{kappa}B activation and MAP kinase phosphorylation.

  6. Docosahexaenoic Acid Inhibits Tumor Promoter-Induced Urokinase-Type Plasminogen Activator Receptor by Suppressing PKCδ- and MAPKs-Mediated Pathways in ECV304 Human Endothelial Cells

    PubMed Central

    Lian, Sen; Xia, Yong; Nguyen, Thi Thinh; Ung, Trong Thuan; Yoon, Hyun Joong; Kim, Nam Ho; Kim, Kyung Keun; Jung, Young Do

    2016-01-01

    The overexpression of urokinase-type plasminogen activator receptor (uPAR) is associated with inflammation and virtually all human cancers. Despite the fact that docosahexaenoic acid (DHA) has been reported to possess anti-inflammatory and anti-tumor properties, the negative regulation of uPAR by DHA is still undefined. Here, we investigated the effect of DHA on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and the underlying molecular mechanisms in ECV304 human endothelial cells. DHA concentration-dependently inhibited TPA-induced uPAR. Specific inhibitors and mutagenesis studies showed that PKCδ, JNK1/2, Erk1/2, NF-κB, and AP-1 were critical for TPA-induced uPAR expression. Application of DHA suppressed TPA-induced translocation of PKCδ, activation of the JNK1/2 and Erk1/2 signaling pathways, and subsequent AP-1 and NF-κB transactivation. In conclusion, these observations suggest a novel role for DHA in reducing uPAR expression and cell invasion by inhibition of PKCδ, JNK1/2, and Erk1/2, and the reduction of AP-1 and NF-κB activation in ECV304 human endothelial cells. PMID:27654969

  7. The central acidic domain of MDM2 is critical in inhibition of retinoblastoma-mediated suppression of E2F and cell growth.

    PubMed

    Sdek, Patima; Ying, Haoqiang; Zheng, Hongwu; Margulis, Alexander; Tang, Xiaoren; Tian, Kui; Xiao, Zhi-Xiong Jim

    2004-12-17

    Retinoblastoma (Rb) protein is a paradigm of tumor suppressors. Inactivation of Rb plays a critical role in the development of human malignancies. MDM2, an oncogene frequently found amplified and overexpressed in a variety of human tumors and cancers, directly interacts and inhibits the p53 tumor suppressor protein. In addition, MDM2 has been shown to stimulate E2F transactivation activity and promote S-phase entry independent of p53, yet the mechanism of which is still not fully understood. In this study, we demonstrate that MDM2 specifically binds to Rb C-pocket and that the central acidic domain of MDM2 is essential for Rb interaction. In addition, we show that overexpression of MDM2 reduces Rb-E2F complexes in vivo. Moreover, the ectopic expression of the wild type MDM2, but not mutant MDM2 defective in Rb interaction, stimulates E2F transactivation activity and inhibits Rb growth suppression function. Taken together, these results suggest that MDM2-mediated inhibition of Rb likely contributes to MDM2 oncogenic activity. PMID:15485814

  8. Surface functionalization of bioactive glasses with natural molecules of biological significance, Part I: Gallic acid as model molecule

    NASA Astrophysics Data System (ADS)

    Zhang, Xin; Ferraris, Sara; Prenesti, Enrico; Verné, Enrica

    2013-12-01

    Gallic acid (3,4,5-trihydroxybenzoic acid, GA) and its derivatives are a group of biomolecules (polyphenols) obtained from plants. They have effects which are potentially beneficial to heath, for example they are antioxidant, anticarcinogenic and antibacterial, as recently investigated in many fields such as medicine, food and plant sciences. The main drawbacks of these molecules are both low stability and bioavailability. In this research work the opportunity to graft GA to bioactive glasses is investigated, in order to deliver the undamaged biological molecule into the body, using the biomaterial surfaces as a localized carrier. GA was considered for functionalization since it is a good model molecule for polyphenols and presents several interesting biological activities, like antibacterial, antioxidant and anticarcinogenic properties. Two different silica based bioactive glasses (SCNA and CEL2), with different reactivity, were employed as substrates. UV photometry combined with the Folin&Ciocalteu reagent was adopted to test the concentration of GA in uptake solution after functionalization. This test verified how much GA consumption occurred with surface modification and it was also used on solid samples to test the presence of GA on functionalized glasses. XPS and SEM-EDS techniques were employed to characterize the modification of material surface properties and functional group composition before and after functionalization.

  9. Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice.

    PubMed

    Paik, Jisun; Haenisch, Michael; Muller, Charles H; Goldstein, Alex S; Arnold, Samuel; Isoherranen, Nina; Brabb, Thea; Treuting, Piper M; Amory, John K

    2014-05-23

    Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN 18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives.

  10. Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice*

    PubMed Central

    Paik, Jisun; Haenisch, Michael; Muller, Charles H.; Goldstein, Alex S.; Arnold, Samuel; Isoherranen, Nina; Brabb, Thea; Treuting, Piper M.; Amory, John K.

    2014-01-01

    Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN 18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives. PMID:24711451

  11. Agent-based model of Fecal Microbial Transplant effect on Bile Acid Metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection

    PubMed Central

    Peer, Xavier; An, Gary

    2014-01-01

    Agent-based modeling is a computational modeling method that represents system-level behavior as arising from multiple interactions between the multiple components that make up a system. Biological systems are thus readily described using agent-based models (ABMs), as multi-cellular organisms can be viewed as populations of interacting cells, and microbial systems manifest as colonies of individual microbes. Intersections between these two domains underlie an increasing number of pathophysiological processes, and the intestinal tract represents one of the most significant locations for these inter-domain interactions, so much so that it can be considered an internal ecology of varying robustness and function. Intestinal infections represent significant disturbances of this internal ecology, and one of the most clinically relevant intestinal infections is Clostridium difficile infection (CDI). CDI is precipitated by the use of broad-spectrum antibiotics, involves the depletion of commensal microbiota, and alterations in bile acid composition in the intestinal lumen. We present an example ABM of CDI (the Clostridium difficile Infection ABM, or CDIABM) to examine fundamental dynamics of the pathogenesis of CDI and its response to treatment with anti-CDI antibiotics and a newer treatment therapy, Fecal Microbial Transplant (FMT). The CDIABM focuses on one specific mechanism of potential CDI suppression: commensal modulation of bile acid composition. Even given its abstraction, the CDIABM reproduces essential dynamics of CDI and its response to therapy, and identifies a paradoxical zone of behavior that provides insight into the role of intestinal nutritional status and the efficacy of anti-CDI therapies. It is hoped that this use case example of the CDIABM can demonstrate the usefulness of both agent-based modeling and the application of abstract functional representation as the biomedical community seeks to address the challenges of increasingly complex diseases with

  12. Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01.

    PubMed

    Kimura, Kotohiko; Huang, Ru Chih C

    2016-01-01

    The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments. PMID:26886430

  13. Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01

    PubMed Central

    Kimura, Kotohiko; Huang, Ru Chih C.

    2016-01-01

    The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments. PMID:26886430

  14. Insulin Resistance, Defective Insulin-Mediated Fatty Acid Suppression, and Coronary Artery Calcification in Subjects With and Without Type 1 Diabetes

    PubMed Central

    Schauer, Irene E.; Snell-Bergeon, Janet K.; Bergman, Bryan C.; Maahs, David M.; Kretowski, Adam; Eckel, Robert H.; Rewers, Marian

    2011-01-01

    OBJECTIVE To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls. RESEARCH DESIGN AND METHODS Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female). RESULTS Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters. CONCLUSIONS Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes. PMID:20978091

  15. p-Sulfonic Acid Calix[4]arene as an Efficient Catalyst for One-Pot Synthesis of Pharmaceutically Significant Coumarin Derivatives under Solvent-Free Condition

    PubMed Central

    Tashakkorian, Hamed; Lakouraj, Moslem Mansour; Rouhi, Mona

    2015-01-01

    One-pot and efficient protocol for preparation of some potent pharmaceutically valuable coumarin derivatives under solvent-free condition via direct coupling using biologically nontoxic organocatalyst, calix[4]arene tetrasulfonic acid (CSA), was introduced. Calix[4]arene sulfonic acid has been incorporated lately as a magnificent and recyclable organocatalyst for the synthesis of some organic compounds. Nontoxicity, solvent-free conditions, good-to-excellent yields for pharmaceutically significant structures, and especially ease of catalyst recovery make this procedure valuable and environmentally benign. PMID:26798517

  16. A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.

    PubMed

    Sanson, Misu; O'Neill, Brian E; Kachroo, Priyanka; Anderson, Jeff R; Flores, Anthony R; Valson, Chandni; Cantu, Concepcion C; Makthal, Nishanth; Karmonik, Christof; Fittipaldi, Nahuel; Kumaraswami, Muthiah; Musser, James M; Olsen, Randall J

    2015-02-01

    Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga). Herein, we report results of studies designed to test the hypothesis that the most commonly occurring SNP, encoding a replacement of arginine for histidine at codon 201 of Mga (H201R), significantly increases virulence. Whole transcriptome analysis revealed that the H201R replacement significantly increased expression of mga and 54 other genes, including many proven virulence factors. Compared to the wild-type strain, a H201R isogenic mutant strain caused significantly larger skin lesions in mice. Serial quantitative bacterial culture and noninvasive magnetic resonance imaging also demonstrated that the isogenic H201R strain was significantly more virulent in a nonhuman primate model of joint infection. These findings show that the H201R replacement in Mga increases the virulence of M59 group A Streptococcus and provide new insight to how a naturally occurring SNP in bacteria contributes to human disease phenotypes.

  17. A naturally occurring single amino acid replacement in multiple gene regulator of group A Streptococcus significantly increases virulence.

    PubMed

    Sanson, Misu; O'Neill, Brian E; Kachroo, Priyanka; Anderson, Jeff R; Flores, Anthony R; Valson, Chandni; Cantu, Concepcion C; Makthal, Nishanth; Karmonik, Christof; Fittipaldi, Nahuel; Kumaraswami, Muthiah; Musser, James M; Olsen, Randall J

    2015-02-01

    Single-nucleotide polymorphisms (SNPs) are the most common source of genetic variation within a species; however, few investigations demonstrate how naturally occurring SNPs may increase strain virulence. We recently used group A Streptococcus as a model pathogen to study bacteria strain genotype-patient disease phenotype relationships. Whole-genome sequencing of approximately 800 serotype M59 group A Streptococcus strains, recovered during an outbreak of severe invasive infections across North America, identified a disproportionate number of SNPs in the gene encoding multiple gene regulator of group A Streptococcus (mga). Herein, we report results of studies designed to test the hypothesis that the most commonly occurring SNP, encoding a replacement of arginine for histidine at codon 201 of Mga (H201R), significantly increases virulence. Whole transcriptome analysis revealed that the H201R replacement significantly increased expression of mga and 54 other genes, including many proven virulence factors. Compared to the wild-type strain, a H201R isogenic mutant strain caused significantly larger skin lesions in mice. Serial quantitative bacterial culture and noninvasive magnetic resonance imaging also demonstrated that the isogenic H201R strain was significantly more virulent in a nonhuman primate model of joint infection. These findings show that the H201R replacement in Mga increases the virulence of M59 group A Streptococcus and provide new insight to how a naturally occurring SNP in bacteria contributes to human disease phenotypes. PMID:25476528

  18. The Significance of Lewis Acid Sites for the Selective Catalytic Reduction of Nitric Oxide on Vanadium-Based Catalysts.

    PubMed

    Marberger, Adrian; Ferri, Davide; Elsener, Martin; Kröcher, Oliver

    2016-09-19

    The long debated reaction mechanisms of the selective catalytic reduction (SCR) of nitric oxide with ammonia (NH3 ) on vanadium-based catalysts rely on the involvement of Brønsted or Lewis acid sites. This issue has been clearly elucidated using a combination of transient perturbations of the catalyst environment with operando time-resolved spectroscopy to obtain unique molecular level insights. Nitric oxide reacts predominantly with NH3 coordinated to Lewis sites on vanadia on tungsta-titania (V2 O5 -WO3 -TiO2 ), while Brønsted sites are not involved in the catalytic cycle. The Lewis site is a mono-oxo vanadyl group that reduces only in the presence of both nitric oxide and NH3 . We were also able to verify the formation of the nitrosamide (NH2 NO) intermediate, which forms in tandem with vanadium reduction, and thus the entire mechanism of SCR. Our experimental approach, demonstrated in the specific case of SCR, promises to progress the understanding of chemical reactions of technological relevance.

  19. The Significance of Lewis Acid Sites for the Selective Catalytic Reduction of Nitric Oxide on Vanadium-Based Catalysts.

    PubMed

    Marberger, Adrian; Ferri, Davide; Elsener, Martin; Kröcher, Oliver

    2016-09-19

    The long debated reaction mechanisms of the selective catalytic reduction (SCR) of nitric oxide with ammonia (NH3 ) on vanadium-based catalysts rely on the involvement of Brønsted or Lewis acid sites. This issue has been clearly elucidated using a combination of transient perturbations of the catalyst environment with operando time-resolved spectroscopy to obtain unique molecular level insights. Nitric oxide reacts predominantly with NH3 coordinated to Lewis sites on vanadia on tungsta-titania (V2 O5 -WO3 -TiO2 ), while Brønsted sites are not involved in the catalytic cycle. The Lewis site is a mono-oxo vanadyl group that reduces only in the presence of both nitric oxide and NH3 . We were also able to verify the formation of the nitrosamide (NH2 NO) intermediate, which forms in tandem with vanadium reduction, and thus the entire mechanism of SCR. Our experimental approach, demonstrated in the specific case of SCR, promises to progress the understanding of chemical reactions of technological relevance. PMID:27553251

  20. Gene Interaction Network Suggests Dioxin Induces a Significant Linkage between Aryl Hydrocarbon Receptor and Retinoic Acid Receptor Beta

    PubMed Central

    Toyoshiba, Hiroyoshi; Yamanaka, Takeharu; Sone, Hideko; Parham, Frederick M.; Walker, Nigel J.; Martinez, Jeanelle; Portier, Christopher J.

    2004-01-01

    Gene expression arrays (gene chips) have enabled researchers to roughly quantify the level of mRNA expression for a large number of genes in a single sample. Several methods have been developed for the analysis of gene array data including clustering, outlier detection, and correlation studies. Most of these analyses are aimed at a qualitative identification of what is different between two samples and/or the relationship between two genes. We propose a quantitative, statistically sound methodology for the analysis of gene regulatory networks using gene expression data sets. The method is based on Bayesian networks for direct quantification of gene expression networks. Using the gene expression changes in HPL1A lung airway epithelial cells after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin at levels of 0.1, 1.0, and 10.0 nM for 24 hr, a gene expression network was hypothesized and analyzed. The method clearly demonstrates support for the assumed network and the hypothesis linking the usual dioxin expression changes to the retinoic acid receptor system. Simulation studies demonstrated the method works well, even for small samples. PMID:15345368

  1. Suppression of the SOS-inducing activity of Trp-P-1 and aflatoxin B1 by meso-dihydroguaiaretic acid from Machilus thunbergii in the Salmonella typhimurium TA1535/pSK1002 umu test.

    PubMed

    Miyazawa, M; Okuno, Y; Oshiro, K; Kasahara, H; Shimamura, H; Nakamura, S; Kameoka, H

    1998-07-01

    The methanol extract from Machilus thunbergii showed a suppressive effect on umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), which requires liver metabolizing enzymes. The methanol extract from M. thunbergii was successively re-extracted with chloroform, butanol and water. A suppressive compound in the chloroform extract fraction was isolated by SiO2 column chromatography and identified as meso-dihydroguaiaretic acid by GC-MS, and 1H- and 13C-NMR spectroscopy. Meso-dihydroguaiaretic acid inhibited of the SOS-inducing activity of Trp-P-1 in the umu test. Gene expression was suppressed by 62% at less than 0.18 mumol/ml, the ID50 value being 0.08 mumol/ml. Compound 1 was also assayed with aflatoxin B1 (AfB1) and showed a suppressive effect. PMID:9720227

  2. The Xanthomonas campestris Type III Effector XopJ Targets the Host Cell Proteasome to Suppress Salicylic-Acid Mediated Plant Defence

    PubMed Central

    Börnke, Frederik

    2013-01-01

    The phytopathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) requires type III effector proteins (T3Es) for virulence. After translocation into the host cell, T3Es are thought to interact with components of host immunity to suppress defence responses. XopJ is a T3E protein from Xcv that interferes with plant immune responses; however, its host cellular target is unknown. Here we show that XopJ interacts with the proteasomal subunit RPT6 in yeast and in planta to inhibit proteasome activity. A C235A mutation within the catalytic triad of XopJ as well as a G2A exchange within the N-terminal myristoylation motif abolishes the ability of XopJ to inhibit the proteasome. Xcv ΔxopJ mutants are impaired in growth and display accelerated symptom development including tissue necrosis on susceptible pepper leaves. Application of the proteasome inhibitor MG132 restored the ability of the Xcv ΔxopJ to attenuate the development of leaf necrosis. The XopJ dependent delay of tissue degeneration correlates with reduced levels of salicylic acid (SA) and changes in defence- and senescence-associated gene expression. Necrosis upon infection with Xcv ΔxopJ was greatly reduced in pepper plants with reduced expression of NPR1, a central regulator of SA responses, demonstrating the involvement of SA-signalling in the development of XopJ dependent phenotypes. Our results suggest that XopJ-mediated inhibition of the proteasome interferes with SA-dependent defence response to attenuate onset of necrosis and to alter host transcription. A central role of the proteasome in plant defence is discussed. PMID:23785289

  3. Suppression Subtractive Hybridization Analysis of Genes Regulated by Application of Exogenous Abscisic Acid in Pepper Plant (Capsicum annuum L.) Leaves under Chilling Stress

    PubMed Central

    Gong, Zhen-Hui; Yin, Yan-Xu; Li, Da-Wei

    2013-01-01

    Low temperature is one of the major factors limiting pepper (Capsicum annuum L.) production during winter and early spring in non-tropical regions. Application of exogenous abscisic acid (ABA) effectively alleviates the symptoms of chilling injury, such as wilting and formation of necrotic lesions on pepper leaves; however, the underlying molecular mechanism is not understood. The aim of this study was to identify genes that are differentially up- or downregulated in ABA-pretreated hot pepper seedlings incubated at 6°C for 48 h, using a suppression subtractive hybridization (SSH) method. A total of 235 high-quality ESTs were isolated, clustered and assembled into a collection of 73 unigenes including 18 contigs and 55 singletons. A total of 37 unigenes (50.68%) showed similarities to genes with known functions in the non-redundant database; the other 36 unigenes (49.32%) showed low similarities or unknown functions. Gene ontology analysis revealed that the 37 unigenes could be classified into nine functional categories. The expression profiles of 18 selected genes were analyzed using quantitative RT-PCR; the expression levels of 10 of these genes were at least two-fold higher in the ABA-pretreated seedlings under chilling stress than water-pretreated (control) plants under chilling stress. In contrast, the other eight genes were downregulated in ABA-pretreated seedlings under chilling stress, with expression levels that were one-third or less of the levels observed in control seedlings under chilling stress. These results suggest that ABA can positively and negatively regulate genes in pepper plants under chilling stress. PMID:23825555

  4. Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2.

    PubMed

    Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie; Klaassen, Curtis D

    2015-01-01

    This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5mg/kg, sc for 4 days) and the genetic alteration of Nrf2 (Nrf2-null, wild-type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5mg/kg, ip for 8h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil-specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2.

  5. Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2

    PubMed Central

    Lu, Yuan-Fu; Liu, Jie; Wu, Kai Connie; Klaassen, Curtis D.

    2014-01-01

    This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5 mg/kg, sc for 4d) and the genetic Nrf2 activation (Nrf2-null, wild-type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5 mg/kg, ip for 8 h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil-specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2. PMID:25280775

  6. Dietary Omega-3 Fatty Acids Suppress Experimental Autoimmune Uveitis in Association with Inhibition of Th1 and Th17 Cell Function

    PubMed Central

    Shoda, Hiromi; Yanai, Ryoji; Yoshimura, Takeru; Nagai, Tomohiko; Kimura, Kazuhiro; Sobrin, Lucia; Connor, Kip M.; Sakoda, Yukimi; Tamada, Koji; Ikeda, Tsunehiko; Sonoda, Koh-Hei

    2015-01-01

    Omega (ω)–3 long-chain polyunsaturated fatty acids (LCPUFAs) inhibit the production of inflammatory mediators and thereby contribute to the regulation of inflammation. Experimental autoimmune uveitis (EAU) is a well-established animal model of autoimmune retinal inflammation. To investigate the potential effects of dietary intake of ω-3 LCPUFAs on uveitis, we examined the anti-inflammatory properties of these molecules in comparison with ω-6 LCPUFAs in a mouse EAU model. C57BL/6 mice were fed a diet containing ω-3 LCPUFAs or ω-6 LCPUFAs for 2 weeks before as well as after the induction of EAU by subcutaneous injection of a fragment of human interphotoreceptor retinoid-binding protein emulsified with complete Freund’s adjuvant. Both clinical and histological scores for uveitis were smaller for mice fed ω-3 LCPUFAs than for those fed ω-6 LCPUFAs. The concentrations of the T helper 1 (Th1) cytokine interferon-γ and the Th17 cytokine interleukin-17 in intraocular fluid as well as the production of these cytokines by lymph node cells were reduced for mice fed ω-3 LCPUFAs. Furthermore, the amounts of mRNAs for the Th1- and Th17-related transcription factors T-bet and RORγt, respectively, were reduced both in the retina and in lymph node cells of mice fed ω-3 LCPUFAs. Our results thus show that a diet enriched in ω-3 LCPUFAs suppressed uveitis in mice in association with inhibition of Th1 and Th17 cell function. PMID:26393358

  7. Suppression of MMP-9 and FAK expression by pomolic acid via blocking of NF-κB/ERK/mTOR signaling pathways in growth factor-stimulated human breast cancer cells.

    PubMed

    Park, Ji-Hyun; Cho, Yoon Young; Yoon, Seong Woo; Park, Byoungduck

    2016-09-01

    The expression of matrix metalloproteinase-9 (MMP-9) and the phosphorylation of focal adhesion kinase (FAK) have been implicated in the invasion, metastasis and cell motility of cancer cells. It is considered that epidermal growth factor (EGF) may increase cell motility, an event involved in cancer cell invasion and metastasis. Pomolic acid (PA), an active triterpenoid from Euscaphis japonica, is known to inhibit the proliferation of a variety of cancer cells, but the effect of PA on the invasiveness of cancer cells is largely unknown. In this study, we first determined the molecular mechanism by which PA inhibits the migratory and invasive abilities of highly metastatic MDA-MB‑231 cells. Transwell invasion, wound-healing assay and F-actin reorganization showed that PA significantly inhibits the EGF-induced invasion, migration and cell motility by reducing expression of MMP-9 and FAK phosphorylation. In particular, PA potently suppressed the phosphorylation of nuclear factor (NF)-κB, extraceullar signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, PA treatment inhibited the DNA binding activity of NF-κB and activator protein (AP)-1, which is known to mediate the expression of EGFR and MMP-9. These results suggest that PA may be a potential therapeutic candidate for treatment of breast cancer metastasis. PMID:27573547

  8. Investigating the significance of zero-point motion in small molecular clusters of sulphuric acid and water

    SciTech Connect

    Stinson, Jake L.; Kathmann, Shawn M.; Ford, Ian J.

    2014-01-14

    The nucleation of particles from trace gases in the atmosphere is an important source of cloud condensation nuclei (CCN), and these are vital for the formation of clouds in view of the high supersaturations required for homogeneous water droplet nucleation. The methods of quantum chemistry have increasingly been employed to model nucleation due to their high accuracy and efficiency in calculating configurational energies; and nucleation rates can be obtained from the associated free energies of particle formation. However, even in such advanced approaches, it is typically assumed that the nuclei have a classical nature, which is questionable for some systems. The importance of zero-point motion (also known as quantum nuclear dynamics) in modelling small clusters of sulphuric acid and water is tested here using the path integral molecular dynamics (PIMD) method at the density functional theory (DFT) level of theory. We observe a small zero-point effect on the the equilibrium structures of certain clusters. One configuration is found to display a bimodal behaviour at 300 K in contrast to the stable ionised state suggested from a zero temperature classical geometry optimisation. The general effect of zero-point motion is to promote the extent of proton transfer with respect to classical behaviour. We thank Prof. Angelos Michaelides and his group in University College London (UCL) for practical advice and helpful discussions. This work benefited from interactions with the Thomas Young Centre through seminar and discussions involving the PIMD method. SMK was supported by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences. JLS and IJF were supported by the IMPACT scheme at UCL and by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences. We are grateful for use of the UCL Legion High Performance Computing Facility and the

  9. Modification of ion transport in lipid bilayer membranes in the presence of 2,4-dichlorophenoxyacetic acid. II. Suppression of tetraphenylborate conductance and changes of interfacial potentials.

    PubMed

    Smejtek, P; Paulis-Illangasekare, M

    1979-06-01

    It has been shown that the blocking of negatively charged tetraphenylborate ion transport in phosphatidylcholine (PC)-cholesterol membranes by the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is dominated by suppression of TPhB- diffusion across the membrane interior, rather than by the decrease of adsorption of TPhB- ions at the membrane surface. The blocking effect can be associated with the decrease of electric potential inside the membrane with respect to that of the aqueous medium, this decreases being proportional to the concentration of 2,4-D in the aqueous solution. It has been estimated that 25 - 30% of the total 2,4-D-induced change of the potential difference is between the plane of absorption of TPhB- and the aqueous solution, and the remaining fraction is between the membrane interior and the absorption plane. The results of this study support the dipolar hypothesis of 2,4-D action in lipid membranes. These conclusions are further supported by measurements changes of electric potential difference across air/water and air/lipid monolayer/water interfaces. It has been found that the electric potential of the nonpolar side of the interface decreases in the presence of neutral molecules of 2,4-D and that this effect becomes more prominent in presence of electrolyte. We have confirmed that PC-cholesterol monolayer cannot be considered as a model for half of the bilayer membrane because of the disagreement between the changes of the interfacial potential difference of PC-cholesterol monolayers and those determined from studied of transport of positive and negative ions across bilayer membranes. In contract, we have found close agreement between the 2,4-D-induced changes of electric potential of the lipid hydrocarbon region in glycerolmonooleate (GMO) membranes and GMO monolayers. We suggest that the action of 2,4-D in lipid membranes is not associated with the changes of orientation of dipoles of lipids constituting the membranes, but rather with a layer

  10. Serum Sialic Acid Level Is Significantly Associated with Nonalcoholic Fatty Liver Disease in a Nonobese Chinese Population: A Cross-Sectional Study

    PubMed Central

    Lu, Zhenya; Ma, Han; Xu, Chengfu; Shao, Zhou; Cen, Chao; Li, Youming

    2016-01-01

    Background/Aim. To investigate the association between serum sialic acid (SA) levels and nonalcoholic fatty liver disease (NAFLD) in a nonobese Chinese population. Methods. A cross-sectional study was performed among the 5916 adults who took their annual health examinations at International Health Care Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, from December 2013 to November 2014. Results. A total of 693 (11.71%) subjects fulfilled the diagnostic criteria of NAFLD, and NAFLD patients had significantly higher serum SA levels than controls (P < 0.001). The prevalence of NAFLD was positively associated with serum SA levels (P for trend <0.001). Serum sialic acid levels are significantly associated with features of metabolic syndrome (Ps < 0.01). Multivariate logistic regression analysis showed that serum SA level was significantly associated with risk for NAFLD (odds ratio: 1.018, 95%; confidence interval: 1.007–1.030; P = 0.002). Conclusions. Our results suggest for the first time that NAFLD patients had higher serum SA level than controls, and increased serum SA level is significantly associated with risk for NAFLD in a large nonobese Chinese population. PMID:27042666

  11. Significant Enrichment of Polyunsaturated Fatty Acids (PUFAs) in the Lipids Extracted by Supercritical CO2 from the Livers of Australian Rock Lobsters (Jasus edwardsii).

    PubMed

    Nguyen, Trung T; Zhang, Wei; Barber, Andrew R; Su, Peng; He, Shan

    2015-05-13

    Australian rock lobster (Jasus edwardsii) liver contains approximately 24.3% (w/w) lipids, which can contain a high amount of polyunsaturated fatty acids (PUFAs). However, this material has been found to be contaminated with arsenic (240 mg/kg) and cadmium (8 mg/kg). The high level of contaminants in the raw material and the large amount of PUFAs in the lipids prove a significant challenge in the extraction of high-quality lipids from this byproduct by conventional methods. Supercritical carbon dioxide (SC-CO2) extraction is a highly promising technology for lipid extraction with advantages including low contamination and low oxidation. The technique was optimized to achieve nearly 94% extraction of lipids relative to conventional Soxhlet extraction in Australian rock lobster liver at conditions of 35 MPa and 50 °C for 4 h. The extracted lipids are significantly enriched in PUFAs at 31.3% of total lipids, 4 times higher than those in the lipids recovered by Soxhlet extraction (7.8%). Specifically, the concentrations of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in SC-CO2 extraction are 7 times higher than those obtained by Soxhlet extraction. Moreover, very small amounts of toxic heavy metals such as lead (Pb), arsenic (As), mercury (Hg), and cadmium (Cd) were detected in the SC-CO2-extracted lipids, 0.5-27 times lower than those in the Soxhlet-extracted lipids, which are 40-200 times lower than the regulatory limit maximum values. The low levels of contaminants and the high proportion of PUFAs (dominated by DHA and EPA) found in the SC-CO2-extracted lipids from Australian rock lobster liver suggest that the material could potentially be used as a valuable source of essential fatty acids for human consumption. PMID:25905456

  12. Antigen-specific suppression in genetic responder mice to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). Characterization of conventional and hybridoma-derived factors produced by suppressor T cells from mice injected as neonates with syngeneic GAT macrophages.

    PubMed

    Sorensen, C M; Pierce, C W

    1982-12-01

    Spleen cells from C57BL/10 mice injected with syngeneic B10 L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)-pulsed macrophages (GAT-M phi) within 18 h of birth were unable to respond to soluble GAT, GAT-methylated bovine serum albumin, or B10 GAT-M phi as adults. Spleen cells from these neonatally treated mice responded at control levels to GAT presented in allogeneic M phi and to sheep erythrocytes. Partially purified T cells from these neonatally treated mice suppressed responses by syngeneic virgin, but not primed, spleen cells in an antigen-specific manner and acted during the early phases of the response. These responder GAT-specific suppressor T cells (GAT-TSR) were sensitive to anti-Thy-1 + C and 500-rad irradiation and have the phenotype Ly-1-2+, I-J+; GAT-TSR cells can only suppress responses by spleen cells syngeneic with the GAT-TSR cells at the I-J subregion of H-2. Restimulation of these Ts cells with syngeneic GAT-M phi induces an antigen-specific suppressor factor within the supernatant fluid. The factor, GAT-TsFR, is a glycoprotein with a molecular weight between 48,000 and 63,000, as determined by gel filtration chromatography using isotonic buffers; it bears serologically detectable determinants encoded by the I-J subregion of the H-2 complex, has an antigen-binding site for GAT and L-glutamic acid50-L-tyrosine50, and shares idiotypic determinants with anti-GAT antibodies. The presence of GAT-TsFR in the first 36 h of in vitro culture is required for significant suppression. Furthermore, only responses by spleen cell syngeneic with the cells producing GAT-TsFR at the I-J subregion are suppressed. The fusion of GAT-TsFR-producing cells with BW5147 resulted in generation of two hybridomas with properties and characteristics identical to those of the conventional GAT-TsFR with one exception: conventional and hybridoma 372.D6.5 GAT-TsFR only suppress responses by spleen cells of the I-Jb haplotype, whereas suppression mediated by the second hybridoma

  13. Suppression of human cervical cancer cell lines Hela and DoTc2 4510 by a mixture of lysine, proline, ascorbic acid, and green tea extract.

    PubMed

    Roomi, M W; Ivanov, V; Kalinovsky, T; Niedzwiecki, A; Rath, M

    2006-01-01

    Cervical cancer, the second most common cancer in women, once metastasized, leads to poor prognosis. We investigated the antitumor effect of a nutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid, and green tea extract on human cervical cancer cells Hela (CCL-2) and DoTc2 4510 by measuring cell proliferation (MTT assay), modulation of matrix metalloproteinases (MMP)-2 and MMP-9) expression (gelatinase zymography), and cancer cell invasive potential (Matrigel). NM showed significant antiproliferative effect on CCL-2 and DoTc2 4510 cancer cells. The NM inhibited CCL-2 expression of MMP-2 and MMP-9 in a dose-dependent fashion, with virtual total inhibition of MMP-2 at 1000 microg/mL and MMP-9 at 500 microg/mL NM. Untreated DoTc2 4510 cells showed MMP-9 expression, which was enhanced with phorbol 12-myristate 13-acetate treatment. NM inhibited MMP-9 expression in a dose-dependent fashion, with virtual inhibition at 500 microg/mL. Invasion of human cervical cancer cells CCL-2 and DoTc2 4510 through Matrigel decreased in a dose-dependent fashion, with 100% inhibition at 500 microg/mL NM (P < 0.0001) and 1000 microg/mL NM (P < 0.0001), respectively. Our results suggest that the mixture of lysine, proline, arginine, ascorbic acid, and green tea extract has potential in the treatment of cervical cancer by inhibiting critical steps in cancer development and spread.

  14. Explosive decomposition of a melamine-cyanuric acid supramolecular assembly for fabricating defect-rich nitrogen-doped carbon nanotubes with significantly promoted catalysis.

    PubMed

    Zhao, Zhongkui; Dai, Yitao; Ge, Guifang; Wang, Guiru

    2015-05-26

    A facile and scalable approach for fabricating structural defect-rich nitrogen-doped carbon nanotubes (MCSA-CNTs) through explosive decomposition of melamine-cyanuric acid supramolecular assembly is presented. In comparison to pristine carbon nanotubes, MCSA-CNT exhibits significantly enhanced catalytic performance in oxidant- and steam-free direct dehydrogenation of ethylbenzene, demonstrating the potential for metal-free clean and energy-saving styrene production. This finding also opens a new horizon for preparing highly-efficient carbocatalysts rich in structural defect sites for diverse transformations.

  15. Explosive decomposition of a melamine-cyanuric acid supramolecular assembly for fabricating defect-rich nitrogen-doped carbon nanotubes with significantly promoted catalysis.

    PubMed

    Zhao, Zhongkui; Dai, Yitao; Ge, Guifang; Wang, Guiru

    2015-05-26

    A facile and scalable approach for fabricating structural defect-rich nitrogen-doped carbon nanotubes (MCSA-CNTs) through explosive decomposition of melamine-cyanuric acid supramolecular assembly is presented. In comparison to pristine carbon nanotubes, MCSA-CNT exhibits significantly enhanced catalytic performance in oxidant- and steam-free direct dehydrogenation of ethylbenzene, demonstrating the potential for metal-free clean and energy-saving styrene production. This finding also opens a new horizon for preparing highly-efficient carbocatalysts rich in structural defect sites for diverse transformations. PMID:25900736

  16. Plant growth hormones suppress the development of Harpophora maydis, the cause of late wilt in maize.

    PubMed

    Degani, Ofir; Drori, Ran; Goldblat, Yuval

    2015-01-01

    Late wilt, a severe vascular disease of maize caused by the fungus Harpophora maydis, is characterized by rapid wilting of maize plants before tasseling and until shortly before maturity. The pathogen is currently controlled by resistant maize cultivars, but the disease is constantly spreading to new areas. The plant's late phenological stage at which the disease appears suggests that plant hormones may be involved in the pathogenesis. This work revealed that plant growth hormones, auxin (Indole-3-acetic acid) and cytokinin (kinetin), suppress H. maydis in culture media and in a detached root assay. Kinetin, and even more auxin, caused significant suppression of fungus spore germination. Gibberellic acid did not alter colony growth rate but had a signal suppressive effect on the pathogens' spore germination. In comparison, ethylene and jasmonic acid, plant senescing and defense response regulators, had minor effects on colony growth and spore germination rate. Their associate hormone, salicylic acid, had a moderate suppressive effect on spore germination and colony growth rate, and a strong influence when combined with auxin. Despite the anti-fungal auxin success in vitro, field experiments with dimethylamine salt of  2,4-dichlorophenoxyacetic acid (that mimics the influence of auxin) failed to suppress the late wilt. The lines of evidence presented here reveal the suppressive influence of the three growth hormones studied on fungal development and are important to encourage further and more in-depth examinations of this intriguing hormonal complex regulatory and its role in the maize-H. maydis interactions. PMID:25649030

  17. Plant growth hormones suppress the development of Harpophora maydis, the cause of late wilt in maize.

    PubMed

    Degani, Ofir; Drori, Ran; Goldblat, Yuval

    2015-01-01

    Late wilt, a severe vascular disease of maize caused by the fungus Harpophora maydis, is characterized by rapid wilting of maize plants before tasseling and until shortly before maturity. The pathogen is currently controlled by resistant maize cultivars, but the disease is constantly spreading to new areas. The plant's late phenological stage at which the disease appears suggests that plant hormones may be involved in the pathogenesis. This work revealed that plant growth hormones, auxin (Indole-3-acetic acid) and cytokinin (kinetin), suppress H. maydis in culture media and in a detached root assay. Kinetin, and even more auxin, caused significant suppression of fungus spore germination. Gibberellic acid did not alter colony growth rate but had a signal suppressive effect on the pathogens' spore germination. In comparison, ethylene and jasmonic acid, plant senescing and defense response regulators, had minor effects on colony growth and spore germination rate. Their associate hormone, salicylic acid, had a moderate suppressive effect on spore germination and colony growth rate, and a strong influence when combined with auxin. Despite the anti-fungal auxin success in vitro, field experiments with dimethylamine salt of  2,4-dichlorophenoxyacetic acid (that mimics the influence of auxin) failed to suppress the late wilt. The lines of evidence presented here reveal the suppressive influence of the three growth hormones studied on fungal development and are important to encourage further and more in-depth examinations of this intriguing hormonal complex regulatory and its role in the maize-H. maydis interactions.

  18. α-lipoic acid protects against hypoxia/reoxygenation-induced injury in human umbilical vein endothelial cells through suppression of apoptosis and autophagy

    PubMed Central

    ZHANG, JINGJING; DENG, HOULIANG; LIU, LI; LIU, XIAOXIA; ZUO, XIALIN; XU, QIAN; WU, ZHUOMIN; PENG, XIAOBIN; JI, AIMIN

    2015-01-01

    α-lipoic acid (ALA) is known as a powerful antioxidant, which has been reported to have protective effects against various cardiovascular diseases. The present study aimed to determine whether ALA pre- or post-treatment induced protective effects against hypoxia/reoxygenation-induced injury via inhibition of apoptosis and autophagy in human umbilical vein endothelial cells (HUVECs). In order to simulate the conditions of hypoxia/reoxygenation, HUVECs were subjected to 4 h of oxygen-glucose deprivation (OGD) followed by 12 h of reoxygenation. For the pre-treatment, ALA was added to the buffer 12 h prior to OGD, whereas for the post-treatment, ALA was added at the initiation of reoxygenation. The results demonstrated that ALA pre- or post-treatment significantly reduced lactate dehydrogenase (LDH) release induced through hypoxia/reoxygenation in HUVECs in a dose-dependent manner; of note, 1 mM ALA pre- or post-treatment exhibited the most potent protective effects. In addition, ALA significantly reduced hypoxia/reoxygenation-induced loss of mitochondrial membrane potential, apoptosis and the expression of cleaved caspase-3 in HUVECs. In the presence of the specific autophagy inhibitor 3-methyladenine, hypoxia/reoxygenation-induced apoptosis was significantly reduced. Furthermore, the formation of autophagosomes, cytosolic microtubule-associated protein 1A/1B-light chain 3 ratio and beclin1 levels significantly increased following hypoxia/reoxygenation injury; however, all of these effects were ameliorated following pre- or post-treatment with ALA. The results of the present study suggested that ALA may provide beneficial protection against hypoxia/reoxygenation-induced injury via attenuation of apoptosis and autophagy in HUVECs. PMID:25684163

  19. Alleviation of lead toxicity by 5-aminolevulinic acid is related to elevated growth, photosynthesis, and suppressed ultrastructural damages in oilseed rape.

    PubMed

    Tian, Tian; Ali, Basharat; Qin, Yebo; Malik, Zaffar; Gill, Rafaqat A; Ali, Shafaqat; Zhou, Weijun

    2014-01-01

    Lead (Pb) is a widely spread pollutant and leads to diverse morphological and structural changes in the plants. In this study, alleviating role of 5-aminolevulinic acid (ALA) in oilseed rape (Brassica napus L.) was investigated with or without foliar application of ALA (25 mg L(-1)) in hydroponic environment under different Pb levels (0, 100, and 400 µM). Outcomes stated that plant morphology and photosynthetic attributes were reduced under the application of Pb alone. However, ALA application significantly increased the plant growth and photosynthetic parameters under Pb toxicity. Moreover, ALA also lowered the Pb concentration in shoots and roots under Pb toxicity. The microscopic studies depicted that exogenously applied ALA ameliorated the Pb stress and significantly improved the cell ultrastructures. After application of ALA under Pb stress, mesophyll cell had well-developed nucleus and chloroplast having a number of starch granules. Moreover, micrographs illustrated that root tip cell contained well-developed nucleus, a number of mitochondria, and golgi bodies. These results proposed that under 15-day Pb-induced stress, ALA improved the plant growth, chlorophyll content, photosynthetic parameters, and ultrastructural modifications in leaf mesophyll and root tip cells of the B. napus plants.

  20. Alleviation of Lead Toxicity by 5-Aminolevulinic Acid Is Related to Elevated Growth, Photosynthesis, and Suppressed Ultrastructural Damages in Oilseed Rape

    PubMed Central

    Tian, Tian; Qin, Yebo; Gill, Rafaqat A.; Ali, Shafaqat

    2014-01-01

    Lead (Pb) is a widely spread pollutant and leads to diverse morphological and structural changes in the plants. In this study, alleviating role of 5-aminolevulinic acid (ALA) in oilseed rape (Brassica napus L.) was investigated with or without foliar application of ALA (25 mg L−1) in hydroponic environment under different Pb levels (0, 100, and 400 µM). Outcomes stated that plant morphology and photosynthetic attributes were reduced under the application of Pb alone. However, ALA application significantly increased the plant growth and photosynthetic parameters under Pb toxicity. Moreover, ALA also lowered the Pb concentration in shoots and roots under Pb toxicity. The microscopic studies depicted that exogenously applied ALA ameliorated the Pb stress and significantly improved the cell ultrastructures. After application of ALA under Pb stress, mesophyll cell had well-developed nucleus and chloroplast having a number of starch granules. Moreover, micrographs illustrated that root tip cell contained well-developed nucleus, a number of mitochondria, and golgi bodies. These results proposed that under 15-day Pb-induced stress, ALA improved the plant growth, chlorophyll content, photosynthetic parameters, and ultrastructural modifications in leaf mesophyll and root tip cells of the B. napus plants. PMID:24683549

  1. Soy milk suppresses cholesterol-induced inflammatory gene expression and improves the fatty acid profile in the skin of SD rats.

    PubMed

    Lee, Seung-Min; Kim, Yunhye; Choi, Hye jung; Choi, Jina; Yi, Yue; Yoon, Sun

    2013-01-01

    Recently, an elevation in skin cholesterol level has been implicated in skin inflammation. Given the potential therapeutic effects of soy on low grade inflammatory diseases, we hypothesized that a CHOL diet could promote an inflammatory response in skin and that soy milk (SM) or fermented soy milk (F.SM) could prevent this cholesterol-induced skin inflammation. To test this hypothesis, freeze-dried SM or F.SM was provided as a protein replacement for 20% of the casein in the diets of Sprague-Dawley (SD) rats. The animals were divided into the following groups: (1) control group (CTRL), AIN76A diet without cholesterol, (2) high cholesterol (CHOL) group, AIN76A with 1% (w/w) cholesterol, (3) SM group, CHOL diet with freeze-dried SM, and (4) F.SM group, CHOL diet with F.SM. In the CHOL group, the expression levels of pro-inflammatory genes, including IL-1β, IL-1α, iNOS, and COX-2, were elevated. In comparison, the SM and F.SM groups displayed the lowered expression of IL-1β, COX-2, F4/80, and Cd68, an increase of a n-3/n-6 ratio, and a reduction in the estimated desaturase activities of delta 5 desaturase (D5D) and steaoryl CoA desaturase (SCD-1). In particular, F.SM significantly increased the proportion of dihomo-γ-linolenic acid (DGLA) in skin fatty acid (FA) composition compared with the CHOL group. Here we present evidence that SM or F.SM could alleviate the inflammatory response in the skin that is triggered by excess dietary cholesterol by reducing the expression of pro-inflammatory genes. This response could be partly associated with a decreased in macrophages in skin and/or by modulation of the skin's FA composition.

  2. Methods for suppressing isomerization of olefin metathesis products

    SciTech Connect

    Firth, Bruce E.; Kirk, Sharon E.; Gavaskar, Vasudeo S.

    2015-09-22

    A method for suppressing isomerization of an olefin metathesis product produced in a metathesis reaction includes adding an isomerization suppression agent to a mixture that includes the olefin metathesis product and residual metathesis catalyst from the metathesis reaction under conditions that are sufficient to passivate at least a portion of the residual metathesis catalyst. The isomerization suppression agent is phosphorous acid, a phosphorous acid ester, phosphinic acid, a phosphinic acid ester or combinations thereof. Methods of refining natural oils are described.

  3. ETMB-RBF: Discrimination of Metal-Binding Sites in Electron Transporters Based on RBF Networks with PSSM Profiles and Significant Amino Acid Pairs

    PubMed Central

    Ou, Yu-Yen; Chen, Shu-An; Wu, Sheng-Cheng

    2013-01-01

    Background Cellular respiration is the process by which cells obtain energy from glucose and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation–reduction reactions. In these oxidation–reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain. Methods We propose a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins. Results We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Compared with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88. Conclusions We have developed a novel approach based on PSSM profiles and significant amino acid pairs for identifying metal-binding sites from electron transport proteins. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins

  4. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens.

    PubMed

    Montesinos, Pau; Rayón, Chelo; Vellenga, Edo; Brunet, Salut; González, José; González, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; González, José D; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Félix; Milone, Gustavo; de la Serna, Javier; Pérez, Inmaculada; Pérez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A

    2011-02-10

    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56(+) (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56(+) APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56(+) APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56(-) APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56(+) APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin-derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

  5. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells.

    PubMed

    Chuang, Cheng-Hung; Liu, Chia-Hua; Lu, Ta-Jung; Hu, Miao-Lin

    2014-12-15

    Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. PMID:25447407

  6. Gardenia jasminoides extracts and gallic acid inhibit lipopolysaccharide-induced inflammation by suppression of JNK2/1 signaling pathways in BV-2 cells

    PubMed Central

    Lin, Wen-Hung; Kuo, Heng-Hung; Ho, Li-Hsing; Tseng, Ming-Lang; Siao, An-Ci; Hung, Chang-Tsen; Jeng, Kee-Ching; Hou, Chien-Wei

    2015-01-01

    Objective(s): Gardenia jasminoides Ellis (GJ, Cape Jasmine Fruit, Zhi Zi) has been traditionally used for the treatment of infectious hepatitis, aphthous ulcer, and trauma; however, the direct evidence is lacking. Materials and Methods: We investigated the effect of the GJ extract (GJ) and gallic acid (GA) on lipopolysaccharide (LPS) induced inflammation of BV-2 microglial cells and acute liver injury in Sprague-Dawley (SD) rats. Results: Our results showed that the GJ extract and GA reduced LPS-induced nitric oxide (NO), interleukin (IL)-1, IL-6, reactive oxygen species (ROS), and prostaglandin (PGE2) production in BV-2 cells. The GJ extract and GA significantly decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in LPS-treated rats. Furthermore, the water extract, but not the ethanol extract, of the GJ dose-dependently inhibited LPS-induced JNK2/1 and slightly p38 mitogen-activated protein kinases (MAPK), and cyclooxygenase-2 (COX-2) expression in BV-2 cells. Conclusion: Taken together, these results indicate that the protective mechanism of the GJ extract involves an antioxidant effect and inhibition of JNK2/1 MAP kinase and COX-2 expressions in LPS-induced inflammation of BV-2 cells. PMID:26221479

  7. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage.

    PubMed

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-06-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.

  8. Amplification of an MFS transporter encoding gene penT significantly stimulates penicillin production and enhances the sensitivity of Penicillium chrysogenum to phenylacetic acid.

    PubMed

    Yang, Jing; Xu, Xinxin; Liu, Gang

    2012-11-20

    Penicillin is historically important as the first discovered drug against bacterial infections in human. Although the penicillin biosynthetic pathway and regulatory mechanism have been well studied in Penicillium chrysogenum, the compartmentation and molecular transport of penicillin or its precursors are still poorly understood. In search of the genomic database, more than 830 open reading frames (ORFs) were found to encode transmembrane proteins of P. chrysogenum. In order to investigate their roles on penicillin production, one of them (penT) was selected and cloned. The deduced protein of penT belongs to the major facilitator superfamily (MFS) and contains 12 transmembrane spanning domains (TMS). During fermentation, the transcription of penT was greatly induced by penicillin precursors phenylacetic acid (PAA) and phenoxyacetic acid (POA). Knock-down of penT resulted in significant decrease of penicillin production, while over-expression of penT under the promoter of trpC enhanced the penicillin production. Introduction of an additional penT in the wild-type strain of P. chrysogenum doubled the penicillin production and enhanced the sensitivity of P. chrysogenum to the penicillin precursors PAA or POA. These results indicate that penT stimulates penicillin production probably through enhancing the translocation of penicillin precursors across fungal cellular membrane.

  9. An industry perspective on the use of “atoxigenic” strains of Aspergillus flavus as biological control agents and the significance of cyclopiazonic acid

    PubMed Central

    King, Eileen D; (Bobby) Bassi, Albeit B; Ross, David C; Druebbisch, Bernd

    2011-01-01

    Several nonaflatoxigenic strains of Aspergillus flavus have been registered in the United States to reduce aflatoxin accumulation in maize and other crops, but there may be unintended negative consequences if these strains produce cyclopiazonic acid (CPA). AF36, a nonaflatoxigenic, CPA-producing strain has been shown to produce CPA in treated maize and peanuts. Alternative strains, including Afla-Guard® brand biocontrol agent and K49, do not produce CPA and can reduce both aflatoxin and CPA in treated crops. Chronic toxicity of CPA has not been studied, and recent animal studies show significant harmful effects from short-term exposure to CPA at low doses. Grower and industry confidence in this approach must be preserved through transparency. PMID:22844262

  10. Gambogic acid synergistically potentiates cisplatin-induced apoptosis in non-small-cell lung cancer through suppressing NF-κB and MAPK/HO-1 signalling

    PubMed Central

    Wang, L-H; Li, Y; Yang, S-N; Wang, F-Y; Hou, Y; Cui, W; Chen, K; Cao, Q; Wang, S; Zhang, T-Y; Wang, Z-Z; Xiao, W; Yang, J-Y; Wu, C-F

    2014-01-01

    Background: Gambogic acid (GA) has been reported to have potent anticancer activity and is authorised to be tested in phase II clinical trials for treatment of non-small-cell lung cancer (NSCLC). The present study aims to investigate whether GA would be synergistic with cisplatin (CDDP) against the NSCLC. Methods: 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI) isobologram, western blot, quantitative PCR, flow cytometry, electrophoretic mobility shift assay, xenograft tumour models and terminal deoxynucleotide transferase-mediated dUTP nick-end labelling analysis were used in this study. Results: The cell viability results showed that sequential CDDP-GA treatment resulted in a strong synergistic action in A549, NCI-H460, and NCI-H1299 cell lines, whereas the reverse sequence and simultaneous treatments led to a slight synergistic or additive action. Increased sub-G1 phase cells and enhanced PARP cleavage demonstrated that the sequence of CDDP-GA treatment markedly increased apoptosis in comparison with other treatments. Furthermore, the sequential combination could enhance the activation of caspase-3, -8, and 9, increase the expression of Fas and Bax, and decrease the expression of Bcl-2, survivin and X-inhibitor of apoptosis protein (X-IAP) in A549 and NCI-H460 cell lines. In addition, increased apoptosis was correlated with enhanced reactive oxygen species generation. Importantly, it was found that, followed by CDDP treatment, GA could inhibit NF-κB and mitogen-activated protein kinase (MAPK)/heme oxygenase-1 (HO-1) signalling pathways, which have been validated to reduce ROS release and confer CDDP resistance. The roles of NF-κB and MAPK pathways were further confirmed by using specific inhibitors, which significantly increased ROS release and apoptosis induced by the sequential combination of CDDP and GA. Moreover, our results indicated that the combination of CDDP and GA exerted increased antitumour effects on A549 xenograft

  11. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

    SciTech Connect

    Chuang, Cheng-Hung; Liu, Chia-Hua; Lu, Ta-Jung; Hu, Miao-Lin

    2014-12-15

    Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

  12. Significant association between glycemic status and increased estimated postglomerular resistance in nondiabetic subjects - study of inulin and para-aminohippuric acid clearance in humans.

    PubMed

    Yasumoto, Mari; Tsuda, Akihiro; Ishimura, Eiji; Uedono, Hideki; Ohno, Yoshiteru; Ichii, Mitsuru; Ochi, Akinobu; Nakatani, Shinya; Mori, Katsuhito; Uchida, Junji; Emoto, Masanori; Nakatani, Tatsuya; Inaba, Masaaki

    2015-03-01

    We investigated whether glomerular hemodynamic parameters in nondiabetic subjects, including healthy subjects, are associated with glycemic status indices, by simultaneous measurement of inulin (Cin) and para-aminohippuric acid (CPHA) clearance. Twenty-six subjects (age 49.5 ± 13.3 years; 13 men and 13 women; 14 healthy subjects and 12 subjects with mild proteinuria) were enrolled. Cin and CPAH were measured simultaneously. All 26 subjects were nondiabetics. Estimated preglomerular resistance, estimated postglomerular resistance, and estimated glomerular hydrostatic pressure (Pglo) were calculated according to Gomez' formula. Pglo correlated significantly and positively with hemoglobin A1c (HbA1c) in both healthy subjects (r = 0.532, P = 0.0498) and subjects with mild proteinuria (r = 0.681, P = 0.015). While there was no significant correlation between estimated preglomerular resistance and HbA1c, estimated postglomerular resistance correlated significantly and positively with HbA1c both in healthy subjects (r = 0.643, P = 0.013) and subjects with mild proteinuria (r = 0.589, P = 0.044). Glomerular filtration fraction, estimated Pglo and estimated postglomerular resistance in total subjects were associated significantly with HbA1c after adjustment for age, gender, and body mass index. These results demonstrate that, even in nondiabetic subjects, glycemic status is associated with estimated postglomerular resistance, but not estimated preglomerular resistance. It is suggested that increased estimated postglomerular resistance associated with higher HbA1c levels, even within the normal range, causes increased estimated Pglo, leading to increased FF. Thus, hemodynamic abnormalities associated with higher HbA1c levels may be related to glomerular hypertension, even in nondiabetic subjects.

  13. Suppression of NF-κB signaling and P-glycoprotein function by gambogic acid synergistically potentiates adriamycin -induced apoptosis in lung cancer.

    PubMed

    Wang, Li-Hui; Yang, Jing-Yu; Yang, Sheng-Nan; Li, Yi; Ping, Guan-Fang; Hou, Yue; Cui, Wei; Wang, Zhen-Zhong; Xiao, Wei; Wu, Chun-Fu

    2014-01-01

    Gambogic acid (GA) has been approved by the Chinese Food and Drug Administration for the treatment of lung cancer in clinical trials. However, whether GA has chemosensitizing properties when combined with other chemotherapy agents in the treatment of lung cancer is not known. Here we investigated the effects of GA combined with adriamycin (ADM), a common chemotherapy agent, in regard to their activities and the possible mechanisms against lung cancer in vitro and in vivo. Cell viability results showed that sequential GA-ADM treatment was synergistic, while the reverse sequence and simultaneous treatments were antagonistic or additive, in lung cancer cells and ADM resistant cells, but not in normal cells. The combined use of GA and ADM synergistically displayed apoptosis-inducing activities in lung cancer cells. Moreover, GA in combination with ADM could promote PARP cleavage, enhance caspases activation and decrease the expression of anti-apoptotic proteins in lung cancer cells. The combined use of GA and ADM decreased the expression of P-glycoprotein and increased the accumulation of ADM in lung cancer cells. Furthermore, it was found that, prior to ADM treatment, GA could inhibit NF-κB signaling pathways, which have been validated to confer ADM resistance. The critical role of NF-κB was further confirmed by using PDTC, a NF-κB inhibitor, which significantly increased apoptosis induction by the combination of GA and ADM and inhibited ADM-induced ABCB1 upregulation. Importantly, our results indicated that the combination of GA and ADM exerted enhanced anti-tumor effects on A549 xenograft models through inhibiting NF-κB and P-glycoprotein, and attenuated ADM-induced cardiotoxicity. Collectively, these findings indicate that GA sensitizes lung cancer cells to ADM in vitro and in vivo, providing a rationale for the combined use of GA and ADM in lung cancer chemotherapy.

  14. The Prevention of Diabetic Cardiomyopathy by Non-Mitogenic Acidic Fibroblast Growth Factor Is Probably Mediated by the Suppression of Oxidative Stress and Damage

    PubMed Central

    Zhang, Chi; Zhang, Linbo; Chen, Shali; Feng, Biao; Lu, Xuemian; Bai, Yang; Liang, Guang; Tan, Yi; Shao, Minglong; Skibba, Melissa; Jin, Litai; Li, Xiaokun; Chakrabarti, Subrata; Cai, Lu

    2013-01-01

    Background Emerging evidence showed the beneficial effect of acidic fibroblast growth factor (aFGF) on heart diseases. The present study investigated whether non-mitogenic aFGF (nm-aFGF) can prevent diabetic cardiomyopathy and the underlying mechanisms, if any. Methodology/Principal Findings Type 1 diabetes was induced in mice by multiple intraperitoneal injections of low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with or without nm-aFGF at 10 µg/kg daily for 1 and 6 months. Blood pressure and cardiac function were assessed. Cardiac H9c2 cell, human microvascular endothelial cells, and rat cardiomyocytes were exposed to high glucose (25 mM) for mimicking an in vitro diabetic condition for mechanistic studies. Oxidative stress, DNA damage, cardiac hypertrophy and fibrosis were assessed by real-time qPCR, immunofluorescent staining, Western blotting, and pathological examination. Nm-aFGF significantly prevented diabetes-induced hypertension and cardiac dysfunction at 6 months. Mechanistic studies demonstrated that nm-aFGF showed the similar preventive effect as the native aFGF on high glucose-induced oxidative stress (increase generation of reactive oxygen species) and damage (cellular DNA oxidation), cell hypertrophy, and fibrotic response (increased mRNA expression of fibronectin) in three kinds of cells. These in vitro findings were recaptured by examining the heart of the diabetic mice with and without nm-aFGF. Conclusions These results suggest that nm-aFGF can prevent diabetic cardiomyopathy, probably through attenuation of cardiac oxidative stress, hypertrophy, and fibrosis. PMID:24349248

  15. METHOD OF SUPPRESSING GASTROINTESTINAL UREASE ACTIVITY

    DOEpatents

    Visek, W.J.

    1963-04-23

    This patent shows a method of increasing the growth rate of chicks. Certain diacyl substituted ureas such as alloxan, murexide, and barbituric acid are added to their feed, thereby suppressing gastrointestinal urease activity and thus promoting growth. (AEC)

  16. Avian serum. cap alpha. /sub 1/-glycoprotein, hemopexin, differing significantly in both amino acid and carbohydrate composition from mammalian (. beta. -glycoprotein) counter parts

    SciTech Connect

    Goldfarb, V.; Trimble, R.B.; Falco, M.D.; Liem, H.H.; Metcalfe, S.A.; Wellner, D.; Muller-Eberhard, U.

    1986-10-21

    The physicochemical characteristics of chicken hemopexin, which can be isolated by heme-agarose affinity chromatography, is compared with representative mammalian hemopexins of rat, rabbit, and human. The avian polypeptide chain appears to be slightly longer (52 kDa) than the human, rat, or rabbit forms (49 kDa), and also the glycoprotein differs from the mammalian hemopexins in being an ..cap alpha../sub 1/-glycoprotein instead of a ..beta../sub 1/-glycoprotein. The distinct electrophoretic mobility probably arises from significant differences in the amino acid composition of the chicken form, which, although lower in serine and particularly in lysine, has a much higher glutamine/glutamate and agrinine content, and also a higher proline, glycine, and histidine content, than the mammalian hemopexins. Compositional analyses and /sup 125/I concanavalin A and /sup 125/I wheat germ agglutinin binding suggest that chicken hemopexin has a mixture of three fucose-free N-linked bi- and triantennary oligosaccharides. In contrast, human hemopexin has give N-linked oligosaccharides and an additional O-linked glycan blocking the N-terminal threonine residue, while the rabbit form has four N-linked oligosaccharides. In keeping with the finding of a simpler carbohydrate structure, the avian hemopexin shows only a single band on polyacrylamide gel electrophoresis under both nondenaturing and denaturing conditions, whereas the hemopexins of the three mammalian species tested show several bands. In contrast, the isoelectric focusing pattern of chicken hemopexin is very complex, revealing at least nine bands between pH 4.0 and pH band 5.0, while the other hemopexins show a broad smear of multiple ill-defined bands in the same region.Results indicate the hemopexin of avians differs substantially from the hemopexins of mammals, which show a notable similarity with regard to carbohydrate structure and amino acid composition.

  17. Biophysical studies of a ruthenium(II) polypyridyl complex binding to DNA and RNA prove that nucleic acid structure has significant effects on binding behaviors.

    PubMed

    Xu, Hong; Liang, Yi; Zhang, Peng; Du, Fen; Zhou, Bing-Rui; Wu, Jun; Liu, Jian-Hong; Liu, Zhi-Gang; Ji, Liang-Nian

    2005-08-01

    The interactions of a metal complex [Ru(phen)(2)PMIP](2+) {Ru=ruthenium, phen=1,10-phenanthroline, PMIP=2-(4-methylphenyl)imidazo[4,5-f]1,10-phenanthroline} with yeast tRNA and calf thymus DNA (CT DNA) have been investigated comparatively by UV-vis spectroscopy, fluorescence spectroscopy, viscosity measurements, isothermal titration calorimetry (ITC), as well as equilibrium dialysis and circular dichroism (CD). Spectroscopic studies together with ITC and viscosity measurements indicate that both binding modes of the Ru(II) polypyridyl complex to yeast tRNA and CT DNA are intercalation and yeast tRNA binding of the complex is stronger than CT DNA binding. ITC experiments show that the interaction of the complex with yeast tRNA is driven by a moderately favorable enthalpy decrease in combination with a moderately favorable entropy increase, while the binding of the complex to CT DNA is driven by a large favorable enthalpy decrease with a less favorable entropy increase. The results from equilibrium dialysis and CD suggest that both interactions are enantioselective and the Delta enantiomer of the complex may bind more favorably to both yeast tRNA and CT DNA than the Lambda enantiomer does, and that the complex is a better candidate for an enantioselective binder to yeast tRNA than to CT DNA. Taken together, these results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes.

  18. Analysis of nine food additives in red wine by ion-suppression reversed-phase high-performance liquid chromatography using trifluoroacetic acid and ammonium acetate as ion-suppressors.

    PubMed

    Zhao, Yong-Gang; Chen, Xiao-Hong; Yao, Shan-Shan; Pan, Sheng-Dong; Li, Xiao-Ping; Jin, Mi-Cong

    2012-01-01

    A reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed for the simultaneous determination of nine food additives, i.e., acesulfame, saccharin, caffeine, aspartame, benzoic acid, sorbic acid, stevioside, dehydroacetic acid and neotame in red wine. The effects of ion-suppressors, i.e., trifluoroacetic acid (TFA) and ammonium acetate (AmAc) on retention behavior of nine food additives in RP-HPLC separation were discussed in detail. The relationships between retention factors of solutes and volume percent of ion-suppressors in the mobile-phase systems of acetonitrile-TFA aqueous solution and acetonitrile-TFA-AmAc aqueous solution were quantitatively established, respectively. The results showed that the ion suppressors had not only an ion suppression effect, but also an organic modification effect on the acidic analytes. The baseline separation of nine food additives was completed by a gradient elution with acetonitrile-TFA(0.01%, v/v)-AmAc(2.5 mmol L(-1)) aqueous solution as the mobile phase. The recoveries were between 80.2 - 99.5% for all analytes with RSDs in the range of 1.5 - 8.9%. The linearities were in the range of 0.2 - 100.0 mg L(-1) with determination coefficients (r(2)) higher than 0.9991 for all analytes. The limits of quantification (LOQs) were between 0.53 - 0.99 mg L(-1). The applicability of the proposed method to detect and quantify food additives has been demonstrated in the analysis of 30 real samples.

  19. Carnosic acid suppresses the production of amyloid-β 1-42 and 1-43 by inducing an α-secretase TACE/ADAM17 in U373MG human astrocytoma cells.

    PubMed

    Yoshida, Hidemi; Meng, Pengfei; Matsumiya, Tomoh; Tanji, Kunikazu; Hayakari, Ryo; Xing, Fei; Wang, Liang; Tsuruga, Kazushi; Tanaka, Hiroshi; Mimura, Junsei; Kosaka, Kunio; Itoh, Ken; Takahashi, Ippei; Imaizumi, Tadaatsu

    2014-02-01

    Amyloid beta (Aβ) peptides are key molecules in the pathogenesis of Alzheimer's disease (AD). The sequential cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates Aβ peptides; however, the alternate cleavage of APP by the α- and γ-secretases decreases Aβ production. We previously reported that carnosic acid (CA), a phenolic diterpene compound found in the labiate herbs rosemary and sage, suppresses Aβ (1-40 and 1-42) production by activating α-secretase in cultured SH-SY5Y human neuroblastoma cells (Neurosci. Res. 2013; 75: 94-102). Here, we investigated the effect of CA on the production of Aβ peptides (1-40, 1-42 and 1-43) in U373MG human astrocytoma cells. The treatment of cells with CA suppressed Aβ40/42/43 release (55-71% decrease at 50μM). CA treatment enhanced the mRNA expressions of an α-secretase TACE (tumor necrosis factor-α-converting enzyme, also called a disintegrin and metalloproteinase-17, ADAM17); however, the β-secretase BACE1 (β-site APP-cleaving enzyme-1) was not increased by CA. Knockdown of TACE by siRNA reduced soluble-APPα release enhanced by CA and partially recovered the CA-suppressed Aβ40/42/43 release. These results suggest that CA reduces Aβ production, at least partially, by activating TACE in human astroglial cells. The use of CA may have a potential in the prevention of Aβ-mediated diseases. PMID:24295810

  20. Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPAR α/γ activity in microvascular endothelial cells.

    PubMed

    Madonna, Rosalinda; Salerni, Sara; Schiavone, Deborah; Glatz, Jan F; Geng, Yong-Jian; De Caterina, Raffaele

    2011-09-01

    Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10(-8) and 10(-7) M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥ 24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ± 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy. PMID:21727988

  1. Rosmarinic Acid Methyl Ester Inhibits LPS-Induced NO Production via Suppression of MyD88- Dependent and -Independent Pathways and Induction of HO-1 in RAW 264.7 Cells.

    PubMed

    So, Yangkang; Lee, Seung Young; Han, Ah-Reum; Kim, Jin-Baek; Jeong, Hye Gwang; Jin, Chang Hyun

    2016-01-01

    In this study, we investigated the anti-inflammatory effect of rosmarinic acid methyl ester (RAME) isolated from a mutant cultivar of Perilla frutescens (L.) Britton. We found that RAME inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with an IC50 of 14.25 µM, in RAW 264.7 cells. RAME inhibited the LPS-induced expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, interferon-β, and inducible nitric oxide synthase (iNOS). Moreover, RAME suppressed the activation of nuclear factor kappa B. These results suggest that the downregulation of iNOS expression by RAME was due to myeloid differentiation primary response gene 88 (MyD88)-dependent and -independent pathways. Furthermore, RAME induced the expression of heme oxygenase-1 (HO-1) through activation of nuclear factor-erythroid 2-related factor 2. Treatment with tin protoporphyrin, an inhibitor of HO-1, reversed the RAME-induced suppression of NO production. Taken together, RAME isolated from P. frutescens inhibited NO production in LPS-treated RAW 264.7 cells through simultaneous induction of HO-1 and inhibition of MyD88-dependent and -independent pathways. PMID:27548124

  2. Ursolic Acid Attenuates Diabetic Mesangial Cell Injury through the Up-Regulation of Autophagy via miRNA-21/PTEN/Akt/mTOR Suppression

    PubMed Central

    Lu, Xinxing; Fan, Qiuling; Xu, Li; Li, Lin; Yue, Yuan; Xu, Yanyan; Su, Yan; Zhang, Dongcheng; Wang, Lining

    2015-01-01

    Objective To investigate the effect of ursolic acid on autophagy mediated through the miRNA-21-targeted phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in rat mesangial cells cultured under high glucose (HG) conditions. Methods Rat glomerular mesangial cells were cultured under normal glucose, HG, HG with the PI3K inhibitor LY294002 or HG with ursolic acid conditions. Cell proliferation and hypertrophy were assayed using an MTT assay and the ratio of total protein to cell number, respectively. The miRNA-21 expression was detected using RT-qPCR. The expression of phosphatase and tensin homolog (PTEN)/AKT/mTOR signaling signatures, autophagy-associated protein and collagen I was detected by western blotting and RT-qPCR. Autophagosomes were observed using electron microscopy. Results Compared with mesangial cells cultured under normal glucose conditions, the cells exposed to HG showed up-regulated miRNA-21 expression, down-regulated PTEN protein and mRNA expression, up-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and down-regulated LC3II expression. Ursolic acid and LY294002 inhibited HG-induced mesangial cell hypertrophy and proliferation, down-regulated p85PI3K, pAkt, pmTOR, p62/SQSTMI, and collagen I expression and up-regulated LC3II expression. However, LY294002 did not affect the expression of miRNA-21 and PTEN. Ursolic acid down-regulated miRNA-21 expression and up-regulated PTEN protein and mRNA expression. Conclusions Ursolic acid inhibits the glucose-induced up-regulation of mesangial cell miRNA-21 expression, up-regulates PTEN expression, inhibits the activation of PI3K/Akt/mTOR signaling pathway, and enhances autophagy to reduce the accumulation of the extracellular matrix and ameliorate cell hypertrophy and proliferation. PMID:25689721

  3. Clinical significance of smear positivity for acid-fast bacilli after ≥5 months of treatment in patients with drug-susceptible pulmonary tuberculosis

    PubMed Central

    Kang, Hyung Koo; Jeong, Byeong-Ho; Lee, Hyun; Park, Hye Yun; Jeon, Kyeongman; Huh, Hee Jae; Ki, Chang-Seok; Lee, Nam Yong; Koh, Won-Jung

    2016-01-01

    Abstract Patients with pulmonary tuberculosis (TB) with acid-fast bacilli (AFB)-positive sputum smear at 5 months or later during treatment are considered to be cases of treatment failure according to World Health Organization guidelines. This study evaluated the proportion, clinical characteristics, and significance of positive sputum smears after ≥5 months of standard treatment in patients with drug-susceptible pulmonary TB. This was a retrospective cohort study of 1611 patients with culture-confirmed drug-susceptible pulmonary TB who received standard anti-TB treatment from January 2009 to February 2014. Forty-one patients (2.5%) who were smear-positive after ≥5 months of treatment and 123 age- and sex-matched control patients were evaluated. Among the 41 smear-positive patients, culture of the sputum specimens yielded Mycobacterium tuberculosis (MTB) in 1 patient (2.4%), nontuberculous mycobacteria (NTM) in 7 (17.1%), and no growth in the remaining 33 patients (80.5%). Treatment was successfully completed in 40 patients (97.6%) with prolongation of the continuation phase regimens without change to second-line anti-TB treatment. In patients with smear positivity after ≥5 months of treatment compared with controls, cavitation on chest radiographs (53.7% vs. 25.2%, P = 0.001), bilateral involvement (51.2% vs. 30.1%, P = 0.01) and combined pleural effusion (26.8% vs. 10.6%, P = 0.01) were found more frequently at the time of treatment initiation, and paradoxical response occurred more commonly (19.5% vs. 3.3%, P = 0.002) during treatment. Smear-positive sputum after ≥5 months of standard anti-TB treatment was mainly because of nonviable MTB bacilli or NTM in patients with drug-susceptible pulmonary TB. AFB smear alone should not be used to assess treatment failure and careful examination of microbiologic status, including culture and drug susceptibility testing, is needed before making changes to retreatment regimens or empirical second

  4. Clinical significance of smear positivity for acid-fast bacilli after ≥5 months of treatment in patients with drug-susceptible pulmonary tuberculosis.

    PubMed

    Kang, Hyung Koo; Jeong, Byeong-Ho; Lee, Hyun; Park, Hye Yun; Jeon, Kyeongman; Huh, Hee Jae; Ki, Chang-Seok; Lee, Nam Yong; Koh, Won-Jung

    2016-08-01

    Patients with pulmonary tuberculosis (TB) with acid-fast bacilli (AFB)-positive sputum smear at 5 months or later during treatment are considered to be cases of treatment failure according to World Health Organization guidelines. This study evaluated the proportion, clinical characteristics, and significance of positive sputum smears after ≥5 months of standard treatment in patients with drug-susceptible pulmonary TB.This was a retrospective cohort study of 1611 patients with culture-confirmed drug-susceptible pulmonary TB who received standard anti-TB treatment from January 2009 to February 2014. Forty-one patients (2.5%) who were smear-positive after ≥5 months of treatment and 123 age- and sex-matched control patients were evaluated.Among the 41 smear-positive patients, culture of the sputum specimens yielded Mycobacterium tuberculosis (MTB) in 1 patient (2.4%), nontuberculous mycobacteria (NTM) in 7 (17.1%), and no growth in the remaining 33 patients (80.5%). Treatment was successfully completed in 40 patients (97.6%) with prolongation of the continuation phase regimens without change to second-line anti-TB treatment. In patients with smear positivity after ≥5 months of treatment compared with controls, cavitation on chest radiographs (53.7% vs. 25.2%, P = 0.001), bilateral involvement (51.2% vs. 30.1%, P = 0.01) and combined pleural effusion (26.8% vs. 10.6%, P = 0.01) were found more frequently at the time of treatment initiation, and paradoxical response occurred more commonly (19.5% vs. 3.3%, P = 0.002) during treatment.Smear-positive sputum after ≥5 months of standard anti-TB treatment was mainly because of nonviable MTB bacilli or NTM in patients with drug-susceptible pulmonary TB. AFB smear alone should not be used to assess treatment failure and careful examination of microbiologic status, including culture and drug susceptibility testing, is needed before making changes to retreatment regimens or empirical second-line anti

  5. Environmental risk assessment of airborne trichloroacetic acid--a contribution to the discussion on the significance of anthropogenic and natural sources.

    PubMed

    Ahlers, Jan; Regelmann, Jürgen; Riedhammer, Caroline

    2003-07-01

    In environmental risk assessments the question has to be answered, whether risk reduction measures are necessary in order to protect the environment. If the combination of natural and anthropogenic sources of a chemical substance leads to an unacceptable risk, the man-made emissions have to be reduced. In this case the proportions of the anthropogenic and natural emissions have to be quantified. Difficulties and possible solutions are discussed in the scope of the OECD- and EU-risk assessments of trichloroacetic acid (TCA) and tetrachloroethylene. In the atmosphere, TCA is formed by photo-oxidative degradation of tetrachloroethylene (PER) and 1,1,1-trichloroethane. The available data on atmospheric chemistry indicate that tetrachloroethylene is the more important pre-cursor. With its high water solubility and low volatility, TCA is adsorbed onto aerosol particles and precipitated during rainfalls. Extended monitoring in rainwater confirmed the global distribution of airborne TCA. TCA reaches soils by dry and wet deposition. In addition formation of TCA from tetrachloroethylene in plants was observed. Consequently, high concentrations were detected in needles, leaves and in forest soil especially in mountain regions. The effect assessment revealed that plants exposed via soil are the most sensitive species compared to other terrestrial organisms. A PNECsoil of 2.4 microg/kg dw was derived from a long-term study with pine and spruce seedlings. When this PNEC is compared with the measured concentrations of TCA in soil, in certain regions a PEC/PNEC ratio >1 is obtained. This clearly indicates a risk to the terrestrial ecosystem, with the consequence that risk reduction measures are deemed necessary. To quantify the causes of the high levels of TCA in certain soils, and to investigate the geographical extent of the problem, intensive and widespread monitoring of soil, air and rainwater for TCA and tetrachloroethylene would be necessary to be able to perform a full mass

  6. High temperature suppression of dioxins.

    PubMed

    Zhan, Ming-Xiu; Chen, Tong; Fu, Jian-Ying; Lin, Xiao-Qing; Lu, Sheng-Yong; Li, Xiao-Dong; Yan, Jian-Hua; Buekens, Alfons

    2016-03-01

    Combined Sulphur-Nitrogen inhibitors, such as sewage sludge decomposition gases (SDG), thiourea and amidosulphonic acid have been observed to suppress the de novo synthesis of dioxins effectively. In this study, the inhibition of PCDD/Fs formation from model fly ash was investigated at unusually high temperatures (650 °C and 850 °C), well above the usual range of de novo tests (250-400 °C). At 650 °C it was found that SDG evolving from dried sewage sludge could suppress the formation of 2,3,7,8-substituted PCDD/Fs with high efficiency (90%), both in weight units and in I-TEQ units. Additionally, at 850 °C, three kinds of sulphur-amine or sulphur-ammonium compounds were tested to inhibit dioxins formation during laboratory-scale tests, simulating municipal solid waste incineration. The suppression efficiencies of PCDD/Fs formed through homogeneous gas phase reactions were all above 85% when 3 wt. % of thiourea (98.7%), aminosulphonic acid (96.0%) or ammonium thiosulphate (87.3%) was added. Differences in the ratio of PCDFs/PCDDs, in weight average chlorination level and in the congener distribution of the 17 toxic PCDD/Fs indicated that the three inhibitors tested followed distinct suppression pathways, possibly in relation to their different functional groups of nitrogen. Furthermore, thiourea reduced the (weight) average chlorinated level. In addition, the thermal decomposition of TUA was studied by means of thermogravimetry-fourier transform infrared spectroscopy (TG-FTIR) and the presence of SO2, SO3, NH3 and nitriles (N≡C bonds) was shown in the decomposition gases; these gaseous inhibitors might be the primary dioxins suppressants.

  7. Identification of daidzein as a ligand of retinoic acid receptor that suppresses expression of matrix metalloproteinase-9 in HaCaT cells.

    PubMed

    Oh, Hyeon-Jeong; Kang, Young-Gyu; Na, Tae-Young; Kim, Hyeon-Ji; Park, Jun Seong; Cho, Won-Jea; Lee, Mi-Ock

    2013-08-25

    Retinoids have been used as therapeutics for diverse skin diseases, but their side effects limit clinical usage. Here, we report that extracts of two soybeans, Glycine max and Rhynchosia nulubilis, and their ethyl acetate fractions increased the transcriptional activity of retinoic acid receptors (RARs), and that daidzin and genistin were the major constituents of the active fractions. Daidzin and its aglycone, daidzein, induced transcriptional activity of RAR and RARγ. FRET analysis demonstrated that daidzein, but not daidzin, bound both RAR and RARγ with EC50 values of 28μM and 40μM, respectively. Daidzein increased expression of mRNA of RARγ through direct binding of RAR and recruitment of p300 to the RARγ2 promoter. Further, mRNA and gelatinolytic activity of matrix metalloproteinase-9 were decreased by daidzein in HaCaT cells. Together, these results indicate that daidzein functions as a ligand of RAR that could be a candidate therapeutic for skin diseases.

  8. Growth hormone suppression test

    MedlinePlus

    GH suppression test; Glucose loading test; Acromegaly - blood test; Gigantism - blood test ... is not changed and stays high during the suppression test, the provider will suspect gigantism or acromegaly. ...

  9. Dexamethasone suppression test

    MedlinePlus

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medication. Afterward, your blood is drawn ...

  10. The mealybug Phenacoccus solenopsis suppresses plant defense responses by manipulating JA-SA crosstalk.

    PubMed

    Zhang, Peng-Jun; Huang, Fang; Zhang, Jin-Ming; Wei, Jia-Ning; Lu, Yao-Bin

    2015-03-20

    Induced plant defenses against herbivores are modulated by jasmonic acid-, salicylic acid-, and ethylene-signaling pathways. Although there is evidence that some pathogens suppress plant defenses by interfering with the crosstalk between different signaling pathways, such evidence is scarce for herbivores. Here, we demonstrate that the mealybug Phenacoccus solenopsis suppresses the induced defenses in tomato. We found that exogenous JA, but not SA, significantly decreased mealybug feeding time and reduced nymphal performance. In addition, constitutive activation of JA signaling in 35s::prosys plants reduced mealybug survival. These data indicate that the JA signaling pathway plays a key role in mediating the defense responses against P. solenopsis. We also found that mealybug feeding decreased JA production and JA-dependent defense gene expression, but increased SA accumulation and SA-dependent gene expression. In SA-deficient plants, mealybug feeding did not suppress but activated JA accumulation, indicating that the suppression of JA-regulated defenses depends on the SA signaling pathway. Mealybugs benefit from suppression of JA-regulated defenses by exhibiting enhanced nymphal performance. These findings confirm that P. solenopsis manipulates plants for its own benefits by modulating the JA-SA crosstalk and thereby suppressing induced defenses.

  11. The mealybug Phenacoccus solenopsis suppresses plant defense responses by manipulating JA-SA crosstalk

    PubMed Central

    Zhang, Peng-Jun; Huang, Fang; Zhang, Jin-Ming; Wei, Jia-Ning; Lu, Yao-Bin

    2015-01-01

    Induced plant defenses against herbivores are modulated by jasmonic acid-, salicylic acid-, and ethylene-signaling pathways. Although there is evidence that some pathogens suppress plant defenses by interfering with the crosstalk between different signaling pathways, such evidence is scarce for herbivores. Here, we demonstrate that the mealybug Phenacoccus solenopsis suppresses the induced defenses in tomato. We found that exogenous JA, but not SA, significantly decreased mealybug feeding time and reduced nymphal performance. In addition, constitutive activation of JA signaling in 35s::prosys plants reduced mealybug survival. These data indicate that the JA signaling pathway plays a key role in mediating the defense responses against P. solenopsis. We also found that mealybug feeding decreased JA production and JA-dependent defense gene expression, but increased SA accumulation and SA-dependent gene expression. In SA-deficient plants, mealybug feeding did not suppress but activated JA accumulation, indicating that the suppression of JA-regulated defenses depends on the SA signaling pathway. Mealybugs benefit from suppression of JA-regulated defenses by exhibiting enhanced nymphal performance. These findings confirm that P. solenopsis manipulates plants for its own benefits by modulating the JA-SA crosstalk and thereby suppressing induced defenses. PMID:25790868

  12. Galeterone and VNPT55 induce proteasomal degradation of AR/AR-V7, induce significant apoptosis via cytochrome c release and suppress growth of castration resistant prostate cancer xenografts in vivo.

    PubMed

    Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Purushottamachar, Puranik; Ramamurthy, Vidya P; Njar, Vincent C O

    2015-09-29

    Galeterone (Gal) is a first-in-class multi-target oral small molecule that will soon enter pivotal phase III clinical trials in castration resistant prostate cancer (CRPC) patients. Gal disrupts androgen receptor (AR) signaling via inhibition of CYP17, AR antagonism and AR degradation. Resistance to current therapy is attributed to up-regulation of full-length AR (fAR), splice variants AR (AR-Vs) and AR mutations. The effects of gal and VNPT55 were analyzed on f-AR and AR-Vs (AR-V7/ARv567es) in LNCaP, CWR22Rv1 and DU145 (transfected with AR-Vs) human PC cells in vitro and CRPC tumor xenografts. Galeterone/VNPT55 decreased fAR/AR-V7 mRNA levels and implicates Mdm2/CHIP enhanced ubiquitination of posttranslational modified receptors, targeting them for proteasomal degradation. Gal and VNPT55 also induced significant apoptosis in PC cells via increased Bax/Bcl2 ratio, cytochrome-c release with concomitant cleavage of caspase 3 and PARP. More importantly, gal and VNPT55 exhibited strong in vivo anti-CRPC activities, with no apparent host toxicities. This study demonstrate that gal and VNPT55 utilize cell-based mechanisms to deplete both fAR and AR-Vs. Importantly, the preclinical activity profiles, including profound apoptotic induction and inhibition of CRPC xenografts suggest that these agents offer considerable promise as new therapeutics for patients with CRPC and those resistant to current therapy.

  13. α-Lipoic Acid Inhibits Expression of IL-8 by Suppressing Activation of MAPK, Jak/Stat, and NF-κB in H. pylori-Infected Gastric Epithelial AGS Cells.

    PubMed

    Choi, Ji Hyun; Cho, Soon Ok; Kim, Hyeyoung

    2016-01-01

    The epithelial cytokine response, associated with reactive oxygen species (ROS), is important in Helicobacter pylori (H. pylori)-induced inflammation. H. pylori induces the production of ROS, which may be involved in the activation of mitogen-activated protein kinases (MAPK), janus kinase/signal transducers and activators of transcription (Jak/Stat), and oxidant-sensitive transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and thus, expression of interleukin-8 (IL-8) in gastric epithelial cells. α-lipoic acid, a naturally occurring thiol compound, is a potential antioxidant. It shows beneficial effects in treatment of oxidant-associated diseases including diabetes. The present study is purposed to investigate whether α-lipoic acid inhibits expression of inflammatory cytokine IL-8 by suppressing activation of MAPK, Jak/Stat, and NF-κB in H. pylori-infected gastric epithelial cells. Gastric epithelial AGS cells were pretreated with or without α-lipoic acid for 2 h and infected with H. pylori in a Korean isolate (HP99) at a ratio of 300:1. IL-8 mRNA expression was analyzed by RT-PCR analysis. IL-8 levels in the medium were determined by enzyme-linked immunosorbent assay. NF-κB-DNA binding activity was determined by electrophoretic mobility shift assay. Phospho-specific and total forms of MAPK and Jak/Stat were assessed by Western blot analysis. ROS levels were determined using dichlorofluorescein fluorescence. As a result, H. pylori induced increases in ROS levels, mRNA, and protein levels of IL-8, as well as the activation of MAPK [extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38], Jak/Stat (Jak1/2, Stat3), and NF-κB in AGS cells, which was inhibited by α-lipoic acid. In conclusion, α-lipoic acid may be beneficial for prevention and/or treatment of H. pylori infection-associated gastric inflammation.

  14. α-Lipoic Acid Inhibits Expression of IL-8 by Suppressing Activation of MAPK, Jak/Stat, and NF-κB in H. pylori-Infected Gastric Epithelial AGS Cells

    PubMed Central

    Choi, Ji Hyun; Cho, Soon Ok

    2016-01-01

    The epithelial cytokine response, associated with reactive oxygen species (ROS), is important in Helicobacter pylori (H. pylori)-induced inflammation. H. pylori induces the production of ROS, which may be involved in the activation of mitogen-activated protein kinases (MAPK), janus kinase/signal transducers and activators of transcription (Jak/Stat), and oxidant-sensitive transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and thus, expression of interleukin-8 (IL-8) in gastric epithelial cells. α-lipoic acid, a naturally occurring thiol compound, is a potential antioxidant. It shows beneficial effects in treatment of oxidant-associated diseases including diabetes. The present study is purposed to investigate whether α-lipoic acid inhibits expression of inflammatory cytokine IL-8 by suppressing activation of MAPK, Jak/Stat, and NF-κB in H. pylori-infected gastric epithelial cells. Gastric epithelial AGS cells were pretreated with or without α-lipoic acid for 2 h and infected with H. pylori in a Korean isolate (HP99) at a ratio of 300:1. IL-8 mRNA expression was analyzed by RT-PCR analysis. IL-8 levels in the medium were determined by enzyme-linked immunosorbent assay. NF-κB-DNA binding activity was determined by electrophoretic mobility shift assay. Phospho-specific and total forms of MAPK and Jak/Stat were assessed by Western blot analysis. ROS levels were determined using dichlorofluorescein fluorescence. As a result, H. pylori induced increases in ROS levels, mRNA, and protein levels of IL-8, as well as the activation of MAPK [extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38], Jak/Stat (Jak1/2, Stat3), and NF-κB in AGS cells, which was inhibited by α-lipoic acid. In conclusion, α-lipoic acid may be beneficial for prevention and/or treatment of H. pylori infection-associated gastric inflammation. PMID:26632410

  15. Nitric oxide suppresses the inhibitory effect of abscisic acid on seed germination by S-nitrosylation of SnRK2 proteins.

    PubMed

    Wang, Pengcheng; Zhu, Jian-Kang; Lang, Zhaobo

    2015-01-01

    Nitric oxide (NO) plays important roles in plant development, and biotic and abiotic stress responses. In a recent study, we showed that endogenous NO negatively regulates abscisic acid (ABA) signaling in guard cells by inhibiting sucrose nonfermenting 1 (SNF1)-related protein kinase 2.6 (SnRK2.6)/open stomata 1(OST1) through S-nitrosylation. Application of NO breaks seed dormancy and alleviates the inhibitory effect of ABA on seed germination and early seedling growth, but it is unclear how NO functions at the stages of seed germination and early seedling development. Here, we show that like SnRK2.6, SnRK2.2 can be inactivated by S-nitrosoglutathione (GSNO) treatment through S-nitrosylation. SnRK2.2 and the closely related SnRK2.3 are known to play redundant roles in ABA inhibition of seed germination in Arabidopsis. We found that treatment with the NO donor SNP phenocopies the snrk2.2snrk2.3 double mutant in conferring ABA insensitivity at the stages of seed germination and early seedling growth. Our results suggest that NO negatively regulates ABA signaling in germination and early seedling growth through S-nitrosylation of SnRK2.2 and SnRK2.3.

  16. Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt/β-catenin signaling in developing cleft palate

    PubMed Central

    Hu, X; Gao, J; Liao, Y; Tang, S; Lu, F

    2013-01-01

    Retinoic acid (RA) contributes to cleft palate; however, the cellular and molecular mechanisms responsible for the deleterious effects on the developing palate are unclear. Wnt signaling is a candidate pathway in the cleft palate and is associated with RA in organ development; thus, we aim to investigate whether RA-induced cleft palate also results from altered Wnt signaling. Administration of RA to mice altered cell proliferation and apoptosis in craniofacial tissues by regulating molecules controlling cell cycle and p38 MAPK signaling, respectively. This altered cell fate by RA is a crucial mechanism contributing to 100% incidence of cleft palate. Moreover, Wnt/β-catenin signaling was completely inhibited by RA in the early developing palate via its binding and activation with RA receptor (RAR) and is responsible for RA-induced cleft palate. Furthermore, PI3K/Akt signaling was also involved in actions of RA. Our findings help in elucidating the mechanisms of RA-induced cleft palate. PMID:24176856

  17. Inhibition of transforming growth factor-beta-induced liver fibrosis by a retinoic acid derivative via the suppression of Col 1A2 promoter activity.

    PubMed

    Yang, Kun-Lin; Chang, Wen-Teng; Hung, Kuo-Chen; Li, Eric I C; Chuang, Chia-Chang

    2008-08-22

    Transforming growth factor-beta1 (TGF-beta1) mediates expression of collagen 1A2 (Col 1A2) gene via a synergistic cooperation between Smad2/Smad3 and Sp1, both act on the Col 1A2 gene promoter. In our previous study, we reported that a retinoic acid derivative obtained from Phellinus linteus (designated PL) antagonizes TGF-beta-induced liver fibrosis through regulation of ROS and calcium influx. In this continuing study we seek further the effect of PL on the Smad signaling pathway. We used a Col 1A2 promoter-luciferase construct to study the action of PL on Smad through TGF-beta. We found that PL decreases the promoter activity of Col 1A2, hinders the translocalization of phosphorylated Smad2/3-Smad 4 complex from cytosol into nucleus and inhibits Sp1 binding activity. These results suggest that PL inhibits TGF-beta1-induced Col 1A2 promoter activity through blocking ROS and calcium influx as well as impeding Sp1 binding and translocalization of pSmad 2/3-Smad4 complex into nucleus.

  18. A single amino acid (Asp159) from the dog prion protein suppresses the toxicity of the mouse prion protein in Drosophila.

    PubMed

    Sanchez-Garcia, J; Jensen, K; Zhang, Y; Rincon-Limas, D E; Fernandez-Funez, P

    2016-11-01

    Misfolding of the prion protein (PrP) is the key step in the transmission of spongiform pathologies in humans and several animals. Although PrP is highly conserved in mammals, a few changes in the sequence of endogenous PrP are proposed to confer protection to dogs, which were highly exposed to prion during the mad-cow epidemics. D159 is a unique amino acid found in PrP from dogs and other canines that was shown to alter surface charge, but its functional relevance has never been tested in vivo. Here, we show in transgenic Drosophila that introducing the N159D substitution on mouse PrP decreases its turnover. Additionally, mouse PrP-N159D demonstrates no toxicity and accumulates no pathogenic conformations, suggesting that a single D159 substitution is sufficient to prevent PrP conformational change and pathogenesis. Understanding the mechanisms mediating the protective activity of D159 is likely to lessen the burden of prion diseases in humans and domestic animals. PMID:27477054

  19. Nitric oxide suppresses the inhibitory effect of abscisic acid on seed germination by S-nitrosylation of SnRK2 proteins

    PubMed Central

    Wang, Pengcheng; Zhu, Jian-Kang; Lang, Zhaobo

    2015-01-01

    Nitric oxide (NO) plays important roles in plant development, and biotic and abiotic stress responses. In a recent study, we showed that endogenous NO negatively regulates abscisic acid (ABA) signaling in guard cells by inhibiting sucrose nonfermenting 1 (SNF1)-related protein kinase 2.6 (SnRK2.6)/open stomata 1(OST1) through S-nitrosylation. Application of NO breaks seed dormancy and alleviates the inhibitory effect of ABA on seed germination and early seedling growth, but it is unclear how NO functions at the stages of seed germination and early seedling development. Here, we show that like SnRK2.6, SnRK2.2 can be inactivated by S-nitrosoglutathione (GSNO) treatment through S-nitrosylation. SnRK2.2 and the closely related SnRK2.3 are known to play redundant roles in ABA inhibition of seed germination in Arabidopsis. We found that treatment with the NO donor SNP phenocopies the snrk2.2snrk2.3 double mutant in conferring ABA insensitivity at the stages of seed germination and early seedling growth. Our results suggest that NO negatively regulates ABA signaling in germination and early seedling growth through S-nitrosylation of SnRK2.2 and SnRK2.3. PMID:26024299

  20. Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells

    PubMed Central

    Kim, Seong-Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe-Youn; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eunji; Baek, Nam-In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong-Tai

    2015-01-01

    Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients. PMID:26412148

  1. Fear-induced suppression of nociceptive behaviour and activation of Akt signalling in the rat periaqueductal grey: role of fatty acid amide hydrolase.

    PubMed

    Butler, Ryan K; Ford, Gemma K; Hogan, Michelle; Roche, Michelle; Doyle, Karen M; Kelly, John P; Kendall, David A; Chapman, Victoria; Finn, David P

    2012-01-01

    The endocannabinoid system regulates nociception and aversion and mediates fear-conditioned analgesia (FCA). We investigated the effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which inhibits the catabolism of the endocannabinoid anandamide and related N-acylethanolamines, on expression of FCA and fear and pain related behaviour per se in rats. We also examined associated alterations in the expression of the signal transduction molecule phospho-Akt in the periaqueductal grey (PAG) by immunoblotting. FCA was modelled by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. URB597 (0.3 mg/kg, i.p.) enhanced FCA and increased fear-related behaviour in formalin-treated rats. Conditioned fear per se in non-formalin-treated rats was associated with increased expression of phospho-Akt in the PAG. URB597 reduced the expression of fear-related behaviour in the early part of the trial, an effect that was accompanied by attenuation of the fear-induced increase in phospho-Akt expression in the PAG. Intra-plantar injection of formalin also reduced the fear-induced increase in phospho-Akt expression. These data provide evidence for a role of FAAH in FCA, fear responding in the presence or absence of nociceptive tone, and fear-evoked increases in PAG phospho-Akt expression. In addition, the results suggest that fear-evoked activation of Akt signalling in the PAG is abolished in the presence of nociceptive tone.

  2. The significance of C16 fatty acids in the sn-2 positions of glycerolipids in the photosynthetic growth of Synechocystis sp. PCC6803.

    PubMed

    Okazaki, Kumiko; Sato, Norihiro; Tsuji, Noriko; Tsuzuki, Mikio; Nishida, Ikuo

    2006-06-01

    Most extant cyanobacteria contain C16 fatty acids in the sn-2 positions of glycerolipids, which are regulated by lysophosphatidic acid acyltransferase (LPAAT; EC 2.3.1.51). Synechocystis sp. PCC6803 contains sll1848, sll1752, and slr2060 as putative acyltransferase genes. sll1848 was recently reported to encode an indispensable palmitoyl-specific LPAAT; however, here we show that each of the three genes is dispensable. Delta1848 and Delta1848 Delta2060 cells had markedly higher contents of stearate (18:0), oleate (18:1), and linoleate (18:2) in place of palmitate (16:0) in the sn-2 positions, suggesting that Delta1848 Delta2060 cells incorporate 18:0 and 18:1 in the sn-2 positions. The levels of sll1752 transcripts increased in Delta1848 Delta2060 cells. This was accompanied by increased LPAAT activity toward 18:0 coenzyme A and its derivative in the membrane fraction. From these findings, together with the activity of a recombinant sll1752 protein and complementation of the Escherichia coli LPAAT mutant plsC, we conclude that sll1752 encodes a second LPAAT that prefers stearoyl and oleoyl substrates. Delta1848 Delta2060 cells grew slowly at 30 degrees C at lower cell density, and exhibited more severe damage at 20 degrees C than wild-type cells. Furthermore, Delta1848 Delta2060 cells exhibited photoinhibition more severely than wild-type cells. A phycobilisome core-membrane linker protein (slr0335) was also found to be susceptible to protein extraction under our conditions; its content decreased in the membrane fractions of Delta1848 Delta2060 cells. We conclude that C16 fatty acids in sn-2 positions are preferred in the photosynthetic growth of this cyanobacterium, despite sll1752 orthologs being conserved in most cyanobacteria. However, no sll1752 ortholog is conserved among photosynthetic eukaryotes including Cyanidioschyzon merolae.

  3. [Biochemical evaluation of damage due to lead: importance and significance of erythrocyte zinc-protoporhyrin IX and urinary amino acid determination].

    PubMed

    Sanguinetti, F; Dompè, M; Ronca, G

    1977-01-01

    The early detection of lead intoxitation needs practical, simple, reproducible and diagnostically valid screening test. The determination of ALA-D (delta-amino-levulinic acid-dehydratase) in erythrocytes is one of the most reliable test for the evaluation of the occupational exposure to lead. However this test is difficult to standardize, sensible to lead contamination of laboratory glassware and the activity of enzyme decreases rapidly if stored. The determination of erythrocytes ZPP (zinco-protoporphyrin IX) was proposed as useful, alternative test. The protoporphyrin IX is a metabolic intermediate in heme biosynthesis; in erythrocytes is present as free form and zinc-boundend compound. The ZPP give high values only in lead intoxication and sideropenic anemia. The ALA-D and ZPP in erythrocytes were measured and compared in a group of workers exposed to lead. We have shown a good correlation between these two biochemical parameters. Aminoacid excretion in urine from workers exposed to lead was measured and compared with other biochemical parameters of intoxication. All lead workers examined had excessive urinary CP (coproporphyrin) and ALA (delta-amino-levulinic acid) excretion. An abnormal excretion of glycine was present in eight workers (32%), whereas in other four (15%) the glycinuria was at limit of normal values. An abnormal excretion of lysine was present in six workers (21%). The last data appear very interesting because the action of lead in lysine metabolism was not known. PMID:603137

  4. Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance.

    PubMed

    Thurston, J H; Hauhart, R E

    1992-04-01

    Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of beta-oxidation. The present study shows for the first time that in developing mice, when panthothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the beta-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of beta-oxidation and other CoA- and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase. PMID:1570210

  5. Binding to plasma lipoproteins of chlorophenoxyisobutyric, tibric and nicotinic acids and their esters: its significance for the mechanism of lipid lowering by clofibrate and related drugs.

    PubMed

    Beaumont, J L; Dachet, C

    1976-01-01

    The binding of chlorophenoxyisobutyric (CPIB), tibric (TA) and nicotinic (NA) acids and CPIB ethyl ester (Clofibrate), TA and NA isopropyl esters (TAPE and NAPE) to human lipoproteins of low density of different classes (LDL2, LDL1 and VLDL) and high density (HDL) were studied by equilibrium dialysis and Sephadex gel filtration. Clofibrate and TAPE bound strongly to lipoproteins, but their acids, CPIB and TA and also NA and NAPE, did not bind. In the same experimental conditions, Clofibrate and TAPE bound only weakly to human serum albumin (HSA) and CPIB bound to HSA with a Ka of 3.3 X 10(5) M(-1) for 1 site of high affinity. The Clofibrate and TAPE bound to lipoproteins did not dissociate either during dialysis or during filtration on Sephadex G 25. The binding percentage remained constant for all drug concentrations studied, and the molar ratio of bound drug rose linearly with increasing concentrations. This suggests that the interaction may be irreversible, and there is some evidence that binding may induce irreversible changes in the lipoprotein molecules. These results, and those already found in experiments made with three other drugs related to Clofibrate, lead to the proposal that in their interaction with lipoproteins, the phenyl groups are necessary and the esterification is contributory. The possible role of this interaction in the lipid-lowering effect of the drugs is discussed with special reference to their possible implication in lipoprotein synthesis within the intestinal and hepatic cells.

  6. Acetic acid treatment in S. cerevisiae creates significant energy deficiency and nutrient starvation that is dependent on the activity of the mitochondrial transcriptional complex Hap2-3-4-5.

    PubMed

    Kitanovic, Ana; Bonowski, Felix; Heigwer, Florian; Ruoff, Peter; Kitanovic, Igor; Ungewiss, Christin; Wölfl, Stefan

    2012-01-01

    Metabolic pathways play an indispensable role in supplying cellular systems with energy and molecular building blocks for growth, maintenance and repair and are tightly linked with lifespan and systems stability of cells. For optimal growth and survival cells rapidly adopt to environmental changes. Accumulation of acetic acid in stationary phase budding yeast cultures is considered to be a primary mechanism of chronological aging and induction of apoptosis in yeast, which has prompted us to investigate the dependence of acetic acid toxicity on extracellular conditions in a systematic manner. Using an automated computer controlled assay system, we investigated and model the dynamic interconnection of biomass yield- and growth rate-dependence on extracellular glucose concentration, pH conditions and acetic acid concentration. Our results show that toxic concentrations of acetic acid inhibit glucose consumption and reduce ethanol production. In absence of carbohydrates uptake, cells initiate synthesis of storage carbohydrates, trehalose and glycogen, and upregulate gluconeogenesis. Accumulation of trehalose and glycogen, and induction of gluconeogenesis depends on mitochondrial activity, investigated by depletion of the Hap2-3-4-5 complex. Analyzing the activity of glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PYK), and glucose-6-phosphate dehydrogenase (G6PDH) we found that while high acetic acid concentration increased their activity, lower acetic acids concentrations significantly inhibited these enzymes. With this study we determined growth and functional adjustment of metabolism to acetic acid accumulation in a complex range of extracellular conditions. Our results show that substantial acidification of the intracellular environment, resulting from accumulation of dissociated acetic acid in the cytosol, is required for acetic acid toxicity, which creates a state of energy deficiency and nutrient starvation.

  7. Acetic acid treatment in S. cerevisiae creates significant energy deficiency and nutrient starvation that is dependent on the activity of the mitochondrial transcriptional complex Hap2-3-4-5

    PubMed Central

    Kitanovic, Ana; Bonowski, Felix; Heigwer, Florian; Ruoff, Peter; Kitanovic, Igor; Ungewiss, Christin; Wölfl, Stefan

    2012-01-01

    Metabolic pathways play an indispensable role in supplying cellular systems with energy and molecular building blocks for growth, maintenance and repair and are tightly linked with lifespan and systems stability of cells. For optimal growth and survival cells rapidly adopt to environmental changes. Accumulation of acetic acid in stationary phase budding yeast cultures is considered to be a primary mechanism of chronological aging and induction of apoptosis in yeast, which has prompted us to investigate the dependence of acetic acid toxicity on extracellular conditions in a systematic manner. Using an automated computer controlled assay system, we investigated and model the dynamic interconnection of biomass yield- and growth rate-dependence on extracellular glucose concentration, pH conditions and acetic acid concentration. Our results show that toxic concentrations of acetic acid inhibit glucose consumption and reduce ethanol production. In absence of carbohydrates uptake, cells initiate synthesis of storage carbohydrates, trehalose and glycogen, and upregulate gluconeogenesis. Accumulation of trehalose and glycogen, and induction of gluconeogenesis depends on mitochondrial activity, investigated by depletion of the Hap2-3-4-5 complex. Analyzing the activity of glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PYK), and glucose-6-phosphate dehydrogenase (G6PDH) we found that while high acetic acid concentration increased their activity, lower acetic acids concentrations significantly inhibited these enzymes. With this study we determined growth and functional adjustment of metabolism to acetic acid accumulation in a complex range of extracellular conditions. Our results show that substantial acidification of the intracellular environment, resulting from accumulation of dissociated acetic acid in the cytosol, is required for acetic acid toxicity, which creates a state of energy deficiency and nutrient starvation. PMID:23050242

  8. Effective suppressibility of chaos.

    PubMed

    López, Álvaro G; Seoane, Jesús M; Sanjuán, Miguel A F

    2013-06-01

    Suppression of chaos is a relevant phenomenon that can take place in nonlinear dynamical systems when a parameter is varied. Here, we investigate the possibilities of effectively suppressing the chaotic motion of a dynamical system by a specific time independent variation of a parameter of our system. In realistic situations, we need to be very careful with the experimental conditions and the accuracy of the parameter measurements. We define the suppressibility, a new measure taking values in the parameter space, that allows us to detect which chaotic motions can be suppressed, what possible new choices of the parameter guarantee their suppression, and how small the parameter variations from the initial chaotic state to the final periodic one are. We apply this measure to a Duffing oscillator and a system consisting on ten globally coupled Hénon maps. We offer as our main result tool sets that can be used as guides to suppress chaotic dynamics. PMID:23822472

  9. Fire Suppression and Response

    NASA Technical Reports Server (NTRS)

    Ruff, Gary A.

    2004-01-01

    This report is concerned with the following topics regarding fire suppression:What is the relative effectiveness of candidate suppressants to extinguish a representative fire in reduced gravity, including high-O2 mole fraction, low -pressure environments? What are the relative advantages and disadvantages of physically acting and chemically-acting agents in spacecraft fire suppression? What are the O2 mole fraction and absolute pressure below which a fire cannot exist? What effect does gas-phase radiation play in the overall fire and post-fire environments? Are the candidate suppressants effective to extinguish fires on practical solid fuels? What is required to suppress non-flaming fires (smoldering and deep seated fires) in reduced gravity? How can idealized space experiment results be applied to a practical fire scenario? What is the optimal agent deployment strategy for space fire suppression?

  10. A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo.

    PubMed

    Kulcsár, Gyula; Gaál, Dezső; Kulcsár, Péter I; Schulcz, Ákos; Czömpöly, Tamás

    2013-03-01

    Previously we have hypothesized that the small molecules which are selectively accumulated in cancer cells might participate in a non-immunological antitumor surveillance mechanism. We demonstrated earlier that a mixture of experimentally selected substances ("active mixture", AM: L-arginine, L-histidine, L-methionine, L-phenylalanine, L-tyrosine, L-tryptophan, L-ascorbate, D-biotin, pyridoxine, riboflavin, adenine, L(-)malate) possesses a selective toxic effect in vitro on a variety of tumor cell lines, and we have shown that the AM selectively induces apoptosis of cancer cells in vitro. To explore the in vivo significance of our earlier findings we examined the antitumor effect of AM in Colon 26 murine colorectal adenocarcinoma, B16 murine melanoma, MXT murine mammary carcinoma, S180 murine sarcoma, P388 murine lymphoid leukemia, HL-60 human promyeloid leukemia, PC-3 human prostate carcinoma, and HT-29 human colon carcinoma tumor models. Treatment of tumor bearing mice with AM inhibited the growth of the tumors investigated, with an inhibitory effect ranging from 40 to 69%. The AM had a comparable antitumor effect with 5-fluorouracil and cisplatin in the Colon-26 tumor model, and combined treatment with AM and 5-fluorouracil or cisplatin resulted in an enhanced tumor growth inhibitory effect. The AM induced apoptosis through the mitochondrial pathway and induced G1 arrest in PC-3 cells and increased the number of apoptotic cells in PC-3 xenografts. These findings suggest that the AM might offer an interesting perspective in the treatment of cancer and in combination with other treatments may offer hope for a more effective cancer therapy.

  11. Burst suppression probability algorithms: state-space methods for tracking EEG burst suppression

    NASA Astrophysics Data System (ADS)

    Chemali, Jessica; Ching, ShiNung; Purdon, Patrick L.; Solt, Ken; Brown, Emery N.

    2013-10-01

    Objective. Burst suppression is an electroencephalogram pattern in which bursts of electrical activity alternate with an isoelectric state. This pattern is commonly seen in states of severely reduced brain activity such as profound general anesthesia, anoxic brain injuries, hypothermia and certain developmental disorders. Devising accurate, reliable ways to quantify burst suppression is an important clinical and research problem. Although thresholding and segmentation algorithms readily identify burst suppression periods, analysis algorithms require long intervals of data to characterize burst suppression at a given time and provide no framework for statistical inference. Approach. We introduce the concept of the burst suppression probability (BSP) to define the brain's instantaneous propensity of being in the suppressed state. To conduct dynamic analyses of burst suppression we propose a state-space model in which the observation process is a binomial model and the state equation is a Gaussian random walk. We estimate the model using an approximate expectation maximization algorithm and illustrate its application in the analysis of rodent burst suppression recordings under general anesthesia and a patient during induction of controlled hypothermia. Main result. The BSP algorithms track burst suppression on a second-to-second time scale, and make possible formal statistical comparisons of burst suppression at different times. Significance. The state-space approach suggests a principled and informative way to analyze burst suppression that can be used to monitor, and eventually to control, the brain states of patients in the operating room and in the intensive care unit.

  12. In vitro Th1 cytokine-independent Th2 suppressive effects of bifidobacteria.

    PubMed

    Iwabuchi, Noriyuki; Takahashi, Noritoshi; Xiao, Jin-zhong; Miyaji, Kazuhiro; Iwatsuki, Keiji

    2007-01-01

    A comparison between 17 strains of lactic acid bacteria and 15 strains of bifidobacteria indicated that bifidobacteria induced significantly lower levels of interleukin-12 (IL-12) in murine splenic cells. The present study aims to evaluate the effect and mechanism of Bifidobacterium longum BB536, a probiotic strain, in suppressing antigen-induced Th2 immune response in vitro. BB536 suppressed immunoglobulin (Ig) E and IL-4 production by ovalbumin-sensitized splenic cells, but induction of Th1-inducing cytokine production, such as IL-12 and gamma interferon (IFN-gamma) tended to be lower compared with lactic acid bacteria. Neutralization with antibodies to IL-12, IFN-gamma, IL-10 and transforming growth factor beta indicated negative involvement of Th1-inducing cytokines and regulatory cytokines in the suppression of Th2 immune response by BB536, especially when treated at higher doses of BB536 (>10 microg cells/ml). Furthermore, BB536 induced the maturation of immature bone marrow-derived dendritic cells (BM-DCs), and suppressed antigen-induced IL-4 production mediated by BM-DCs. These results suggested that BB536 suppressed Th2 immune responses, partially independent of Th1-inducing cytokines and independent of regulatory cytokines, mediated by antigen-presenting cells such as dendritic cells.

  13. Fatty Acid binding protein 7 is a molecular marker in adenoid cystic carcinoma of the salivary glands: implications for clinical significance.

    PubMed

    Phuchareon, Janyaporn; Overdevest, Jonathan B; McCormick, Frank; Eisele, David W; van Zante, Annemieke; Tetsu, Osamu

    2014-12-01

    Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the salivary glands. Its diagnosis is difficult due to overlapping features with other salivary tumors. Gene expression analysis may complement traditional diagnostic methods. We searched gene expression patterns in the Gene Expression Omnibus (GEO) database and in our tumor and normal samples. The biologic and prognostic potential of the identified genes was analyzed. The GEO data set of primary xenografted ACCs revealed that expression of five genes, engrailed homeobox 1 (EN1), fatty acid binding protein 7 (FABP7), hemoglobin epsilon 1, MYB, and versican (VCAN), was dramatically increased. mRNA expression of EN1, FABP7, MYB, and VCAN distinguished our sporadic ACCs from normal tissues and benign tumors. FABP7 expression appeared to be regulated differently from EN1 and MYB and was crossly correlated with poor prognosis in our ACC cohort. Immunohistochemistry showed that FABP7 protein was predominantly expressed in the nucleus of myoepithelial cells of both tubular and cribriform subtypes. In contrast, in the solid subtype, which is often associated with a lower survival rate, FABP7 protein was uniformly expressed in cancerous cells. One case with cribriform architecture and the highest level of FABP7 mRNA showed strong FABP7 staining in both duct-type epithelial and myoepithelial cells, suggesting that diffuse expression of FABP7 protein might be related to aggressive tumor behavior and poor prognosis. We propose FABP7 as a novel biomarker in ACC. The molecule may be useful in diagnosis and for identifying more effective therapies targeting this protein or upstream molecules that regulate it.

  14. The retinoblastoma protein: multitasking to suppress tumorigenesis.

    PubMed

    Vormer, Tinke L; Hansen, Jacob B; Te Riele, Hein

    2015-01-01

    Tumor suppressor activity of the retinoblastoma protein pRB is preserved despite loss of interaction with E2F transcription factors (E2F) or proteins harboring a leucine-x-cysteine-x-glutamic acid motif (LxCxE, where x is any amino acid). This indicates that pRB uses several parallel pathways to suppress tumorigenesis, which may also include E2F- and LxCxE-independent interactions. PMID:27308398

  15. The retinoblastoma protein: multitasking to suppress tumorigenesis

    PubMed Central

    Vormer, Tinke L.; Hansen, Jacob B; te Riele, Hein

    2015-01-01

    Tumor suppressor activity of the retinoblastoma protein pRB is preserved despite loss of interaction with E2F transcription factors (E2F) or proteins harboring a leucine-x-cysteine-x-glutamic acid motif (LxCxE, where x is any amino acid). This indicates that pRB uses several parallel pathways to suppress tumorigenesis, which may also include E2F- and LxCxE-independent interactions. PMID:27308398

  16. Mechanism of suppression of piperacillin resistance in enterobacteria by tazobactam.

    PubMed Central

    Kadima, T A; Weiner, J H

    1997-01-01

    Resistance to piperacillin in several isolates of Citrobacter freundii and Enterobacter cloacae was investigated and confirmed to occur at a frequency of 10(-7) to 10(-6). Development of resistance to piperacillin was significantly suppressed by tazobactam but not by clavulanic acid. To elucidate the mechanism by which resistance suppression occurs, the effect of piperacillin plus tazobactam on the induction of AmpC beta-lactamase was analyzed by monitoring the beta-galactosidase activity of an inducible ampC-lacZ gene fusion in Escherichia coli. The combination exerted no inhibitory effect on AmpC beta-lactamase induction. Tazobactam also had no effect on the accumulation of a key intermediate in the AmpC beta-lactamase induction pathway, 1,6-anhydromurotripeptide, in an ampD mutant strain of E. coli. However, the addition of tazobactam to liquid cultures of E. cloacae 40001 in the presence of piperacillin at four times the MIC caused a delay in the recovery of the culture to piperacillin-induced stress. At 16 times the MIC, a complete suppression of regrowth occurred. Analysis of culture viability on piperacillin plates showed that the culture recovery was due to growth by moderately resistant mutants preexisting in the cell population, which at 16 times the MIC became susceptible to the combination. Evidence from the kinetics of inhibition of the E. cloacae 40001 AmpC beta-lactamase by clavulanic acid, sulbactam, and tazobactam and from the effects of these drugs on the frequency of resistance to piperacillin suggests that the suppressive effect of tazobactam on the appearance of resistance is primarily mediated by the beta-lactamase inhibitory activity. PMID:9333044

  17. Understanding the Chemistry of the Actinides in HL Waste Tank Systems: Actinide Speciation in Oxalic Acid Solutions in the Presence of Significant Quantities of Aluminum, Iron, and Manganese

    SciTech Connect

    Clark, Sue

    2006-07-30

    The overall goal of this research plan is to provide a thermodynamic basis for describing actinide speciation over a range of tank-like conditions, including elevated temperature, elevated OH- concentrations, and the presence of various organic ligands. With support from DOE's EMSP program, we have made significant progress towards measuring thermodynamic parameters for actinide complexation as a function of temperature. We have used the needs of the ESP modelers to guide our work to date, and we have made important progress defining the effect of temperature for actinide complexation by organic, and for hydrolysis of the hexa- and pentvalent oxidation states.

  18. ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43

    PubMed Central

    Lim, Liangzhong; Wei, Yuanyuan; Lu, Yimei; Song, Jianxing

    2016-01-01

    TAR-DNA-binding protein-43 (TDP-43) C-terminus encodes a prion-like domain widely presented in RNA-binding proteins, which functions to form dynamic oligomers and also, amazingly, hosts most amyotrophic lateral sclerosis (ALS)-causing mutations. Here, as facilitated by our previous discovery, by circular dichroism (CD), fluorescence and nuclear magnetic resonance (NMR) spectroscopy, we have successfully determined conformations, dynamics, and self-associations of the full-length prion-like domains of the wild type and three ALS-causing mutants (A315E, Q331K, and M337V) in both aqueous solutions and membrane environments. The study decodes the following: (1) The TDP-43 prion-like domain is intrinsically disordered only with some nascent secondary structures in aqueous solutions, but owns the capacity to assemble into dynamic oligomers rich in β-sheet structures. By contrast, despite having highly similar conformations, three mutants gained the ability to form amyloid oligomers. The wild type and three mutants all formed amyloid fibrils after incubation as imaged by electron microscopy. (2) The interaction with nucleic acid enhances the self-assembly for the wild type but triggers quick aggregation for three mutants. (3) A membrane-interacting subdomain has been identified over residues Met311-Gln343 indispensable for TDP-43 neurotoxicity, which transforms into a well-folded Ω-loop-helix structure in membrane environments. Furthermore, despite having very similar membrane-embedded conformations, three mutants will undergo further self-association in the membrane environment. Our study implies that the TDP-43 prion-like domain appears to have an energy landscape, which allows the assembly of the wild-type sequence into dynamic oligomers only under very limited condition sets, and ALS-causing point mutations are sufficient to remodel it to more favor the amyloid formation or irreversible aggregation, thus supporting the emerging view that the pathologic aggregation

  19. Plant, cell, and molecular mechanisms of abscisic-acid regulation of stomatal apertures. In vivo phosphorylation of phosphoenolpyruvate carboxylase in guard cells of Vicia faba L. is enhanced by fusicoccin and suppressed by abscisic acid

    SciTech Connect

    Du, Z.; Aghoram, K.; Outlaw, W.H. Jr.

    1996-12-31

    Plants regulate water loss and CO{sub 2} gain by modulating the aperture sizes of stomata that penetrate the epidermis. Aperture size itself is increased by osmolyte accumulation and consequent turgor increase in the pair of guard cells that flank each stoma. Guard-cell phosphoenolpyruvate carboxylase, which catalyzes the regulated step leading to malate synthesis, is crucial for charge and pH maintenance during osmolyte accumulation. Regulation of this cytosolic enzyme by effectors is well documented, but additional regulation by posttranslational modification is predicted by the alteration of PEPC kinetics during stomatal opening. In this study, the authors have investigated whether this alteration is associated with the phosphorylation status of this enzyme. Using sonicated epidermal peels (isolated guard cells) pre-loaded with {sub 32}PO{sub 4}, the authors induced stomatal opening and guard-cell malate accumulation by incubation with 5 {micro}M fusicoccin (FC). In corroboratory experiments, guard cells were incubated with 5 {micro}M fusicoccin (FC). In corroboratory experiments, guard cells were incubated with the FC antagonist, 10 {micro}M abscisic acid (ABA). The phosphorylation status of PEPC was assessed by immunoprecipitation, electrophoresis, immunoblotting, and autoradiography. PEPC was phosphorylated when stomata were stimulated to open, and phosphorylation was lessened by incubation with ABA.

  20. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism.

    PubMed Central

    Tessari, P; Nosadini, R; Trevisan, R; De Kreutzenberg, S V; Inchiostro, S; Duner, E; Biolo, G; Marescotti, M C; Tiengo, A; Crepaldi, G

    1986-01-01

    To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present. PMID:3519679

  1. Effects of tic suppression: ability to suppress, rebound, negative reinforcement, and habituation to the premonitory urge.

    PubMed

    Specht, Matt W; Woods, Douglas W; Nicotra, Cassandra M; Kelly, Laura M; Ricketts, Emily J; Conelea, Christine A; Grados, Marco A; Ostrander, Rick S; Walkup, John T

    2013-01-01

    The comprehensive behavioral intervention for tics (CBIT) represents a safe, effective non-pharmacological treatment for Tourette's disorder that remains underutilized as a treatment option. Contributing factors include the perceived negative consequences of tic suppression and the lack of a means through which suppression results in symptom improvement. Participants (n = 12) included youth ages 10-17 years with moderate-to-marked tic severity and noticeable premonitory urges who met Tourette's or chronic tic disorder criteria. Tic frequency and urge rating data were collected during an alternating sequence of tic freely or reinforced tic suppression periods. Even without specific instructions regarding how to suppress tics, youth experienced a significant, robust (72%), stable reduction in tic frequency under extended periods (40 min) of contingently reinforced tic suppression in contrast to periods of time when tics were ignored. Following periods of prolonged suppression, tic frequency returned to pre-suppression levels. Urge ratings did not show the expected increase during the initial periods of tic suppression, nor a subsequent decline in urge ratings during prolonged, effective tic suppression. Results suggest that environments conducive to tic suppression result in reduced tic frequency without adverse consequences. Additionally, premonitory urges, underrepresented in the literature, may represent an important enduring etiological consideration in the development and maintenance of tic disorders.

  2. Anti-timothy IgE formation: suppression with antigen D-dGl conjugates.

    PubMed

    Malley, A; Deppe, L

    1980-01-01

    Antigen D fragments (AgD1 and AgD2) and chemically synthesized quercetin-glutathione were conjugated to the synthetic polypeptide copolymer of D-glutamic acid and D-lysine (dGL). These conjugates were tested at varying epitope densities to determine their ability to suppress a secondary anti-antigen B IgE response. The data showed that all of the conjugates used with epitope densities of 5-20 groups per dGL produced significant dose-dependent suppression of a secondary IgE response. The duration of the observed suppression was short (about 30 days), but could be extended by additional treatment with the conjugate prior to the loss of unresponsiveness.

  3. Significant improvement in crow's feet after treatment with Jet-M and a mixed solution of copper-GHK, oligo-hyaluronic acid, rhodiolar extract, tranexamic acid, and β-glucan (GHR formulation).

    PubMed

    Byun, Sang-Young; Chae, Je-Byeong; Na, Jung-Im; Park, Kyoung-Chan

    2016-10-01

    Jet-M (Tav-Tech Ltd., Israel) is an instrument for skin resurfacing. When it sprays microdroplets of solution or shoots air on the skin, exfoliation and stretching of superficial layers can occur. Thus, it will increase percutaneous absorption of vitamins and other cosmetic agents. A cosmetic preparation containing copper-glycyl-L-histidyl-L-lysine, oligo-hyaluronic acid, rhodiolar extract, tranexamic acid, and β-glucan was used with Jet-M in one patient. Anesthesia was not administered and there was no pain during the treatment. A male aged 59 years was treated once a week for 12 weeks. In the clinical photographs, wrinkles around the treated eye were greatly decreased. Skin biopsies were taken from treated and untreated areas. Hematoxylin and eosin and Masson's trichrome staining showed increased collagen production in the upper dermis. On the other hand, collagen IV production was slightly increased. Fibrillin-1 and procollagen type 1 were greatly increased and tropoelastin was also increased. There was no adverse effect during and after treatment.

  4. Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells

    PubMed Central

    ZHAO, BING; HU, MENGCAI

    2013-01-01

    Gallic acid is a trihydroxybenzoic acid, also known as 3,4,5-trihydroxybenzoic acid, which is present in plants worldwide, including Chinese medicinal herbs. Gallic acid has been shown to have cytotoxic effects in certain cancer cells, without damaging normal cells. The objective of the present study was to determine whether gallic acid is able to inhibit human cervical cancer cell viability, proliferation and invasion and suppress cervical cancer cell-mediated angiogenesis. Treatment of HeLa and HTB-35 human cancer cells with gallic acid decreased cell viability in a dose-dependent manner. BrdU proliferation and tube formation assays indicated that gallic acid significantly decreased human cervical cancer cell proliferation and tube formation in human umbilical vein endothelial cells, respectively. Additionally, gallic acid decreased HeLa and HTB-35 cell invasion in vitro. Western blot analysis demonstrated that the expression of ADAM17, EGFR, p-Akt and p-Erk was suppressed by gallic acid in the HeLa and HTB-35 cell lines. These data indicate that the suppression of ADAM17 and the downregulation of the EGFR, Akt/p-Akt and Erk/p-Erk signaling pathways may contribute to the suppression of cancer progression by Gallic acid. Gallic acid may be a valuable candidate for the treatment of cervical cancer. PMID:24843386

  5. Influence of mineral amendment on disease suppressive activity of Pseudomonas fluorescens to Fusarium wilt of chickpea.

    PubMed

    Saikia, Ratul; Varghese, Saju; Singh, Bhim Pratap; Arora, Dilip K

    2009-01-01

    Fusarium wilt caused by Fusarium oxysporum f. sp. ciceri causes considerable yield loss of chickpea. Pseudomonas fluorescens4-92 (Pf4-92) strain can suppress the disease. Amendment of zinc EDTA and copper EDTA could n