Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

NASA Astrophysics Data System (ADS)

Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

2016-05-01

Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

[The combination effects of antibacterial agents against clinical isolated multiple-drug resistant Pseudomonas aeruginosa].

PubMed

Maesaki, Shigefumi; Yamaguchi, Toshiyuki; Sasaki, Kazumasa; Hashikita, Giichi; Shibuya, Shunsuke; Watanabe, Masaharu; Takayama, Sadao; Kawakami, Sayoko; Nagasawa, Mitsuaki; Suzuki, Noriyasu; Uchida, Takashi; Okabe, Tadashi; Kobayashi, Sugako

2006-02-01

The effectiveness of antibacterial agents against 70 strains of clinically isolated multiple-drug resistant Pseudomonas aeruginosa (MDRP) was measured by the micro dilution method. Fifty of all strains (71%) produced metallo-beta-lactamase and the IMP-1 gene was detected by polymerase chain reaction (PCR). The MIC90 (the minimum inhibitory concentration of an antibiotic necessary to inhibit the growth of 90% of bacterial strains) values of biapenem (BIPM), meropenem (MEPM), tazobactam/piperacillin (TAZ/PIPC), sulbactam/ cefoperazone (SBT/CPZ), cefepime (CFPM), ciprofloxacin (CPFX), pazufloxacin (PZFX), amikacin (AMK) and aztreonam (AZT) were found to be 265, 512, 256, 512, 512, 64, 128, 128 and 128 microg/mL, respectively. The in vitro combination effects of antibacterial agents were examined against 62 strains of MDRP and the synergy or additive effects were evaluated by fractional inhibitory concentration (FIC) index calculated by the checkerboard method. The combination of AMK and AZT showed synergy effects on 15/59 (25.4%) strains of MDRP. The synergy and additive effects on the MDRP strains were also found by the other antibacterial agents combination such as TAZ/PIPC and AMK, CFPM and AMK, and SBT/CPZ and AZT. These results suggested the necessity of further investigation of clinical usefulness.

Antibody specificities of children living in a malaria endemic area to inhibitory and blocking epitopes on MSP-1 19 of Plasmodium falciparum.

PubMed

Omosun, Y O; Adoro, S; Anumudu, C I; Odaibo, A B; Uthiapibull, C; Holder, A A; Nwagwu, M; Nwuba, R I

2009-03-01

Merozoite surface protein-1(19) (MSP-1(19)) specific antibodies which include processing inhibitory, blocking and neutral antibodies have been identified in individuals exposed to Plasmodium falciparum. Here we intend to look at the effect of single and multiple amino acid substitutions of MSP-1(19) on the recognition by polyclonal antibodies from children living in Igbo-Ora, Nigeria. This would provide us with information on the possibility of eliciting mainly processing inhibitory antibodies with a recombinant MSP-1(19) vaccine. Blood was collected from children in the rainy season and binding of anti-MSP-1(19) antibodies to modified mutants of MSP-1(19) was analysed by ELISA. The MSP-1(19) mutant proteins with single substitutions at positions 22 (Leu-->Arg), 43 (Glu-->Leu) and 53 (Asn-->Arg) and the MSP-1(19) mutant protein with multiple substitutions at positions 27+31+34+43 (Glu-->Tyr, Leu-->Arg, Tyr-->Ser, Glu-->Leu); which had inhibitory epitopes; had the highest recognition. Children recognised both sets of mutants with different age groups having different recognition levels. The percentage of malaria positive individuals (32-80%) with antibodies that bound to the mutants MSP-1(19) containing epitopes that recognise only processing inhibitory and not blocking antibodies, were significantly different from those with antibodies that did not bind to these mutants (21-28%). The amino acid substitutions that abolished the binding of blocking antibodies without affecting the binding of inhibitory antibodies are of particular interest in the design of MSP-1(19) based malaria vaccines. Although these MSP-1(19) mutants have not been found in natural population, their recognition by polyclonal antibodies from humans naturally infected with malaria is very promising for the future use of MSP-1(19) mutants in the design of a malaria vaccine.

Theory of mind and executive function: working-memory capacity and inhibitory control as predictors of false-belief task performance.

PubMed

Mutter, Brigitte; Alcorn, Mark B; Welsh, Marilyn

2006-06-01

This study of the relationship between theory of mind and executive function examined whether on the false-belief task age differences between 3 and 5 ears of age are related to development of working-memory capacity and inhibitory processes. 72 children completed tasks measuring false belief, working memory, and inhibition. Significant age effects were observed for false-belief and working-memory performance, as well as for the false-alarm and perseveration measures of inhibition. A simultaneous multiple linear regression specified the contribution of age, inhibition, and working memory to the prediction of false-belief performance. This model was significant, explaining a total of 36% of the variance. To examine the independent contributions of the working-memory and inhibition variables, after controlling for age, two hierarchical multiple linear regressions were conducted. These multiple regression analyses indicate that working memory and inhibition make small, overlapping contributions to false-belief performance after accounting for age, but that working memory, as measured in this study, is a somewhat better predictor of false-belief understanding than is inhibition.

Empirical prediction and validation of antibacterial inhibitory effects of various plant essential oils on common pathogenic bacteria.

PubMed

Akdemir Evrendilek, Gulsun

2015-06-02

In this study, fractional compound composition, antioxidant capacity, and phenolic substance content of 14 plant essential oils-anise (Pimpinella anisum), bay leaves (Laurus nobilis), cinnamon bark (Cinnamomum verum), clove (Eugenia caryophyllata), fennel (Foeniculum vulgare), hop (Humulus lupulus), Istanbul oregano (Origanum vulgare subsp. hirtum), Izmir oregano (Origanum onites), mint (Mentha piperita), myrtus (Myrtus communis), orange peel (Citrus sinensis), sage (Salvia officinalis), thyme (Thymbra spicata), and Turkish oregano (Origanum minutiflorum)--were related to inhibition of 10 bacteria through multiple linear or non-linear (M(N)LR) models-four Gram-positive bacteria of Listeria innocua, coagulase-negative staphylococci, Staphylococcus aureus, and Bacillus subtilis, and six Gram-negative bacteria of Yersinia enterocolitica, Salmonella Enteritidis, Salmonella Typhimurium, Proteus mirabilis, Escherichia coli O157:H7, and Klebsiella oxytoca. A total of 65 compounds with different antioxidant capacity, phenolic substance content and antibacterial properties were detected with 14 plant essential oils. The best-fit M(N)LR models indicated that relative to anise essential oil, the essential oils of oreganos, cinnamon, and thyme had consistently high inhibitory effects, while orange peel essential oil had consistently a low inhibitory effect. Regression analysis indicated that beta-bisabolene (Turkish and Istanbul oreganos), and terpinolene (thyme) were found to be the most inhibitory compounds regardless of the bacteria type tested. Copyright © 2015 Elsevier B.V. All rights reserved.

Unsupervised learning of contextual constraints in neural networks for simultaneous visual processing of multiple objects

NASA Astrophysics Data System (ADS)

Marshall, Jonathan A.

1992-12-01

A simple self-organizing neural network model, called an EXIN network, that learns to process sensory information in a context-sensitive manner, is described. EXIN networks develop efficient representation structures for higher-level visual tasks such as segmentation, grouping, transparency, depth perception, and size perception. Exposure to a perceptual environment during a developmental period serves to configure the network to perform appropriate organization of sensory data. A new anti-Hebbian inhibitory learning rule permits superposition of multiple simultaneous neural activations (multiple winners), while maintaining contextual consistency constraints, instead of forcing winner-take-all pattern classifications. The activations can represent multiple patterns simultaneously and can represent uncertainty. The network performs parallel parsing, credit attribution, and simultaneous constraint satisfaction. EXIN networks can learn to represent multiple oriented edges even where they intersect and can learn to represent multiple transparently overlaid surfaces defined by stereo or motion cues. In the case of stereo transparency, the inhibitory learning implements both a uniqueness constraint and permits coactivation of cells representing multiple disparities at the same image location. Thus two or more disparities can be active simultaneously without interference. This behavior is analogous to that of Prazdny's stereo vision algorithm, with the bonus that each binocular point is assigned a unique disparity. In a large implementation, such a NN would also be able to represent effectively the disparities of a cloud of points at random depths, like human observers, and unlike Prazdny's method

Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles.

PubMed

Janciauskiene, S

2001-03-26

Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. The molecular structure and physical properties of serpins permit these proteins to adopt a number of variant conformations under physiological conditions including the native inhibitory form and several inactive, non-inhibitory forms, such as complexes with protease or other ligands, cleaved, polymerised and oxidised. Alterations of a serpin which affect its structure and/or secretion and thus reduce its functional levels may result in pathology. Serpin dysfunction has been implicated in thrombosis, emphysema, liver cirrhosis, immune hypersensitivity and mental disorders. The loss of inhibitory activity of serpins necessarily results in an imbalance between proteases and their inhibitors, but it may also have other physiological effects through the generation of abnormal concentrations of modified, non-inhibitory forms of serpins. Although these forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, the important questions of which conditions result in generation of different molecular forms of serpins, what biological function these forms have, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Elucidation of the biological activities of non-inhibitory forms of serpins may provide useful insights into the pathogenesis of diseases and suggest new therapeutic strategies.

Inhibitory effects of magnolol and honokiol on human calcitonin aggregation

PubMed Central

Guo, Caiao; Ma, Liang; Zhao, Yudan; Peng, Anlin; Cheng, Biao; Zhou, Qiaoqiao; Zheng, Ling; Huang, Kun

2015-01-01

Amyloid formation is associated with multiple amyloidosis diseases. Human calcitonin (hCT) is a typical amyloidogenic peptide, its aggregation is associated with medullary carcinoma of the thyroid (MTC), and also limits its clinical application. Magnolia officinalis is a traditional Chinese herbal medicine; its two major polyphenol components, magnolol (Mag) and honokiol (Hon), have displayed multiple functions. Polyphenols like flavonoids and their derivatives have been extensively studied as amyloid inhibitors. However, the anti-amyloidogenic property of a biphenyl backbone containing polyphenols such as Mag and Hon has not been reported. In this study, these two compounds were tested for their effects on hCT aggregation. We found that Mag and Hon both inhibited the amyloid formation of hCT, whereas Mag showed a stronger inhibitory effect; moreover, they both dose-dependently disassembled preformed hCT aggregates. Further immuno-dot blot and dynamic light scattering studies suggested Mag and Hon suppressed the aggregation of hCT both at the oligomerization and the fibrillation stages, while MTT-based and dye-leakage assays demonstrated that Mag and Hon effectively reduced cytotoxicity caused by hCT aggregates. Furthermore, isothermal titration calorimetry indicated Mag and Hon both interact with hCT. Together, our study suggested a potential anti-amyloidogenic property of these two compounds and their structure related derivatives. PMID:26324190

Inhibition of Fatty Acid Metabolism Reduces Human Myeloma Cells Proliferation

PubMed Central

Tirado-Vélez, José Manuel; Joumady, Insaf; Sáez-Benito, Ana; Cózar-Castellano, Irene; Perdomo, Germán

2012-01-01

Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40–70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma. PMID:23029529

Inhibitory control in young children and its role in emerging internalization.

PubMed

Kochanska, G; Murray, K; Jacques, T Y; Koenig, A L; Vandegeest, K A

1996-04-01

We examined inhibitory control as a quality of temperament that contributes to internalization. Children were assessed twice, at 26-41 months (N = 103) and at 43-56 months (N = 99), on repeated occasions, in multiple observational contexts and using parental reports. Comprehensive behavioral batteries incorporating multiple tasks were designed to measure inhibitory control at toddler and preschool age. They had good internal consistencies, corresponded with maternal ratings, and were developmentally sensitive. Individual children's performance was significantly correlated across both assessments, indicating stable individual differences. Girls surpassed boys at both ages. Children's internalization was observed while they were alone with prohibited objects, with a mundane chore, playing games that occasioned cheating, being induced to violate standards of conduct, and assessed using maternal reports. Inhibitory control was significantly associated with internalization, both contemporaneously and as a predictor in the longitudinal sense. The implications for considering children's temperament as a significant, yet often neglected contributor to developing internalization are discussed.

Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol.

PubMed

Smeriglio, Antonella; Giofrè, Salvatore V; Galati, Enza M; Monforte, Maria T; Cicero, Nicola; D'Angelo, Valeria; Grassi, Gianpaolo; Circosta, Clara

2018-02-07

Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important. The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications. Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes. Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro. A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions. The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors. The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity. These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors. Copyright © 2018 Elsevier B.V. All rights reserved.

Inhibitory effect of Spirogyra spp. algal extracts against herpes simplex virus type 1 and 2 infection.

PubMed

Deethae, A; Peerapornpisal, Y; Pekkoh, J; Sangthong, P; Tragoolpua, Y

2018-06-01

To determine the antiviral activities of Spirogyra spp. algal extracts against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Spirogyra spp. was extracted using water, ethanol and methanol. Aqueous extract of Spirogyra spp. had the lowest toxicity on Vero cells with the 50% cytotoxicity concentration (CC 50 ) of 4363·30 μg ml -1 . As for potent inhibitory effect, the ethanolic extract presented the highest inhibition of viral infection on HSV-1 in the treatment during viral attachment on Vero cells with 50% inhibitory concentration (IC 50 ) and selective index (SI) values of 164·20 and 2·17 μg ml -1 . However, the methanolic extract showed the highest inhibition of HSV-2 when treated during viral attachment with IC 50 and SI values of 75·03 and 3·34 μg ml -1 . The methanolic extract of Spirogyra spp. also demonstrated significant virucidal effects on viral particles. Therefore, anti-HSV activity at various stages of the viral multiplication cycle was shown. The main active compounds in the active fractions of Spirogyra spp. ethanolic extract against HSV were found to be alkaloids, essential oils and terpenoids. The highest anti-HSV activity was obtained from the ethanolic extract of Spirogyra spp. The extract inhibited the HSV viral particles and the inhibition was during the viral attachment and the viral multiplication. Anti-HSV activity of extract of freshwater green macroalga Spirogyra spp. in Thailand was demonstrated. Therefore, anti-HSV product containing the Spirogyra spp. extract should be developed for treatment of HSV infection. © 2018 The Society for Applied Microbiology.

Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats.

PubMed

Li, Longkai; Shen, Nan; Wang, Nan; Wang, Weidong; Tang, Qingzhu; Du, Xiangning; Carrero, Juan Jesus; Wang, Keping; Deng, Yiyao; Li, Zhitong; Lin, Hongli; Wu, Taihua

2018-06-01

Ultrafiltration failure is a major complication of long-term peritoneal dialysis, resulting in dialysis failure. Peritoneal fibrosis induced by continuous exposure to high glucose dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. Overactivation of several signaling pathways, including transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) pathways, contribute to the development of peritoneal fibrosis. Therefore, simultaneously blocking multiple signaling pathways might be a potential novel method of treating peritoneal fibrosis. Previously, we showed that core fucosylation, an important posttranslational modification of the TGF-β1 receptors, can regulate the activation of TGF-β1 signaling in renal interstitial fibrosis. However, it remains unclear whether core fucosylation affects the progression of peritoneal fibrosis. Herein, we show that core fucosylation was enriched in the peritoneal membrane of rats accompanied by peritoneal fibrosis induced by a high glucose dialysate. Blocking core fucosylation dramatically attenuated peritoneal fibrosis in the rat model achieved by simultaneously inactivating the TGF-β1 and PDGF signaling pathways. Next the protective effects of blocking core fucosylation and imatinib (a selective PDGF receptor inhibitor) on peritoneal fibrosis were compared and found to exhibit a greater inhibitory effect over imatinib alone, suggesting that blocking activation of multiple signaling pathways may have superior inhibitory effects on the development of peritoneal fibrosis. Thus, core fucosylation is essential for the development of peritoneal fibrosis by regulating the activation of multiple signaling pathways. This may be a potential novel target for drug development to treat peritoneal fibrosis. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Polysorbate 80 and polymyxin B inhibit Stenotrophomonas maltophilia biofilm.

PubMed

Malinowski, Adam M; McClarty, Bryan M; Robinson, Carolyn; Spear, William; Sanchez, Maria; Sparkes, Timothy C; Brooke, Joanna S

2017-02-01

Stenotrophomonas maltophilia is an opportunistic multiple-drug-resistant human pathogen that forms biofilms on implanted medical devices. We examined the potential inhibitory activity of polysorbate 80 and polymyxin B against S. maltophilia. A combination of subMIC polymyxin B and polysorbate 80 was the most effective inhibitor of growth and biofilm formation. Copyright © 2016 Elsevier Inc. All rights reserved.

Potent inhibition of angiotensin AT1 receptor signaling by RGS8: importance of the C-terminal third exon part of its RGS domain.

PubMed

Song, Dan; Nishiyama, Mariko; Kimura, Sadao

2016-10-01

R4/B subfamily RGS (regulator of G protein signaling) proteins play roles in regulation of many GPCR-mediated responses. Multiple RGS proteins are usually expressed in a cell, and it is difficult to point out which RGS protein species are functionally important in the cell. To evaluate intrinsic potency of these RGS proteins, we compared inhibitory effects of RGS1, RGS2, RGS3, RGS4, RGS5, RGS8 and RGS16 on AT1 receptor signaling. Intracellular Ca(2+) responses to angiotensin II were markedly attenuated by transiently expressed RGS2, RGS3 and RGS8, compared to weak inhibition by RGS1, RGS4, RGS5 and RGS16. N-terminally deleted RGS2 (RGS2 domain) lost this potent inhibitory effect, whereas RGS domains of RGS3 and RGS8 showed strong inhibition similar to those of the full-length proteins. To investigate key determinants that specify the differences in potency, we constructed chimeric domains by replacing one or two of three exon parts of RGS8 domain with the corresponding part of RGS5. The chimeric RGS8 domains containing the first or the second exon part of RGS5 showed strong inhibitory effects similar to that of wild type RGS8, but the chimeric domain with the third exon part of RGS5 lost its activity. On the contrary, replacement of the third exon part of RGS5 with the corresponding residues of RGS8 increased the inhibitory effect. The role of the third exon part of RGS8 domain was further confirmed with the chimeric RGS8/RGS4 domains. These results indicate the potent inhibitory activity of RGS8 among R4/B subfamily proteins and importance of the third exon.

Ned-19 inhibition of parasite growth and multiplication suggests a role for NAADP mediated signalling in the asexual development of Plasmodium falciparum.

PubMed

Suárez-Cortés, Pablo; Gambara, Guido; Favia, Annarita; Palombi, Fioretta; Alano, Pietro; Filippini, Antonio

2017-09-12

Although malaria is a preventable and curable human disease, millions of people risk to be infected by the Plasmodium parasites and to develop this illness. Therefore, there is an urgent need to identify new anti-malarial drugs. Ca 2+ signalling regulates different processes in the life cycle of Plasmodium falciparum, representing a suitable target for the development of new drugs. This study investigated for the first time the effect of a highly specific inhibitor of nicotinic acid adenine dinucleotide phosphate (NAADP)-induced Ca 2+ release (Ned-19) on P. falciparum, revealing the inhibitory effect of this compound on the blood stage development of this parasite. Ned-19 inhibits both the transition of the parasite from the early to the late trophozoite stage and the ability of the late trophozoite to develop to the multinucleated schizont stage. In addition, Ned-19 affects spontaneous intracellular Ca 2+ oscillations in ring and trophozoite stage parasites, suggesting that the observed inhibitory effects may be associated to regulation of intracellular Ca 2+ levels. This study highlights the inhibitory effect of Ned-19 on progression of the asexual life cycle of P. falciparum. The observation that Ned-19 inhibits spontaneous Ca 2+ oscillations suggests a potential role of NAADP in regulating Ca 2+ signalling of P. falciparum.

Potent inhibitory effect of silibinin from milk thistle on skin inflammation stimuli by 12-O-tetradecanoylphorbol-13-acetate.

PubMed

Liu, Wenfeng; Li, Yonglian; Zheng, Xi; Zhang, Kun; Du, Zhiyun

2015-12-01

Silibinin, a major polyphenol in milk thistle, has been reported to have multiple pharmacological activities; therefore, there is an urgent need to well understand how silibinin works on inflammation-associated skin diseases. We herein designed silibinin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated skin inflammation to test its inhibitory effects. It was demonstrated that silibinin, applied topically onto mouse ears following TPA stimulation, effectively down-regulated the expressions of TPA-induced interleukin-1β (IL-1β), interleukin-6 (IL-6), necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. Further mechanistic investigations indicated that silibinin suppressed the expression of IκB kinase (IKK) by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, and thereby suppressing TPA-stimulated nuclear factor-κB (NF-κB) activation. Promisingly, silibinin, used for transdermal application, may be a potent naturally occurring anti-inflammatory agent for the prevention of inflammation-associated skin diseases.

Quantitative structure activity relationship studies of sulfamide derivatives as carbonic anhydrase inhibitor: as antiglaucoma agents.

PubMed

Kumar, Surendra; Singh, Vineet; Tiwari, Meena

2007-07-01

Selective inhibition of ciliary process enzyme i.e. Carbonic Anhydrase-II is an excellent approach in reducing elevated intraocular pressure, thus treating glaucoma. Due to characteristic physicochemical properties of sulphonamide (Inhibition of Carbonic Anhydrase), they are clinically effective against glaucoma. But the non-specificity of sulphonamide derivatives to isozyme, leads to a range of side effects. Presently, the absence of comparative studies related to the binding of the sulphonamides as inhibitors to CA isozymes limits their use. In this paper we have represented "Three Dimensional Quantitative Structure Activity Relationship" study to characterize structural features of Sulfamide derivative [RR'NSO(2)NH(2)] as inhibitors, that are required for selective binding of carbonic anhydrase isozymes (CAI and CAII). In the analysis, stepwise multiple linear regression was performed using physiochemical parameters as independent variable and CA-I and CA-II inhibitory activity as dependent variable, respectively. The best multiparametric QSAR model obtained for CA-I inhibitory activity shows good statistical significance (r= 0.9714) and predictability (Q(2)=0.8921), involving the Electronic descriptors viz. Highest Occupied Molecular Orbital, Lowest Unoccupied Molecular Orbital and Steric descriptors viz. Principal moment of Inertia at X axis. Similarly, CA-II inhibitory activity also shows good statistical significance (r=0.9644) and predictability (Q(2)=0.8699) involving aforementioned descriptors. The predictive power of the model was successfully tested externally using a set of six compounds as test set for CA-I inhibitory activity and a set of seven compounds in case of CA-II inhibitory activity with good predictive squared correlation coefficient, r(2)(pred)=0.6016 and 0.7662, respectively. Overview of analysis favours substituents with high electronegativity and less bulk at R and R' positions of the parent nucleus, provides a basis to design new Sulfamide derivatives possessing potent and selective carbonic anhydrase-II inhibitory activity.

Synergistic anti-inflammatory effects of Nobiletin and Sulforaphane in lipopolysaccharide-stimulated RAW 264.7 cells

PubMed Central

Guo, Shanshan; Qiu, Peiju; Xu, Guang; Wu, Xian; Dong, Ping; Yang, Guanpin; Zheng, Jinkai; McClements, David Julian; Xiao, Hang

2012-01-01

Inflammation plays important roles in initiation and progress of many diseases including cancers in multiple organ sites. Herein, we investigated the anti-inflammatory effects of two dietary compounds, nobiletin (NBN) and sulforaphane (SFN) in combination. Non-cytotoxic concentrations of NBN, SFN, and their combinations were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that combined NBN and SFN treatments produced much stronger inhibitory effects on the production of nitric oxide (NO) than NBN or SFN alone at higher concentrations. These enhanced inhibitory effects were synergistic based on the isobologram analysis. Western blot analysis showed that combined NBN and SFN treatments synergistically decreased iNOS and COX-2 protein expression levels and induced heme oxygenase-1 (HO-1) protein expression. Real-time PCR analysis indicated that low doses of NBN and SFN in combination significantly suppressed LPS-induced upregulation of IL-1 mRNA levels, and synergistically increased HO-1 mRNA levels. Overall our results demonstrated that NBN and SFN in combination produced synergistic effects in inhibiting LPS-induced inflammation in RAW 264.7 cells. PMID:22335189

Platelet Aggregation Inhibitory Effects and Pharmacokinetics of Prasugrel Used in Combination With Aspirin in Healthy Japanese Subjects.

PubMed

Umemura, Kazuo; Ikeda, Yasuhiko; Matsushima, Nobuko; Kondo, Kazunao

2017-07-01

We evaluated the pharmacokinetics and pharmacodynamics of prasugrel used in combination with aspirin in healthy Japanese subjects. All subjects received aspirin 100 mg/day. Subsequently, in the single-administration study, 23 subjects also received prasugrel 20 or 30 mg, and in the multiple-administration study, 20 subjects received a loading dose of prasugrel 20 or 30 mg on day 1, followed by a maintenance dose of prasugrel 5 or 7.5 mg/day, respectively, on days 2-5. In both studies, the plasma concentration of the active metabolite of prasugrel, R-138727, reached a maximum 0.5 hours after administration and rapidly decreased within 4 hours. In the single-administration study, the inhibitory effect on adenosine diphosphate-induced platelet aggregation was significantly higher in the prasugrel 20- and 30-mg groups than in the placebo group at all times (1-144 hours) after administration. In the multiple-administration study, a similar antiplatelet effect was found after both the loading dose and the maintenance dose and was maintained for 3-6 days after the last administration. There were study drug-related adverse events; however, all were mild, and none was clinically significant. © 2016 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential*

PubMed Central

Bloom, Joshua; Metz, Christine; Nalawade, Saisha; Casabar, Julian; Cheng, Kai Fan; He, Mingzhu; Sherry, Barbara; Coleman, Thomas; Forsthuber, Thomas; Al-Abed, Yousef

2016-01-01

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in a broad range of inflammatory and oncologic diseases. MIF is unique among cytokines in terms of its release profile and inflammatory role, notably as an endogenous counter-regulator of the anti-inflammatory effects of glucocorticoids. In addition, it exhibits a catalytic tautomerase activity amenable to the design of high affinity small molecule inhibitors. Although several classes of these compounds have been identified, biologic characterization of these molecules remains a topic of active investigation. In this study, we used in vitro LPS-driven assays to characterize representative molecules from several classes of MIF inhibitors. We determined that MIF inhibitors exhibit distinct profiles of anti-inflammatory activity, especially with regard to TNFα. We further investigated a molecule with relatively low anti-inflammatory activity, compound T-614 (also known as the anti-rheumatic drug iguratimod), and found that, in addition to exhibiting selective MIF inhibition in vitro and in vivo, iguratimod also has additive effects with glucocorticoids. Furthermore, we found that iguratimod synergizes with glucocorticoids in attenuating experimental autoimmune encephalitis, a model of multiple sclerosis. Our work identifies iguratimod as a valuable new candidate for drug repurposing to MIF-relevant diseases, including multiple sclerosis. PMID:27793992

Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities.

PubMed

Chao, Shi-Wei; Chen, Liang-Chieh; Yu, Chia-Chun; Liu, Chang-Yi; Lin, Tony Eight; Guh, Jih-Hwa; Wang, Chen-Yu; Chen, Chun-Yung; Hsu, Kai-Cheng; Huang, Wei-Jan

2018-01-01

Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC 50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Anesthesia modifies subthreshold critical slowing down in a stochastic Hodgkin-Huxley-like model with inhibitory synaptic input

NASA Astrophysics Data System (ADS)

Bukoski, Alex; Steyn-Ross, D. A.; Pickett, Ashley F.; Steyn-Ross, Moira L.

2018-06-01

The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by γ -aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic-induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold.

Sub-inhibitory concentrations of heavy metals facilitate the horizontal transfer of plasmid-mediated antibiotic resistance genes in water environment.

PubMed

Zhang, Ye; Gu, April Z; Cen, Tianyu; Li, Xiangyang; He, Miao; Li, Dan; Chen, Jianmin

2018-06-01

Although widespread antibiotic resistance has been mostly attributed to the selective pressure generated by overuse and misuse of antibiotics, recent growing evidence suggests that chemicals other than antibiotics, such as certain metals, can also select and stimulate antibiotic resistance via both co-resistance and cross-resistance mechanisms. For instance, tetL, merE, and oprD genes are resistant to both antibiotics and metals. However, the potential de novo resistance induced by heavy metals at environmentally-relevant low concentrations (much below theminimum inhibitory concentrations [MICs], also referred as sub-inhibitory) has hardly been explored. This study investigated and revealed that heavy metals, namely Cu(II), Ag(I), Cr(VI), and Zn(II), at environmentally-relevant and sub-inhibitory concentrations, promoted conjugative transfer of antibiotic resistance genes (ARGs) between E. coli strains. The mechanisms of this phenomenon were further explored, which involved intracellular reactive oxygen species (ROS) formation, SOS response, increased cell membrane permeability, and altered expression of conjugation-relevant genes. These findings suggest that sub-inhibitory levels of heavy metals that widely present in various environments contribute to the resistance phenomena via facilitating horizontal transfer of ARGs. This study provides evidence from multiple aspects implicating the ecological effect of low levels of heavy metals on antibiotic resistance dissemination and highlights the urgency of strengthening efficacious policy and technology to control metal pollutants in the environments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Interactions among catechol-O-methyltransferase genotype, parenting, and sex predict children’s internalizing symptoms and inhibitory control: Evidence for differential susceptibility

PubMed Central

SULIK, MICHAEL J.; EISENBERG, NANCY; SPINRAD, TRACY L.; LEMERY-CHALFANT, KATHRYN; SWANN, GREGORY; SILVA, KASSONDRA M.; REISER, MARK; STOVER, DARYN A.; VERRELLI, BRIAN C.

2015-01-01

We used sex, observed parenting quality at 18 months, and three variants of the catechol-O-methyltransferase gene (Val158Met [rs4680], intron1 [rs737865], and 3′-untranslated region [rs165599]) to predict mothers’ reports of inhibitory and attentional control (assessed at 42, 54, 72, and 84 months) and internalizing symptoms (assessed at 24, 30, 42, 48, and 54 months) in a sample of 146 children (79 male). Although the pattern for all three variants was very similar, Val158Met explained more variance in both outcomes than did intron1, the 3′-untranslated region, or a haplotype that combined all three catechol-O-methyltransferase variants. In separate models, there were significant three-way interactions among each of the variants, parenting, and sex, predicting the intercepts of inhibitory control and internalizing symptoms. Results suggested that Val158Met indexes plasticity, although this effect was moderated by sex. Parenting was positively associated with inhibitory control for methionine–methionine boys and for valine–valine/valine–methionine girls, and was negatively associated with internalizing symptoms for methionine–methionine boys. Using the “regions of significance” technique, genetic differences in inhibitory control were found for children exposed to high-quality parenting, whereas genetic differences in internalizing were found for children exposed to low-quality parenting. These findings provide evidence in support of testing for differential susceptibility across multiple outcomes. PMID:25159270

Maximizing Exposure Therapy: An Inhibitory Learning Approach

PubMed Central

Craske, Michelle G.; Treanor, Michael; Conway, Chris; Zbozinek, Tomislav; Vervliet, Bram

2014-01-01

Exposure therapy is an effective approach for treating anxiety disorders, although a substantial number of individuals fail to benefit or experience a return of fear after treatment. Research suggests that anxious individuals show deficits in the mechanisms believed to underlie exposure therapy, such as inhibitory learning. Targeting these processes may help improve the efficacy of exposure-based procedures. Although evidence supports an inhibitory learning model of extinction, there has been little discussion of how to implement this model in clinical practice. The primary aim of this paper is to provide examples to clinicians for how to apply this model to optimize exposure therapy with anxious clients, in ways that distinguish it from a ‘fear habituation’ approach and ‘belief disconfirmation’ approach within standard cognitive-behavior therapy. Exposure optimization strategies include 1) expectancy violation, 2) deepened extinction, 3) occasional reinforced extinction, 4) removal of safety signals, 5) variability, 6) retrieval cues, 7) multiple contexts, and 8) affect labeling. Case studies illustrate methods of applying these techniques with a variety of anxiety disorders, including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, specific phobia, and panic disorder. PMID:24864005

Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies.

PubMed

Zhang, Zhiqing; Li, Shaowei; Gu, Ying; Xia, Ningshao

2016-11-18

Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immune deficiency syndrome (AIDS), a global epidemic for more than three decades. HIV-1 replication is primarily controlled through antiretroviral therapy (ART) but this treatment does not cure HIV-1 infection. Furthermore, there is increasing viral resistance to ART, and side effects associated with long-term therapy. Consequently, there is a need of alternative candidates for HIV-1 prevention and therapy. Recent advances have discovered multiple broadly neutralizing antibodies against HIV-1. In this review, we describe the key epitopes on the HIV-1 Env protein and the reciprocal broadly neutralizing antibodies, and discuss the ongoing clinical trials of broadly neutralizing and inhibitory antibody therapy as well as antibody combinations, bispecific antibodies, and methods that improve therapeutic efficacy by combining broadly neutralizing antibodies (bNAbs) with latency reversing agents. Compared with ART, HIV-1 therapeutics that incorporate these broadly neutralizing and inhibitory antibodies offer the advantage of decreasing virus load and clearing infected cells, which is a promising prospect in HIV-1 prevention and treatment.

Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

PubMed

Gao, R; Penzes, P

2015-01-01

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

Multiple effects of the special AT-rich binding protein 1 (SATB1) in colon carcinoma.

PubMed

Frömberg, Anja; Rabe, Michael; Aigner, Achim

2014-12-01

SATB1 (special AT-rich binding protein 1) is a global chromatin organizer regulating the expression of a large number of genes. Overexpression has been found in various solid tumors and positively correlated with prognostic and clinicopathological properties. In colorectal cancer (CRC), SATB1 overexpression and its correlation with poor differentiation, invasive depth, TNM (tumor, nodes, metastases) stage and prognosis have been demonstrated. However, more detailed studies on the SATB1 functions in CRC are warranted. In this article, we comprehensively analyze the cellular and molecular role of SATB1 in CRC cell lines with different SATB1 expression levels by using RNAi-mediated knockdown. Using siRNAs with different knockdown efficacies, we demonstrate antiproliferative, cell cycle-inhibitory and proapoptotic effects of SATB1 knockdown in a SATB1 gene dose-dependent manner. Tumor growth inhibition is confirmed in vivo in a subcutaneous tumor xenograft mouse model using stable knockdown cells. The in-depth analysis of cellular effects reveals increased activities of caspases-3, -7, -8, -9 and other mediators of apoptotic pathways. Similarly, the analysis of E- and N-cadherin, slug, twist, β-catenin and MMP7 indicates SATB1 effects on epithelial-mesenchymal transition (EMT) and matrix breakdown. Our results also establish SATB1 effects on receptor tyrosine kinases and (proto-)oncogenes such as HER receptors and Pim-1. Taken together, this suggests a more complex molecular interplay between tumor-promoting and possible inhibitory effects in CRC by affecting multiple pathways and molecules involved in proliferation, cell cycle, EMT, invasion and cell survival. © 2014 UICC.

A chalcone with potent inhibiting activity against biofilm formation by nontypeable Haemophilus influenzae.

PubMed

Kunthalert, Duangkamol; Baothong, Sudarat; Khetkam, Pichit; Chokchaisiri, Suwadee; Suksamrarn, Apichart

2014-10-01

Nontypeable Haemophilus influenzae (NTHi), an important human respiratory pathogen, frequently causes biofilm infections. Currently, resistance of bacteria within the biofilm to conventional antimicrobials poses a major obstacle to effective medical treatment on a global scale. Novel agents that are effective against NTHi biofilm are therefore urgently required. In this study, a series of natural and synthetic chalcones with various chemical substituents were evaluated in vitro for their antibiofilm activities against strong biofilm-forming strains of NTHi. Of the test chalcones, 3-hydroxychalcone (chalcone 8) exhibited the most potent inhibitory activity, its mean minimum biofilm inhibitory concentration (MBIC50 ) being 16 μg/mL (71.35 μM), or approximately sixfold more active than the reference drug, azithromycin (MBIC50 419.68 μM). The inhibitory activity of chalcone 8, which is a chemically modified chalcone, appeared to be superior to those of the natural chalcones tested. Significantly, chalcone 8 inhibited biofilm formation by all studied NTHi strains, indicating that the antibiofilm activities of this compound occur across multiple strong-biofilm forming NTHi isolates of different clinical origins. According to antimicrobial and growth curve assays, chalcone 8 at concentrations that decreased biofilm formation did not affect growth of NTHi, suggesting the biofilm inhibitory effect of chalcone 8 is non-antimicrobial. In terms of structure-activity relationship, the possible substituent on the chalcone backbone required for antibiofilm activity is discussed. These findings indicate that 3-hydroxychalcone (chalcone 8) has powerful antibiofilm activity and suggest the potential application of chalcone 8 as a new therapeutic agent for control of NTHi biofilm-associated infections. © 2014 The Societies and Wiley Publishing Asia Pty Ltd.

Alternaria toxin-induced resistance in rose plants against rose aphid (Macrosiphum rosivorum): effect of tenuazonic acid.

PubMed

Yang, Fa-zhong; Yang, Bin; Li, Bei-bei; Xiao, Chun

2015-04-01

Many different types of toxins are produced by the fungus, Alternaria alternata (Fr.) Keissler. Little is known, however, regarding the influence of these toxins on insects. In this study, we investigated the toxin-induced inhibitory effects of the toxin produced by A. alternata on the rose aphid, Macrosiphum rosivorum, when the toxin was applied to leaves of the rose, Rosa chinensis. The results demonstrated that the purified crude toxin was non-harmful to rose plants and rose aphids, but had an intensive inhibitory effect on the multiplication of aphids. The inhibitory index against rose aphids reached 87.99% when rose plants were sprayed with the toxin solution at a low concentration. Further results from bioassays with aphids and high performance liquid chromatography (HPLC) analyses demonstrated that tenuazonic acid (TeA) was one of the most important resistance-related active components in the crude toxin. The content of TeA was 0.1199% in the crude toxin under the HPLC method. Similar to the crude toxin, the inhibitory index of pure TeA reached 83.60% 15 d after the rose plants were sprayed with pure TeA solution at the lower concentration of 0.060 μg/ml, while the contents of residual TeA on the surface and in the inner portion of the rose plants were only 0.04 and 0.00 ng/g fresh weight of TeA-treated rose twigs, respectively, 7 d after the treatment. Our results show that TeA, an active component in the A. alternata toxin, can induce the indirect plant-mediated responses in rose plants to intensively enhance the plant's resistances against rose aphids, and the results are very helpful to understand the plant-mediated interaction between fungi and insects on their shared host plants.

Inhibitory activity and mechanism of inhibition of the N-[[(4-benzoylamino)phenyl]sulfonyl]amino acid aldose reductase inhibitors.

PubMed

DeRuiter, J; Mayfield, C A

1990-11-15

A series of substituted N-[[(4-benzoylamino)phenyl]sulfonyl]amino acids (BAPS-amino acids) were synthesized by established methods, and the stereochemistry of the products was confirmed by HPLC analysis after chiral derivatization. When tested against aldose reductase (alditol:NADP+ oxidoreductase; EC 1.1.1.21; ALR2) isolated from rat lens, all of the BAPS-amino acids were determined to be significantly more inhibitory than the corresponding N-(phenylsulfonyl)amino acids. Structure-inhibition and enzyme kinetic analyses suggest that the BAPS-amino acids inhibit ALR2 by a mechanism similar to the N-(phenylsulfonyl)amino acids. However, multiple inhibition analyses indicate that the increased inhibitory activity of the BAPS-amino acids is a result of interaction with multiple sites present on ALR2. Enzyme specificity studies with several of the BAPS-amino acids demonstrated that these compounds do not produce significant inhibition of other nucleotide-requiring enzymes including aldehyde reductase (alcohol: NADP+ oxidoreductase; EC 1.1.1.2; ALR1).

Intervention effects of five cations and their correction on hemolytic activity of tentacle extract from the jellyfish Cyanea capillata

PubMed Central

2017-01-01

Cations have generally been reported to prevent jellyfish venom-induced hemolysis through multiple mechanisms by spectrophotometry. Little attention has been paid to the potential interaction between cations and hemoglobin, potentially influencing the antagonistic effect of cations. Here, we explored the effects of five reported cations, La3+, Mn2+, Zn2+, Cu2+ and Fe2+, on a hemolytic test system and the absorbance of hemoglobin, which was further used to measure their effects on the hemolysis of tentacle extract (TE) from the jellyfish Cyanea capillata. All the cations displayed significant dose-dependent inhibitory effects on TE-induced hemolysis with various dissociation equilibrium constant (Kd) values as follows: La3+ 1.5 mM, Mn2+ 93.2 mM, Zn2+ 38.6 mM, Cu2+ 71.9 μM and Fe2+ 32.8 mM. The transparent non-selective pore blocker La3+ did not affect the absorbance of hemoglobin, while Mn2+ reduced it slightly. Other cations, including Zn2+, Cu2+ and Fe2+, greatly decreased the absorbance with Kd values of 35.9, 77.5 and 17.6 mM, respectively. After correction, the inhibitory Kd values were 1.4 mM, 45.8 mM, 128.5 μM and 53.1 mM for La3+, Zn2+, Cu2+ and Fe2+, respectively. Mn2+ did not inhibit TE-induced hemolysis. Moreover, the inhibitory extent at the maximal given dose of all cations except La3+ was also diminished. These corrected results from spectrophotometry were further confirmed by direct erythrocyte counting under microscopy. Our results indicate that the cations, except for La3+, can interfere with the absorbance of hemoglobin, which should be corrected when their inhibitory effects on hemolysis by jellyfish venoms are examined. The variation in the inhibitory effects of cations suggests that the hemolysis by jellyfish venom is mainly attributed to the formation of non-selective cation pore complexes over other potential mechanisms, such as phospholipases A2 (PLA2), polypeptides, protease and oxidation. Blocking the pore-forming complexes may be a primary strategy to improve the in vivo damage and mortality from jellyfish stings due to hemolytic toxicity. PMID:28503385

Interaction of inhibitory and facilitatory effects of conditioning trials on long-term memory formation

PubMed Central

Hosono, Shouhei; Matsumoto, Yukihisa

2016-01-01

Animals learn through experience and consolidate the memories into long-time storage. Conditioning parameters to induce protein synthesis-dependent long-term memory (LTM) have been the subject of extensive studies in many animals. Here we found a case in which a conditioning trial inhibits or facilitates LTM formation depending on the intervals from preceding trials. We studied the effects of conditioning parameters on LTM formation in olfactory conditioning of maxillary-palpi extension response with sucrose reward in the cockroach Periplaneta americana. We found, at first, that translation- and transcription-dependent LTM forms 1 h after training, the fastest so far reported in insects. Second, we observed that multiple-trial training with an intertrial interval (ITI) of 20 or 30 sec, often called massed training, is more effective than spaced training for LTM formation, an observation that differs from the results of most studies in other animals. Third, we found that a conditioning trial inhibits LTM formation when the intervals from preceding trials were in the range of 10–16 min. This inhibitory effect is pairing-specific and is not due to decreased motivation for learning (overtraining effect). To our knowledge, no similar inhibition of LTM formation by a conditioning trial has been reported in any animals. We propose a model to account for the effects of trial number and ITIs on LTM formation. Olfactory conditioning in cockroaches should provide pertinent materials in which to study neuronal and molecular mechanisms underlying the inhibitory and facilitatory processes for LTM formation. PMID:27918270

Dissociable Roles of Right Inferior Frontal Cortex and Anterior Insula in Inhibitory Control: Evidence from Intrinsic and Task-Related Functional Parcellation, Connectivity, and Response Profile Analyses across Multiple Datasets

PubMed Central

Ryali, Srikanth; Chen, Tianwen; Li, Chiang-Shan R.

2014-01-01

The right inferior frontal cortex (rIFC) and the right anterior insula (rAI) have been implicated consistently in inhibitory control, but their differential roles are poorly understood. Here we use multiple quantitative techniques to dissociate the functional organization and roles of the rAI and rIFC. We first conducted a meta-analysis of 70 published inhibitory control studies to generate a commonly activated right fronto-opercular cortex volume of interest (VOI). We then segmented this VOI using two types of features: (1) intrinsic brain activity; and (2) stop-signal task-evoked hemodynamic response profiles. In both cases, segmentation algorithms identified two stable and distinct clusters encompassing the rAI and rIFC. The rAI and rIFC clusters exhibited several distinct functional characteristics. First, the rAI showed stronger intrinsic and task-evoked functional connectivity with the anterior cingulate cortex, whereas the rIFC had stronger intrinsic and task-evoked functional connectivity with dorsomedial prefrontal and lateral fronto-parietal cortices. Second, the rAI showed greater activation than the rIFC during Unsuccessful, but not Successful, Stop trials, and multivoxel response profiles in the rAI, but not the rIFC, accurately differentiated between Successful and Unsuccessful Stop trials. Third, activation in the rIFC, but not rAI, predicted individual differences in inhibitory control abilities. Crucially, these findings were replicated in two independent cohorts of human participants. Together, our findings provide novel quantitative evidence for the dissociable roles of the rAI and rIFC in inhibitory control. We suggest that the rAI is particularly important for detecting behaviorally salient events, whereas the rIFC is more involved in implementing inhibitory control. PMID:25355218

Attention problems, inhibitory control, and intelligence index overlapping genetic factors: a study in 9-, 12-, and 18-year-old twins.

PubMed

Polderman, Tinca J C; de Geus, Eco J C; Hoekstra, Rosa A; Bartels, Meike; van Leeuwen, Marieke; Verhulst, Frank C; Posthuma, Danielle; Boomsma, Dorret I

2009-05-01

It is assumed that attention problems (AP) are related to impaired executive functioning. We investigated the association between AP and inhibitory control and tested to what extent the association was due to genetic factors shared with IQ. Data were available from 3 independent samples of 9-, 12-, and 18-year-old twins and their siblings (1,209 participants). AP were assessed with checklists completed by multiple informants. Inhibitory control was measured with the Stroop Color Word Task (Stroop, 1935), and IQ with the Wechsler Intelligence Scale for Children (Wechsler et al., 2002) or Wechsler Adult Intelligence Scale (Wechsler, 1997). AP and inhibitory control were only correlated in the 12-year-old cohort (r = .18), but appeared non-significant after controlling for IQ. Significant correlations existed between AP and IQ in 9- and 12-year olds (r = -.26/-.34). Inhibitory control and IQ were correlated in all cohorts (r = -.16, -.24 and -.35, respectively). Genetic factors that influenced IQ also influenced inhibitory control. We conclude that the association between AP and inhibitory control as reported in the literature may largely derive from genetic factors that are shared with IQ.

Inhibitory effect of standardized cannabis sativa extract and its ingredient cannabidiol on rat and human bladder contractility.

PubMed

Capasso, Raffaele; Aviello, Gabriella; Borrelli, Francesca; Romano, Barbara; Ferro, Matteo; Castaldo, Luigi; Montanaro, Vittorino; Altieri, Vincenzo; Izzo, Angelo A

2011-04-01

To evaluate the effect of a Cannabis sativa extract enriched in cannabidiol (CBD) botanic drug substance (BDS) and pure CBD, on bladder contractility in vitro. Cannabis based-medicines, including CBD-enriched extracts, have been shown to reduce urinary urgency, incontinence episodes, frequency, and nocturia in patients with multiple sclerosis. Strips were cut from male Wistar rats and the human bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation, acetylcholine, KCl, and α,β-methylene adenosine triphosphate. CBD BDS significantly reduced the contractions induced by acetylcholine, but not those induced with electrical field stimulation, KCl, or α,β-methylene adenosine triphosphate in the isolated rat bladder. The inhibitory effect of CBD BDS was not significantly modified by the cannabinoid or opioid receptor antagonists or by modulators of calcium levels, but it was increased by ruthenium red and capsazepine, 2 transient receptor potential vanilloid type-1 blockers. In humans, CBD BDS and pure CBD significantly reduced acetylcholine-induced contractions, an effect that was not changed by the transient receptor potential vanilloid type-1 blockers. Our data have suggested that CBD BDS reduces cholinergic-mediated contractility and that this effect is modulated by transient receptor potential vanilloid type-1 in rats but not in humans. CBD is the chemical ingredient of CBD BDS responsible for such activity. If confirmed in vivo, such results could provide a pharmacologic basis to explain, at least in part, the efficacy of Cannabis medicines in reducing incontinence episodes in patients with multiple sclerosis. Copyright © 2011 Elsevier Inc. All rights reserved.

The plasticity of descending controls in pain: translational probing.

PubMed

Bannister, Kirsty; Dickenson, A H

2017-07-01

Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α 2 -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT 3 receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT 7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Mechanistic study of intertypic nucleoprotein complex formation and its inhibitory effect toward influenza A virus.

PubMed

Narkpuk, Jaraspim; Jaru-Ampornpan, Peera; Subali, Theressa; Bertulfo, Fatima Carla T; Wongthida, Phonphimon; Jongkaewwattana, Anan

2015-11-01

Co-infection of influenza A and B viruses (IAV and IBV) results in marked decreases in IAV replication. Multiple mechanisms have been proposed for this phenomenon. Recently, we reported that IBV nucleoprotein (BNP) alone can suppress IAV replication and proposed an inhibition model in which BNP binds IAV nucleoprotein (ANP) and disrupts IAV polymerase complexes. Here, using mutagenesis and co-immunoprecipitation, we determined the protein motifs mediating the intertypic ANP-BNP complex and showed that it specifically interferes with ANP׳s interaction with the PB2 subunit of the IAV polymerase but not with the other subunit PB1. We further demonstrated that BNP only suppresses growth of IAVs but not other RNA viruses. However, different IAV strains display varied sensitivity toward the BNP׳s inhibitory effect. Together, our data provide mechanistic insights into intertypic nucleoprotein complex formation and highlight the role of BNP as a potential broad-spectrum anti-IAV agent. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiple trial inhibitory avoidance acquisition and retrieval are resistant to chronic stress.

PubMed

Raya, J; Girardi, C E N; Esumi, L A; Ferreira, L B T; Hipólide, D C

2018-02-01

Chronic mild stress (CMS) is a widely accepted animal model relevant to depression that among other consequences, is chiefly known to induce anhedonia, often assessed as decreased preference for sucrose solution. CMS is also known to affect cognition, particularly memory tasks. In this study we have employed the multiple-trial inhibitory avoidance memory task (MTIA) to assess CMS effects on memory acquisition and retrieval. MTIA consists of repeated exposures to the unconditioned stimulus until a learning criterion is reached. Wistar rats underwent CMS for 5 weeks, and sucrose consumption was assessed once a week. At the end of CMS, animals were evaluated in the MTIA task. Overall decreased sucrose solution preference was highly variable. Further analyses showed that a subset of animals expressed resilience while another subset was sensitive to stress. CMS did not affect the number of acquisition sessions before reaching criterion or retrieval latency of MTIA task in neither sensitive nor resilient groups. Although tasks that assess learning ability in animal models relevant to depression indicate cognitive deficits, the ability to learn the association between compartment crossing and the aversive electric foot shock, which is strongly dependent on emotional aspects, was intact. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers.

PubMed

Prochniewicz, Ewa; Lowe, Dawn A; Spakowicz, Daniel J; Higgins, LeeAnn; O'Conor, Kate; Thompson, LaDora V; Ferrington, Deborah A; Thomas, David D

2008-02-01

To understand the molecular mechanism of oxidation-induced inhibition of muscle contractility, we have studied the effects of hydrogen peroxide on permeabilized rabbit psoas muscle fibers, focusing on changes in myosin purified from these fibers. Oxidation by 5 mM peroxide decreased fiber contractility (isometric force and shortening velocity) without significant changes in the enzymatic activity of myofibrils and isolated myosin. The inhibitory effects were reversed by treating fibers with dithiothreitol. Oxidation by 50 mM peroxide had a more pronounced and irreversible inhibitory effect on fiber contractility and also affected enzymatic activity of myofibrils, myosin, and actomyosin. Peroxide treatment also affected regulation of contractility, resulting in fiber activation in the absence of calcium. Electron paramagnetic resonance of spin-labeled myosin in muscle fibers showed that oxidation increased the fraction of myosin heads in the strong-binding structural state under relaxing conditions (low calcium) but had no effect under activating conditions (high calcium). This change in the distribution of structural states of myosin provides a plausible explanation for the observed changes in both contractile and regulatory functions. Mass spectroscopy analysis showed that 50 mM but not 5 mM peroxide induced oxidative modifications in both isoforms of the essential light chains and in the heavy chain of myosin subfragment 1 by targeting multiple methionine residues. We conclude that 1) inhibition of muscle fiber contractility via oxidation of myosin occurs at high but not low concentrations of peroxide and 2) the inhibitory effects of oxidation suggest a critical and previously unknown role of methionines in myosin function.

Effects of prenatal substance exposure on neurocognitive correlates of inhibitory control success and failure.

PubMed

Roos, Leslie E; Beauchamp, Kathryn G; Pears, Katherine C; Fisher, Philip A; Berkman, Elliot T; Capaldi, Deborah

2017-01-01

Adolescents with prenatal substance (drug and alcohol) exposure exhibit inhibitory control (IC) deficits and aberrations in associated neural function. Nearly all research to date examines exposure to individual substances, and a minimal amount is known about the effects of heterogeneous exposure-which is more representative of population exposure levels. Using functional magnetic resonance imaging (fMRI), we investigated IC (Go/NoGo) in heterogeneously exposed (n = 7) vs. control (n = 7) at-risk adolescents (ages 13-17). The fMRI results indicated multiple IC processing differences consistent with a more immature developmental profile for exposed adolescents (Exposed  >  Nonexposed: NoGo > Go: right ventrolateral prefrontal cortex, right cuneus, and left inferior parietal lobe; NoGo > false alarm: occipital lobe; Go > false alarm: right anterior prefrontal cortex). Simple effects suggest exposed adolescents exhibited exaggerated correct trial but decreased incorrect trial activation. Results provide initial evidence that prenatal exposure across substances creates similar patterns of atypical brain activation to IC success and failure.

Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons

NASA Technical Reports Server (NTRS)

Scrogin, K. E.; Johnson, A. K.; Schmid, H. A.

1998-01-01

The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons.

PubMed

Scrogin, K E; Johnson, A K; Schmid, H A

1998-12-01

The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

A comparison of the effects of the dopamine partial agonists aripiprazole and (-)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro.

PubMed

O'Connor, John J; Lowry, John P

2012-07-05

The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10μM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10μM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole's inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was greater than a 100-fold shift for the 10μM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D(2) ligands remains controversial. Copyright © 2012 Elsevier B.V. All rights reserved.

Inhibitory Effects of 4'-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears.

PubMed

Wu, Xian; Song, Mingyue; Rakariyatham, Kanyasiri; Zheng, Jinkai; Wang, Minqi; Xu, Fei; Gao, Zili; Xiao, Hang

2015-12-30

Nobiletin (NOB) is major citrus flavonoid with many health-promoting benefits. We reported previously that 4'-demethylnobiletin (4DN), a major metabolite of NOB, significantly inhibited lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages. In this study, we further studied the anti-inflammatory effects of 4DN in TPA-induced skin inflammation in mice. We demonstrated that topical application of 4DN decreased TPA-induced ear edema by >88 ± 4.77% in mice. This inhibitory effect was associated with inhibition on TPA-induced up-regulation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Immunoblotting results showed that 4DN resulted in profound effects on multiple proteins related with inflammation and carcinogenesis. 4DN significantly decreased the expression levels of iNOS, COX-2, and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and increased the levels of HO-1 and NQO1 in TPA-treated mice. Overall, the results demonstrated that 4DN had strong anti-inflammatory effects in vivo, which provided a scientific basis for using NOB to inhibit inflammation-driven diseases.

Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells.

PubMed

Guo, Huaijian; Cruz-Munoz, Mario-Ernesto; Wu, Ning; Robbins, Michael; Veillette, André

2015-01-01

Signaling lymphocytic activation molecule F7 (SLAMF7) is a receptor present on immune cells, including natural killer (NK) cells. It is also expressed on multiple myeloma (MM) cells. This led to development of an anti-SLAMF7 antibody, elotuzumab, showing efficacy against MM. SLAMF7 mediates activating or inhibitory effects in NK cells, depending on whether cells express or do not express the adaptor EAT-2. Since MM cells lack EAT-2, we elucidated the inhibitory effectors of SLAMF7 in EAT-2-negative NK cells and tested whether these effectors were triggered in MM cells. SLAMF7-mediated inhibition in NK cells lacking EAT-2 was mediated by SH2 domain-containing inositol phosphatase 1 (SHIP-1), which was recruited via tyrosine 261 of SLAMF7. Coupling of SLAMF7 to SHIP-1 required Src kinases, which phosphorylated SLAMF7. Although MM cells lack EAT-2, elotuzumab did not induce inhibitory signals in these cells. This was at least partly due to a lack of CD45, a phosphatase required for Src kinase activation. A defect in SLAMF7 function was also observed in CD45-deficient NK cells. Hence, SLAMF7-triggered inhibition is mediated by a mechanism involving Src kinases, CD45, and SHIP-1 that is defective in MM cells. This defect might explain why elotuzumab eliminates MM cells by an indirect mechanism involving the activation of NK cells. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes.

PubMed

Wei, Wei; Wang, Xiao-Jing

2016-12-07

We developed a circuit model of spiking neurons that includes multiple pathways in the basal ganglia (BG) and is endowed with feedback mechanisms at three levels: cortical microcircuit, corticothalamic loop, and cortico-BG-thalamocortical system. We focused on executive control in a stop signal task, which is known to depend on BG across species. The model reproduces a range of experimental observations and shows that the newly discovered feedback projection from external globus pallidus to striatum is crucial for inhibitory control. Moreover, stopping process is enhanced by the cortico-subcortical reverberatory dynamics underlying persistent activity, establishing interdependence between working memory and inhibitory control. Surprisingly, the stop signal reaction time (SSRT) can be adjusted by weights of certain connections but is insensitive to other connections in this complex circuit, suggesting novel circuit-based intervention for inhibitory control deficits associated with mental illness. Our model provides a unified framework for inhibitory control, decision making, and working memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibitory effects of crude extracts from several plants on postharvest pathogens of citrus

NASA Astrophysics Data System (ADS)

Gong, Mingfu; Guan, Qinlan; Xu, Shanshan

2018-04-01

China is one of the most important origin of citrus. Enormous economic losses was caused by fungal diseases in citrus harvest storage every year. The effective antimicrobial substances of garlic, ginger, celery and pepper were extracted by ethanol extraction and water extraction respectively. The inhibitory effects of the crude extract on Penicillium sp. caused fungal diseases in citrus harvest storage were also determined. The results showed that the extracts of garlic, ginger and celery had inhibitory effect on P. sp., but the extracts of pepper had no inhibitory effect on P. sp.. The garlic ethanol extracts had the best inhibitory effect on P. citrinum.

Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

PubMed Central

Duncan, Christopher J. A.; Sheehy, Susanne H.; Ewer, Katie J.; Douglas, Alexander D.; Collins, Katharine A.; Halstead, Fenella D.; Elias, Sean C.; Lillie, Patrick J.; Rausch, Kelly; Aebig, Joan; Miura, Kazutoyo; Edwards, Nick J.; Poulton, Ian D.; Hunt-Cooke, Angela; Porter, David W.; Thompson, Fiona M.; Rowland, Ros; Draper, Simon J.; Gilbert, Sarah C.; Fay, Michael P.; Long, Carole A.; Zhu, Daming; Wu, Yimin; Martin, Laura B.; Anderson, Charles F.; Lawrie, Alison M.; Hill, Adrian V. S.; Ellis, Ruth D.

2011-01-01

Background Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. Methods In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. Results A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = −0.93 [95% CI: −1.0, −0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = −0.93 [95% CI: −0.99, −0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5–9], control group median 9 days [range 7–9]). Conclusions Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. Trial Registration ClinicalTrials.gov [NCT00984763] PMID:21799809

Dissociable Fronto-Operculum-Insula Control Signals for Anticipation and Detection of Inhibitory Sensory Cue.

PubMed

Cai, Weidong; Chen, Tianwen; Ide, Jaime S; Li, Chiang-Shan R; Menon, Vinod

2017-08-01

The ability to anticipate and detect behaviorally salient stimuli is important for virtually all adaptive behaviors, including inhibitory control that requires the withholding of prepotent responses when instructed by external cues. Although right fronto-operculum-insula (FOI), encompassing the anterior insular cortex (rAI) and inferior frontal cortex (rIFC), involvement in inhibitory control is well established, little is known about signaling mechanisms underlying their differential roles in detection and anticipation of salient inhibitory cues. Here we use 2 independent functional magnetic resonance imaging data sets to investigate dynamic causal interactions of the rAI and rIFC, with sensory cortex during detection and anticipation of inhibitory cues. Across 2 different experiments involving auditory and visual inhibitory cues, we demonstrate that primary sensory cortex has a stronger causal influence on rAI than on rIFC, suggesting a greater role for the rAI in detection of salient inhibitory cues. Crucially, a Bayesian prediction model of subjective trial-by-trial changes in inhibitory cue anticipation revealed that the strength of causal influences from rIFC to rAI increased significantly on trials in which participants had higher anticipation of inhibitory cues. Together, these results demonstrate the dissociable bottom-up and top-down roles of distinct FOI regions in detection and anticipation of behaviorally salient cues across multiple sensory modalities. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Breast Milk of HIV-Positive Mothers Has Potent and Species-Specific In Vivo HIV-Inhibitory Activity

PubMed Central

Wahl, Angela; Baker, Caroline; Spagnuolo, Rae Ann; Stamper, Lisa W.; Fouda, Genevieve G.; Permar, Sallie R.; Hinde, Katie; Kuhn, Louise; Bode, Lars; Aldrovandi, Grace M.

2015-01-01

ABSTRACT Despite the nutritional and health benefits of breast milk, breast milk can serve as a vector for mother-to-child HIV transmission. Most HIV-infected infants acquire HIV through breastfeeding. Paradoxically, most infants breastfed by HIV-positive women do not become infected. This is potentially attributed to anti-HIV factors in breast milk. Breast milk of HIV-negative women can inhibit HIV infection. However, the HIV-inhibitory activity of breast milk from HIV-positive mothers has not been evaluated. In addition, while significant differences in breast milk composition between transmitting and nontransmitting HIV-positive mothers have been correlated with transmission risk, the HIV-inhibitory activity of their breast milk has not been compared. This knowledge may significantly impact the design of prevention approaches in resource-limited settings that do not deny infants of HIV-positive women the health benefits of breast milk. Here, we utilized bone marrow/liver/thymus humanized mice to evaluate the in vivo HIV-inhibitory activity of breast milk obtained from HIV-positive transmitting and nontransmitting mothers. We also assessed the species specificity and biochemical characteristics of milk's in vivo HIV-inhibitory activity and its ability to inhibit other modes of HIV infection. Our results demonstrate that breast milk of HIV-positive mothers has potent HIV-inhibitory activity and indicate that breast milk can prevent multiple routes of infection. Most importantly, this activity is unique to human milk. Our results also suggest multiple factors in breast milk may contribute to its HIV-inhibitory activity. Collectively, our results support current recommendations that HIV-positive mothers in resource-limited settings exclusively breastfeed in combination with antiretroviral therapy. IMPORTANCE Approximately 240,000 children become infected with HIV annually, the majority via breastfeeding. Despite daily exposure to virus in breast milk, most infants breastfed by HIV-positive women do not acquire HIV. The low risk of breastfeeding-associated HIV transmission is likely due to antiviral factors in breast milk. It is well documented that breast milk of HIV-negative women can inhibit HIV infection. Here, we demonstrate, for the first time, that breast milk of HIV-positive mothers (nontransmitters and transmitters) inhibits HIV transmission. We also demonstrate that breast milk can prevent multiple routes of HIV acquisition and that this activity is unique to human milk. Collectively, our results support current guidelines which recommend that HIV-positive women in resource-limited settings exclusively breastfeed in combination with infant or maternal antiretroviral therapy. PMID:26292320

Excitatory and Inhibitory Interactions in Localized Populations of Model Neurons

PubMed Central

Wilson, Hugh R.; Cowan, Jack D.

1972-01-01

Coupled nonlinear differential equations are derived for the dynamics of spatially localized populations containing both excitatory and inhibitory model neurons. Phase plane methods and numerical solutions are then used to investigate population responses to various types of stimuli. The results obtained show simple and multiple hysteresis phenomena and limit cycle activity. The latter is particularly interesting since the frequency of the limit cycle oscillation is found to be a monotonic function of stimulus intensity. Finally, it is proved that the existence of limit cycle dynamics in response to one class of stimuli implies the existence of multiple stable states and hysteresis in response to a different class of stimuli. The relation between these findings and a number of experiments is discussed. PMID:4332108

Locally excitatory, globally inhibitory oscillator networks: theory and application to scene segmentation

NASA Astrophysics Data System (ADS)

Wang, DeLiang; Terman, David

1995-01-01

A novel class of locally excitatory, globally inhibitory oscillator networks (LEGION) is proposed and investigated analytically and by computer simulation. The model of each oscillator corresponds to a standard relaxation oscillator with two time scales. The network exhibits a mechanism of selective gating, whereby an oscillator jumping up to its active phase rapidly recruits the oscillators stimulated by the same pattern, while preventing other oscillators from jumping up. We show analytically that with the selective gating mechanism the network rapidly achieves both synchronization within blocks of oscillators that are stimulated by connected regions and desynchronization between different blocks. Computer simulations demonstrate LEGION's promising ability for segmenting multiple input patterns in real time. This model lays a physical foundation for the oscillatory correlation theory of feature binding, and may provide an effective computational framework for scene segmentation and figure/ground segregation.

A corticothalamic switch: controlling the thalamus with dynamic synapses

PubMed Central

Crandall, Shane R.; Cruikshank, Scott J.; Connors, Barry W.

2015-01-01

SUMMARY Corticothalamic neurons provide massive input to the thalamus. This top-down projection may allow cortex to regulate sensory processing by modulating the excitability of thalamic cells. Layer 6 corticothalamic neurons monosynaptically excite thalamocortical cells, but also indirectly inhibit them by driving inhibitory cells of the thalamic reticular nucleus. Whether corticothalamic activity generally suppresses or excites the thalamus remains unclear. Here we show that the corticothalamic influence is dynamic, with the excitatory-inhibitory balance shifting in an activity-dependent fashion. During low-frequency activity corticothalamic effects are mainly suppressive, whereas higher frequency activity (even a short bout of gamma frequency oscillations) converts the corticothalamic influence to enhancement. The mechanism of this switching depends upon distinct forms of short-term synaptic plasticity across multiple corticothalamic circuit components. Our results reveal an activity-dependent mechanism by which corticothalamic neurons can bidirectionally switch the excitability and sensory throughput of the thalamus, possibly to meet changing behavioral demands. PMID:25913856

One-year enzyme-linked immunosorbent assay follow-up of human interleukin for Da cells/leukemia inhibitory factor in blood and urine of 22 kidney transplant recipients.

PubMed

Morel, D; Taupin, J L; Combe, C; Potaux, L; Gualde, N; Moreau, J F

1994-12-15

The cytokine human interleukin for Da cells/leukemia inhibitory factor (HILDA/LIF) exerts multiple biological effects in vitro. In mice, high circulating levels of HILDA/LIF induce a wide range of pathophysiological events, some of them closely involved with immunological and inflammatory responses. Using a sandwich ELISA recognizing the natural human HILDA/LIF molecule with a threshold of 50 pg/ml in urine and 150 pg/ml in plasma, we monitored the urine and plasma HILDA/LIF levels of 22 patients in their first year after a kidney transplant. HILDA/LIF urine excretion is increased during acute rejection, and infections also trigger heavy HILDA/LIF plasma concentrations or urine excretion. In addition, this study raises the question of HILDA/LIF involvement in post-kidney-transplant phenomena such as hypercalcemia, osteoporosis, or the reversal of anemia.

Childhood Maltreatment and Its Effect on Neurocognitive Functioning: Timing and Chronicity Matter

PubMed Central

Cowell, Raquel A.; Cicchetti, Dante; Rogosch, Fred A.; Toth, Sheree L.

2015-01-01

Childhood maltreatment represents a complex stressor, with the developmental timing, duration, frequency, and type of maltreatment varying with each child (Barnett, Manly, & Cicchetti, 1993; Cicchetti & Manly, 2001). Multiple brain regions and neural circuits are disrupted by the experience of child maltreatment (Cicchetti & Toth, in press; DeBellis et al., 2002; McCrory & Viding, 2010; Teicher, Anderson, & Polcari, 2012). These neurobiological compromises indicate the impairment of a number of important cognitive functions, including working memory and inhibitory control. The present study extends prior research by examining the effect of childhood maltreatment on neurocognitive functioning based on developmental timing of maltreatment, including onset, chronicity, and recency, in a sample of 3- to 9-year-old nonmaltreated (n = 136) and maltreated children (n = 223). Maltreated children performed more poorly on inhibitory control and working memory tasks than nonmaltreated children. Group differences between maltreated children based on the timing of maltreatment and the chronicity of maltreatment also were evident. Specifically, children who were maltreated during infancy, and children with a chronic history of maltreatment, exhibited significantly poorer inhibitory control and working memory performance than children without a history of maltreatment. The results suggest that maltreatment occurring during infancy, a period of major brain organization, disrupts normative structure and function, and these deficits are further instantiated by the prolonged stress of chronic maltreatment during the early years of life. PMID:25997769

Inhibitory effects of antihistamines, diphenhydramine and chlorpheniramine, on proton currents in BV2 microglial cells.

PubMed

Kim, Jiwon; Song, Jin-Ho

2017-03-05

Microglial NADPH oxidase is a major source of toxic reactive oxygen species produced during chronic neuroinflammation. Voltage-gated proton channel (H V 1) functions to maintain the intense activity of NADPH oxidase, and channel inhibition alleviates the pathology of neurodegenerative diseases such as ischemic stroke and multiple sclerosis associated with oxidative neuroinflammation. Antagonists of histamine H 1 receptors have beneficial effects against microglia-mediated oxidative stress and neurotoxicity. We examined the effects of the H 1 antihistamines, diphenhydramine and chlorpheniramine, on proton currents in BV2 microglial cells recorded using the whole-cell patch clamp technique. Diphenhydramine and chlorpheniramine reduced the proton currents with almost the same potency, yielding IC 50 values of 42 and 43μM, respectively. Histamine did not affect proton currents, excluding the involvement of histamine receptors in their action. Neither drug shifted the voltage-dependence of activation or the reversal potential of the proton currents, even though diphenhydramine slowed the activation and deactivation kinetics. The inhibitory effects of the two antihistamines on proton currents could be utilized to develop therapeutic agents for neurodegenerative diseases and other diseases associated with H V 1 proton channel abnormalities. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

PubMed

Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

1995-07-01

In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality.

Interactive contributions of self-regulation deficits and social motivation to psychopathology: Unraveling divergent pathways to aggressive behavior and depressive symptoms

PubMed Central

RUDOLPH, KAREN D.; TROOP-GORDON, WENDY; LLEWELLYN, NICOLE

2015-01-01

Poor self-regulation has been implicated as a significant risk factor for the development of multiple forms of psychopathology. This research examined the proposition that self-regulation deficits differentially predict aggressive behavior and depressive symptoms, depending on children’s social approach versus avoidance motivation. A prospective, multiple-informant approach was used to test this hypothesis in 419 children (M age = 8.92, SD = 0.36). Parents rated children’s inhibitory control. Children completed measures of social approach–avoidance motivation and depressive symptoms. Teachers rated children’s aggressive behavior. As anticipated, poor inhibitory control predicted aggressive behavior in boys with high but not low approach motivation and low but not high avoidance motivation, whereas poor inhibitory control predicted depressive symptoms in girls with high but not low avoidance motivation. This research supports several complementary theoretical models of psychopathology and provides insight into the differential contributions of poor self-regulation to maladaptive developmental outcomes. The findings suggest the need for targeted intervention programs that consider heterogeneity among children with self-regulatory deficits. PMID:23627953

Combinatorial cytotoxic effects of Curcuma longa and Zingiber officinale on the PC-3M prostate cancer cell line

PubMed Central

Kurapati, Kesava Rao V.; Samikkannu, Thangavel; Kadiyala, Dakshayani B.; Zainulabedin, Saiyed M.; Gandhi, Nimisha; Sathaye, Sadhana S.; Indap, Manohar A.; Boukli, Nawal; Rodriguez, Jose W.; Nair, Madhavan P.N.

2015-01-01

Background Many plant-derived products exhibit potent chemopreventive activity against animal tumor models as well as rodent and human cancer cell lines. They have low side effects and toxicity and presumably modulate the factors that are critical for cell proliferation, differentiation, senescence and apoptosis. The present study investigates the effects of some medicinal plant extracts from generally recognized as safe plants that may be useful in the prevention and treatment of cancer. Methods Clonogenic assays using logarithmically-growing cells were performed to test the effect. The cytotoxic effects of Curcuma longa and Zingiber officinale were studied using sulforhodamine B assay, tetrazolium dye assay, colony morphology and microscopic analysis. Results Out of the 13 lyophilized plant-derived extracts evaluated for growth-inhibitory effects on the PC-3M prostate cancer cell line, two extracts derived from C. longa and Z. officinale showed significant inhibitory effects on colony-forming ability. The individual and augmentative effects of these two extracts were tested for their narrow range effective lower concentration on PC-3M in clonogenic assays. At relatively lower concentrations, C. longa showed significant inhibition of colony formation in clonogenic assays; whereas at same concentrations Z. officinale showed only moderate inhibitory effects. However, when both the agents were tested together at the same concentrations, the combined effects were much more significant than their individual ones. On normal prostate epithelial cells both C. longa and Z. officinale had similar effects but at a lower magnitude. These observations were confirmed by several cytotoxicity assays involving the morphological appearance of the colonies, microscopic observations, per cent inhibition in comparison to control by sulforhodamine B and tetrazolium dye assay. Conclusions From these observations, it was concluded that the combined effects of C. longa and Z. officinale are much greater than their individual effects, suggesting the role of multiple components and their synergistic mode of actions to elicit stronger beneficial effects. PMID:23072849

Group I but not group II NPV induces antiviral effects in mammalian cells.

PubMed

Liang, Changyong; Song, Jianhua; Hu, Zhihong; Chen, Xinwen

2006-10-01

Nucleopolyhedrovirus (NPV) is divided into Group I and Group II based on the phylogenetic analysis. It has been reported that Group I NPVs such as Autographa californica multiple NPV (AcMNPV) can transduce mammalian cells, while Group II NPVs such as Helicoverpa armigera single NPV (HaSNPV) cannot. Here we report that AcMNPV was capable of stimulating antiviral activity in human hepatoma cells (SMMC-7721) manifested by inhibition of Vesicular Stomatitis virus (VSV) replication. In contrast, the HaSNPV and the Spodoptera exigua multiple NPV (SeMNPV) of group II had no inhibitory effect on VSV. Recombinant AcMNPV was shown to induce interferons alpha/beta even in the absence of transgene expression in human SMMC-7721 cells, while it mediated transgene expression in BHK and L929 mammalian cells without an ensuing antiviral activity.

NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals.

PubMed

Bakker, A B; Wu, J; Phillips, J H; Lanier, L L

2000-01-01

A delicate balance between positive and negative signals regulates NK cell effector function. Activation of NK cells may be initiated by the triggering of multiple adhesion or costimulatory molecules, and can be counterbalanced by inhibitory signals induced by receptors for MHC class I. A common pathway of inhibitory signaling is provided by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic domains of these receptors which mediate the recruitment of SH2 domain-bearing tyrosine phosphate-1 (SHP-1). In contrast to the extensive progress that has been made regarding the negative regulation of NK cell function, our knowledge of the signals that activate NK cells is still poor. Recent studies of the activating receptor complexes have shed new light on the induction of NK cell effector function. Several NK receptors using novel adaptors with immunoreceptor tyrosine-based activation motifs (ITAMs) and with PI 3-kinase recruiting motifs have been implicated in NK cell stimulation.

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

PubMed

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor.

PubMed

Peled, Michael; Tocheva, Anna S; Sandigursky, Sabina; Nayak, Shruti; Philips, Elliot A; Nichols, Kim E; Strazza, Marianne; Azoulay-Alfaguter, Inbar; Askenazi, Manor; Neel, Benjamin G; Pelzek, Adam J; Ueberheide, Beatrix; Mor, Adam

2018-01-16

Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti-PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule-associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-linked lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD-1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP.

Automated microbial metabolism laboratory. [design of advanced labeled release experiment based on single addition of soil and multiple sequential additions of media into test chambers

NASA Technical Reports Server (NTRS)

1974-01-01

The design and rationale of an advanced labeled release experiment based on single addition of soil and multiple sequential additions of media into each of four test chambers are outlined. The feasibility for multiple addition tests was established and various details of the methodology were studied. The four chamber battery of tests include: (1) determination of the effect of various atmospheric gases and selection of that gas which produces an optimum response; (2) determination of the effect of incubation temperature and selection of the optimum temperature for performing Martian biochemical tests; (3) sterile soil is dosed with a battery of C-14 labeled substrates and subjected to experimental temperature range; and (4) determination of the possible inhibitory effects of water on Martian organisms is performed initially by dosing with 0.01 ml and 0.5 ml of medium, respectively. A series of specifically labeled substrates are then added to obtain patterns in metabolic 14CO2 (C-14)O2 evolution.

UV-A radiation effects on higher plants: Exploring the known unknown.

PubMed

Verdaguer, Dolors; Jansen, Marcel A K; Llorens, Laura; Morales, Luis O; Neugart, Susanne

2017-02-01

Ultraviolet-A radiation (UV-A: 315-400nm) is a component of solar radiation that exerts a wide range of physiological responses in plants. Currently, field attenuation experiments are the most reliable source of information on the effects of UV-A. Common plant responses to UV-A include both inhibitory and stimulatory effects on biomass accumulation and morphology. UV-A effects on biomass accumulation can differ from those on root: shoot ratio, and distinct responses are described for different leaf tissues. Inhibitory and enhancing effects of UV-A on photosynthesis are also analysed, as well as activation of photoprotective responses, including UV-absorbing pigments. UV-A-induced leaf flavonoids are highly compound-specific and species-dependent. Many of the effects on growth and development exerted by UV-A are distinct to those triggered by UV-B and vary considerably in terms of the direction the response takes. Such differences may reflect diverse UV-perception mechanisms with multiple photoreceptors operating in the UV-A range and/or variations in the experimental approaches used. This review highlights a role that various photoreceptors (UVR8, phototropins, phytochromes and cryptochromes) may play in plant responses to UV-A when dose, wavelength and other conditions are taken into account. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis.

PubMed

Wang, Ming; Chen, Dan-Qian; Chen, Lin; Cao, Gang; Zhao, Hui; Liu, Dan; Vaziri, Nosratola D; Guo, Yan; Zhao, Ying-Yong

2018-07-01

Tubulo-interstitial fibrosis is the final pathway in the progression of chronic kidney disease (CKD) to kidney failure. The renin-angiotensin system (RAS) plays a major role in CKD progression. Hence, we determined the efficacy of novel RAS inhibitors isolated from Poria cocos against renal fibrosis. Effects of three novel tetracyclic triterpenoid compounds, poricoic acid ZC (PZC), poricoic acid ZD (PZD) and poricoic acid ZE (PZE), were investigated on TGFβ1- and angiotensin II (AngII)-treated HK-2 cells and unilateral ureteral obstruction (UUO) in mice. Immunofluorescence staining, quantitative real-time PCR, siRNA, co-immunoprecipitation and Western blot analyses were used to evaluate expression of key molecules in RAS, Wnt/β-catenin and TGFβ/Smad pathways. Addition of the above compounds to culture media and their administration to UUO mice: (i) significantly attenuated epithelial-to-mesenchymal transition and extracellular matrix production in TGFβ1- and AngII-treated HK-2 cells and UUO mice by inhibiting Wnt/β-catenin pathway activation and Smad3 phosphorylation; (ii) selectively inhibited Smad3 phosphorylation by blocking the interaction of TGFBR1 with Smad3; and (iii) specifically inhibited Smad3 activation. PZC and PZD showed a strong inhibitory effect on all RAS components, and PZE showed a strong inhibitory effect on renin. Furthermore, the secolanostane tetracyclic triterpenoids, PZC and PZD, showed a stronger inhibitory effect than the lanostane tetracyclic triterpenoid PZE. Therefore, compounds with secolanostance skeleton showed stronger bioactivity than those with lanostance skeleton. The secolanostane tetracyclic triterpenoids effectively blocked RAS by simultaneously targeting multiple RAS components and lanostane tetracyclic triterpenoids inhibited renin and protected against tubulo-interstitial fibrosis. © 2018 The British Pharmacological Society.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

PubMed Central

Noordam, Lisanne; Sprengers, Dave; Boor, Patrick P. C.; Mancham, Shanta; Menon, Anand G.; Lange, Johan F.; Burger, Pim J. W. A.; Brandt, Alexandra; Galjart, Boris; Kwekkeboom, Jaap; Bruno, Marco J.

2018-01-01

ABSTRACT Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

Model of visual contrast gain control and pattern masking

NASA Technical Reports Server (NTRS)

Watson, A. B.; Solomon, J. A.

1997-01-01

We have implemented a model of contrast gain and control in human vision that incorporates a number of key features, including a contrast sensitivity function, multiple oriented bandpass channels, accelerating nonlinearities, and a devisive inhibitory gain control pool. The parameters of this model have been optimized through a fit to the recent data that describe masking of a Gabor function by cosine and Gabor masks [J. M. Foley, "Human luminance pattern mechanisms: masking experiments require a new model," J. Opt. Soc. Am. A 11, 1710 (1994)]. The model achieves a good fit to the data. We also demonstrate how the concept of recruitment may accommodate a variant of this model in which excitatory and inhibitory paths have a common accelerating nonlinearity, but which include multiple channels tuned to different levels of contrast.

Inhibitory control in bulimic-type eating disorders: a systematic review and meta-analysis.

PubMed

Wu, Mudan; Hartmann, Mechthild; Skunde, Mandy; Herzog, Wolfgang; Friederich, Hans-Christoph

2013-01-01

The aim of this meta-analysis was to summarise data from neuropsychological studies on inhibitory control to general and disease-salient (i.e., food/eating, body/shape) stimuli in bulimic-type eating disorders (EDs). A systematic literature search was conducted to identify eligible experimental studies. The outcome measures studied included the performance on established inhibitory control tasks in bulimic-type EDs. Effect sizes (Hedges' g) were pooled using random-effects models. For inhibitory control to general stimuli, 24 studies were included with a total of 563 bulimic-type ED patients: 439 had bulimia nervosa (BN), 42 had anorexia nervosa of the binge/purge subtype (AN-b), and 82 had binge eating disorder (BED). With respect to inhibitory control to disease-salient stimuli, 12 studies were included, representing a total of 218 BN patients. A meta-analysis of these studies showed decreased inhibitory control to general stimuli in bulimic-type EDs (g = -0.32). Subgroup analysis revealed impairments with a large effect in the AN-b group (g = -0.91), impairments with a small effect in the BN group (g = -0.26), and a non-significant effect in the BED group (g = -0.16). Greater impairments in inhibitory control were observed in BN patients when confronted with disease-salient stimuli (food/eating: g = -0.67; body/shape: g = -0.61). In conclusion, bulimic-type EDs showed impairments in inhibitory control to general stimuli with a small effect size. There was a significantly larger impairment in inhibitory control to disease salient stimuli observed in BN patients, constituting a medium effect size.

Endotoxin induction of an inhibitor of plasminogen activator in bovine pulmonary artery endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

The effects of bacterial lipopolysaccharide (endotoxin) on the fibrinolytic activity of bovine pulmonary artery endothelial cells were examined. Endotoxin suppressed the net fibrinolytic activity of cell extracts and conditioned media in a dose-dependent manner. The effects of endotoxin required at least 6 h for expression. Cell extracts and conditioned media contained a 44-kDa urokinase-like plasminogen activator. Media also contained multiple plasminogen activators with molecular masses of 65-75 and 80-100 kDa. Plasminogen activators in extracts and media were unchanged by treatment of cells with endotoxin. Diisopropyl fluorophosphate (DFP)-abolished fibrinolytic activity of extracts and conditioned media. DFP-treated samples from endotoxin-treated but notmore » untreated cells inhibited urokinase and tissue plasminogen activator, but not plasmin. Inhibitory activity was lost by incubation at pH 3 or heating to 56/sup 0/C for 10 min. These treatments did not affect inhibitory activity of fetal bovine serum. Incubation of /sup 125/I-urokinase with DFP-treated medium from endotoxin-treated cells produced an inactive complex with an apparent molecular mass of 80-85 kDa.« less

Targeting the ubiquitin-proteasome system for cancer treatment: discovering novel inhibitors from nature and drug repurposing.

PubMed

Soave, Claire L; Guerin, Tracey; Liu, Jinbao; Dou, Q Ping

2017-12-01

In the past 15 years, the proteasome has been validated as an anti-cancer drug target and 20S proteasome inhibitors (such as bortezomib and carfilzomib) have been approved by the FDA for the treatment of multiple myeloma and some other liquid tumors. However, there are shortcomings of clinical proteasome inhibitors, including severe toxicity, drug resistance, and no effect in solid tumors. At the same time, extensive research has been conducted in the areas of natural compounds and old drug repositioning towards the goal of discovering effective, economical, low toxicity proteasome-inhibitory anti-cancer drugs. A variety of dietary polyphenols, medicinal molecules, metallic complexes, and metal-binding compounds have been found to be able to selectively inhibit tumor cellular proteasomes and induce apoptotic cell death in vitro and in vivo, supporting the clinical success of specific 20S proteasome inhibitors bortezomib and carfilzomib. Therefore, the discovery of natural proteasome inhibitors and researching old drugs with proteasome-inhibitory properties may provide an alternative strategy for improving the current status of cancer treatment and even prevention.

Ibrutinib-A double-edge sword in cancer and autoimmune disorders.

PubMed

Kokhaei, Parviz; Jadidi-Niaragh, Farhad; Sotoodeh Jahromi, Abdolreza; Osterborg, Anders; Mellstedt, Håkan; Hojjat-Farsangi, Mohammad

2016-01-01

Targeted therapies have appeared as new treatment options for several disease types, including cancer and autoimmune disorders. Of several targets, tyrosine kinases (TKs) are among the most promising. Overexpression of TKs provides a target for novel therapeutic agents, including small molecule inhibitors of tyrosine kinases (TKI). Ibrutinib (PCI-32765) is a TKI of Bruton's tyrosine kinase (Btk), a key kinase of the B-cell receptor signaling pathway that plays a significant role in the proliferation, differentiation and survival of B cells. In addition to inhibitory effects, recent studies have shown that ibrutinib has multiple immunomodulatory effects. It binds covalently to IL-2 inducible tyrosine kinase (Itk) in T lymphocytes and suppresses the survival of T-helper (Th) 2 cells. This changes the balance of Th1/Th2 cells toward Th1 subset, which are the main immune cells targeting tumor cells. The dual activity of ibrutinib has paid a great attention and several studies are evaluating the anti-tumor and immunomodulatory effects in cancer, autoimmune disorders and infectious diseases. In this article we review the inhibitory and immunomodulatory effects of ibrutinib in B-cell malignancies, autoimmune diseases and infections, as well as the communication between the Ror1 receptor tyrosine kinase and BCR and effects of ibrutinib on this crosstalk.

Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects.

PubMed

Vu, Thuy; Ma, Peiming; Chen, Jiyun Sunny; de Hoon, Jan; Van Hecken, Anne; Yan, Lucy; Wu, Liviawati Sutjandra; Hamilton, Lisa; Vargas, Gabriel

2017-09-01

Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87-91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.

Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma

PubMed Central

Niedźwiecka, Katarzyna; Augustyniak, Daria; Majkowska-Skrobek, Grażyna; Cal-Bąkowska, Magdalena; Ko, Young H.; Pedersen, Peter L.; Goffeau, Andre

2016-01-01

In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death. PMID:27582536

Linear summation of outputs in a balanced network model of motor cortex.

PubMed

Capaday, Charles; van Vreeswijk, Carl

2015-01-01

Given the non-linearities of the neural circuitry's elements, we would expect cortical circuits to respond non-linearly when activated. Surprisingly, when two points in the motor cortex are activated simultaneously, the EMG responses are the linear sum of the responses evoked by each of the points activated separately. Additionally, the corticospinal transfer function is close to linear, implying that the synaptic interactions in motor cortex must be effectively linear. To account for this, here we develop a model of motor cortex composed of multiple interconnected points, each comprised of reciprocally connected excitatory and inhibitory neurons. We show how non-linearities in neuronal transfer functions are eschewed by strong synaptic interactions within each point. Consequently, the simultaneous activation of multiple points results in a linear summation of their respective outputs. We also consider the effects of reduction of inhibition at a cortical point when one or more surrounding points are active. The network response in this condition is linear over an approximately two- to three-fold decrease of inhibitory feedback strength. This result supports the idea that focal disinhibition allows linear coupling of motor cortical points to generate movement related muscle activation patterns; albeit with a limitation on gain control. The model also explains why neural activity does not spread as far out as the axonal connectivity allows, whilst also explaining why distant cortical points can be, nonetheless, functionally coupled by focal disinhibition. Finally, we discuss the advantages that linear interactions at the cortical level afford to motor command synthesis.

Glutathione may have implications in the design of 3-bromopyruvate treatment protocols for both fungal and algal infections as well as multiple myeloma.

PubMed

Niedźwiecka, Katarzyna; Dyląg, Mariusz; Augustyniak, Daria; Majkowska-Skrobek, Grażyna; Cal-Bąkowska, Magdalena; Ko, Young H; Pedersen, Peter L; Goffeau, Andre; Ułaszewski, Stanisław

2016-10-04

In different fungal and algal species, the intracellular concentration of reduced glutathione (GSH) correlates closely with their susceptibility to killing by the small molecule alkylating agent 3-bromopyruvate (3BP). Additionally, in the case of Cryptococcus neoformans cells 3BP exhibits a synergistic effect with buthionine sulfoximine (BSO), a known GSH depletion agent. This effect was observed when 3BP and BSO were used together at concentrations respectively of 4-5 and almost 8 times lower than their Minimal Inhibitory Concentration (MIC). Finally, at different concentrations of 3BP (equal to the half-MIC, MIC and double-MIC in a case of fungi, 1 mM and 2.5 mM for microalgae and 25, 50, 100 μM for human multiple myeloma (MM) cells), a significant decrease in GSH concentration is observed inside microorganisms as well as tumor cells. In contrast to the GSH concentration decrease, the presence of 3BP at concentrations corresponding to sub-MIC values or half maximal inhibitory concentration (IC50) clearly results in increasing the expression of genes encoding enzymes involved in the synthesis of GSH in Cryptococcus neoformans and MM cells. Moreover, as shown for the first time in the MM cell model, the drastic decrease in the ATP level and GSH concentration and the increase in the amount of ROS caused by 3BP ultimately results in cell death.

Binding and Inhibitory Effect of the Dyes Amaranth and Tartrazine on Amyloid Fibrillation in Lysozyme.

PubMed

Basu, Anirban; Suresh Kumar, Gopinatha

2017-02-16

Interaction of two food colorant dyes, amaranth and tartrazine, with lysozyme was studied employing multiple biophysical techniques. The dyes exhibited hypochromic changes in the presence of lysozyme. The intrinsic fluorescence of lysozyme was quenched by both dyes; amaranth was a more efficient quencher than tartrazine. The equilibrium constant of amaranth was higher than that of tartarzine. From FRET analysis, the binding distances for amaranth and tartrazine were calculated to be 4.51 and 3.93 nm, respectively. The binding was found to be dominated by non-polyelectrolytic forces. Both dyes induced alterations in the microenvironment surrounding the tryptophan and tyrosine residues of the protein, with the alterations being comparatively higher for the tryptophans than the tyrosines. The interaction caused significant loss in the helicity of lysozyme, the change being higher with amaranth. The binding of both dyes was exothermic. The binding of amaranth was enthalpy driven, while that of tartrazine was predominantly entropy driven. Amaranth delayed lysozyme fibrillation at 25 μM, while tartrazine had no effect even at 100 μM. Nevertheless, both dyes had a significant inhibitory effect on fibrillogenesis. The present study explores the potential antiamyloidogenic property of these azo dyes used as food colorants.

Astilbin alleviates sepsis-induced acute lung injury by inhibiting the expression of macrophage inhibitory factor in rats.

PubMed

Zhang, Hong-Bo; Sun, Li-Chao; Zhi, Li-da; Wen, Qian-Kuan; Qi, Zhi-Wei; Yan, Sheng-Tao; Li, Wen; Zhang, Guo-Qiang

2017-10-01

Sepsis is a systemic inflammatory response syndrome caused by severe infections. Astilbin is a dihydroflavonol derivative found in many medicinal and food plants with multiple pharmacological functions. To investigate the effects of astilbin on sepsis-induced acute lung injury (ALI), cecal ligation and puncture was performed on rats to establish a sepsis-induced ALI model; these rats were then treated with astilbin at different concentrations. Lung injury scores, including lung wet/dry ratio, protein leakage, myeloperoxidase activity, and inflammatory cell infiltration were determined to evaluate the effects of astilbin on sepsis-induced ALI. We found that astilbin treatment significantly attenuates sepsis-induced lung injury and improves survival rate, lung injury scores, lung wet/dry ratio, protein leakage, myeloperoxidase activity, and inflammatory cell infiltration. Astilbin treatment also dramatically decreased the production of inflammatory cytokines and chemokines in bronchoalveolar lavage fluid. Further, astilbin treatment inhibited the expression and production of macrophage inhibitory factor (MIF), which inhibits the inflammatory response. Collectively, these data suggest that astilbin has a protective effect against sepsis-induced ALI by inhibiting MIF-mediated inflammatory responses. This study provides a molecular basis for astilbin as a new medical treatment for sepsis-induced ALI.

Comparison of the inhibitory effects of cilostazol, acetylsalicylic acid and ticlopidine on platelet functions ex vivo. Randomized, double-blind cross-over study.

PubMed

Ikeda, Y; Kikuchi, M; Murakami, H; Satoh, K; Murata, M; Watanabe, K; Ando, Y

1987-05-01

A randomized double-blind cross-over study was conducted to determine the inhibitory effects of acetylsalicylic acid (ASA), ticlopidine (TP) and cilostazol (OPC-13013; in the following briefly called CS), a new antithrombotic agent on platelet functions ex vivo. Nine patients with cerebral thrombosis were enrolled in this study. Patients were given each of the three drugs for one week in a complete cross-over design according to a randomization schedule, followed by a wash-out period with a placebo for one week. It was found that CS and TP significantly inhibited platelet aggregation induced by ADP. Collagen- and arachidonic acid-induced platelet aggregation was all inhibited by CS, TP and ASA. Duncan's multiple range test to compare the anti-platelet effects of the three drugs revealed that: CS greater than ASA and TP greater than ASA in inhibiting ADP-induced platelet aggregation and CS greater than TP and ASA greater than TP in inhibiting arachidonic acid-induced platelet aggregation. These results may suggest that CS is superior to ASA and TP in inhibiting platelet aggregation ex vivo.

Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

PubMed Central

Hong, In-Sun

2016-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

Isolation of proanthocyanidins from red wine, and their inhibitory effects on melanin synthesis in vitro.

PubMed

Fujimaki, Takahiro; Mori, Shoko; Horikawa, Manabu; Fukui, Yuko

2018-05-15

The red wines made from Vitis vinifera were identified as skin-whitening effectors by using in vitro assays. OPCs in the wine were evaluated for tyrosinase activity and melanogenesis. Strong tyrosinase inhibitory activity was observed in fractions with high oligomeric proanthocyanidin (OPC) content. Among OPC dimers, a strong inhibitory effect on tyrosinase was observed with OPCs which contain (+)-catechin as an upper unit. Melanogenesis inhibitory effect was observed with OPCs which have (-)-epicatechin as upper units. Also, OPC trimers, upper and middle units joined with 4 → 8 bonds, showed stronger effects compared to trimers with 4 → 6 linkages. Interestingly, (-)-epicatechin-(4β → 8)-(-)-epicatechin 3-O-gallate, which is a unique component of grapes has potent inhibitory effects on both tyrosinase and melanogenesis. Our data provide structural information about such active compounds. These results suggest that red wines containing OPC, have high melanogenesis inhibitory effect and are supposed to have skin-whitening effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibitory effects of Bacillus subtilis on plant pathogens of conservatory in high latitudes

NASA Astrophysics Data System (ADS)

Xue, Chun-Mei; Wang, Xue; Yang, Jia-Li; Zhang, Yue-Hua

2018-03-01

Researching the effect of three kinds of Bacillus and their mixed strains inhibitory on common fungal diseases of conservatory vegetables. The results showed that B. megaterium culture medium had a significant inhibition effect on Cucumber Fusarium wilt, and the inhibition rate was up to 84.36%; B. mucilaginosus and B. megaterium sterile superna-tant had an obvious inhibitory effect on brown disease of eggplant, and the inhibition rate as high as 85.49%; B. subtilis sterile supernatant had a good inhibitory effect on the spore germination of C. Fusarium wilt, and the inhibition rate was 76.83%. The results revealed that Bacillus had a significant inhibitory effect on five common fungal pathogens. Three kinds of Bacillus can be used for the prevention and control of common fungal diseases in conservatory vegetables.

Lactoferricin B-derived peptides with inhibitory effects on ECE-dependent vasoconstriction.

PubMed

Fernández-Musoles, Ricardo; López-Díez, José Javier; Torregrosa, Germán; Vallés, Salvador; Alborch, Enrique; Manzanares, Paloma; Salom, Juan B

2010-10-01

Endothelin-converting enzyme (ECE), a key peptidase in the endothelin (ET) system, cleaves inactive big ET-1 to produce active ET-1, which binds to ET(A) receptors to exert its vasoconstrictor and pressor effects. ECE inhibition could be beneficial in the treatment of hypertension. In this study, a set of eight lactoferricin B (LfcinB)-derived peptides, previously characterized in our laboratory as angiotensin-converting enzyme (ACE) inhibitory peptides, was examined for their inhibitory effects on ECE. In vitro inhibitory effects on ECE activity were assessed using both the synthetic fluorogenic peptide substrate V (FPS V) and the natural substrate big ET-1. To study vasoactive effects, an ex vivo functional assay was developed using isolated rabbit carotid artery segments. With FPS V, only four LfcinB-derived peptides induced inhibition of ECE activity, whereas the eight peptides showed ECE inhibitory effects with big ET-1 as substrate. Regarding the ex vivo assays, six LfcinB-derived peptides showed inhibition of big ET-1-induced, ECE-dependent vasoconstriction. A positive correlation between the inhibitory effects of LfcinB-derived peptides on ECE activity when using big ET-1 and the inhibitory effects on ECE-dependent vasoconstriction was shown. ECE-independent vasoconstriction induced by ET-1 was not affected, thus discarding effects of LfcinB-derived peptides on ET(A) receptors or intracellular signal transduction mechanisms. In conclusion, a combined in vitro and ex vivo method to assess the effects of potentially antihypertensive peptides on the ET system has been developed and applied to show the inhibitory effects on ECE-dependent vasoconstriction of six LfcinB-derived peptides, five of which were dual vasopeptidase (ACE/ECE) inhibitors. Copyright © 2010 Elsevier Inc. All rights reserved.

Anti-inflammatory and analgesic activity of novel oral aspirin-loaded nanoemulsion and nano multiple emulsion formulations generated using ultrasound cavitation.

PubMed

Tang, Siah Ying; Sivakumar, Manickam; Ng, Angela Min-Hwei; Shridharan, Parthasarathy

2012-07-01

The present study investigated the anti-inflammatory and analgesic activities of novel aspirin oil-in-water (O/W) nanoemulsion and water-in-oil-in-water (W/O/W) nano multiple emulsion formulations generated using ultrasound cavitation techniques. The anti-inflammatory activities of nanoemulsion and nano multiple emulsion were determined using the λ-carrageenan-induced paw edema model. The analgesic activities of both nanoformulations were determined using acetic acid-induced writhing response and hot plate assay. For comparison, the effect of pretreatment with blank nanoemulsion and reference aspirin suspension were also studied for their anti-inflammatory and antinociceptive activities. The results showed that oral administration of nanoemulsion and nano multiple emulsion containing aspirin (60 mg/kg) significantly reduced paw edema induced by λ-carrageenan injection. Both nanoformulations decreased the number of abdominal constriction in acetic acid-induced writhing model. Pretreatment with nanoformulations led to a significant increase in reaction time in hot plate assay. Nanoemulsion demonstrated an enhanced anti-inflammatory and analgesic effects compared to reference suspension while nano multiple emulsion exhibited a mild inhibitory effects in the three experimental animal model tests. The results obtained for nano multiple emulsion were relatively lower than reference. However, administration of blank nanoemulsion did not alter the nociceptive response significantly though it showed slight anti-inflammatory effect. These experimental studies suggest that nanoemulsion and nano multiple emulsion produced a pronounced anti-inflammatory and analgesic effects in rats and may be candidates as new nanocarriers for pharmacological NSAIDs in the treatment of inflammatory disorders and alleviating pains. Copyright © 2012 Elsevier B.V. All rights reserved.

A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways.

PubMed

Yang, Dayun; Luo, Wensong; Wang, Jichuang; Zheng, Min; Liao, Xin-Hua; Zhang, Nan; Lu, Wenxian; Wang, Long; Chen, Ai-Zheng; Wu, Wen-Guo; Liu, Hekun; Wang, Shi-Bin; Zhou, Xiao Zhen; Lu, Kun Ping

2018-01-10

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher C max and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC 50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans. Copyright © 2017 Elsevier B.V. All rights reserved.

The Design of New HIV-IN Tethered Bifunctional Inhibitors using Multiple Microdomain Targeted Docking.

PubMed

Ciubotaru, Mihai; Musat, Mihaela Georgiana; Surleac, Marius; Ionita, Elena; Petrescu, Andrei Jose; Abele, Edgars; Abele, Ramona

2018-04-05

Currently used antiretroviral HIV therapy drugs exclusively target critical groups in the enzymes essential for the viral life cycle. Increased mutagenesis of their genes, changes these viral enzymes which once mutated can evade therapeutic targeting, effects which confer drug resistance. To circumvent this, our review addresses a strategy to design and derive HIV-Integrase (HIV-IN) inhibitors which simultaneously target two IN functional domains, rendering it inactive even if the enzyme accumulates many mutations. First we review the enzymatic role of IN to insert the copied viral DNA into a chromosome of the host T lymphocyte, highlighting its main functional and structural features to be subjected to inhibitory action. From a functional and structural perspective we present all classes of HIV-IN inhibitors with their most representative candidates. For each chosen compound we also explain its mechanism of IN inhibition. We use the recently resolved cryo EM IN tetramer intasome DNA complex [1] onto which we dock various reference IN inhibitory chemical scaffolds such as to target adjacent functional IN domains. Pairing compounds with complementary activity, which dock in the vicinity of a IN structural microdomain, we design bifunctional new drugs which may not only be more resilient to IN mutations but also may be more potent inhibitors than their original counterparts. In the end of our review we propose synthesis pathways to link such paired compounds with enhanced synergistic IN inhibitory effects. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Lentivirus-mediated shRNA silencing of LAMP2A inhibits the proliferation of multiple myeloma cells].

PubMed

Li, Lixuan; Li, Jia

2015-05-01

To study the effects of lentivirus-mediated short hairpin RNA (shRNA) silencing of lysosome-associated membrane protein type 2A (LAMP2A) expression on the proliferation of multiple myeloma cells. The constructed shRNA lentiviral vector was applied to infect human multiple myeloma cell line MM.1S, and stable expression cell line was obtained by puromycin screening. Western blotting was used to verify the inhibitory effect on LAMP2A protein expression. MTT assay was conducted to detect the effect of knocked-down LAMP2A on MM.1S cell proliferation, and the anti-tumor potency of suberoylanilide hydroxamic acid (SAHA) against the obtained MM.1S LAMP2A(shRNA) stable cell line. Lactate assay was performed to observe the impact of low LAMP2A expression on cell glycolysis. The stable cell line with low LAMP2A expression were obtained with the constructed human LAMP2A-shRNA lentiviral vector. Down-regulation of LAMP2A expression significantly inhibited MM.1S cell proliferation and enhanced the anti-tumor activity of SAHA. Interestingly, decreased LAMP2A expression also inhibited MM.1S cell lactic acid secretion. Down-regulation of LAMP2A expression could inhibit cell proliferation in multiple myeloma cells.

Emergent gamma synchrony in all-to-all interneuronal networks.

PubMed

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P; Talathi, Sachin S

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization.

Emergent gamma synchrony in all-to-all interneuronal networks

PubMed Central

Ratnadurai-Giridharan, Shivakeshavan; Khargonekar, Pramod P.; Talathi, Sachin S.

2015-01-01

We investigate the emergence of in-phase synchronization in a heterogeneous network of coupled inhibitory interneurons in the presence of spike timing dependent plasticity (STDP). Using a simple network of two mutually coupled interneurons (2-MCI), we first study the effects of STDP on in-phase synchronization. We demonstrate that, with STDP, the 2-MCI network can evolve to either a state of stable 1:1 in-phase synchronization or exhibit multiple regimes of higher order synchronization states. We show that the emergence of synchronization induces a structural asymmetry in the 2-MCI network such that the synapses onto the high frequency firing neurons are potentiated, while those onto the low frequency firing neurons are de-potentiated, resulting in the directed flow of information from low frequency firing neurons to high frequency firing neurons. Finally, we demonstrate that the principal findings from our analysis of the 2-MCI network contribute to the emergence of robust synchronization in the Wang-Buzsaki network (Wang and Buzsáki, 1996) of all-to-all coupled inhibitory interneurons (100-MCI) for a significantly larger range of heterogeneity in the intrinsic firing rate of the neurons in the network. We conclude that STDP of inhibitory synapses provide a viable mechanism for robust neural synchronization. PMID:26528174

Coumarins with α-glucosidase and α-amylase inhibitory activities from the flower of Edgeworthia gardneri.

PubMed

Zhao, Deng-Gao; Zhou, Ai-Yu; Du, Zhiyun; Zhang, Yu; Zhang, Kun; Ma, Yan-Yan

2015-12-01

The flower of Edgeworthia gardneri is consumed in beverages in Tibet and has potential health benefits for diabetes. As a part of our continuous studies on dietary supplements for diabetes, two monomers, five dimers and one trimer of coumarins were isolated from the flowers of E. gardneri. One dimer was a new compound (1) and its structure was determined by spectroscopic methods, including multiple NMR techniques and mass spectrometry. The inhibitory activities of all coumarins against α-amylase and α-glucosidase were evaluated. Compound 4 displayed potent inhibitory effect on both α-amylase and α-glucosidase, with an IC50 of 90 and 86μg/mL, respectively. The IC50 of compound 3 against α-glucosidase was 18.7μg/mL, and its inhibition mode was noncompetitive. Based on the fluorescence analysis, the binding constant and the number of binding sites of compound 3 were calculated as 2.05×10(5) and 1.24, respectively. Furthermore, the interaction between compound 3 and α-glucosidase was a spontaneous process that was driven mainly by hydrophobic force. This study could facilitate the utilization of E gardneri as functional food ingredient. Copyright © 2015 Elsevier B.V. All rights reserved.

Azelaic acid: Properties and mode of action.

PubMed

Sieber, M A; Hegel, J K E

2014-01-01

Acne is a common skin disorder that can be problematic for adults as well as for adolescents. It has several key pathophysiological features such as follicular hyperkeratosis, elevated Propionibacterium acnes proliferation, and reactive inflammation, all of which should be targeted for an optimal outcome. Azelaic acid (AzA) has profound anti-inflammatory, antioxidative effects, and is bactericidal against a range of Gram-negative and Gram-positive microorganisms as well, including antibiotic-resistant bacterial strains. In addition, AzA's antikeratinizing effects are inhibitory toward comedones. AzA is effective overall in targeting multiple causes of acne and has been proven to be well tolerated in numerous clinical trials. © 2013 S. Karger AG, Basel.

Effects of NO3(-) and NH4(+) and urea on each other's uptake and incorporation

NASA Technical Reports Server (NTRS)

Huffaker, R. C.; Ward, M. R.

1986-01-01

The purpose was to determine the optimal use by wheat plants of the N sources expected from processing biological waste products, NO3(-),NO2(-)NH4(+), and urea. The approach was to determine the uptake and metabolic products of each N source (from single and multiple component solutions), inhibitory effects of each, feedback inhibition, and overall in vivo regulation of the rates of assimilation of each by wheat plants. Previously, researchers determined the interactions of NO3(-),NO2(-),NH4(+) on each other's uptake and incorporation. The assimilation and some of its effects on NO3(-) and NH4(+) assimilation which have been completed to data are discussed.

Distractor inhibition: principles of operation during selective attention.

PubMed

Wyatt, Natalie; Machado, Liana

2013-02-01

Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in contrast to target amplification, distractor inhibition does not onset earlier or strengthen in response to advance location information. Instead, when the location of the impending distractor was predictable, evidence of inhibitory processing weakened. Furthermore, the results suggest that distractor inhibition does not operate as a compensatory mechanism for target amplification, as evidenced by the lack of an increase in inhibitory effects when reliance on target amplification was disrupted. Unexpected emergence of inhibitory effects for improbable targets provided evidence that distractor inhibition was at work even when no inhibitory effects manifested. Overall, the pattern of inhibitory effects is interpreted as indicating that, although distractor inhibition mounts primarily reactively rather than preemptively, advance information can help prevent overreaction to the distractor. Of course, less overreaction reduces the chances of behavioral inhibitory effects manifesting even when distractor inhibition has contributed to selective attention; thus, interpreting an absence of inhibitory effects should be done cautiously. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Chapter 8. Tea and Cancer Prevention: Epidemiological Studies

PubMed Central

Yuan, Jian-Min; Sun, Canlan; Butler, Lesley M.

2011-01-01

Experimental studies have consistently shown the inhibitory activities of tea extracts on tumorigenesis in multiple model systems. Epidemiologic studies, however, have produced inconclusive results in humans. A comprehensive review was conducted to assess the current knowledge on tea consumption and risk of cancers in humans. In general, consumption of black tea was not associated with lower risk of cancer. High intake of green tea was consistently associated with reduced risk of upper gastrointestinal tract cancers after sufficient control for confounders. Limited data support a protective effect of green tea on lung and hepatocellular carcinogenesis. Although observational studies do not support a beneficial role of tea intake on prostate cancer risk, phase II clinical trials have demonstrated an inhibitory effect of green tea extract against the progression of prostate pre-malignant lesions. Green tea may exert beneficial effects against mammary carcinogenesis in premenopausal women and recurrence of breast cancer. There is no sufficient evidence that supports a protective role of tea intake on the development of cancers of the colorectum, pancreas, urinary tract, glioma, lymphoma, and leukemia. Future prospective observational studies with biomarkers of exposure and phase III clinical trials are required to provide definitive evidence for the hypothesized beneficial effect of tea consumption on cancer formation in humans. PMID:21419224

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

PubMed Central

Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

1995-01-01

In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality. PMID:7621588

Multiple mechanisms switch an electrically coupled, synaptically inhibited neuron between competing rhythmic oscillators.

PubMed

Gutierrez, Gabrielle J; O'Leary, Timothy; Marder, Eve

2013-03-06

Rhythmic oscillations are common features of nervous systems. One of the fundamental questions posed by these rhythms is how individual neurons or groups of neurons are recruited into different network oscillations. We modeled competing fast and slow oscillators connected to a hub neuron with electrical and inhibitory synapses. We explore the patterns of coordination shown in the network as a function of the electrical coupling and inhibitory synapse strengths with the help of a novel visualization method that we call the "parameterscape." The hub neuron can be switched between the fast and slow oscillators by multiple network mechanisms, indicating that a given change in network state can be achieved by degenerate cellular mechanisms. These results have importance for interpreting experiments employing optogenetic, genetic, and pharmacological manipulations to understand circuit dynamics. Copyright © 2013 Elsevier Inc. All rights reserved.

Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism.

PubMed

Naaijen, J; Bralten, J; Poelmans, G; Glennon, J C; Franke, B; Buitelaar, J K

2017-01-10

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.

Chromanyl-isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies.

PubMed

Singh, Gagandeep; Sharma, Anuradha; Kaur, Harpreet; Ishar, Mohan Paul S

2016-02-01

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities. © 2015 John Wiley & Sons A/S.

QSAR Analysis of 2-Amino or 2-Methyl-1-Substituted Benzimidazoles Against Pseudomonas aeruginosa

PubMed Central

Podunavac-Kuzmanović, Sanja O.; Cvetković, Dragoljub D.; Barna, Dijana J.

2009-01-01

A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a combination of various physicochemical, steric, electronic, and structural molecular descriptors. A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the antibacterial activity of the benzimidazole derivatives. The stepwise regression method was used to derive the most significant models as a calibration model for predicting the inhibitory activity of this class of molecules. The best QSAR models were further validated by a leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. To confirm the predictive power of the models, an external set of molecules was used. High agreement between experimental and predicted inhibitory values, obtained in the validation procedure, indicated the good quality of the derived QSAR models. PMID:19468332

Endocrinological control of growth.

PubMed

Sizonenko, P C

1978-01-01

Many endocrinological factors control cellular growth of different tissues (cell multiplication and cell volume) and skeletal growth. The role of neuro-transmitters and of hypothalamic releasing and inhibiting factors of growth hormone secretion will be reviewed. The importance of the somatomedins on cartilage growth will be stressed. Thyroid hormones, androgens, and oestrogens have important stimulating actions on skeletal growth and maturation. Conversely, glucocorticoids have an important inhibitory effect on growth. The precise roles of these hormone factors in the regulation of growth hormone secretion, somatomedin production and tissue growth, particularly the cartilage, remain to be completely elucidated.

Acute effects of alcohol on inhibitory control and simulated driving in DUI offenders.

PubMed

Van Dyke, Nicholas; Fillmore, Mark T

2014-06-01

The public health costs associated with alcohol-related traffic accidents have prompted considerable research aimed at identifying characteristics of individuals who drive under the influence (DUI) in order to improve treatment and prevention strategies. Survey studies consistently show that DUI offenders self-report higher levels of impulsivity compared to their nonoffending counterparts. However, little is known about how individuals with a DUI history respond under alcohol. Inhibitory control is a behavioral component of impulsivity thought to underlie risky drinking and driving behaviors. The present study examined the degree to which DUI drivers display deficits of inhibitory control in response to alcohol and the degree to which alcohol impaired their simulated driving performance. It was hypothesized that DUI offenders would display an increased sensitivity to the acute impairing effects of alcohol on simulated driving performance. Young adult drivers with a history of DUI and a demographically-comparable group of drivers with no history of DUI (controls) were tested following a 0.65 g/kg dose of alcohol and a placebo. Inhibitory control was measured by using a cued go/no-go task. Drivers then completed a driving simulation task that yielded multiple indicators of driving performance, such as within-lane deviation, steering rate, centerline crossings and road edge excursions, and drive speed. Results showed that although DUI offenders self-reported greater levels of impulsivity than did controls, no group differences were observed in the degree to which alcohol impaired inhibitory control and driving performance. The findings point to the need to identify other aspects of behavioral dysfunction underlying the self-reported impulsivity among DUI offenders, and to better understand the specific driving situations that might pose greater risk to DUI offenders. The systematic study of candidate cognitive deficits in DUI offenders will provide important information on their role in risky driving behavior and decisions to drink and drive. Such information is critical for guiding new interventions for DUI offenders that will move treatment beyond general addiction counseling. Copyright © 2014 Elsevier B.V. All rights reserved.

Cognitive declines in healthy aging: evidence from multiple aspects of interference resolution.

PubMed

Pettigrew, Corinne; Martin, Randi C

2014-06-01

The present study tested the hypothesis that older adults show age-related deficits in interference resolution, also referred to as inhibitory control. Although oftentimes considered as a unitary aspect of executive function, various lines of work support the notion that interference resolution may be better understood as multiple constructs, including resistance to proactive interference (PI) and response-distractor inhibition (e.g., Friedman & Miyake, 2004). Using this dichotomy, the present study assessed whether older adults (relative to younger adults) show impaired performance across both, 1, or neither of these interference resolution constructs. To do so, we used multiple tasks to tap each construct and examined age effects at both the single task and latent variable levels. Older adults consistently demonstrated exaggerated interference effects across resistance to PI tasks. Although the results for the response-distractor inhibition tasks were less consistent at the individual task level analyses, age effects were evident on multiple tasks, as well as at the latent variable level. However, results of the latent variable modeling suggested declines in interference resolution are best explained by variance that is common to the 2 interference resolution constructs measured herein. Furthermore, the effect of age on interference resolution was found to be both distinct from declines in working memory, and independent of processing speed. These findings suggest multiple cognitive domains are independently sensitive to age, but that declines in the interference resolution constructs measured herein may originate from a common cause. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Effect of inhibitors of endocytosis and NF-kB signal pathway on folate-conjugated nanoparticle endocytosis by rat Kupffer cells.

PubMed

Tang, Hongbo; Chen, Hongli; Jia, Yajing; Liu, Xiaoyan; Han, Zhaohong; Wang, Aihua; Liu, Qi; Li, Xinlei; Feng, Xin

2017-01-01

The regular accumulation of nanoparticles in the liver makes them hepatotoxic and decreases the circulation time, thus reducing their therapeutic effect. Resolving this problem will be significant in improving bioavailability and reducing side effects. In this study, we reduced the phagocytosis of epirubicin (EPI)-loaded folic acid-conjugated pullulan acetate (FPA/EPI) nanoparticles by Kupffer cells (KCs) through internalization and nuclear factor kappa B (NF-kB) signal pathway inhibitors, thus allowing development of FPA/EPI nanoparticles as a nanodrug delivery system (NDDS) based on our previous study. FPA/EPI nanoparticles were prepared by the dialysis method. Rat KCs were preincubated with the following individual or compound inhibitors: chlorpromazine (CPZ), nystatin (NY), colchicine (Col), amiloride (AMR), and pyrrolidine dithiocarbamate (PDTC). Dose- and time-dependent cellular uptake effects of inhibitors on FPA/EPI nanoparticles were determined through fluorometry. The cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 were tested in culture supernatants by bead-based multiplex flow cytometry. The uptake study demonstrated that inhibitors had an obvious inhibitory effect ( P <0.05 or P <0.01), with NY, AMR and Col all showing time-dependent inhibitory effects. PDTC + NY had the strongest inhibitory effect, with an uptake rate of 14.62%. The levels of the three proinflammatory cytokines were changed significantly by the compound inhibitors. TNF-α was significantly inhibited ( P <0.05 or P <0.01), but IL-1β and IL-6 showed smaller decreases. These results suggested that clathrin- and caveolae-mediated endocytosis were the main routes via which nanoparticles entered KCs and that the NF-kB signal pathway was very important too. In summary, multiple mechanisms, including clathrin- and caveolae-mediated endocytosis, contribute to cytokine production in macrophages following exposure to folic acid-conjugated pullulan acetate nanoparticles. Thus, the endocytosis inhibition strategy has great potential for improving therapy and reducing toxicity of an NDDS in the treatment of cancer.

Feeding deterrent and growth inhibitory activities of PONNEEM, a newly developed phytopesticidal formulation against Helicoverpa armigera (Hubner)

PubMed Central

Packiam, Soosaimanickam Maria; Baskar, Kathirvelu; Ignacimuthu, Savarimuthu

2014-01-01

Objective To assess the feeding deterrent, growth inhibitory and egg hatchability effects of PONNEEM on Helicoverpa armigera (H. armigera). Methods Five oil formulations were prepared at different ratios to assess the feeding deterrent, growth inhibitory and egg hatchability effects on H. armigera. Results Invariably all the newly formulated phytopesticidal oil formulations showed the feeding deterrent and growth inhibitory activities against H. armigera. The maximum feeding deterrent activity of 88.44% was observed at 15 µL/L concentration of PONNEEM followed by formulation A (74.54%). PONNEEM was found to be effective in growth inhibitory activities and egg hatchability at 10 µL/L concentration. It exhibited statistically significant feeding deterrent activity and growth inhibitory activity compared with all the other treatments. Conclusions PONNEEM was found to be effective phytopesticidal formulation to control the larval stage of H. armigera. This is the first report for the feeding deterrent activity of PONNEEM against H. armigera. This newly formulated phytopesticide was patented in India. PMID:25183105

Inhibitory effects of 2'-hydroxychalcones on rat lens aldose reductase and rat platelet aggregation.

PubMed

Lim, S S; Jung, S H; Ji, J; Shin, K H; Keum, S R

2000-11-01

Inhibitory effects of synthetic 2'-hydroxychalcone derivatives on rat lens aldose reductase (RLAR) and on platelet aggregation were investigated for the prevention or the treatment of chronic diabetic complications. 5'-chloro-4,2'-dihydroxychalcone (8) and 5'-chloro-3,2'-dihydroxychalcone (27) exhibited a potent inhibitory effect on rat platelet aggregation induced by ADP (IC50=0.10 and 0.06 mg/ml, respectively) and collagen (IC50=44 and 16 microg/ml, respectively) but showed relatively weak inhibitory activities on RLAR.

Virtual screening for potential inhibitors of bacterial MurC and MurD ligases.

PubMed

Tomašić, Tihomir; Kovač, Andreja; Klebe, Gerhard; Blanot, Didier; Gobec, Stanislav; Kikelj, Danijel; Mašič, Lucija Peterlin

2012-03-01

Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency.

Evaluation of environmental bacterial communities as a factor affecting the growth of duckweed Lemna minor.

PubMed

Ishizawa, Hidehiro; Kuroda, Masashi; Morikawa, Masaaki; Ike, Michihiko

2017-01-01

Duckweed (family Lemnaceae ) has recently been recognized as an ideal biomass feedstock for biofuel production due to its rapid growth and high starch content, which inspired interest in improving their productivity. Since microbes that co-exist with plants are known to have significant effects on their growth according to the previous studies for terrestrial plants, this study has attempted to understand the plant-microbial interactions of a duckweed, Lemna minor , focusing on the growth promotion/inhibition effects so as to assess the possibility of accelerated duckweed production by modifying co-existing bacterial community. Co-cultivation of aseptic L. minor and bacterial communities collected from various aquatic environments resulted in changes in duckweed growth ranging from -24 to +14% compared to aseptic control. A number of bacterial strains were isolated from both growth-promoting and growth-inhibitory communities, and examined for their co-existing effects on duckweed growth. Irrespective of the source, each strain showed promotive, inhibitory, or neutral effects when individually co-cultured with L. minor . To further analyze the interactions among these bacterial strains in a community, binary combinations of promotive and inhibitory strains were co-cultured with aseptic L. minor , resulting in that combinations of promotive-promotive or inhibitory-inhibitory strains generally showed effects similar to those of individual strains. However, combinations of promotive-inhibitory strains tended to show inhibitory effects while only Aquitalea magnusonii H3 exerted its plant growth-promoting effect in all combinations tested. Significant change in biomass production was observed when duckweed was co-cultivated with environmental bacterial communities. Promotive, neutral, and inhibitory bacteria in the community would synergistically determine the effects. The results indicate the possibility of improving duckweed biomass production via regulation of co-existing bacterial communities.

Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages.

PubMed

Lee, Jacinta P W; Foote, Andrew; Fan, Huapeng; Peral de Castro, Celia; Lang, Tali; Jones, Sarah A; Gavrilescu, Nichita; Mills, Kingston H G; Leech, Michelle; Morand, Eric F; Harris, James

2016-06-02

MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]) is a pro-inflammatory cytokine expressed in multiple cells types, including macrophages. MIF plays a pathogenic role in a number of inflammatory diseases and has been linked to tumor progression in some cancers. Previous work has demonstrated that loss of autophagy in macrophages enhances secretion of IL1 family cytokines. Here, we demonstrate that loss of autophagy, by pharmacological inhibition or siRNA silencing of Atg5, enhances MIF secretion by monocytes and macrophages. We further demonstrate that this is dependent on mitochondrial reactive oxygen species (ROS). Induction of autophagy with MTOR inhibitors had no effect on MIF secretion, but amino acid starvation increased secretion. This was unaffected by Atg5 siRNA but was again dependent on mitochondrial ROS. Our data demonstrate that autophagic regulation of mitochondrial ROS plays a pivotal role in the regulation of inflammatory cytokine secretion in macrophages, with potential implications for the pathogenesis of inflammatory diseases and cancers.

Potent inhibitory effects of D-tagatose on the acid production and water-insoluble glucan synthesis of Streptococcus mutans GS5 in the presence of sucrose.

PubMed

Sawada, Daijo; Ogawa, Takaaki; Miyake, Minoru; Hasui, Yoshinori; Yamaguchi, Fuminori; Izumori, Ken; Tokuda, Masaaki

2015-01-01

We examined and compared the inhibitory effects of D-tagatose on the growth, acid production, and water-insoluble glucan synthesis of GS5, a bacterial strain of Streptococcus mutans, with those of xylitol, D-psicose, L-psicose and L-tagatose. GS5 was cultured for 12h in a medium containing 10% (w/v) of xylitol, D-psicose, L-psicose, D-tagatose or L-tagatose, and the inhibitory effect of GS5 growth was assessed. Each sugar showed different inhibitory effects on GS5. Both D-tagatose and xylitol significantly inhibited the acid production and water-insoluble glucan synthesis of GS5 in the presence of 1% (w/v) sucrose. However, the inhibitory effect of acid production by D-tagatose was significantly stronger than that of xylitol in presence of sucrose.

Update on the use of defibrotide.

PubMed

Guglielmelli, Tommasina; Bringhen, Sara; Palumbo, Antonio

2012-03-01

Defibrotide is a polydisperse oligonucleotide obtained from porcine intestinal mucosa and prepared by controlled depolymerization of DNA. It is a nucleic acid polymer, predominantly single-stranded, which has anti-ischemic and anti-thrombotic properties. The efficacy and safety of defibrotide in the treatment of veno-occlusive disease (VOD) occurring after high-dose chemotherapy and hematopoietic stem-cell transplantation is now well established in Phase II - III trials. A recent randomized, Phase III trial in pediatric patients has also demonstrated its role in the prevention of VOD. Preclinical studies reported the inhibitory effects of defibrotide on myeloma cells' growth through an antiangiogenic action and a regulation of the tumor-microenvironment interactions. A recent Phase II trial underlines the efficacy and safety of defibrotide-thalidomide-melphalan combination in the treatment of relapsed/refractory multiple myeloma. Defibrotide may be effective in the prophylaxis and the treatment of veno-occlusive disease. Recent experimental results suggest that defibrotide may belong to the new generation of anti-cancer drugs that can prevent tumor angiogenesis. In multiple myeloma, defibrotide may overcome the prothrombotic effect of thalidomide on endothelial cells. Further preclinical and clinical investigations are needed to assess the precise role of defibrotide in the treatment of patients with multiple myeloma.

Effect of steeping temperature on antioxidant and inhibitory activities of green tea extracts against α-amylase, α-glucosidase and intestinal glucose uptake.

PubMed

Liu, Shuyuan; Ai, Zeyi; Qu, Fengfeng; Chen, Yuqiong; Ni, Dejiang

2017-11-01

The objective of the present study was to evaluate the effect of steeping temperature on the biological activities of green tea, including the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging capacity, α-glucosidase and α-amylase inhibitory activities, and glucose uptake inhibitory activity in Caco-2 cells. Results showed that, with increasing extraction temperature, the polyphenol content increased, which contributed to enhance antioxidant activity and inhibitory effects on α-glucosidase and α-amylase. Green tea steeped at 100°C showed the highest DPPH radical-scavenging activity and inhibitory effects on α-glucosidase and α-amylase activities with EC 50 or IC 50 values of 6.15μg/mL, 0.09mg/mL, and 6.31mg/mL, respectively. However, the inhibitory potential on glucose uptake did not show an upward trend with increasing extraction temperature. Green tea steeped at 60°C had significantly stronger glucose uptake inhibitory activity (p<0.05). The integrated data suggested that steeping temperature should be considered when evaluating the biological activities of green tea. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of oxotremorine and physostigmine on the inhibitory avoidance impairment produced by amitriptyline in male and female mice.

PubMed

Monleón, Santiago; Urquiza, Adoración; Vinader-Caerols, Concepción; Parra, Andrés

2009-12-28

We have previously observed that amitriptyline and other antidepressants produce impairing effects on inhibitory avoidance (also called passive avoidance) in mice of both sexes. In the present study we investigated the involvement of the cholinergic system in the inhibitory avoidance impairment produced by acute amitriptyline in male and female CD1 mice. For this purpose, the effects on said task of acute i.p. administration of several doses of amitriptyline, either alone or in combination with the cholinergic agonists oxotremorine and physostigmine, were evaluated. Pre-training administration of 5, 7.5, 10 or 15 mg/kg of amitriptyline produced a significant impairment of inhibitory avoidance in both males and females. When oxotremorine (0.05 or 0.1 mg/kg) was co-administered with amitriptyline, the antidepressant's impairing effect was partially counteracted, although inhibitory avoidance learning was not significant. Physostigmine (0.15, 0.3 or 0.6 mg/kg) counteracted the impairment produced by amitriptyline, as mice treated with both drugs exhibited inhibitory avoidance learning. These results show that the inhibitory avoidance impairment produced by amitriptyline in male and female mice is mediated, at least partially, by the cholinergic system.

Fe3O4 nanoparticle loaded paclitaxel induce multiple myeloma apoptosis by cell cycle arrest and increase cleavage of caspases in vitro

NASA Astrophysics Data System (ADS)

Yang, Cuiping; He, Xiangfeng; Chen, Junsong; Chen, Dengyu; Liu, Yunjing; Xiong, Fei; Shi, Fangfang; Dou, Jun; Gu, Ning

2013-08-01

Multiple myeloma (MM) still remains an incurable disease in spite of extending the patient survival by new therapies. The hypothesis of cancer stem cells (CSCs) states that although chemotherapy kills most tumor cells, it is believed to leave a reservoir of CSCs that allows the tumor cell propagation. The objective of this research was to evaluate the therapeutic effect of new paclitaxel-Fe3O4 nanoparticles (PTX-NPs) with an average size range of 7.17 ± 1.31 nm on MM CSCs in vitro. The characteristics of CD138-CD34- cells, isolated from human MM RPMI 8226 and NCI-H929 cell lines by the magnetic associated cell sorting method, were identified by the assays of colony formation, cell proliferation, drug resistance, cell migration, and tumorigenicity in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, respectively. Inhibitory effects of PTX-NPs on CD138-CD34- cells were evaluated by a variety of assays in vitro. The results showed that the CD138-CD34- cells were capable of forming colonies, exhibited high proliferative and migratory ability, possessed a strong drug resistance, and had powerful tumorigenicity in NOD/SCID mice compared to non-CD138-CD34- cells. PTX-NPs significantly inhibited CD138- CD34- cell viability and invasive ability, and resulted in G0/G1 cell cycle arrest and apoptosis compared with PTX alone. We concluded that the CD138-CD34- phenotype cells might be CSCs in RPMI 8226 and NCI-H929 cell lines. PTX-NPs had an obvious inhibitory effect on MM CD138-CD34- CSCs. The findings may provide a guideline for PTX-NPs' treatment of MM CSCs in preclinical investigation.

Inhibitory effect of flavonoids from citrus plants on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

PubMed

Iwase, Y; Takemura, Y; Ju-ichi, M; Ito, C; Furukawa, H; Kawaii, S; Yano, M; Mou, X Y; Takayasu, J; Tokuda, H; Nishino, H

2000-06-01

To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities.

PubMed

Elbarbry, Fawzy; Ung, Aimy; Abdelkawy, Khaled

2018-01-01

Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology. The in vitro studies were conducted using fluorescence-based high throughput assays using human c-DNA baculovirus expressed CYP enzymes. For measuring CYP2E1 activity, a validated High-performance liquid chromatography (HPLC) assay was utilized to measure the formation of 6-hydroxychlorzoxazone. The obtained half-maximum inhibitory concentration values with known positive control inhibitors of this study were comparable to the published values indicating accurate experimental techniques. Although QR did not show any significant effect on CYP1A2 and CYP2E1, it exhibited a strong inhibitory effect against CYP2D6 and a moderate effect against CYP2C19 and CYP3A4. On the other hand, TQ demonstrated a strong and a moderate inhibitory effect against CYP3A4 and CYP2C19, respectively. The findings of this study may indicate that consumption of QR or TQ, in the form of food or dietary supplements, with drugs that are metabolized by CYP2C19, CYP2D6, or CYP3A4 may cause significant herb-drug interactions. Neither QR nor TQ has any significant inhibitory effect on the activity of CYP1A2 or CYP2E1 enzymesBoth QR and TQ have a moderate to strong inhibitory effect on CYP3A4 activityQR has a moderate inhibitory effect on CYP2C19 and a strong inhibitory effect on CYP2D6Both QR and TQ are moderate inhibitors of the CYP2C9 activity. Abbreviations used: ABT: Aminobenztriazole, BZF: 7,8 Benzoflavone, CYP: Cytochrome P450, GB: Gingko Biloba, IC 50 : Half-maximum inhibitory concentration, KTZ: Ketoconazole, QND: Quinidine, QR: Quercetin, TCP: Tranylcypromine, TQ: Thymoquinone.

Inhibitory Activity of Avocado Seed Fatty Acid Derivatives (Acetogenins) Against Listeria Monocytogenes.

PubMed

Salinas-Salazar, Carmen; Hernández-Brenes, Carmen; Rodríguez-Sánchez, Dariana Graciela; Castillo, Elena Cristina; Navarro-Silva, Jesús Manuel; Pacheco, Adriana

2017-01-01

High standards regarding Listeria monocytogenes control and consumer demands for food products without synthetic additives represent a challenge to food industry. We determined the antilisterial properties of an enriched acetogenin extract (EAE) from avocado seed, compared it to two commercial antimicrobials (one enriched in avocado acetogenins), and tested purified molecules. Acetogenin composition in pulp and seed of Hass avocado was quantified. EAE were obtained by two sequential centrifuge partition chromatography separations and molecules purified by preparative chromatography and quantified by HPLC-MS-TOF and HPLC-PDA. Avocado seed extracts which are the following two: 1) EAE and 2) the commercially available antimicrobial Avosafe®, presented similar inhibition zones and chemical profiles. Minimum inhibitory concentration (MIC) values of extracts and two isolated acetogenins varied between 7.8 and 15.6 mg/L, were effective at 37 and 4 °C, and showed a bactericidal effect probably caused by increased membrane permeability and lytic effects, evidenced by flow cytometry at 10 and 100× MIC. Activity was comparable to Mirenat®. Most potent acetogenins were Persenone C (5) and A (6), and AcO-avocadenyne (1), the latter exclusively present in seed. Common features of bioactive molecules were the acetyl moiety and multiple unsaturations (2 to 3) in the aliphatic chain, some persenones also featured a trans-enone group. Seeds contained 1.6 times higher levels of acetogenins than pulp (5048.1 ± 575.5 and 3107.0 ± 207.2 mg/kg fresh weight, respectively), and total content in pulp was 199 to 398 times higher than MIC values. Therefore, acetogenin levels potentially consumed by humans are higher than inhibitory concentrations. Results document properties of avocado seed acetogenins as natural antilisterial food additives. © 2016 Institute of Food Technologists®.

TCDD Inhibition of Canonical Wnt Signaling Disrupts Prostatic Bud Formation in Mouse Urogenital Sinus

PubMed Central

Peterson, Richard E.

2013-01-01

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation. PMID:23429912

TCDD inhibition of canonical Wnt signaling disrupts prostatic bud formation in mouse urogenital sinus.

PubMed

Branam, Amanda M; Davis, Nicole M; Moore, Robert W; Schneider, Andrew J; Vezina, Chad M; Peterson, Richard E

2013-05-01

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.

Effect of soluble factors derived from oral cancer cells on the production of interferon-γ from peripheral blood mononuclear cells following stimulation with OK-432.

PubMed

Ohe, Go; Sasai, Akiko; Uchida, Daisuke; Tamatani, Tetsuya; Nagai, Hirokazu; Miyamoto, Youji

2013-08-01

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.

Linear summation of outputs in a balanced network model of motor cortex

PubMed Central

Capaday, Charles; van Vreeswijk, Carl

2015-01-01

Given the non-linearities of the neural circuitry's elements, we would expect cortical circuits to respond non-linearly when activated. Surprisingly, when two points in the motor cortex are activated simultaneously, the EMG responses are the linear sum of the responses evoked by each of the points activated separately. Additionally, the corticospinal transfer function is close to linear, implying that the synaptic interactions in motor cortex must be effectively linear. To account for this, here we develop a model of motor cortex composed of multiple interconnected points, each comprised of reciprocally connected excitatory and inhibitory neurons. We show how non-linearities in neuronal transfer functions are eschewed by strong synaptic interactions within each point. Consequently, the simultaneous activation of multiple points results in a linear summation of their respective outputs. We also consider the effects of reduction of inhibition at a cortical point when one or more surrounding points are active. The network response in this condition is linear over an approximately two- to three-fold decrease of inhibitory feedback strength. This result supports the idea that focal disinhibition allows linear coupling of motor cortical points to generate movement related muscle activation patterns; albeit with a limitation on gain control. The model also explains why neural activity does not spread as far out as the axonal connectivity allows, whilst also explaining why distant cortical points can be, nonetheless, functionally coupled by focal disinhibition. Finally, we discuss the advantages that linear interactions at the cortical level afford to motor command synthesis. PMID:26097452

Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, H.-S., E-mail: huanghs@mail.ncku.edu.t; Liu, Z.-M.; Hong, D.-Y.

2010-04-15

Arsenic is well known as a carcinogen predisposing humans to some severe diseases and also as an effective medicine for treating acute promyelocytic leukemia, syphilis, and psoriasis. Multiple active mechanisms, including cell cycle arrest and apoptosis, have been proposed in therapy; however, the opposing effects of arsenic remain controversial. Our previous study found that arsenic trioxide (ATO)-induced activation of p21{sup WAF1/CIP1} (p21) led to A431 cell death through the antagonistic effects of the signaling of ERK1/2 and JNK1. In the current study, the inhibitory effects of JNK1 on ATO-induced p21 expression were explored. Over-expression of JNK1 in A431 cells couldmore » inhibit p21 expression, which was associated with HDAC1 and TGIF. Using the GST pull-down assay and fluorescence resonance energy transfer analysis, N-terminal domain (amino acids 1-108) of TGIF, critical to its binding with c-Jun, was found. Using reporter assays, requirement of the C-terminal domain (amino acids 138-272) of TGIF to suppress ATO-induced p21 expression was observed. Thus, the domains of TGIF that carried out its inhibitory effects on p21 were identified. Finally, treatment with JNK inhibitor SP600125 could enhance ATO-induced apoptosis of HaCaT keratinocytes by using flow cytometry.« less

Boolean Modeling of Neural Systems with Point-Process Inputs and Outputs. Part I: Theory and Simulations

PubMed Central

Marmarelis, Vasilis Z.; Zanos, Theodoros P.; Berger, Theodore W.

2010-01-01

This paper presents a new modeling approach for neural systems with point-process (spike) inputs and outputs that utilizes Boolean operators (i.e. modulo 2 multiplication and addition that correspond to the logical AND and OR operations respectively, as well as the AND_NOT logical operation representing inhibitory effects). The form of the employed mathematical models is akin to a “Boolean-Volterra” model that contains the product terms of all relevant input lags in a hierarchical order, where terms of order higher than first represent nonlinear interactions among the various lagged values of each input point-process or among lagged values of various inputs (if multiple inputs exist) as they reflect on the output. The coefficients of this Boolean-Volterra model are also binary variables that indicate the presence or absence of the respective term in each specific model/system. Simulations are used to explore the properties of such models and the feasibility of their accurate estimation from short data-records in the presence of noise (i.e. spurious spikes). The results demonstrate the feasibility of obtaining reliable estimates of such models, with excitatory and inhibitory terms, in the presence of considerable noise (spurious spikes) in the outputs and/or the inputs in a computationally efficient manner. A pilot application of this approach to an actual neural system is presented in the companion paper (Part II). PMID:19517238

Flavone inhibits nitric oxide synthase (NOS) activity, nitric oxide production and protein S-nitrosylation in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Wenzhen; Yang, Bingwu; Fu, Huiling

As the core structure of flavonoids, flavone has been proved to possess anticancer effects. Flavone's growth inhibitory functions are related to NO. NO is synthesized by nitric oxide synthase (NOS), and generally increased in a variety of cancer cells. NO regulates multiple cellular responses by S-nitrosylation. In this study, we explored flavone-induced regulations on nitric oxide (NO)-related cellular processes in breast cancer cells. Our results showed that, flavone suppresses breast cancer cell proliferation and induces apoptosis. Flavone restrains NO synthesis by does-dependent inhibiting NOS enzymatic activity. The decrease of NO generation was detected by fluorescence microscopy and flow cytometry. Flavone-inducedmore » inhibitory effect on NOS activity is dependent on intact cell structure. For the NO-induced protein modification, flavone treatment significantly down-regulated protein S-nitrosylation, which was detected by “Biotin-switch” method. The present study provides a novel, NO-related mechanism for the anticancer function of flavone. - Highlights: • Flavone inhibits proliferation and induces apoptosis in MCF-7 cells. • Flavone decreases nitric oxide production by inhibiting NOS enzymatic activity in breast cancer cells. • Flavone down-regulates protein S-nitrosylation.« less

Flavor Enhancer From Catfish (Clarias batrachus) Bekasam Powder and Angiotensin-I-Converting Enzyme (ACE) Inhibitory Activity in Various Dishes

NASA Astrophysics Data System (ADS)

Lestari, Yanesti N.; Murwani, Retno; Agustini, Tri W.

2018-02-01

Flavor enhancer is characterized by high glutamic acid content and it can be obtained from fermented food such as Bekasam. Fermented food had inhibitory effect on Angiotensin-I-Converting Enzyme (ACE) activity which is advantageous for hypertension. However, such activity was not known to sustain in food system. The aim of this research was to study addition of flavour enhancer from Catfish Bekasam Powder (CBP) in various food systems and to determine the ACE inhibitory (ACEI) activity in the food system. Four food system consisted of carrot, champignon, and chicken meat dishes were boiled in water and added with CBP or MSG. Each food system was added with graded level of CBP (0%; 0.5%; 0.8%; 1.1%; and 1,4%) and for control monosodium glutamate (MSG) was used. ACEI activity in each food system and organoleptic test using multiple comparison differentiation on 15 semi-trained panellists were determined. The results showed that there were fluctuation of ACEI activity in the carrot, champignon, and chicken meat dishes (p=0.017; 0.043; and 0.032). The MSG containing dishes showed the lowest ACEI activity. Addition of graded level of CBP on carrot, champignon, and chicken meat dishes were directly proportional to glutamic acid content but inversely proportional to ACEI activity (p<0.05). The addition of commercial MSG on all dishes increased glutamic acid content but reduced ACE-inhibitory activity significantly (p<0.05). Comparing CBP to MSG addition in champignon dish revealed that increasing level of CBP increased the flavour preference of the panellists. On the contrary the higher the addition CBP in noodle and chicken meat dishes the worse were the flavour score (p<0.05). It can be concluded that the addition of CBP as flavour enhancer on various dishes can deliver better flavour and ACE-inhibitory activity than the addition of commercial MSG.

Oxyresveratrol, a Stilbene Compound from Morus alba L. Twig Extract Active Against Trichophyton rubrum.

PubMed

Lu, Hai-Peng; Jia, Ya-Nan; Peng, Ya-Lin; Yu, Yan; Sun, Si-Long; Yue, Meng-Ting; Pan, Min-Hui; Zeng, Ling-Shu; Xu, Li

2017-12-01

Morus alba L. (mulberry) twig is known to have an inhibitory effect on pathogens in traditional Chinese medicine. In the present study, the dermophytic fungus, Trichophyton rubrum, was used to evaluate the inhibitory effect of total M. alba twig extract and extracts obtained using solvents with different polarities by the method of 96-well MTT colorimetry. The main active substance was isolated and identified by tracking its activity. In addition, the inhibitory effects of active extracts and a single active substance were investigated in combination with miconazole nitrate. Our data indicated that ethyl acetate extracts of mulberry twig (TEE) exhibited a desired inhibitory activity on T. rubrum with the minimum inhibitory concentration (MIC) of 1.000 mg/mL. With activity tracking, the main substance showing antimicrobial activity was oxyresveratrol (OXY), which was isolated from TEE. Its MIC for inhibiting the growth of T. rubrum was 0.500 mg/mL. The combined use of miconazole nitrate and OXY showed a synergistic inhibitory effect, as shown by a significant decrease in the MIC of both components. Based on the OXY content in TEE, the contribution rate of OXY to the inhibitory effect of TEE on T. rubrum was 80.52%, so it was determined to be the main antimicrobial substance in M. alba twig. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism

PubMed Central

Naaijen, J; Bralten, J; Poelmans, G; Faraone, Stephen; Asherson, Philip; Banaschewski, Tobias; Buitelaar, Jan; Franke, Barbara; P Ebstein, Richard; Gill, Michael; Miranda, Ana; D Oades, Robert; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Sonuga-Barke, Edmund; Anney, Richard; Mulas, Fernando; Steinhausen, Hans-Christoph; Glennon, J C; Franke, B; Buitelaar, J K

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (n=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (P=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (P=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD. PMID:28072412

EASY-HIT: HIV full-replication technology for broad discovery of multiple classes of HIV inhibitors.

PubMed

Kremb, Stephan; Helfer, Markus; Heller, Werner; Hoffmann, Dieter; Wolff, Horst; Kleinschmidt, Andrea; Cepok, Sabine; Hemmer, Bernhard; Durner, Jörg; Brack-Werner, Ruth

2010-12-01

HIV replication assays are important tools for HIV drug discovery efforts. Here, we present a full HIV replication system (EASY-HIT) for the identification and analysis of HIV inhibitors. This technology is based on adherently growing HIV-susceptible cells, with a stable fluorescent reporter gene activated by HIV Tat and Rev. A fluorescence-based assay was designed that measures HIV infection by two parameters relating to the early and the late phases of HIV replication, respectively. Validation of the assay with a panel of nine reference inhibitors yielded effective inhibitory concentrations consistent with published data and allowed discrimination between inhibitors of early and late phases of HIV replication. Finer resolution of the effects of reference drugs on different steps of HIV replication was achieved in secondary time-of-addition assays. The EASY-HIT assay yielded high Z' scores (>0.9) and signal stabilities, confirming its robustness. Screening of the LOPAC(1280) library identified 10 compounds (0.8%), of which eight were known to inhibit HIV, validating the suitability of this assay for screening applications. Studies evaluating anti-HIV activities of natural products with the EASY-HIT technology led to the identification of three novel inhibitory compounds that apparently act at different steps of HIV-1 replication. Furthermore, we demonstrate successful evaluation of plant extracts for HIV-inhibitory activities, suggesting application of this technology for the surveillance of biological extracts with anti-HIV activities. We conclude that the EASY-HIT technology is a versatile tool for the discovery and characterization of HIV inhibitors.

[Effect of tea extracts, catechin and caffeine against type-I allergic reaction].

PubMed

Shiozaki, T; Sugiyama, K; Nakazato, K; Takeo, T

1997-07-01

The antiallergic effects of green tea, oolong tea, and black tea extracts by hot water were examined. These extracts inhibited the passive cutaneous anaphylaxis (PCA) reaction of rat after oral administration. Three tea catechins, (--)-epigallocatechin (EGC), (--)-epicatechin gallate (ECg), and (--)-epigallocatechin gallate (EGCg) isolated from green tea showed stronger inhibitory effects than that of a green tea extract on the PCA reaction. The inhibitory effects of EGC and EGCg on the PCA reaction were greater than that of ECg. Caffeine also showed a inhibitory effect on the PCA reaction. These results indicate that tea could provide a significant protection against the type-I allergic reaction. These findings also suggest that tea catechins and caffeine play an important role in having an inhibitory effect on the type-I allergic reaction.

Multiple Activities of Punica granatum Linne against Acne Vulgaris.

PubMed

Lee, Chia-Jung; Chen, Lih-Geeng; Liang, Wen-Li; Wang, Ching-Chiung

2017-01-12

Acne is a common skin condition with sebum overproduction, hyperkeratosis, Propionibacterium acnes ( P . acnes ) and Staphylococcus aureus , and inflammation. Punica granatum (pomegranate) is well-known for its anti-inflammatory effects; however, few studies have discussed the anti-acne effects of pomegranate. In this study, we found that pomegranate extract (PG-E) significantly reduced P . acnes -induced edema in Wistar rat ears. Therefore, an evaluation platform using multiple pathogenic mechanisms of acne was established to explore the anti-acne effects of pomegranate. Results showed that PG-E inhibited bacterial growth and lipase activity. Through a bioguided-fractionation-isolation system, four hydrolysable tannins, punicalagin ( 1 ), punicalin ( 2 ), strictinin A ( 3 ), and granatin B ( 4 ), were isolated. Compounds 1 and 2 had greater anti-bacterial activities and anti-testosterone-induced HaCaT proliferative effects than the others. Compounds 1 , 3 , and 4 displayed lipase inhibitory effects. Compound 4 decreased cyclooxygenase-2 expression and downregulated prostaglandin E₂ production in heat-killed P . acnes -treated RAW 246.7 cells. In conclusion, PG-E is abundant in hydrolysable tannins that display multiple anti-acne capacities, including anti-bacterial, anti-lipase, anti-keratinocyte proliferation, and anti-inflammatory actions. Hence, PG-E has great potential in the application of anti-acne and skin-care products, and punicalagin ( 1 ), the most effective component in PG-E, can be employed as a quality control marker.

Multiple Activities of Punica granatum Linne against Acne Vulgaris

PubMed Central

Lee, Chia-Jung; Chen, Lih-Geeng; Liang, Wen-Li; Wang, Ching-Chiung

2017-01-01

Acne is a common skin condition with sebum overproduction, hyperkeratosis, Propionibacterium acnes (P. acnes) and Staphylococcus aureus, and inflammation. Punica granatum (pomegranate) is well-known for its anti-inflammatory effects; however, few studies have discussed the anti-acne effects of pomegranate. In this study, we found that pomegranate extract (PG-E) significantly reduced P. acnes-induced edema in Wistar rat ears. Therefore, an evaluation platform using multiple pathogenic mechanisms of acne was established to explore the anti-acne effects of pomegranate. Results showed that PG-E inhibited bacterial growth and lipase activity. Through a bioguided-fractionation-isolation system, four hydrolysable tannins, punicalagin (1), punicalin (2), strictinin A (3), and granatin B (4), were isolated. Compounds 1 and 2 had greater anti-bacterial activities and anti-testosterone-induced HaCaT proliferative effects than the others. Compounds 1, 3, and 4 displayed lipase inhibitory effects. Compound 4 decreased cyclooxygenase-2 expression and downregulated prostaglandin E2 production in heat-killed P. acnes-treated RAW 246.7 cells. In conclusion, PG-E is abundant in hydrolysable tannins that display multiple anti-acne capacities, including anti-bacterial, anti-lipase, anti-keratinocyte proliferation, and anti-inflammatory actions. Hence, PG-E has great potential in the application of anti-acne and skin-care products, and punicalagin (1), the most effective component in PG-E, can be employed as a quality control marker. PMID:28085116

Synthesis and anti-inflammatory effect of chalcones and related compounds.

PubMed

Hsieh, H K; Lee, T H; Wang, J P; Wang, J J; Lin, C N

1998-01-01

Mast cell and neutrophil degranulations are the important players in inflammatory disorders. Combined with potent inhibition of chemical mediators released from mast cells and neutrophil degranulations, it could be a promising anti-inflammatory agent. 2',5'-Dihydroxychalcone has been reported as a potent chemical mediator and cyclooxygenase inhibitor. In an effort to continually develop potent anti-inflammatory agents, a novel series of chalcone, 2'- and 3'-hydroxychalcones, 2',5'-dihydroxychalcones and flavanones were continually synthesized to evaluate their inhibitory effects on the activation of mast cells and neutrophils and the inhibitory effect on phlogist-induced hind-paw edema in mice. A series of chalcones and related compounds were prepared by Claisen-Schmidt condensation of appropriate acetophenones with appropriate aromatic aldehyde and the anti-inflammatory activities of these synthetic compounds were studied on inhibitory effects on the activation of mast cells and neutrophils. Some chalcones showed strong inhibitory effects on the release of beta-glucuronidase and histamine from rat peritoneal mast cells stimulated with compound 48/80. Almost all chalcones and 4'-hydroxyflavanone exhibited potent inhibitory effects on the release of beta-glucuronidase and lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP). Some chalcones showed potent inhibitory effects on superoxide formation of rat neutrophils stimulated with fMLP/cytochalasin B (CB) or phorbol myristate acetate (PMA). 2',3-Dihydroxy-, 2',5'-dihydroxy-4-chloro-, and 2',5'-dihydroxychalcone showed remarkable inhibitory effects on hind-paw edema induced by polymyxin B in normal as well as in adrenalectomized mice. These results indicated that the anti-inflammatory effects of these compounds were mediated, at least partly, through the suppression of chemical mediators released from mast cells and neutrophils.

Gamma Rhythm Simulations in Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Montgomery, Samuel; Perez, Carlos; Ullah, Ghanim

The different neural rhythms that occur during the sleep-wake cycle regulate the brain's multiple functions. Memory acquisition occurs during fast gamma rhythms during consciousness, while slow oscillations mediate memory consolidation and erasure during sleep. At the neural network level, these rhythms are generated by the finely timed activity within excitatory and inhibitory neurons. In Alzheimer's Disease (AD) the function of inhibitory neurons is compromised due to an increase in amyloid beta (A β) leading to elevated sodium leakage from extracellular space in the hippocampus. Using a Hodgkin-Huxley formalism, heightened sodium leakage current into inhibitory neurons is observed to compromise functionality. Using a simple two neuron system it was observed that as the conductance of the sodium leakage current is increased in inhibitory neurons there is a significant decrease in spiking frequency regarding the membrane potential. This triggers a significant increase in excitatory spiking leading to aberrant network behavior similar to that seen in AD patients. The next step is to extend this model to a larger neuronal system with varying synaptic densities and conductance strengths as well as deterministic and stochastic drives.

Mechanisms underlying electrical and mechanical responses of the bovine retractor penis to inhibitory nerve stimulation and to an inhibitory extract.

PubMed Central

Byrne, N. G.; Muir, T. C.

1985-01-01

The response of the bovine retractor penis (BRP) to stimulation of non-adrenergic, non-cholinergic (NANC) inhibitory nerves and to an inhibitory extract prepared from this muscle have been studied using intracellular microelectrode, sucrose gap and conventional mechanical recording techniques. Both inhibitory nerve stimulation and inhibitory extract hyperpolarized the membrane potential and relaxed spontaneous or guanethidine (3 X 10(-5) M)-induced tone. These effects were accompanied by an increase in membrane resistance. Following membrane potential displacement from an average value of -53 +/- 7 mV (n = 184; Byrne & Muir, 1984) inhibitory potentials to nerve stimulation were abolished at approximately -30 mV; there was no evidence of reversal. Displacement by inward hyperpolarizing current over the range -45 to -60 mV increased the inhibitory response to nerve stimulation and to inhibitory extract; at more negative potential values (above approximately -60 mV) the inhibitory potential decreased and was abolished (approximately -103 mV). There was no evidence of reversal. Removal of [K+]o reversibly reduced hyperpolarization to nerve stimulation and inhibitory extract. No enhancement was observed. Increasing the [K+]o to 20 mM reduced the inhibitory potential to nerve stimulation but this was restored by passive membrane hyperpolarization. Inhibitory potentials were obtained at membrane potential values exceeding that of the estimated EK (-49 mV). [Cl-]o-free or [Cl-]o-deficient solutions reduced and abolished (after some 20-25 min) the hyperpolarization produced by inhibitory nerve stimulation or inhibitory extract. The inhibitory potential amplitude following nerve stimulation was not restored by passive displacement of the membrane potential from -26 to -104 mV approximately. Ouabain (1-5 X 10(-5) M) reduced then (45-60 min later) abolished the inhibitory potential to nerve stimulation. The effects of this drug on the extract were not investigated. It is concluded that the inhibitory response to nerve stimulation and extract in the BRP may involve several ionic species. However, unlike that in gastrointestinal muscles the NANC response in the BRP is accompanied by an increased membrane resistance and does not primarily involve K+. The underlying mechanisms for the inhibitory response to both NANC nerve stimulation and inhibitory extract appear to be similar, compatible with the view that the latter may contain the inhibitory transmitter released from these nerves in this tissue. PMID:4027462

Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi.

PubMed

Rolón, Miriam; Seco, Elena M; Vega, Celeste; Nogal, Juan J; Escario, José A; Gómez-Barrio, Alicia; Malpartida, Francisco

2006-08-01

The growth inhibitory effects on Trypanosoma cruzi of several natural tetraene macrolides and their derivatives were studied and compared with that of amphotericin B. All tetraenes strongly inhibited in vitro multiplication. Proliferation of epimastigotes was arrested by all these drugs at < or =3.6 microM, which were also active on amastigotes proliferating in fibroblasts. Compared with amphotericin B, the compounds were less effective but also less toxic, showing no effect on the proliferation of J774 and NCTC 929 mammalian cells at concentrations active against the parasites. CE-108B (a polyene amide) appeared to be an especially potent trypanocidal compound, with strong in vivo trypanocidal activity and very low or no toxic side effects, and thus should be considered for further studies.

Antihypertensive properties of lactoferricin B-derived peptides.

PubMed

Ruiz-Giménez, Pedro; Ibáñez, Aida; Salom, Juan B; Marcos, Jose F; López-Díez, Jose Javier; Vallés, Salvador; Torregrosa, Germán; Alborch, Enrique; Manzanares, Paloma

2010-06-09

A set of eight lactoferricin B (LfcinB)-derived peptides was examined for inhibitory effects on angiotensin I-converting enzyme (ACE) activity and ACE-dependent vasoconstriction, and their hypotensive effect in spontaneously hypertensive rats (SHR). Peptides were derived from different elongations both at the C-terminal and N-terminal ends of the representative peptide LfcinB(20-25), which is known as the LfcinB antimicrobial core. All of the eight LfcinB-derived peptides showed in vitro inhibitory effects on ACE activity with different IC(50) values. Moreover, seven of them showed ex vivo inhibitory effects on ACE-dependent vasoconstriction. No clear correlation between in vitro and ex vivo inhibitory effects was found. Only LfcinB(20-25) and one of its fragments, F1, generated after a simulated gastrointestinal digestion, showed significant antihypertensive effects in SHR after oral administration. Remarkably, F1 did not show any effect on ACE-dependent vasoconstriction in contrast to the inhibitory effect showed by LfcinB(20-25). In conclusion, two LfcinB-derived peptides lower blood pressure and exhibit potential as orally effective antihypertensive compounds, yet a complete elucidation of the mechanism(s) involved deserves further ongoing research.

Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius

New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated inmore » Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. - Highlights: • VEEV infection activated multiple components of the ERK signaling cascade. • Inhibition of ERK activation using Ag-126 inhibited VEEV multiplication. • Activation of ERK by Ceramide C6 increased infectious titers of TC-83. • Ag-126 inhibited virulent strains of all New World alphaviruses. • Ag-126 treatment increased percent survival of infected cells.« less

No Evidence for Inhibitory Deficits or Altered Reward Processing in ADHD: Data From a New Integrated Monetary Incentive Delay Go/No-Go Task.

PubMed

Demurie, Ellen; Roeyers, Herbert; Wiersema, Jan R; Sonuga-Barke, Edmund

2016-04-01

Cognitive and motivational factors differentially affect individuals with mental health problems such as ADHD. Here we introduce a new task to disentangle the relative contribution of inhibitory control and reward anticipation on task performance in children with ADHD and/or autism spectrum disorders (ASD). Typically developing children, children with ADHD,  ASD, or both disorders worked during separate sessions for monetary or social rewards in go/no-go tasks with varying inhibitory load levels. Participants also completed a monetary temporal discounting (TD) task. As predicted, task performance was sensitive to both the effects of anticipated reward amount and inhibitory load. Reward amount had different effects depending on inhibitory load level. TD correlated with inhibitory control in the ADHD group. The integration of the monetary incentive delay and go/no-go paradigms was successful. Surprisingly, there was no evidence of inhibitory control deficits or altered reward anticipation in the clinical groups. © The Author(s) 2013.

The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer.

PubMed

Wang, Qiwei; Zhang, Xiaotian; Shen, Enyun; Gao, Jing; Cao, Fengqi; Wang, Xiaojuan; Li, Yilin; Tian, Tiantian; Wang, Jingyuan; Chen, Zuhua; Wang, Jiayuan; Shen, Lin

2016-09-28

The anti-HER2 monoclonal antibody trastuzumab is central to the treatment of HER2-positive gastric cancer (GC); however, its responses are limited. HER3 seems to be the preferred dimerization partner with HER2 and is emerging as a key target for complete blockade of downstream pathways and better clinical response. In this study, we report that novel anti-HER3 antibodies (1A5-3D4) that can neutralize multiple modes of HER3 activation, combined with trastuzumab, exhibited synergistic inhibitory effect on the cell proliferation in HER2-positive GC cell lines. Follow-up studies revealed that the combination treatment significantly inhibited phosphorylation of HER3 as well as AKT and ERK signals. In vivo experiments further showed that the anti-tumor effect of trastuzumab was enhanced by its combination with 1A5-3D4 in NCI-N87 xenograft and patient derived xenografts (PDX). Particularly in an HER2-negative whereas neuregulin1 (a ligand of HER3) positive PDX, the combination was also superior to monotherapy. 1A5-3D4 in combination with trastuzumab exhibits a synergistic inhibitory effect on tumor activity, suggesting that targeting both HER2 and HER3 resulted in an improved treatment effects on HER2-positive GC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inhibitory phonetic priming: Where does the effect come from?

PubMed

Dufour, Sophie; Frauenfelder, Ulrich Hans

2016-01-01

Both phonological and phonetic priming studies reveal inhibitory effects that have been interpreted as resulting from lexical competition between the prime and the target. We present a series of phonetic priming experiments that contrasted this lexical locus explanation with that of a prelexical locus by manipulating the lexical status of the prime and the target and the task used. In the related condition of all experiments, spoken targets were preceded by spoken primes that were phonetically similar but shared no phonemes with the target (/bak/-/dεt/). In Experiments 1 and 2, word and nonword primes produced an inhibitory effect of equal size in shadowing and same-different tasks respectively. Experiments 3 and 4 showed robust inhibitory phonetic priming on both word and nonword targets in the shadowing task, but no effect at all in a lexical decision task. Together, these findings show that the inhibitory phonetic priming effect occurs independently of the lexical status of both the prime and the target, and only in tasks that do not necessarily require the activation of lexical representations. Our study thus argues in favour of a prelexical locus for this effect.

Influence of semisynthetic modification of the scaffold of a contact domain of HbS on polymerization: role of flexible surface topology in polymerization inhibition.

PubMed

Sonati, Srinivasulu; Bhutoria, Savita; Prabhakaran, Muthuchidambaran; Acharya, Seetharama A

2018-02-01

A new variant of HbS, HbS-Einstein with a deletion of segment α 23-26 in the B-helix, has been assembled by semisynthetic approach. B-helix of the α chain of cis αβ-dimer of HbS plays dominant role in the quinary interactions of deoxy HbS dimer. This B-helix is the primary scaffold that provides the orientation for the side chains of contact residues of this intermolecular contact domain. The design of HbS-Einstein has been undertaken to map the influence of perturbation of molecular surface topology and the flexibility of surface residues in the polymerization. The internal deletion exerts a strong inhibitory influence on Val-6 (β)-dependent polymerization, comparable to single contact site mutations and not for complete neutralization of Val-6(β)-dependent polymerization. The scaffold modification in cis-dimer is inhibitory, and is without any effect when present on the trans dimer. The flexibility changes in the surface topology in the region of scaffold modification apparently counteracts the intrinsic polymerization potential of the molecule. The inhibition is close to that of Le Lamentin mutation [His-20 (α) → Gln] wherein a mutation engineered without much change in flexibility of the contact domain. Interestingly, the chimeric HbS with swine-human chimeric α chain with multiple non-conservative mutations completely inhibits the Val-6(β)-dependent polymerization. The deformabilities of surface topology of chimeric HbS are comparable to HbS in spite of the multiple contact site mutations in the α-chain. We conclude that the design of antisickling Hbs for gene therapy of sickle cell disease should involve multiple mutations of intermolecular contact sites.

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2016-10-01

Siah1/2 inhibitory peptide that effectively inhibits Siah1/2 activity, which was found to effectively attenuate the growth of prostate cancer tumors in...effectiveness on cell growth with potent toxicity. Second, we set to advance a Siah inhibitory peptide that we recently developed in parallel, as...vivo when transplanted subcutaneously or orthotopically into the prostate site. The assessment of the Siah1/2 inhibitory peptide in genetic models of

Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts.

PubMed

Wu, Chi-Hao; Yen, Gow-Chin

2005-04-20

The objective of this study was to investigate the inhibitory effect of naturally occurring flavonoids on individual stage of protein glycation in vitro using the model systems of delta-Gluconolactone assay (early stage), BSA-methylglyoxal assay (middle stage), BSA-glucose assay, and G.K. peptide-ribose assay (last stage). In the early stage of protein glycation, luteolin, qucertin, and rutin exhibited significant inhibitory activity on HbA1C formation (p < 0.01), which were more effective than that of aminoguanidine (AG, 10 mM), a well-known inhibitor for advanced glycation endproducts (AGEs). For the middle stage, luteolin and rutin developed more significant inhibitory effect on methylglyoxal-medicated protein modification, and the IC50's were 66.1 and 71.8 microM, respectively. In the last stage of glycation, luteolin was found to be potent inhibitors of both the AGEs formation and the subsequent cross-linking of proteins. In addition, phenyl-tert-butyl-nitron served as a spin-trapping agent, and electron spin resonance (ESR) was used to explore the possible mechanism of the inhibitory effect of flavonoids on glycation. The results indicated that protein glycation was accompanied by oxidative reactions, as the ESR spectra showed a clear-cut radical signal. Statistical analysis showed that inhibitory capability of flavonoids against protein glycation was remarkably related to the scavenging free radicals derived from glycoxidation process (r = 0.79, p < 0.01). Consequently, the inhibitory mechanism of flavonoids against glycation was, at least partly, due to their antioxidant properties.

The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo.

PubMed

Uchii, Masako; Sakai, Mariko; Hotta, Yuhei; Saeki, Satoshi; Kimoto, Naoya; Hamaguchi, Akinori; Kitayama, Tetsuya; Kunori, Shunji

2017-11-01

Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Too (mentally) busy to chill: Cognitive load and inhibitory cues interact to moderate triggered displaced aggression.

PubMed

Vasquez, Eduardo A; Howard-Field, Joanna

2016-11-01

Inhibitory information can be expected to reduce triggered displaced aggression by signaling the potential for negative consequences as a result of acting aggressively. We examined how cognitive load might interfere with these aggression-reducing effects of inhibitory cues. Participants (N = 80) were randomly assigned to a condition in a 2 (cognitive load: high/low) × 2 (inhibiting cues: yes/no) between-subjects design. Following procedures in the TDA paradigm, participants received an initial provocation from the experimenter and a subsequent triggering annoyance from another individual. In the inhibitory cue condition, participants were told, before they had the opportunity to aggress, that others would learn of their aggressive responses. In the high cognitive load condition, participants rehearsed a 10-digit number while aggressing. Those in the low cognitive load condition rehearsed a three digit number. We found significant main effects of cognitive load and inhibitory cue, which were qualified by the expected load × inhibitory cue interaction. Thus, inhibitory cues reduced displaced aggression under low-cognitive load. However, when participants in the inhibitory cue condition were under cognitive load, aggression increased, suggesting that mental busyness interfered with the full use of inhibitory information. Aggr. Behav. 42:598-604, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Fermented goats' milk produced with selected multiple starters as a potentially functional food.

PubMed

Minervini, Fabio; Bilancia, Maria Teresa; Siragusa, Sonya; Gobbetti, Marco; Caponio, Francesco

2009-09-01

A screening among five lactic acid bacteria, used alone or in combination, led to select a mixed starter (Streptococcus thermophilus CR12, Lactobacillus casei LC01, Lactobacillus helveticus PR4, Lactobacillus plantarum 1288) capable to produce a fermented goats' milk containing gamma-aminobutyric acid (GABA) and angiotensin-I converting enzyme (ACE)-inhibitory peptides. The fermented milk was characterized by cell counts of lactic acid bacteria not lower than 7.0 log cfu g(-1), even after 45 days of storage at 4 degrees C. Fermentation of goats' milk resulted in the production of ca. 28 mg kg(-1) of GABA. Furthermore the fermented goats' milk had an in vitro ACE-inhibitory activity of ca. 73%. Prolonged cold storage did not significantly affect both the concentration of GABA and the ACE-inhibitory activity. Moreover, the taurine content did not significantly vary during both fermentation and the entire storage period.

The importance of the descending monoamine system for the pain experience and its treatment

PubMed Central

Dickenson, Anthony H

2009-01-01

Brainstem and midbrain areas engage descending facilitatory and inhibitory neurones to potentiate or suppress the passage of sensory inputs from spinal loci to the brain. The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states and can critically determine the efficacy of certain analgesic drugs. There is good evidence for a prominent α2 adrenoceptor-mediated inhibitory system and for 5-HT3 receptor-mediated excitatory control of spinal cord activity that originates in supraspinal areas. Given the multiple roles of these transmitters in pain and functions such as sleep, depression, and anxiety, the link between spinal and supraspinal processing of noxious inputs (via the monoamine transmitters) could be pivotal for linking the sensory and affective components of pain and their common co-morbidities, and also may potentially explain differences in pain scores and treatment outcomes in the patient population. PMID:20948695

The Human Natural Killer Cell Immune Synapse

NASA Astrophysics Data System (ADS)

Davis, Daniel M.; Chiu, Isaac; Fassett, Marlys; Cohen, George B.; Mandelboim, Ofer; Strominger, Jack L.

1999-12-01

Inhibitory killer Ig-like receptors (KIR) at the surface of natural killer (NK) cells induced clustering of HLA-C at the contacting surface of target cells. In this manner, inhibitory immune synapses were formed as human NK cells surveyed target cells. At target/NK cell synapses, HLA-C/KIR distributed into rings around central patches of intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, the opposite orientation to mature murine T cell-activating synapses. This organization of protein was stable for at least 20 min. Cells could support multiple synapses simultaneously, and clusters of HLA-C moved as NK cells crawled over target cells. Clustering required a divalent metal cation, explaining how metal chelators inhibit KIR function. Surprisingly, however, formation of inhibitory synapses was unaffected by ATP depletion and the cytoskeletal inhibitors, colchicine and cytochalsins B and D. Clearly, supramolecular organization within plasma membranes is critical for NK cell immunosurveillance.

Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives.

PubMed

Liu, Jinbing; Chen, Changhong; Wu, Fengyan; Zhao, Liangzhong

2013-07-01

A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest. © 2013 John Wiley & Sons A/S.

Lactoferricin-related peptides with inhibitory effects on ACE-dependent vasoconstriction.

PubMed

Centeno, José M; Burguete, María C; Castelló-Ruiz, María; Enrique, María; Vallés, Salvador; Salom, Juan B; Torregrosa, Germán; Marcos, José F; Alborch, Enrique; Manzanares, Paloma

2006-07-26

A selection of lactoferricin B (LfcinB)-related peptides with an angiotensin I-converting enzyme (ACE) inhibitory effect have been examined using in vitro and ex vivo functional assays. Peptides that were analyzed included a set of sequence-related antimicrobial hexapeptides previously reported and two representative LfcinB-derived peptides. In vitro assays using hippuryl-L-histidyl-L-leucine (HHL) and angiotensin I as substrates allowed us to select two hexapeptides, PACEI32 (Ac-RKWHFW-NH2) and PACEI34 (Ac-RKWLFW-NH2), and also a LfcinB-derived peptide, LfcinB17-31 (Ac-FKCRRWQWRMKKLGA-NH2). Ex vivo functional assays using rabbit carotid arterial segments showed PACEI32 (both D- and L-enantiomers) and LfcinB17-31 have inhibitory effects on ACE-dependent angiotensin I-induced contraction. None of the peptides exhibited in vitro ACE inhibitory activity using bradykinin as the substrate. In conclusion, three bioactive lactoferricin-related peptides exhibit inhibitory effects on both ACE activity and ACE-dependent vasoconstriction with potential to modulate hypertension that deserves further investigation.

Auditory cortical plasticity induced by intracortical microstimulation under pharmacological blockage of inhibitory synapses.

PubMed

Yokota, R; Takahashi, H; Funamizu, A; Uchihara, M; Suzurikawa, J; Kanzaki, R

2006-01-01

Electrical stimulation that can reorganize our neural system has a potential for promising neurorehabilitation. We previously demonstrated that temporally controlled intracortical microstimulation (ICMS) could induce the spike time-dependant plasticity and modify tuning properties of cortical neurons as desired. A 'pairing' ICMS following tone-induced excitatory post-synaptic potentials (EPSPs) produced potentiation in response to the paired tones, while an 'anti-pairing' ICMS preceding the tone-induced EPSPs resulted in depression. However, the conventional ICMS affected both excitatory and inhibitory synapses, and thereby could not quantify net excitatory synaptic effects. In the present work, we evaluated the ICMS effects under a pharmacological blockage of inhibitory inputs. The pharmacological blockage enhanced the ICMS effects, suggesting that inhibitory inputs determine a plastic degree of the neural system. Alternatively, the conventional ICMS had an inadequate timing to control excitatory synaptic inputs, because inhibitory synapse determined the latency of total neural inputs.

Inhibitory effect and mechanism of acarbose combined with gymnemic acid on maltose absorption in rat intestine

PubMed Central

Luo, Hong; Wang, Le Feng; Imoto, Toshiaki; Hiji, Yasutake

2001-01-01

AIM: To compare the combinative and individual effect of acarbose and gymnemic acid (GA) on maltose absorption and hydrolysis in small intestine to determine whether nutrient control in diabetic care can be improved by combination of them. METHODS: The absorption and hydrolysis of maltose were studied by cyclic perfusion of intestinal loops in situ and motility of the intestine was recorded with the intestinal ring in vitro using Wistar rats. RESULTS: The total inhibitory rate of maltose absorption was improved by the combination of GA (0.1 g/L-1.0 g/L) and acarbose (0.1 mmol/L-2.0 mmol/L) throughout their effective duration (P < 0.05, U test of Mann-Whitney), although the improvement only could be seen at a low dosage during the first hour. With the combination, inhibitory duration of acarbose on maltose absorption was prolonged to 3 h and the inhibitory effect onset of GA was fastened to 15 min. GA suppressed the intestinal mobility with a good correlation (r = 0.98) to the inhibitory effect of GA on maltose absorption and the inhibitory effect of 2 mmol/L (high dose) acarbose on maltose hydrolysis was dual modulated by 1 g/L GA in vivo indicating that the combined effects involved the functional alteration of intestinal barriers. CONCLUSION: There are augmented effects of acarbose and GA, which involve pre-cellular and paracellular barriers. Diabetic care can be improved by employing the combination. PMID:11819725

Effects of Display Complexity on Location and Feature Inhibition

PubMed Central

K.Hu, Frank; Fan, Zhiwei; Samuel, Arthur G.; He, ShuChang

2013-01-01

Inhibition of return (IOR) refers to the slowing of reaction times to a target when a preceding stimulus has occupied the same location in space. Recently, we observed a robust inhibitory effect for color and shape in moderately complex displays: It is more difficult to detect a target with a particular nonspatial attribute if a stimulus with the same attribute was recently the focus of attention. Such nonspatial inhibitory effects have not generally been found in simpler displays. In the present study, we test how location-based and nonspatial inhibitory effects vary as a function of display complexity (8, 6, 4 and 2 locations). The results demonstrated that: (1) location based inhibition effects were much stronger in more complex displays, whereas the nonspatial inhibition was only slightly stronger in more complex displays; (2) Nonspatial inhibitory effects emerged at longer SOAs than location-based effects; and (3) Nonspatial inhibition only appeared when cues and targets occurred in the same locations, confirming that pure feature repetition does not produce a cost. Taken together, the results are consistent with perceptual processes based on object files that are organized by spatial location. Using somewhat more complex displays than are most commonly employed provides a more sensitive method to observe the role of inhibitory processes in facilitating visual search. In addition, using a relatively wide set of cue-target timing relationships is necessary in order to clearly see how inhibitory effects operate. PMID:23907617

Effect of crude glycerol-derived inhibitors on ethanol production by Enterobacter aerogenes.

PubMed

Lee, Sang Jun; Kim, Sung Bong; Kang, Seong Woo; Han, Sung Ok; Park, Chulhwan; Kim, Seung Wook

2012-01-01

In this study, ethanol production from pure and crude glycerol using Enterobacter aerogenes ATCC 29007 was evaluated under anaerobic culture conditions. Inhibitory effects of substrate concentrations, pH, and salt concentrations were investigated based on crude glycerol components. Ethanol production was performed with pure glycerol concentrations ranging from 5 to 30 g/L to evaluate the effects of substrate concentration and osmotic pressure. The consumed glycerol was 5-14.33 g/L, and the yield of ethanol was higher than 0.75 mol ethanol/mol glycerol after 24 h of cultivation. To evaluate the inhibitory effects of salts (NaCl and KCl), experiments were performed with 0-20 g/L of each salt. Inhibitory effects of salts were strongest at high salt concentrations. The inhibitory effect of pH was performed in the pH range 4-10, and cell growth and ethanol production were highest at pH 5-6. Also, ethanol production was slightly inhibited at low concentration of crude glycerol comparison with pure glycerol. However, significant inhibitory effects were not observed at 1.5 and 2% crude glycerol which showed higher ethanol production compared to pure glycerol.

No evidence for bilingual cognitive advantages: A test of four hypotheses.

PubMed

von Bastian, Claudia C; Souza, Alessandra S; Gade, Miriam

2016-02-01

The question whether being bilingual yields cognitive benefits is highly controversial with prior studies providing inconsistent results. Failures to replicate the bilingual advantage have been attributed to methodological factors such as comparing dichotomous groups and measuring cognitive abilities separately with single tasks. Therefore, the authors evaluated the 4 most prominent hypotheses of bilingual advantages for inhibitory control, conflict monitoring, shifting, and general cognitive performance by assessing bilingualism on 3 continuous dimensions (age of acquisition, proficiency, and usage) in a sample of 118 young adults and relating it to 9 cognitive abilities each measured by multiple tasks. Linear mixed-effects models accounting for multiple sources of variance simultaneously and controlling for parents' education as an index of socioeconomic status revealed no evidence for any of the 4 hypotheses. Hence, the authors' results suggest that bilingual benefits are not as broad and as robust as has been previously claimed. Instead, earlier effects were possibly due to task-specific effects in selective and often small samples. PsycINFO Database Record (c) 2016 APA, all rights reserved.

In vitro effects of Salvia officinalis L. essential oil on Candida albicans

PubMed Central

Sookto, Tularat; Srithavaj, Theerathavaj; Thaweboon, Sroisiri; Thaweboon, Boonyanit; Shrestha, Binit

2013-01-01

Objective To determine the anticandidal activities of Salvia officinalis L. (S. officinalis) essential oil against Candida albicans (C. albicans) and the inhibitory effects on the adhesion of C. albicans to polymethyl methacrylate (PMMA) resin surface. Methods Disc diffusion method was first used to test the anticandidal activities of the S. officinalis L. essential oil against the reference strain (ATCC 90028) and 2 clinical strains of C. albicans. Then the minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) were determined by modified membrane method. The adhesion of C. albicans to PMMA resin surface was assessed after immersion with S. officinalis L. essential oil at various concentrations of 1×MIC, 0.5×MIC and 0.25×MIC at room temperature for 30 min. One-way ANOVA was used to compare the Candida cell adhesion with the pretreatment agents and Tukey's test was used for multiple comparisons. Results S. officinalis L. essential oil exhibited anticandidal activity against all strains of C. albicans with inhibition zone ranging from 40.5 mm to 19.5 mm. The MIC and MLC of the oil were determined as 2.780 g/L against all test strains. According to the effects on C. albicans adhesion to PMMA resin surface, it was found that immersion in the essential oil at concentrations of 1×MIC (2.780 g/L), 0.5×MIC (1.390 g/L) and 0.25×MIC (0.695 g/L) for 30 min significantly reduced the adhesion of all 3 test strains to PMMA resin surface in a dose dependent manner (P<0.05). Conclusions S. officinalis L. essential oil exhibited anticandidal activities against C. albicans and had inhibitory effects on the adhesion of the cells to PMMA resin surface. With further testing and development, S. officinalis essential oil may be used as an antifungal denture cleanser to prevent candidal adhesion and thus reduce the risk of candida-associated denture stomatitis. PMID:23646301

Incarvine C suppresses proliferation and vasculogenic mimicry of hepatocellular carcinoma cells via targeting ROCK inhibition.

PubMed

Zhang, Ji-Gang; Zhang, Dan-Dan; Wu, Xin; Wang, Yu-Zhu; Gu, Sheng-Ying; Zhu, Guan-Hua; Li, Xiao-Yu; Li, Qin; Liu, Gao-Lin

2015-10-28

Studies have described vasculogenic mimicry (VM) as an alternative circulatory system to blood vessels in multiple malignant tumor types, including hepatocellular carcinoma (HCC). In the current study, we aimed to seek novel and more efficient treatment strategies by targeting VM and explore the underlying mechanisms in HCC cells. Cell counting kit-8 (CCK-8) assay and colony survival assay were performed to explore the inhibitory effect of incarvine C (IVC) on human cancer cell proliferation. Flow cytometry was performed to analyze the cell cycle distribution after DNA staining and cell apoptosis by the Annexin V-PE and 7-AAD assay. The effect of IVC on Rho-associated, coiled-coil-containing protein kinase (ROCK) was determined by western blotting and stress fiber formation assay. The inhibitory role of IVC on MHCC97H cell VM formation was determined by formation of tubular network structures on Matrigel in vitro, real time-qPCR, confocal microscopy and western blotting techniques. We explored an anti-metastatic HCC agent, IVC, derived from traditional Chinese medicinal herbs, and found that IVC dose-dependently inhibited the growth of MHCC97H cells. IVC induced MHCC97H cell cycle arrest at G1 transition, which was associated with cyclin-dependent kinase 2 (CDK-2)/cyclin-E1 degradation and p21/p53 up-regulation. In addition, IVC induced apoptotic death of MHCC97H cells. Furthermore, IVC strongly suppressed the phosphorylation of the ROCK substrate myosin phosphatase target subunit-1 (MYPT-1) and ROCK-mediated actin fiber formation. Finally, IVC inhibited cell-dominant tube formation in vitro, which was accompanied with the down-regulation of VM-key factors as detected by real time-qPCR and immunofluorescence. Taken together, the effective inhibitory effect of IVC on MHCC97H cell proliferation and neovascularization was associated with ROCK inhibition, suggesting that IVC may be a new potential drug candidate for the treatment of HCC.

Inhibitory Effect of Long-Chain Fatty Acids on Biogas Production and the Protective Effect of Membrane Bioreactor

PubMed Central

Dasa, Kris Triwulan; Westman, Supansa Y.; Cahyanto, Muhammad Nur; Niklasson, Claes

2016-01-01

Anaerobic digestion of lipid-containing wastes for biogas production is often hampered by the inhibitory effect of long-chain fatty acids (LCFAs). In this study, the inhibitory effects of LCFAs (palmitic, stearic, and oleic acid) on biogas production as well as the protective effect of a membrane bioreactor (MBR) against LCFAs were examined in thermophilic batch digesters. The results showed that palmitic and oleic acid with concentrations of 3.0 and 4.5 g/L resulted in >50% inhibition on the biogas production, while stearic acid had an even stronger inhibitory effect. The encased cells in the MBR system were able to perform better in the presence of LCFAs. This system exhibited a significantly lower percentage of inhibition than the free cell system, not reaching over 50% at any LCFA concentration tested. PMID:27699172

Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

PubMed

Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

2010-05-31

Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity.

PubMed

Obara, Keisuke; Ogawa, Tsukasa; Chino, Daisuke; Tanaka, Yoshio

2017-01-01

Distigmine bromide (distigmine), a reversible, long-lasting cholinesterase (ChE) inhibitor, is used for the treatment of underactive bladder in Japan and has been shown to potentiate urinary bladder (UB) contractility. We studied the duration of distigmine's potentiating effects on acetylcholine (ACh)-induced UB contraction and its inhibitory effects on ChE activity, and compared that with those of other ChE inhibitors (neostigmine, pyridostigmine, and ambenonium). The duration of potentiating/inhibitory effects of ChE inhibitors, including distigmine, on ACh-induced guinea pig UB contraction/ChE activity was evaluated for 12 h following washout. Dissociation rate constants (k) of the inhibitors were also tentatively calculated based on the time courses of their ChE inhibitory effects. The potentiating effect of distigmine (10 -6  M) on ACh-induced UB contraction and its inhibitory effect on ChE activity were significantly sustained 12 h after washout. The potentiating effect of other ChE inhibitors on ACh-induced UB contraction, however, was sustained only until 3 h after washout. The ChE inhibitory effects of these inhibitors dissipated in a time-dependent manner after washout, with more than 75% of ChE activity restored by 4 h after washout. The k values of ChE inhibitors approached 0.50 h -1 , except for distigmine, where k could not be determined. Compared with that of other ChE inhibitors, the potentiating effect of distigmine on UB contractile function was significantly more sustainable following washout, which was likely associated with its corresponding long-lasting ChE inhibitory effect. Distigmine may associate more strongly with UB ChE than other ChE inhibitors, which would partly explain its sustained effects.

The moderating role of state inhibitory control in the effect of evaluative conditioning on temptation and unhealthy snacking.

PubMed

Haynes, Ashleigh; Kemps, Eva; Moffitt, Robyn

2015-12-01

The current study sought to test the effect of a brief evaluative conditioning intervention on experienced temptation to indulge, and consumption of, unhealthy snack foods. We expected that a training task associating unhealthy food with negative affect would result in lower experienced temptation across the sample, but would lead to lower snack consumption only among individuals with low state inhibitory control. Undergraduate women (N=134) aged 17-25 years were randomised to complete an evaluative conditioning procedure pairing unhealthy food with either positive or negative affect. Snack consumption was subsequently assessed using a taste-test procedure which offered four snack foods for ad libitum consumption. Participants also reported the strength of their experienced temptation to indulge in the foods presented. Additionally, they completed a Stop Signal Task as a measure of state inhibitory control. As predicted, participants in the food negative condition ate less than those in the food positive condition, but this effect was only observed among individuals with low inhibitory control. The same moderation pattern was observed for the effect of evaluative conditioning on temptation: only participants with low inhibitory control reported feeling less tempted by the snack foods in the food negative condition compared to the food positive condition. In addition, temptation mediated the effect of evaluative conditioning on intake for individuals with low inhibitory control. Findings suggest that evaluative conditioning of unhealthy food stimuli could be especially useful for reducing temptation and consumption of unhealthy snacks in situations where individuals experience low inhibitory control capacity. Copyright © 2015 Elsevier Inc. All rights reserved.

Abnormal response to methylphenidate across multiple fMRI procedures in cocaine use disorder: feasibility study.

PubMed

Moeller, Scott J; Konova, Anna B; Tomasi, Dardo; Parvaz, Muhammad A; Goldstein, Rita Z

2016-07-01

The indirect dopamine agonist methylphenidate remediates cognitive deficits in psychopathology, but the individual characteristics that determine its effects on the brain are not known. We aimed to determine whether targeted dopaminergically modulated traits and individual differences could predict neural response to methylphenidate across multiple functional magnetic resonance imaging (fMRI) procedures. We combined neural measures from three separate procedures (two inhibitory control tasks differing in their degree of emotional salience and resting-state functional connectivity) during methylphenidate (20 mg oral, versus randomized and counterbalanced placebo) and correlated these aggregated responses with cocaine use disorder diagnosis (22 cocaine abusers, 21 controls), symptoms of attention deficit hyperactivity disorder, and working memory capacity. Cocaine abusers, relative to controls, had a lower response in the dorsolateral prefrontal cortex to methylphenidate across all three procedures, driven by responses to the two inhibitory control tasks; reduced methylphenidate fMRI response in this region further correlated with more frequent cocaine use. Cocaine abuse (and its frequency), associated with lower tonic dopamine levels, correlated with a reduction in activation to methylphenidate (versus placebo). These initial results provide feasibility to the idea that multimodal fMRI tasks can be meaningfully aggregated, and that these aggregated procedures show a common disruption in addiction in a highly anticipated region relevant to cognitive control. Results also suggest that drug use frequency may represent an important modulatory variable in interpreting the efficacy of pharmacologically enhanced cognitive interventions in addiction.

Inhibitory effects of different ATP-sensitive potassium channel openers on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle.

PubMed

Badawi, Jasmin Katrin; Ding, Andrea; Bross, Stephan

2008-02-01

The inhibitory effects of different potassium channel openers (PCOs) on electrically generated and carbachol-induced contractions of porcine and human detrusor muscle were examined. PCOs could be an interesting substance class for treatment of detrusor overactivity. Experiments were performed on muscle strips suspended in a tissue bath. Human tissue originated from patients who underwent total cystectomy. The concentration-relaxation curves of the first-generation PCOs cromakalim and pinacidil and the untypical PCO minoxidil were performed using carbachol-precontracted detrusor muscle strips of pigs and humans. Additionally, the inhibitory effects of cromakalim, pinacidil and minoxidil on electrically generated contractions of porcine detrusor muscle were examined. Furthermore, the inhibitory effect of the second-generation, bladder-selective PCO ZM 226600 on electrically generated contractions of the human detrusor muscle was determined. Frequency-response curves were performed before and after incubation with one PCO used in two different concentrations. In humans, cromakalim and pinacidil led to a maximum decrease of 73.5 and 68.4% and showed mean pD2 values of 6.65 and 5.5, respectively. In pigs, cromakalim and pinacidil led to a maximum decrease of 90.6 and 93.6% and showed mean pD2 values of 6.39 and 5.01, respectively. Minoxidil did not significantly decrease the precontraction at the highest used concentration in both species. Cromakalim exhibited the biggest inhibitory effect being significant at 10(-5) and 10(-6) M. Pinacidil showed only a significant inhibitory effect at 10(-5) M which was smaller than that of cromakalim. At 3 x 10(-6) M only a very small effect occurred at 1 Hz. Minoxidil did not inhibit the contractions at both examined concentrations except for a very small effect at 1 Hz. In humans, ZM 226600 exhibited at 10(-6) and 10(-5) M a significant inhibitory effect. At 10(-7) M it was only significant at one frequency.

Effects of exposure in single and multiple contexts on fear renewal: The moderating role of threat-specific and nonspecific emotionality.

PubMed

Olatunji, Bunmi O; Tomarken, Andrew; Wentworth, Brian; Fritzsche, Laura

2017-03-01

The current study examines effects of exposure in multiple contexts on fear reduction and renewal and the moderating effect of baseline threat-specific and nonspecific emotionality. Snake-fearful participants received a negative or neutral emotion induction and were randomized to video exposure to a snake in a single context, multiple context, or a no exposure control group. Anxiety in response to video presentations of a snake was significantly reduced in the two exposure groups compared to the control group, especially among those with heightened baseline threat-specific emotionality as indicated by snake anxiety ratings at baseline. Although the two exposure groups did not differ in responding when confronted with a novel snake, both exposure groups reported significantly lower snake anxiety and arousal than the control group. Subsequent analysis did show that compared to controls, the single context group demonstrated greater increase in anxiety and arousal from post-exposure to exposure to the novel snake among those with heightened snake anxiety at baseline. Furthermore, the multiple context group was less avoidant and less fearful than the single context group on a post-exposure behavioral test. The study used an analogue exposure paradigm with an analogue sample and findings may not be generalizable to a clinical population. These findings suggest that baseline threat-specific emotionality influences fear reduction and renewal. The benefits of exposure in multiple contexts are discussed in relation to a distinct pattern of symptom change that is in line with an inhibitory learning approach. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of aqueous and alcoholic Stevia (Stevia rebaudiana) extracts against Streptococcus mutans and Lactobacillus acidophilus in comparison to chlorhexidine: An in vitro study

PubMed Central

Ajagannanavar, Sunil Lingaraj; Shamarao, Supreetha; Battur, Hemant; Tikare, Shreyas; Al-Kheraif, Abdulaziz Abdullah; Al Sayed, Mohammed Sayed Al Esawy

2014-01-01

Introduction: Stevia (S. rebaudiana) a herb which has medicinal value and was used in ancient times as a remedy for a great diversity of ailments and sweetener. Leaves of Stevia contain a high concentration of Stevioside and Rebaudioside which are supposed to be sweetening agents. Aim: To compare the efficacy of aqueous and alcoholic S. rebaudiana extract against Streptococcus mutans and Lactobacillus acidophilus in comparison to chlorhexidine. Materials and Methods: In the first part of the study, various concentrations of aqueous and ethanolic Stevia extract were prepared in the laboratory of Pharmacy College. It was then subjected to microbiological assay to determine its zone of inhibition using Agar disk diffusion test and minimum inhibitory concentration (MIC) using serial broth dilution method against Streptococcus mutans and Lactobacillus acidophilus. Chlorhexidine was used as a positive control. One way Analysis of Variance (ANOVA) test was used for multiple group comparisons followed by Tukey post hoc for group wise comparisons. Results: Minimum inhibitory concentration (MIC) of aqueous and ethnolic Stevia extract against Streptococcus mutans and Lactobacillus acidophilus were 25% and 12.5% respectively. Mean zone of inhibition of the aqueous and alcoholic Stevia extracts against Streptococcus mutans at 48 hours were 22.8 mm and 26.7 mm respectively. Mean zone of inhibition of the aqueous and alcoholic Stevia extracts against Lactobacillus acidophilus at 48 hours were 14.4 mm and 15.1 mm respectively. Mean zone of inhibition of the chlorhexidine against Streptococcus mutans and Lactobacillus acidophilus at 48 hours was 20.5 and 13.2 respectively. Conclusion: The inhibitory effect shown by alcoholic Stevia extract against Streptococcus mutans and Lactobacillus acidophilus was superior when compared with that of aqueous form and was inferior when compared with Chlorhexidine. PMID:25558451

Prolyl endopeptidase and thrombin inhibitory diterpenoids from the bark of Xylopia aethiopica.

PubMed

Diderot, Noungoue Tchamo; Silvere, Ngouela; Yasin, Amsha; Zareen, Seema; Fabien, Zelefack; Etienne, Tsamo; Choudhary, M Iqbal; Atta-Ur-Rahman

2005-09-01

The inhibitory effects of seven diterpenes, belonging to three different structural classes and isolated from the bark of Xylopia aethiopica, were investigated against the enzymes prolyl endopeptidase (PEP) and alpha-thrombin. Five compounds exhibited inhibitory activity against them.

Plasticity of inhibitory processes and associated far-transfer effects in older adults.

PubMed

Ji, Yang; Wang, Jun; Chen, Tianyong; Du, Xin; Zhan, Yi

2016-08-01

Inhibition deficit plays a crucial part in cognitive aging; however, few studies have systematically investigated the plasticity of various inhibitory processes among older adults. We studied the plasticity of 3 inhibitory processes (access, deletion, and restraint) and the extent of far transfer of inhibition training to other general cognitive abilities. Thirty-six participants (aged 60 years and above, M = 70.06, SD = 5.53) were randomly assigned to an adaptive training group that received 12 sessions of training covering 3 inhibitory processes or an active control group that received 4 sessions of mental health lectures. Participants in both groups completed pre- and posttest assessments, in which behavioral and electrophysiological measures were used to evaluate potential transfer effects. Direct training gains were observed for trained tasks of all inhibitory processes, but near-transfer effects were only found within untrained tasks associated with deletion at a composite score level. Furthermore, far-transfer effects were demonstrated for fluid intelligence (Gf) but not for working memory or other general cognitive abilities. Near transfer to deletion and far transfer to Gf persisted at a 3-month follow-up assessment session. We discussed differences in plasticity between the 3 inhibitory processes as well as their possible associations with far transfer to Gf. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Glu-Phe from onion (Allium Cepa L.) attenuates lipogenesis in hepatocytes.

PubMed

Lee, Yu Geon; Cho, Jeong-Yong; Hwang, Eom Ji; Jeon, Tae-Il; Moon, Jae-Hak

2017-07-01

A Glu-Phe (EF) was isolated from onion (Allium cepa L. cv. Sunpower). The chemical structure of EF was determined by nuclear magnetic resonance and electrospray ionization-mass (ESI-MS) spectroscopy. We showed that EF reduced lipid accumulation in mouse hepatocytes by inhibiting the expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its lipogenic target genes. We also found that AMP-activated protein kinase (AMPK) was required for the inhibitory effect of EF on lipid accumulation in mouse hepatocytes. Furthermore, EF was qualified in nine onion cultivars by selective multiple reaction-monitoring detection of liquid chromatography-ESI-MS. These results suggest that EF could contribute to the beneficial effect of onion supplement in maintaining hepatic lipid homeostasis.

[Quantitative evaluation of inhibitory effects of epileptic spikes on theta rhythms in the network of hippocampal CA3 and entorhinal cortex in patients with temporal lobe epilepsy].

PubMed

Ge, Man-Ling; Guo, Jun-Dan; Chen, Sheng-Hua; Zhang, Ji-Chang; Fu, Xiao-Xuan; Chen, Yu-Min

2017-02-25

Epileptic spike is an indicator of hyper-excitability and hyper-synchrony in the neural networks. The inhibitory effects of spikes on theta rhythms (4-8 Hz) might be helpful to understand the mechanism of epileptic damage on the cognitive functions. To quantitatively evaluate the inhibitory effects of spikes on theta rhythms, intracerebral electroencephalogram (EEG) recordings with both sporadic spikes (SSs) and spike-free transient period between adjacent spikes were selected in 4 patients in the status of rapid eyes movement (REM) sleep with temporal lobe epilepsy (TLE) under the pre-surgical monitoring. The electrodes of hippocampal CA3 and entorhinal cortex (EC) were employed, since CA3 and EC built up one of key loops to investigate cognition and epilepsy. These SSs occurred only in CA3, only in EC, or in both CA3 and EC synchronously. Theta power was respectively estimated around SSs and during the spike-free transient period by Gabor wavelet transform and Hilbert transform. The intermittent extent was then estimated to represent for the loss of theta rhythms during the spike-free transient period. The following findings were obtained: (1) The prominent rhythms were in theta frequency band; (2) The spikes could transiently reduce theta power, and the inhibitory effect was severer around SSs in both CA3 and EC synchronously than that around either SSs only in EC or SSs only in CA3; (3) During the spike-free transient period, theta rhythms were interrupted with the intermittent theta rhythms left and theta power level continued dropping, implying the inhibitory effect was sustained. Additionally, the intermittent extent of theta rhythms was converged to the inhibitory extent around SSs; (4) The average theta power level during the spike-free transient period might not be in line with the inhibitory extent of theta rhythms around SSs. It was concluded that the SSs had negative effects on theta rhythms transiently and directly, the inhibitory effects aroused by SSs sustained during the spike-free transient period and were directly related to the intermittent extent. It was indicated that the loss of theta rhythms might qualify exactly the sustained inhibitory effects on theta rhythms aroused by spikes in EEG. The work provided an argumentation about the relationship between the transient negative impact of interictal spike and the loss of theta rhythms during spike-free activity for the first time, offered an intuitive methodology to estimate the inhibitory effect of spikes by EEG, and might be helpful to the analysis of EEG rhythms based on local field potentials (LFPs) in deep brain.

Selective functional interactions between excitatory and inhibitory cortical neurons and differential contribution to persistent activity of the slow oscillation.

PubMed

Tahvildari, Babak; Wölfel, Markus; Duque, Alvaro; McCormick, David A

2012-08-29

The neocortex depends upon a relative balance of recurrent excitation and inhibition for its operation. During spontaneous Up states, cortical pyramidal cells receive proportional barrages of excitatory and inhibitory synaptic potentials. Many of these synaptic potentials arise from the activity of nearby neurons, although the identity of these cells is relatively unknown, especially for those underlying the generation of inhibitory synaptic events. To address these fundamental questions, we developed an in vitro submerged slice preparation of the mouse entorhinal cortex that generates robust and regular spontaneous recurrent network activity in the form of the slow oscillation. By performing whole-cell recordings from multiple cell types identified with green fluorescent protein expression and electrophysiological and/or morphological properties, we show that distinct functional subpopulations of neurons exist in the entorhinal cortex, with large variations in contribution to the generation of balanced excitation and inhibition during the slow oscillation. The most active neurons during the slow oscillation are excitatory pyramidal and inhibitory fast spiking interneurons, receiving robust barrages of both excitatory and inhibitory synaptic potentials. Weak action potential activity was observed in stellate excitatory neurons and somatostatin-containing interneurons. In contrast, interneurons containing neuropeptide Y, vasoactive intestinal peptide, or the 5-hydroxytryptamine (serotonin) 3a receptor, were silent. Our data demonstrate remarkable functional specificity in the interactions between different excitatory and inhibitory cortical neuronal subtypes, and suggest that it is the large recurrent interaction between pyramidal neurons and fast spiking interneurons that is responsible for the generation of persistent activity that characterizes the depolarized states of the cortex.

The role of nitric oxide in melanoma.

PubMed

Yarlagadda, Keerthi; Hassani, John; Foote, Isaac P; Markowitz, Joseph

2017-12-01

Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself. Copyright © 2017 Elsevier B.V. All rights reserved.

The putative interplay between DJ-1/NRF2 and Dimethyl Fumarate: A potentially important pharmacological target.

PubMed

Vavougios, George; Zarogiannis, Sotirios G; Doskas, Triantafylos

2018-04-01

Recent research has outlined that Dimethyl Fumarate (DMF) functions as a gene regulator via multiple pathways, critical among which is the NRF2 cytoprotective cascade. PARK7/DJ-1 is a multifunctional protein that acts as a redox sensor and effector of multiple cytoprotective pathways, including NRF2. Specifically, it prevents the association of NRF2 with its inhibitor KEAP1, allowing NRF2 to enter the nucleus and mediate cytoprotective and antioxidant cascades. It is our hypothesis that while the NRF2-KEAP1 inhibitory complex is reported the main pharmacological target for DMF's NRF dependent functions, no study to date has explored the effects of DMF on DJ-1's expression, and vice-versa, the possibility of a regulatory inadequacy in the upstream, oxidant-responsive DJ-1 activator of the NRF2 cascade. Copyright © 2018 Elsevier B.V. All rights reserved.

A study on trypsin, Aspergillus flavus and Bacillus sp. protease inhibitory activity in Cassia tora (L.) syn Senna tora (L.) Roxb. seed extract.

PubMed

Tripathi, Vinayak R; Kumar, Shailendra; Garg, Satyendra K

2011-07-12

Proteases play an important role in virulence of many human, plant and insect pathogens. The proteinaceous protease inhibitors of plant origin have been reported widely from many plant species. The inhibitors may potentially be used for multiple therapeutic applications in viral, bacterial, fungal diseases and physiological disorders. In traditional Indian medicine system, Cassia tora (Senna tora) is reportedly effective in treatment of skin and gastrointestinal disorders. The present study explores the protease inhibitory activity of the above plant seeds against trypsin, Aspergillus flavus and Bacillus sp. proteases. The crushed seeds of Cassia tora were washed thoroughly with acetone and hexane for depigmentation and defatting. The proteins were fractionated by ammonium sulphate (0-30, 30-60, 60-90%) followed by dialysis and size exclusion chromatography (SEC). The inhibitory potential of crude seed extract and most active dialyzed fraction against trypsin and proteases was established by spot test using unprocessed x-ray film and casein digestion methods, respectively. Electrophoretic analysis of most active fraction (30-60%) and SEC elutes were carried employing Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Gelatin SDS-PAGE. Inhibition of fungal spore germination was studied in the presence of dialyzed active inhibitor fraction. Standard deviation (SD) and ANOVA were employed as statistical tools. The crude seeds' extract displayed strong antitryptic, bacterial and fungal protease inhibitory activity on x-ray film. The seed protein fraction 30-60% was found most active for trypsin inhibition in caseinolytic assay (P < 0.001). The inhibition of caseinolytic activity of the proteases increased with increasing ratio of seed extract. The residual activity of trypsin, Aspergillus flavus and Bacillus sp. proteases remained only 4, 7 and 3.1%, respectively when proteases were incubated with 3 mg ml-1 seed protein extract for 60 min. The inhibitory activity was evident in gelatin SDS-PAGE where a major band (~17-19 kD) of protease inhibitor (PI) was detected in dialyzed and SEC elute. The conidial germination of Aspergillus flavus was moderately inhibited (30%) by the dialyzed seed extract. Cassia tora seed extract has strong protease inhibitory activity against trypsin, Aspergillus flavus and Bacillus sp. proteases. The inhibitor in Cassia tora may attenuate microbial proteases and also might be used as phytoprotecting agent. © 2011 Tripathi et al; licensee BioMed Central Ltd.

Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.

PubMed

Ding, Ning; Li, Xitao; Shi, Yunfei; Ping, Lingyan; Wu, Lina; Fu, Kai; Feng, Lixia; Zheng, Xiaohui; Song, Yuqin; Pan, Zhengying; Zhu, Jun

2015-06-20

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.

Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma

PubMed Central

Ding, Ning; Li, Xitao; Shi, Yunfei; Ping, Lingyan; Wu, Lina; Fu, Kai; Feng, Lixia; Zheng, Xiaohui; Song, Yuqin; Pan, Zhengying; Zhu, Jun

2015-01-01

The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment. PMID:25944695

nRGD modified lycobetaine and octreotide combination delivery system to overcome multiple barriers and enhance anti-glioma efficacy.

PubMed

Chen, Tijia; Song, Xu; Gong, Ting; Fu, Yao; Yang, Liuqing; Zhang, Zhirong; Gong, Tao

2017-08-01

For glioma as one of the most common and lethal primary brain tumors, the presence of BBB, BBTB, vasculogenic mimicry (VM) channels and tumor-associated macrophages (TAMs) are key biological barriers. Here, a novel drug delivery system which could efficiently deliver drugs to glioma by overcoming multi-barriers and increase antitumor efficacy through multi-therapeutic mechanisms was well developed. In this study, a multi-target peptide nRGD was used to transport across the BBB, mediate tumor penetration and target TAMs. Lycobetaine (LBT) was adopted to kill glioma cells and octreotide (OCT) was co-delivered to inhibit VM channels and prevent angiogenesis. LBT-OCT liposomes (LPs) showed controlled release profile in vitro, increased uptake efficiency, improved inhibitory effect against glioma cells and VM formation, and enhanced BBB-crossing capability. The median survival time of glioma-bearing mice administered with LBT-OCT LPs-nRGD was significantly longer than LBT-OCT LPs (P<0.01). Besides, nRGD achieved a stronger inhibitory effect against tumor associated macrophages (TAMs) compared to LPs-iRGD treatment groups in vivo. Thus, LPs-nRGD represented a promising versatile delivery platform for combination drug therapy in glioma treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Deglutitive Inhibition, Latency Between Swallow and Esophageal Contractions and Primary Esophageal Motor Disorders

PubMed Central

Jafari, Jafar

2012-01-01

Swallowing induces an inhibitory wave that is followed by a contractile wave along the esophageal body. Deglutitive inhibition in the skeletal muscle of the esophagus is controlled in the brain stem whilst in the smooth muscle, an intrinsic peripheral control mechanism is critical. The latency between swallow and contractions is determined by the pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle. A wave of inhibition precedes a swallow-induced peristaltic contraction in the smooth muscle part of the human oesophagus involving both circular and longitudinal muscles in a peristaltic fashion. Deglutitive inhibition is necessary for drinking liquids which requires multiple rapid swallows (MRS). During MRS the esophageal body remains inhibited until the last of the series of swallows and then a peristaltic contraction wave follows. A normal response to MRS requires indemnity of both inhibitory and excitatory mechanisms and esophageal muscle. MRS has recently been used to assess deglutitive inhibition in patients with esophageal motor disorders. Examples with impairment of deglutitive inhibition are achalasia of the LES and diffuse esophageal spasm. PMID:22323983

Deglutitive inhibition, latency between swallow and esophageal contractions and primary esophageal motor disorders.

PubMed

Sifrim, Daniel; Jafari, Jafar

2012-01-01

Swallowing induces an inhibitory wave that is followed by a contractile wave along the esophageal body. Deglutitive inhibition in the skeletal muscle of the esophagus is controlled in the brain stem whilst in the smooth muscle, an intrinsic peripheral control mechanism is critical. The latency between swallow and contractions is determined by the pattern of activation of the inhibitory and excitatory vagal pathways, the regional gradients of inhibitory and excitatory myenteric nerves, and the intrinsic properties of the smooth muscle. A wave of inhibition precedes a swallow-induced peristaltic contraction in the smooth muscle part of the human oesophagus involving both circular and longitudinal muscles in a peristaltic fashion. Deglutitive inhibition is necessary for drinking liquids which requires multiple rapid swallows (MRS). During MRS the esophageal body remains inhibited until the last of the series of swallows and then a peristaltic contraction wave follows. A normal response to MRS requires indemnity of both inhibitory and excitatory mechanisms and esophageal muscle. MRS has recently been used to assess deglutitive inhibition in patients with esophageal motor disorders. Examples with impairment of deglutitive inhibition are achalasia of the LES and diffuse esophageal spasm.

Inhibitory effects of some plant essential oils against Arcobacter butzleri and potential for rosemary oil as a natural food preservative.

PubMed

Irkin, Reyhan; Abay, Secil; Aydin, Fuat

2011-03-01

We investigated the inhibitory activity of commercially marketed essential oils of mint, rosemary, orange, sage, cinnamon, bay, clove, and cumin against Arcobacter butzleri and Arcobacter skirrowii and the effects of the essential oil of rosemary against A. butzleri in a cooked minced beef system. Using the disc diffusion method to determine the inhibitory activities of these plant essential oils against strains of Arcobacter, we found that those of rosemary, bay, cinnamon, and clove had strong inhibitory activity against these organisms, whereas the essential oils of cumin, mint, and sage failed to show inhibitory activity against most of the Arcobacter strains tested. The 0.5% (vol/wt) essential oil of rosemary was completely inhibitory against A. butzleri in the cooked minced beef system at 4°C. These essential oils may be further investigated as a natural solution to the food industry by creating an additional barrier (hurdle technology) to inhibit the growth of Arcobacter strains.

N-octanoyl-dopamine is a potent inhibitor of platelet function.

PubMed

Ait-Hsiko, Lamia; Kraaij, Tineke; Wedel, Johannes; Theisinger, Bastian; Theisinger, Sonja; Yard, Benito; Bugert, Peter; Schedel, Angelika

2013-01-01

Dopamine (DA) is a co-agonist for platelet activation; yet, donor DA treatment is associated with improved transplantation outcome in renal and heart recipients. Recently, N-octanoyl-dopamine (NOD) was developed which displays superior effects compared to DA in terms of graft protecting properties. Whereas DA is a known platelet co-agonist, the effect of NOD on platelet function is unknown. This is a hypothesis generating study with the aim to assess the effects and molecular mechanisms of NOD and NOD-like compounds on platelet function. The influence of DA, NOD, and NOD-like compounds on platelet responses to classical agonists (adenosine 5'-diphosphate (ADP), U46619) was investigated in six healthy donors by applying whole blood aggregometry (Multiplate®) and flow cytometry for Pac-1, CD62P, and CD63 expression. Changes in platelet cAMP concentrations were assessed by ELISA. While DA showed synergy in platelet activation by ADP and U46619, NOD caused significant inhibition of platelet function both in whole blood aggregometry and flow cytometry. The inhibitory effect of NOD was not mediated via cAMP levels. The nonredox-active NOD-analog N-octanoyl-tyramine had no effects on platelet function. Acetylated NOD conferred to NOD by intracellular esterases showed similar inhibitory effects as NOD. In contrast to DA, NOD is a potent inhibitor of platelet function most likely through intracellular redox-active processes. This adds to the overall protective effect of NOD on pre-transplantation injury and makes NOD an attractive candidate compound for donor or organ conditioning prior to transplantation.

Effects of sales promotions, weight status, and impulsivity on purchases in a supermarket.

PubMed

Nederkoorn, Chantal

2014-05-01

Several environmental factors contribute to increased food consumption and play a role in the prevalence of obesity, like portion size, accessibility and relative price of high caloric foods, food commercials, and sales promotions. However, not everyone seems equally sensitive to these environmental cues and both obesity and impulsivity appears to play a role. In this study, food purchases in an internet supermarket are tested in 118 participants, with or without sales promotions for snack foods. Both weight status and response inhibition, an index of impulsivity, are measured. Participants with less inhibitory control purchased in total more calories from the internet supermarket then participants with more inhibitory control. In addition, sales promotion, weight status, and inhibitory control appeared to interact in their effect on snack food purchases: participants with less inhibitory control and overweight bought more calories of snacks in the sales promotions condition, but not in the control condition. For the other participants, with normal weight and/or high inhibitory control, sales promotions had no effect on their purchases of calories of snacks. It seems that especially the combination of low inhibitory control and overweight makes participants vulnerable for environmental cues. Copyright © 2013 The Obesity Society.

Production of the angiotensin I converting enzyme inhibitory peptides and isolation of four novel peptides from jellyfish (Rhopilema esculentum) protein hydrolysate.

PubMed

Liu, Xin; Zhang, Miansong; Shi, Yaping; Qiao, Ruojin; Tang, Wei; Sun, Zhenliang

2016-07-01

Angiotensin I converting enzyme (ACE) plays an important role in regulating blood pressure in the human body. ACE inhibitory peptides derived from food proteins could exert antihypertensive effects without side effects. Jellyfish (Rhopilema esculentum) is an important fishery resource suitable for production of ACE inhibitory peptides. The objective of this study was to optimize the hydrolysis conditions for production of protein hydrolysate from R. esculentum (RPH) with ACE inhibitory activity, and to isolate and identify the ACE inhibitory peptides from RPH. Rhopilema esculentum protein was hydrolyzed with Compound proteinase AQ to produce protein hydrolysate with ACE inhibitory activity, and the hydrolysis conditions were optimized using response surface methodology. The optimum parameters for producing peptides with the highest ACE inhibitory activity were as follows: hydrolysis time 3.90 h, hydrolysis temperature 58 °C, enzyme:substrate ratio 2.8% and pH 7.60. Under these conditions, the ACE inhibitory rate reached 32.21%. In addition, four novel ACE inhibitory peptides were isolated, and their amino acids sequences were identified as Val-Gly-Pro-Tyr, Phe-Thr-Tyr-Val-Pro-Gly, Phe-Thr-Tyr-Val-Pro-Gly-Ala and Phe-Gln-Ala-Val-Trp-Ala-Gly, respectively. The IC50 value of the purified peptides for ACE inhibitory activity was 8.40, 23.42, 21.15 and 19.11 µmol L(-1) . These results indicate that the protein hydrolysate prepared from R. esculentum might be a commercial competitive source of ACE inhibitory ingredients to be used in functional foods. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

Early adversity, RSA, and inhibitory control: evidence of children's neurobiological sensitivity to social context.

PubMed

Skowron, Elizabeth A; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M; Teti, Douglas M; Ammerman, Robert T

2014-07-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children's inhibitory control. Children's respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent-child challenge tasks moderated the effects of child maltreatment (CM) status on children's independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. © 2013 Wiley Periodicals, Inc.

Early Adversity, RSA, and Inhibitory Control: Evidence of Children’s Neurobiological Sensitivity to Social Context

PubMed Central

Skowron, Elizabeth A.; Cipriano-Essel, Elizabeth; Gatzke-Kopp, Lisa M.; Teti, Douglas M.; Ammerman, Robert T.

2014-01-01

This study examined parasympathetic physiology as a moderator of the effects of early adversity (i.e., child abuse and neglect) on children’s inhibitory control. Children’s respiratory sinus arrhythmia (RSA) was assessed during a resting baseline, two joint challenge tasks with mother, and an individual frustration task. RSA assessed during each of the joint parent–child challenge tasks moderated the effects of child maltreatment (CM) status on children’s independently-assessed inhibitory control. No moderation effect was found for RSA assessed at baseline or in the child-alone challenge task. Among CM-exposed children, lower RSA levels during the joint task predicted the lowest inhibitory control, whereas higher joint task RSA was linked to higher inhibitory control scores that were indistinguishable from those of non-CM children. Results are discussed with regard to the importance of considering context specificity (i.e., individual and caregiver contexts) in how biomarkers inform our understanding of individual differences in vulnerability among at-risk children. PMID:24142832

Fraction from human and rat liver which is inhibitory for proliferation of liver cells.

PubMed

Chen, T S; Ottenweller, J; Luke, A; Santos, S; Keeting, P; Cuy, R; Lea, M A

1989-01-01

A comparative study was undertaken with human and rat liver of a fraction reported to have growth inhibitory activity when prepared from rat liver. Fractions which were soluble in 70% ethanol and insoluble in 87% ethanol were prepared from liver cytosols. Electrophoretic analysis under denaturing conditions indicated that there were several quantitative or qualitative differences in the fractions from the two species. Fractions from both human and rat liver were found to be inhibitory for the incorporation of 3H-thymidine into DNA of foetal chick hepatocytes. Under conditions in which the rat fraction inhibited precursor incorporation into DNA of rat liver epithelial cells there was not a significant inhibitory effect with the fraction from human liver. DNA synthesis in a rat hepatoma cell line was not significantly inhibited by preparations from either species. The data suggested that corresponding fractions from both rat and human liver could have inhibitory effects on precursor incorporation into DNA but the magnitude of the effects and target cell specificity may differ.

Language control in bilingual language comprehension: evidence from the maze task

PubMed Central

Wang, Xin

2015-01-01

Most empirical evidence on switch costs is based on bilingual production and interpreted as a result of inhibitory control. It is unclear whether such a top–down control process exists in language switching during comprehension. This study investigates whether a non-lexical switch cost is involved in reading code-switched sentences and its relation to language dominance with cross-script bilingual readers. A maze task is adopted in order to separate top–down inhibitory effects, from lexical effects driven by input. The key findings are: (1) switch costs were observed in both L1–L2 and L2–L1 directions; (2) these effects were driven by two mechanisms: lexical activation and inhibitory control; (3) language dominance modulated the lexical effects, but did not affect the inhibitory effects. These results suggest that a language control mechanism is involved in bilingual reading, even though the control process is not driven by selection as in production. At the theoretical level, these results lend support for the Inhibitory Control model during language switching in comprehension; while the BIA/BIA+ model needs to incorporate a top–down control mechanism to be able to explain the current findings. PMID:26347675

Enzyme inhibitory and radical scavenging effects of some antidiabetic plants of Turkey.

PubMed

Orhan, Nilüfer; Hoçbaç, Sanem; Orhan, Didem Deliorman; Asian, Mustafa; Ergun, Fatma

2014-06-01

Ethnopharmacological field surveys demonstrated that many plants, such as Gentiana olivieri, Helichrysum graveolens, Helichrysum plicatum ssp. plicatum, Juniperus oxycedrus ssp. oxycedrus, Juniperus communis var. saxatilis, Viscum album (ssp. album, ssp. austriacum), are used as traditional medicine for diabetes in different regions of Anatolia. The present study was designed to evaluate the in vitro antidiabetic effects of some selected plants, tested in animal models recently. α-glucosidase and α-amylase enzyme inhibitory effects of the plant extracts were investigated and Acarbose was used as a reference drug. Additionally, radical scavenging capacities were determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) ABTS radical cation scavenging assay and total phenolic content of the extracts were evaluated using Folin Ciocalteu method. H. graveolens ethanol extract exhibited the highest inhibitory activity (55.7 % ± 2.2) on α-amylase enzyme. Additionally, J. oxycedrus hydro-alcoholic leaf extract had potent α-amylase inhibitory effect, while the hydro-alcoholic extract of J. communis fruit showed the highest α-glucosidase inhibitory activity (IC50: 4.4 μg/ml). Results indicated that, antidiabetic effect of hydro-alcoholic extracts of H. graveolens capitulums, J. communis fruit and J. oxycedrus leaf might arise from inhibition of digestive enzymes.

Inhibition of Aspergillus niger and Aspergillus flavus by some herbs and spices.

PubMed

Yin, M C; Cheng, W S

1998-01-01

The inhibitory effect of water-soluble extracts of garlic bulbs, green garlic, green onions, hot peppers, ginger, Chinese parsley, and basil on the growth of Aspergillus niger and Aspergillus flavus was examined. Garlic bulbs, green garlic, and green onions showed an inhibitory effect against these two fungi. The influence of heat, acid, and salt upon the inhibitory effect of these three herbs was further studied. Increasing the temperature from 60 to 100 degrees C resulted in a significant (P < 0.05) decrease in the inhibitory effect of garlic bulbs against the fungi tested. Green garlic and green onion lost their antifungal activity against A. niger after being treated at 80 and 60 degrees, respectively. For A. flavus, the inhibitory effect of green garlic declined significantly (P < 0.05) with an increase in temperature. However, the antifungal activity of green onions against A. flavus was heat stable. For both fungi tested in this study, the antifungal activity of these spice plants was not affected by acid treatments at pH values 2, 4, or 6, or salt by treatments at concentrations of 0.1, 0.2, 0.3, and 0.4 M (P > 0.05).

Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways.

PubMed

Wang, Wei; Cao, Xuehong; Liu, Changjin; Liu, Lieju

2012-02-01

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A "bell"-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current (I (cap)) by WIN was at a concentration of 10(-9) M, and at this concentration I (cap) was reduced by 95 ± 1.6%. When the concentration of WIN was at 10(-6) M, it displayed a stimulatory effect on I (cap). In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I (cap). We found that the inhibitory effect of WIN on I (cap) was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-βs/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I(cap). These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I (cap); however, G protein-coupled receptors CB1 or CB2 were not involved.

Harmane inhibits serotonergic dorsal raphe neurons in the rat.

PubMed

Touiki, Khalid; Rat, Pascal; Molimard, Robert; Chait, Abderrahman; de Beaurepaire, Renaud

2005-11-01

Harmane and norharmane (two beta-carbolines) are tobacco components or products. The effects of harmane and norharmane on serotonergic raphe neurons remain unknown. Harmane and norharmane are inhibitors of the monoamine oxidases A (MAO-A) and B (MAO-B), respectively. To study the effects of harmane, norharmane, befloxatone (MAOI-A), and selegiline (MAOI-B) on the firing of serotonergic neurons. To compare the effects of these compounds to those of nicotine (whose inhibitory action on serotonergic neurons has been previously described). The effects of cotinine, a metabolite of nicotine known to interact with serotonergic systems, are also tested. In vivo electrophysiological recordings of serotonergic dorsal raphe neurons in the anaesthetized rat. Nicotine, harmane, and befloxatone inhibited serotonergic dorsal raphe neurons. The other compounds had no effects. The inhibitory effect of harmane (rapid and long-lasting inhibition) differed from that of nicotine (short and rapidly reversed inhibition) and from that of befloxatone (slow, progressive, and long-lasting inhibition). The inhibitory effects of harmane and befloxatone were reversed by the 5-HT1A antagonist WAY 100 635. Pretreatment of animals with p-chlorophenylalanine abolished the inhibitory effect of befloxatone, but not that of harmane. Nicotine, harmane, and befloxatone inhibit the activity of raphe serotonergic neurons. Therefore, at least two tobacco compounds, nicotine and harmane, inhibit the activity of serotonergic neurons. The mechanism by which harmane inhibits serotonergic dorsal raphe neurons is likely unrelated to a MAO-A inhibitory effect.

In vitro antagonistic growth effects of Lactobacillus fermentum and lactobacillus salivarius and their fermentative broth on periodontal pathogens.

PubMed

Chen, Ling-Ju; Tsai, Hsiu-Ting; Chen, Wei-Jen; Hsieh, Chu-Yang; Wang, Pi-Chieh; Chen, Chung-Shih; Wang, Lina; Yang, Chi-Chiang

2012-10-01

As lactobacilli possess an antagonistic growth property, these bacteria may be beneficial as bioprotective agents for infection control. However, whether the antagonistic growth effects are attributed to the lactobacilli themselves or their fermentative broth remains unclear. The antagonistic growth effects of Lactobacillus salivarius and Lactobacillus fermentum as well as their fermentative broth were thus tested using both disc agar diffusion test and broth dilution method, and their effects on periodontal pathogens, including Streptococcus mutans, Streptococcus sanguis, and Porphyromonas gingivalis in vitro at different concentrations and for different time periods were also compared. Both Lactobacillus salivarius and Lactobacillus fermentum and their concentrated fermentative broth were shown to inhibit significantly the growth of Streptococcus mutans, Streptococcus sanguis, and Porphyromonas gingivalis, although different inhibitory effects were observed for different pathogens. The higher the counts of lactobacilli and the higher the folds of concentrated fermentative broth, the stronger the inhibitory effects are observed. The inhibitory effect is demonstrated to be dose-dependent. Moreover, for the lactobacilli themselves, Lactobacillus fermentum showed stronger inhibitory effects than Lactobacillus salivarius. However, the fermentative broth of Lactobacillus fermentum showed weaker inhibitory effects than that of Lactobacillus salivarius. These data suggested that lactobacilli and their fermentative broth exhibit antagonistic growth activity, and consumption of probiotics or their broth containing lactobacilli may benefit oral health.

Does inhibitory control training improve health behaviour? A meta-analysis.

PubMed

Allom, Vanessa; Mullan, Barbara; Hagger, Martin

2016-06-01

Inhibitory control training has been hypothesised as a technique that will improve an individual's ability to overrule impulsive reactions in order to regulate behaviour consistent with long-term goals. A meta-analysis of 19 studies of inhibitory control training and health behaviours was conducted to determine the effect of inhibitory control training on reducing harmful behaviours. Theoretically driven moderation analyses were also conducted to determine whether extraneous variables account for heterogeneity in the effect; in order to facilitate the development of effective intervention strategies. Moderators included type of training task, behaviour targeted, measurement of behaviour and training duration. A small but homogeneous effect of training on behaviour was found, d(+)  = 0.378, CI95 = [0.258, 0.498]. Moderation analyses revealed that the training paradigm adopted, and measurement type influenced the size of the effect such that larger effects were found for studies that employed go/no-go (GNG) training paradigms rather than stop-signal task paradigms, and objective outcome measures that were administered immediately yielded the largest and most consistent effects on behaviour. Results suggest that GNG inhibitory control training paradigms can influence health behaviour, but perhaps only in the short-term. Future research is required to systematically examine the influence of training duration, and the longevity of the training effect. Determining these factors could provide the basis for cost-effective and efficacious health-promoting interventions.

New Aldehyde Reductase Genes of Saccharomyces cerevisiae Contribute In Situ Detoxification of Lignocellulose-to-Ethanol Conversion Inhibitiors

USDA-ARS?s Scientific Manuscript database

Furfural and 5-hydroxymethylfurfural (HMF) are inhibitory compounds commonly encountered during lignocellulose-to-ethanol conversion for cleaner transportation fuels. It is possible to in situ detoxify the aldehyde inhibitors by tolerant ethanologenic yeast strains. Multiple gene-mediated reductio...

Residential Mobility, Inhibitory Control, and Academic Achievement in Preschool

ERIC Educational Resources Information Center

Schmitt, Sara A.; Finders, Jennifer K.; McClelland, Megan M.

2015-01-01

The present study investigated the direct effects of residential mobility on children's inhibitory control and academic achievement during the preschool year. It also explored fall inhibitory control and academic skills as mediators linking residential mobility and spring achievement. Participants included 359 preschool children (49% female)…

Residential Mobility, Inhibitory Control, and Academic Achievement in Preschool

ERIC Educational Resources Information Center

Schmitt, Sara A.; Finders, Jennifer K.; McClelland, Megan M.

2015-01-01

Research Findings: The present study investigated the direct effects of residential mobility on children's inhibitory control and academic achievement during the preschool year. It also explored fall inhibitory control and academic skills as mediators linking residential mobility and spring achievement. Participants included 359 preschool children…

Dynamical responses to external stimuli for both cases of excitatory and inhibitory synchronization in a complex neuronal network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2017-10-01

For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli S ( t ) (applied to a fraction of neurons) are investigated by varying the driving amplitude A of S ( t ). Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus S ( t ) makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while S ( t ) makes a destructive effect on inhibitory non-stimulated FS interneurons (i.e., it breaks up original inhibitory synchronization in the non-stimulated sub-population). As results of these different effects of S ( t ), the type and degree of dynamical response (e.g., synchronization enhancement or suppression), characterized by the dynamical response factor [Formula: see text] (given by the ratio of synchronization degree in the presence and absence of stimulus), are found to vary in a distinctly different way, depending on the synaptic-coupling type. Furthermore, we also measure the matching degree between the dynamics of the two sub-populations of stimulated and non-stimulated neurons in terms of a "cross-correlation" measure [Formula: see text]. With increasing A , based on [Formula: see text], we discuss the cross-correlations between the two sub-populations, affecting the dynamical responses to S ( t ).

Inhibitory effects of Citrus hassaku extract and its flavanone glycosides on melanogenesis.

PubMed

Itoh, Kimihisa; Hirata, Noriko; Masuda, Megumi; Naruto, Shunsuke; Murata, Kazuya; Wakabayashi, Keitaro; Matsuda, Hideaki

2009-03-01

The 50% ethanolic extract (CH-ext) obtained from the unripe fruit of Citrus hassaku exhibited significant tyrosinase inhibitory activity. The CH-ext showed antioxidant activity, such as superoxide dismutase (SOD)-like activity and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Activity-guided fractionation of the CH-ext indicated that flavanone glycoside-rich fractions showed potent tyrosinase inhibitory activity. Further examination revealed that the tyrosinase inhibitory activity and antioxidant activity of the CH-ext were attributable to naringin and neohesperidin, respectively. The CH-ext showed inhibition of melanogenesis without any effects on cell proliferation in cultured murine B16 melanoma cells after glucosamine exposure. The topical application of the CH-ext to the dorsal skin of brownish guinea pigs showed in vivo preventive effects against UVB-induced pigmentation.

Cholinesterase inhibitors from the roots of Harpagophytum procumbens.

PubMed

Bae, Yoon Ho; Cuong, To Dao; Hung, Tran Manh; Kim, Jeong Ah; Woo, Mi Hee; Byeon, Jeong Su; Choi, Jae Sue; Min, Byung Sun

2014-01-01

Inhibition of cholinesterase has been proposed to be a therapeutic target for the treatment of Alzheimer's diseases. In our preliminary screening study on the acetylcholinesterase (AChE) inhibitory activity, an ethyl acetate soluble fraction of the roots of Harpagophytum procumbens (Pedaliaceae) was found to inhibit AChE activity at the concentration of 100 μg/mL. Ten compounds (1-10) were isolated from the active fraction and evaluated for their inhibitory effect on AChE and butyrylcholinesterase (BChE). Among the isolates, verbascosides (5, 6, and 8) containing a caffeoyl and a 3,4-dihydroxyphenethyl groups in their structures, showed effective AChE inhibitory activity and also possessed BChE inhibitory activity. The findings suggest that verbascoside derivatives may be partially related to the anti-Alzheimer effect of this medicinal plant.

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

PubMed

Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Commercial valerian interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes.

PubMed

Ortiz, José G; Rassi, Nicole; Maldonado, Patricia M; González-Cabrera, Silvia; Ramos, Igmeris

2006-09-01

Valeriana officinalis extracts are used in folkloric medicine for their sedative, hypnotic and tranquilizer effects. Using [3H]flunitrazepam binding as an indicator, the interactions of commercial Valerian extracts with GABA(A) receptors were examined. There was considerable fluctuation among the different extracts, some mildly enhanced [3H]flunitrazepam binding, others had no effect and others had inhibitory effects, independent of standardization by valerenic acid. Central depression can also be accomplished by a reduction of excitatory transmission. Valerian extracts had modest inhibitory effects on [3H]MK-801 binding, an indicator of NMDA-Valerian interactions. Spectral analyses (UV region) did not show marked differences among the different extracts. The inhibitory effects of one of the extracts on [3H]flunitrazepam binding was somewhat stable, while on [3H]MK-801 binding the inhibitory effects were lost within months. These results suggest that particular care should be taken in analysing and interpreting results from commercial Valerian preparations. Copyright (c) 2006 John Wiley & Sons, Ltd.

Diosgenin inhibits superoxide generation in FMLP-activated mouse neutrophils via multiple pathways.

PubMed

Lin, Y; Jia, R; Liu, Y; Gao, Y; Zeng, X; Kou, J; Yu, B

2014-12-01

Diosgenin possesses anti-inflammatory and anticancer properties. Activated neutrophils produce high concentrations of the superoxide anion which is involved in the pathophysiology of inflammation-related diseases and cancer. In the present study, the inhibitory effect and possible mechanisms of diosgenin on superoxide generation were investigated in mouse bone marrow neutrophils. Diosgenin potently and concentration-dependently inhibited the extracellular and intracellular superoxide anion generation in Formyl-Met-Leu-Phe (FMLP)- activated neutrophils, with IC50 values of 0.50 ± 0.08 μM and 0.66 ± 0.13 μM, respectively. Such inhibition was not mediated by scavenging the superoxide anion or by a cytotoxic effect. Diosgenin inhibited the phosphorylation of p47phox and membrane translocation of p47phox and p67phox, and thus blocking the assembly of nicotinamide adenine dinucleotide phosphate oxidase. Moreover, cellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) expression were also effectively increased by diosgenin. It attenuated FMLP-induced increase of phosphorylation of cytosolic phospholipase A (cPLA2), p21-activated kinase (PAK), Akt, p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK). Our data indicate that diosgenin exhibits inhibitory effects on superoxide anion production through the blockade of cAMP, PKA, cPLA2, PAK, Akt and MAPKs signaling pathways. The results may explain the clinical implications of diosgenin in the treatment of inflammation-related disorders.

Quantitative structure-activity relationship of the curcumin-related compounds using various regression methods

NASA Astrophysics Data System (ADS)

Khazaei, Ardeshir; Sarmasti, Negin; Seyf, Jaber Yousefi

2016-03-01

Quantitative structure activity relationship were used to study a series of curcumin-related compounds with inhibitory effect on prostate cancer PC-3 cells, pancreas cancer Panc-1 cells, and colon cancer HT-29 cells. Sphere exclusion method was used to split data set in two categories of train and test set. Multiple linear regression, principal component regression and partial least squares were used as the regression methods. In other hand, to investigate the effect of feature selection methods, stepwise, Genetic algorithm, and simulated annealing were used. In two cases (PC-3 cells and Panc-1 cells), the best models were generated by a combination of multiple linear regression and stepwise (PC-3 cells: r2 = 0.86, q2 = 0.82, pred_r2 = 0.93, and r2m (test) = 0.43, Panc-1 cells: r2 = 0.85, q2 = 0.80, pred_r2 = 0.71, and r2m (test) = 0.68). For the HT-29 cells, principal component regression with stepwise (r2 = 0.69, q2 = 0.62, pred_r2 = 0.54, and r2m (test) = 0.41) is the best method. The QSAR study reveals descriptors which have crucial role in the inhibitory property of curcumin-like compounds. 6ChainCount, T_C_C_1, and T_O_O_7 are the most important descriptors that have the greatest effect. With a specific end goal to design and optimization of novel efficient curcumin-related compounds it is useful to introduce heteroatoms such as nitrogen, oxygen, and sulfur atoms in the chemical structure (reduce the contribution of T_C_C_1 descriptor) and increase the contribution of 6ChainCount and T_O_O_7 descriptors. Models can be useful in the better design of some novel curcumin-related compounds that can be used in the treatment of prostate, pancreas, and colon cancers.

Randomized controlled trial of maternal omega-3 long-chain PUFA supplementation during pregnancy and early childhood development of attention, working memory, and inhibitory control.

PubMed

Gould, Jacqueline F; Makrides, Maria; Colombo, John; Smithers, Lisa G

2014-04-01

Docosahexaenoic acid (DHA) accumulates in the hippocampus and frontal lobes of the fetal brain during the last trimester of pregnancy. These areas of the brain contribute to attention and working memory and inhibitory control (WMIC). We evaluated the effect of maternal omega-3 (n-3) long-chain polyunsaturated fatty acid supplementation in pregnancy on child attention and WMIC. A total of 185 term-born children of mothers who were randomly allocated to consume 800 mg DHA/d (treatment) or a placebo (control) from ∼20 wk of gestation until birth were assessed with multiple measures of attention and WMIC at a mean (± SD) of 27 ± 2 mo. Primary outcomes were the average time it took to be distracted when playing with a toy (distractibility) and the accuracy of remembering a new hiding location while inhibiting a learned response to search in the previous location (WMIC). Assessments were completed by 81 children in the treatment group (mean ± SD age: 835 ± 50.4 d) and 77 children in the control group (839 ± 65.6 d). There was no effect of supplementation on primary outcomes [distractibility mean difference: -0.2 s (95% CI: -0.7, 0.4 s); WMIC mean difference: 8.9 mm (95% CI: -10.6, 28.3 mm)]. There was no difference between DHA-supplemented and control groups except that treatment-group children looked away from the toys fewer times than controls when presented with multiple toys competing for attention but less accurately remembered a repeated hiding location. These secondary effects were not consistent with any other outcomes and may have been a result of chance. Cord plasma DHA was not consistently associated with attention and WMIC. Maternal DHA supplementation during pregnancy does not enhance attention or WMIC in term-born preschoolers. The DHA for Maternal and Infant Outcomes trial was registered at www.anzctr.org.au as ACTRN1260500056906.

Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl)methanol derivatives

PubMed Central

Kim, Do Hyun; Kim, Su Jeong; Ullah, Sultan; Yun, Hwi Young; Chun, Pusoon; Moon, Hyung Ryong

2017-01-01

The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 μM, and five of the PDTM derivatives (PDTM3, PDTM7–PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 μM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 μM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7–PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition. PMID:28352157

The Antifungal Inhibitory Concentration Effectiveness Test From Ethanol Seed Arabica Coffee (Coffea arabica) Extract Against The Growth Of Candida albicans Patient Isolate With In Vitro Method

NASA Astrophysics Data System (ADS)

Satria Rakatama, Adam; Pramono, Andri; Yulianti, Retno

2018-03-01

Candida albicans are the most frequent cause of Vulvovaginalis Candidiasis infection. Its treatment using antifungal drugs, are oftenly caused side effects. The reduction of C.albicans growth and the reduction of antifungal drugs side effect, were our main purposed. Our study objective is determine the effectiveness of inhibitory power of arabica coffee seed ethanol extract on the growth of C.albicans patient isolates. The type of this research is experimental research. Kirby-bauer method with the Saboraud Dextrose Agar (SDA) media was used in this experiment. Inhibitory zone was observed around the disc, to determine the inhibitory power. The results showed that the inhibitory zone was formed on arabica coffee seed ethanol extract on 10%, 20%, 40%, and 80% concentration. Kruskal-Wallis test results (p<0,05) showed that there was a significant difference in mean between the concentration groups tested against the treatment group. The inhibitory zone was formed because of biochemical compound in arabica coffee seed such as caffeine, phenol, alkaloids, flavonoids, and saponins. Inhibitory zone in C.albicans patient isolates were smaller compared with C.albicans ATCC 90028 as gold standard. This showed that the virulence of C.albicans from patients isolates were higher. We concluded that arabica coffee seed ethanol extract could inhibiting the growth of C.albicans patient isolates. Optimization of coffee seed ethanol extract to obtain maximum active ingredients still needs to be done. This knowledge is expected to be used for the beginning manufacturer antifungal drug from natural product.

Multilingual Stroop Performance: Effects of Trilingualism and Proficiency on Inhibitory Control

ERIC Educational Resources Information Center

Marian, Viorica; Blumenfeld, Henrike K.; Mizrahi, Elena; Kania, Ursula; Cordes, Anne-Kristin

2013-01-01

Previous research suggests that multilinguals' languages are constantly co-activated and that experience managing this co-activation changes inhibitory control function. The present study examined language interaction and inhibitory control using a colour-word Stroop task. Multilingual participants were tested in their three most proficient…

PAM multiplicity marks genomic target sites as inhibitory to CRISPR-Cas9 editing.

PubMed

Malina, Abba; Cameron, Christopher J F; Robert, Francis; Blanchette, Mathieu; Dostie, Josée; Pelletier, Jerry

2015-12-08

In CRISPR-Cas9 genome editing, the underlying principles for selecting guide RNA (gRNA) sequences that would ensure for efficient target site modification remain poorly understood. Here we show that target sites harbouring multiple protospacer adjacent motifs (PAMs) are refractory to Cas9-mediated repair in situ. Thus we refine which substrates should be avoided in gRNA design, implicating PAM density as a novel sequence-specific feature that inhibits in vivo Cas9-driven DNA modification.

PAM multiplicity marks genomic target sites as inhibitory to CRISPR-Cas9 editing

PubMed Central

Malina, Abba; Cameron, Christopher J. F.; Robert, Francis; Blanchette, Mathieu; Dostie, Josée; Pelletier, Jerry

2015-01-01

In CRISPR-Cas9 genome editing, the underlying principles for selecting guide RNA (gRNA) sequences that would ensure for efficient target site modification remain poorly understood. Here we show that target sites harbouring multiple protospacer adjacent motifs (PAMs) are refractory to Cas9-mediated repair in situ. Thus we refine which substrates should be avoided in gRNA design, implicating PAM density as a novel sequence-specific feature that inhibits in vivo Cas9-driven DNA modification. PMID:26644285

Lipopolysaccharide treatment reduces rat platelet aggregation independent of intracellular reactive-oxygen species generation.

PubMed

Lopes-Pires, M Elisa; Casarin, André L; Pereira-Cunha, Fernanda G; Lorand-Metze, Irene; Antunes, Edson; Marcondes, Sisi

2012-01-01

High production of reactive-oxygen species (ROS) by blood cells is involved in damage of the vascular endothelium and multiple organ dysfunction in sepsis. However, little is known about the intraplatelet ROS production in sepsis and its consequences on platelet reactivity. In this study, we evaluated whether the treatment of rats with lipopolysaccharide (LPS) affects platelet aggregation through intraplatelet ROS generation. Rats were injected with LPS (1 mg/kg, i.p.), and at 2 to 72 h thereafter, adenosine diphosphate (ADP) (3-10 µM) induced platelet aggregation was evaluated. Production of ROS in platelets was measured by flow cytometry using 2',7'-dichlorofluorescein diacetate (DCFH-DA). Treatment of rats with LPS time-dependently inhibited ADP-induced platelet aggregation within 72 h. The inhibitory effect of LPS on platelet aggregation was further increased when the platelets were incubated with polyethylene glycol-superoxide dismutase (PEG-SOD; 30 U/mL), polyethylene glycol-catalase (PEG-CAT; 1000 U/mL) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10 µM). The ROS production in non-stimulated platelets did not differ between control and LPS-treated rats. However, in ADP-activated platelets, generation of ROS was increased by 3.0- and 7.0-fold, as evaluated at 8 and 48 h after LPS injection, respectively. This increased ROS production was significantly reduced when platelets were incubated in vitro with DPI, PEG-SOD or PEG-CAT. In contrast, treatment of rats with N-acetylcysteine (150 mg/kg, i.p.) significantly reduced the inhibitory effect of LPS on platelet aggregation, and prevented the increased ROS production by in vivo LPS. Our results indicate that the increased intraplatelet ROS production does not contribute to the inhibitory effect of LPS on platelet aggregation; however, the maintenance of redox balance in LPS-treated rats is fundamental to restore the normal platelet response in these animals.

Stop feeling: inhibition of emotional interference following stop-signal trials.

PubMed

Kalanthroff, Eyal; Cohen, Noga; Henik, Avishai

2013-01-01

Although a great deal of literature has been dedicated to the mutual links between emotion and the selective attention component of executive control, there is very little data regarding the links between emotion and the inhibitory component of executive control. In the current study we employed an emotional stop-signal task in order to examine whether emotion modulates and is modulated by inhibitory control. Results replicated previous findings showing reduced inhibitory control [longer stop-signal reaction time (SSRT)] following negative, compared to neutral pictures. Most importantly, results show decreased emotional interference following stop-signal trials. These results show that the inhibitory control component of executive control can serve to decrease emotional effects. We suggest that inhibitory control and emotion have a two-way connection in which emotion disrupts inhibitory control and activation of inhibitory control disrupts emotion.

Melatonin as a multifunctional anti-cancer molecule: Implications in gastric cancer.

PubMed

Asghari, Mohammad Hossein; Moloudizargari, Milad; Ghobadi, Emad; Fallah, Marjan; Abdollahi, Mohammad

2017-09-15

Gastric cancer (GC) is a predominant malignancy with a high mortality rate affecting a large population worldwide. The etiology of GC is multifactorial spanning from various genetic determinants to different environmental causes. Current tretaments of GC are not efficient enough and require improvements to minimize the adverse effects. Melatonin, a naturally occurring compound with known potent inhibitory effects on cancer cells is one of the major candidates which can be recruited herein. Here we reviewed the articles conducted on the therapeutic effects of melatonin in gastric cancer in various models. The results are classified according to different aspects of cancer pathogenesis and the molecular mechanisms by which melatonin exerts its effects. Melatonin could be used to combat GC exploiting its effects on multiple aspects of its pathogenesis, including formation of cancer cells, tumor growth and angiogenesis, differentiation and metastasis as well as enhancing the anti-tumor immunity. Melatonin is a pleiotropic anti-cancer molecule that affects malignant cells via multiple mechanisms. It has been shown to benefit cancer patients indirectly by reducing side effects of current therapies which have been discussed in this review. This field of research is still underdeveloped and may serve as an interesting subject for further studies aiming at the molecular mechanisms of melatonin and novel treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel synthetic kojic acid-methimazole derivatives inhibit mushroom tyrosinase and melanogenesis.

PubMed

Chen, Ming-Jen; Hung, Chih-Chuan; Chen, Yan-Ru; Lai, Shih-Ting; Chan, Chin-Feng

2016-12-01

In this study, two kojic acid-methimazole (2-mercapto-1-methylimidazole, MMI, 1) derivatives, 5-hydroxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 4) and 5-methoxy-2-{[(1-methyl-1H-imidazol-2-yl)thio]methyl}-4H-pyran-4-one (compound 5), were synthesized to examine their inhibitory kinetics on mushroom tyrosinase. Compound 4 exhibited a potent inhibitory effect on monophenolase activity in a dose-dependent manner, with an IC 50 value of 0.03 mM. On diphenolase activity, compound 4 exhibited a less inhibitory effect (IC 50  = 1.29 mM) but was stronger than kojic acid (IC 50  = 1.80 mM). Kinetic analysis indicated that compound 4 was both as a noncompetitive monophenolase and diphenolase inhibitor. By contrast, compound 5 exhibited no inhibitory effects on mushroom tyrosinase activity. The IC 50 value of compound 4 for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity was 4.09 mM, being much higher than the IC 50 of compound 4 for inhibiting the tyrosinase activity. The results indicated that the antioxidant activity of compound 4 may be partly related to the potent inhibitory effect on mushroom tyrosinase. Compound 4 also exerted a potent inhibitory effect on intracellular melanin formation in B16/F10 murine melanoma cells, and caused no cytotoxicity. Furthermore, compound 4 induced no adverse effects on the Hen's egg test-chorioallantoic membrane (HET-CAM). Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

All set! Evidence of simultaneous attentional control settings for multiple target colors.

PubMed

Irons, Jessica L; Folk, Charles L; Remington, Roger W

2012-06-01

Although models of visual search have often assumed that attention can only be set for a single feature or property at a time, recent studies have suggested that it may be possible to maintain more than one attentional control setting. The aim of the present study was to investigate whether spatial attention could be guided by multiple attentional control settings for color. In a standard spatial cueing task, participants searched for either of two colored targets accompanied by an irrelevantly colored distractor. Across five experiments, results consistently showed that nonpredictive cues matching either target color produced a significant spatial cueing effect, while irrelevantly colored cues did not. This was the case even when the target colors could not be linearly separated from irrelevantly cue colors in color space, suggesting that participants were not simply adopting one general color set that included both target colors. The results could not be explained by intertrial priming by previous targets, nor could they be explained by a single inhibitory set for the distractor color. Overall, the results are most consistent with the maintenance of multiple attentional control settings.

Influence of predator density on nonindependent effects of multiple predator species.

PubMed

Griffen, Blaine D; Williamson, Tucker

2008-02-01

Interactions between multiple predator species are frequent in natural communities and can have important implications for shared prey survival. Predator density may be an important component of these interactions between predator species, as the frequency of interactions between species is largely determined by species density. Here we experimentally examine the importance of predator density for interactions between predator species and subsequent impacts on prey. We show that aggressive interactions between the predatory shore crabs Carcinus maenas and Hemigrapsus sanguineus increased with predator density, yet did not increase as fast as negative interactions between conspecifics. At low density, interactions between conspecific and heterospecific predators had similar inhibitory impacts on predator function, whereas conspecific interference was greater than interference from heterospecifics at high predator density. Thus the impact of conspecific interference at high predator density was sufficient in itself that interactions with a second predator species had no additional impact on per capita predation. Spatial and temporal variability in predator density is a ubiquitous characteristic of natural systems that should be considered in studies of multiple predator species.

[Evaluate drug interaction of multi-components in Morus alba leaves based on α-glucosidase inhibitory activity].

PubMed

Ji, Tao; Su, Shu-Lan; Guo, Sheng; Qian, Da-Wei; Ouyang, Zhen; Duan, Jin-Ao

2016-06-01

Column chromatography was used for enrichment and separation of flavonoids, alkaloids and polysaccharides from the extracts of Morus alba leaves; glucose oxidase method was used with sucrose as the substrate to evaluate the multi-components of M. alba leaves in α-glucosidase inhibitory models; isobole method, Chou-Talalay combination index analysis and isobolographic analysis were used to evaluate the interaction effects and dose-effect characteristics of two components, providing scientific basis for revealing the hpyerglycemic mechanism of M. alba leaves. The components analysis showed that flavonoid content was 5.3%; organic phenolic acids content was 10.8%; DNJ content was 39.4%; and polysaccharide content was 18.9%. Activity evaluation results demonstrated that flavonoids, alkaloids and polysaccharides of M. alba leaves had significant inhibitory effects on α-glucosidase, and the inhibitory rate was increased with the increasing concentration. Alkaloids showed most significant inhibitory effects among these three components. Both compatibility of alkaloids and flavonoids, and the compatibility of alkaloids and polysaccharides demonstrated synergistic effects, but the compatibility of flavonoids and polysaccharides showed no obvious synergistic effects. The results have confirmed the interaction of multi-components from M. alba leaves to regulate blood sugar, and provided scientific basis for revealing hpyerglycemic effectiveness and mechanism of the multi-components from M. alba leaves. Copyright© by the Chinese Pharmaceutical Association.

Inhibitory effect of Xenorhabdus nematophila TB on plant pathogens Phytophthora capsici and Botrytis cinerea in vitro and in planta

PubMed Central

Fang, Xiangling; Zhang, Manrang; Tang, Qian; Wang, Yonghong; Zhang, Xing

2014-01-01

Entomopathogenic bacteria Xenorhabdus spp. produce secondary metabolites with potential antimicrobial activity for use in agricultural productions. This study evaluated the inhibitory effect of X. nematophila TB culture on plant pathogens Botrytis cinerea and Phytophthora capsici. The cell-free filtrate of TB culture showed strong inhibitory effects (>90%) on mycelial growth of both pathogens. The methanol-extracted bioactive compounds (methanol extract) of TB culture also had strong inhibitory effects on mycelial growth and spore germinations of both pathogens. The methanol extract (1000 μg/mL) and cell-free filtrate both showed strong therapeutic and protective effects (>70%) on grey mold both in detached tomato fruits and plants, and leaf scorch in pepper plants. This study demonstrates X. nematophila TB produces antimicrobial metabolites of strong activity on plant pathogens, with great potential for controlling tomato grey mold and pepper leaf scorch and being used in integrated disease control to reduce chemical application. PMID:24599183

Inhibitory effect of Xenorhabdus nematophila TB on plant pathogens Phytophthora capsici and Botrytis cinerea in vitro and in planta.

PubMed

Fang, Xiangling; Zhang, Manrang; Tang, Qian; Wang, Yonghong; Zhang, Xing

2014-03-06

Entomopathogenic bacteria Xenorhabdus spp. produce secondary metabolites with potential antimicrobial activity for use in agricultural productions. This study evaluated the inhibitory effect of X. nematophila TB culture on plant pathogens Botrytis cinerea and Phytophthora capsici. The cell-free filtrate of TB culture showed strong inhibitory effects (>90%) on mycelial growth of both pathogens. The methanol-extracted bioactive compounds (methanol extract) of TB culture also had strong inhibitory effects on mycelial growth and spore germinations of both pathogens. The methanol extract (1000 μg/mL) and cell-free filtrate both showed strong therapeutic and protective effects (>70%) on grey mold both in detached tomato fruits and plants, and leaf scorch in pepper plants. This study demonstrates X. nematophila TB produces antimicrobial metabolites of strong activity on plant pathogens, with great potential for controlling tomato grey mold and pepper leaf scorch and being used in integrated disease control to reduce chemical application.

Inhibitory effects of polyphenols in leaves of Artemisia princeps PAMP on protein fragmentation by Cu(II)-H2O2 in vitro.

PubMed

Toda, Shizuo

2004-01-01

The leaves of Artemisia princeps PAMP have traditionally been used as teas and foods in Japan. Polyphenols in Artemisia plants have been shown to have inhibitory effects against biological damages. The inhibitory effects of polyphenols in the leaves of A. princeps PAMP were investigated on protein fragmentation induced by Cu(II)-H(2)O(2) in vitro. The total polyphenol content in the leaves of A. princeps PAMP was 4.58%. The condensed tannin content was 0.62% by vanillin assay and 0.14% by proanthrocyanidin assay. The polyphenols in the leaves of A. princeps PAMP inhibited bovine albumin fragmentation by Cu(II)-H(2)O(2). The effects of polyphenols in the leaves of A. princeps PAMP were similar to those of tannic acid, studied as a related polyphenol. These results demonstrated that the leaves of A. princeps PAMP have inhibitory effects on protein fragmentation damage.

Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission.

PubMed

Thio, L L; Wong, M; Yamada, K A

2000-01-25

To determine the effect of the ketone bodies beta-hydroxybutyrate (betaHB) and acetoacetate (AA) on excitatory and inhibitory neurotransmission in the mammalian CNS. The ketogenic diet is presumed to be an effective anticonvulsant regimen for some children with medically intractable seizures. However, its mechanism of action remains a mystery. According to one hypothesis, ketone bodies have anticonvulsant properties. The authors examined the effect of betaHB and AA on excitatory and inhibitory synaptic transmission in rat hippocampal-entorhinal cortex slices and cultured hippocampal neurons. In cultured neurons, their effect was also directly assayed on postsynaptic receptor properties. Finally, their ability to prevent spontaneous seizures was determined in a hippocampal-entorhinal cortex slice model. betaHB and AA did not alter synaptic transmission in these models. The anticonvulsant properties of the ketogenic diet do not result from a direct effect of ketone bodies on the primary voltage and ligand gated ion channels mediating excitatory or inhibitory neurotransmission in the hippocampus.

Inhibitory effects of furanocoumarin derivatives in Kampo extract medicines on P-glycoprotein at the blood-brain barrier.

PubMed

Iwanaga, Kazunori; Yoneda, Shinji; Hamahata, Yukimi; Miyazaki, Makoto; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Kakemi, Masawo

2011-01-01

Furanocoumarin derivatives, known as components of grapefruit juice, showing inhibitory effects against P-glycoprotein (P-gp) in the intestine are also contained in the plants of rutaceae and umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of byakangelicol and rivulobirin A, known as furanocoumarins showing P-gp inhibitory effect using Caco-2 monolayer, against P-gp at the blood-brain barrier (BBB) under both in vitro and in vivo conditions. First we studied the membrane permeability of furanocoumarins to clarify whether they can be absorbed from the intestine. Both furanocoumarins showed high permeability through the Caco-2 monolayer, suggesting that they can easily reach the systemic circulation after oral administration. Then, we evaluated the effect of these furanocoumarins on the uptake of calcein acetoxymethyl ester (calcein-AM), a P-gp substrate, into bovine brain microvascular endothelial cells (BBMEC). Both furanocoumarins significantly increased the uptake amount of calcein-AM into BBMEC by the inhibition of P-gp at the BBB in vitro. Next we also investigated the P-gp inhibitory effect of these furanocoumarins at the rat BBB in vivo using verapamil as a P-gp substrate. Both furanocoumarins increased the B/P ratio of verapamil compared to the control, even under in vivo conditions; however, the extent of the inhibitory effect was much lower than in vitro condition. In conclusion, byakangelicol and rivulobirin A may inhibit P-gp expressed at the BBB even under in vivo conditions. Further studies using Kampo extract medicines under in vivo condition are necessary for safe drug therapy.

Response inhibition moderates the association between drug use and risky sexual behavior.

PubMed

Nydegger, Liesl A; Ames, Susan L; Stacy, Alan W; Grenard, Jerry L

2014-09-01

HIV infection is problematic among all drug users, not only injection drug users. Drug users are at risk for contracting HIV by engaging in risky sexual behaviors. The present study sought to determine whether inhibitory processes moderate the relationship between problematic drug use and HIV-risk behaviors (unprotected sex and multiple sex partners). One hundred ninety-six drug offenders enrolled in drug education programs were administered a battery of computer-based assessments. Measures included a cued go/no-go assessment of inhibitory processes, the Drug Abuse Screening Test (DAST) assessment of problematic drug use, and self-report assessment of condom use and multiple sex partners. Findings revealed that response inhibition assessed by the proportion of false alarms on the cued go/no-go moderated the relationship between problematic drug use and an important measure of HIV risk (condom nonuse) among drug offenders. However, response inhibition did not moderate the relationship between problematic drug use and another measure of HIV risk: multiple sex partners. Among this sample of drug offenders, we have found a relationship between problematic drug use and condom nonuse, which is exacerbated by poor control of inhibition. These findings have implications for the development of HIV intervention components among high-risk populations.

Quantitative evaluation of inhibitory effect of various substances on anaerobic ammonia oxidation (anammox).

PubMed

Nakamura, Tomotaka; Harigaya, Yuhki; Kimura, Yuya; Kuroiwa, Megumi; Kurata, Yuhri; Isaka, Kazuichi; Suwa, Yuichi

2017-09-01

The inhibitory effect of 20 substances of various chemical species on the anaerobic ammonia oxidation (anammox) activity of an enrichment culture, predominated by Candidatus Brocadia, was determined systematically by using a 15 N tracer technique. The initial anammox rate was determined during first 25 min with a small-scale anaerobic batch incubation supplemented with possible inhibitors. Although Cu 2+ and Mn 2+ did not inhibit anammox, the remaining 18 substances [Ni 2+ , Zn 2+ , Co 2+ , [Formula: see text] , Fe 2+ , 4 amines, ethylenediaminetetraacetic acid (EDTA), ethylenediamine-N,N'-bis (2-hydroxyphenylacetic acid) (EDDHA), citric acid, nitrilotriacetic acid (NTA), N,N-dimethylacetamide (DMA), 1,4-dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) and tetrahydrofuran (THF)] were inhibitory. Inhibitory effect of NTA, EDDHA, THF, DMF, DMA and amines on anammox was first determined in this study. Inhibitory effects of metals were re-evaluated because chelators, which may interfere inhibitory effect, have been used to dissolve metal salts into assay solution. The relative anammox activities as a function of concentration of each substance were described successfully (R 2  > 0.91) either with a linear inhibition model or with a Michaelis-Menten-based inhibition model. IC 50 values were estimated based on either model, and were compared. The IC 50 values of the 4 chelators (0.06-2.7 mM) and 5 metal ions (0.02-1.09 mM) were significantly lower than those of the 4 amines (10.6-29.1 mM) and 5 organic solvents (3.5-82 mM). Although it did not show any inhibition within 25 min, 0.1 mM Cu 2+ completely inhibited anammox activity in 240 min, suggesting that the inhibitory effect caused by Cu 2+ is time-dependent. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

[Comparison of anti-angiogenic effect in vitro between ranibizumab and bevacizumab].

PubMed

Souto, Alexandre Cupello; Maricato, Juliana Terzi; Denapoli, Priscila Martins Andrade; Sallum, Juliana Maria Ferraz; Han, Sang Won

2011-01-01

To evaluate the comparative in-vitro antiangiogenic effect of Bevacizumab and Ranibizumab. Endothelial venous umbilical cells culture (ECV304) cultivated in F12 media with addition of 10% Fetal Bovine Serum, were plaqued and treated with clinically relevant concentrations of Bevacizumab and Ranibizumab just after the scratch done in the middle of the culture (scratch methodology). Measurements of the linear size of the area free of cell proliferation were done 24, 48 and 72 hours after the scratch day point. All the experiments were done in triplicate and statistical analysis were done with T-student test. Inhibitory effect was observed just at the concentrations of 0.5 and 0.7 mg/ml in both drugs. At 0.7 mg/ml, Ranibizumab demonstrated a more potent proliferative inhibitory effect than Bevacizumab. At the same concentration, Ranibizumab was three times more potent than Ranibizumab. Inhibitory effect was observed just in the first 24 hours for both drugs. Ranibizumab demonstrates an increased effect when compared to Bevacizumab and this is related more to the different molar rate of each drug than related to a real better proliferative inhibitory effect.

Synchrony and neural coding in cerebellar circuits

PubMed Central

Person, Abigail L.; Raman, Indira M.

2012-01-01

The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons. Possible answers come from accumulating evidence that subsets of Purkinje cells synchronize their firing during behaviors that require the cerebellum. Consistent with models predicting that coherent activity of inhibitory networks has the capacity to dictate firing patterns of target neurons, recent experimental work supports the idea that inhibitory synchrony may regulate the response of cerebellar nuclear cells to Purkinje inputs, owing to the interplay between unusually fast inhibitory synaptic responses and high rates of intrinsic activity. Data from multiple laboratories lead to a working hypothesis that synchronous inhibitory input from Purkinje cells can set the timing and rate of action potentials produced by cerebellar nuclear cells, thereby relaying information out of the cerebellum. If so, then changing spatiotemporal patterns of Purkinje activity would allow different subsets of inhibitory neurons to control cerebellar output at different times. Here we explore the evidence for and against the idea that a synchrony code defines, at least in part, the input–output function between the cerebellar cortex and nuclei. We consider the literature on the existence of simple spike synchrony, convergence of Purkinje neurons onto nuclear neurons, and intrinsic properties of nuclear neurons that contribute to responses to inhibition. Finally, we discuss factors that may disrupt or modulate a synchrony code and describe the potential contributions of inhibitory synchrony to other motor circuits. PMID:23248585

Self-restraint spillover: Inhibitory control disrupts appetite regulation among ruminators.

PubMed

Schlinkert, Caroline; Koole, Sander L

2017-10-23

People can use inhibitory control to temporarily inhibit their personal preferences to achieve their long-term goals. According to the ego fixation model (Koole et al., 2014), ruminators have difficulties relaxing inhibitory control, leading them to continue inhibiting their personal needs, even when this is no longer required by the situation. Inhibitory control may thus disrupt healthy appetite regulation among ruminators. Among 324 Dutch undergraduate students (218 women; M age  = 21.5), different inhibitory control states were manipulated by varying whether or not participants exerted inhibitory control (Study 1) or priming high versus low inhibitory control (Study 2). All participants then performed a food-tasting task. Healthy appetite regulation was defined as a positive correlation between level of food deprivation and preference for high-calorie foods. For taste ratings, the interaction between inhibitory control and rumination was significant in each study: Inhibitory control disrupted healthy appetite regulation in taste preferences among ruminators, but not among non-ruminators. For eating behavior, the same interaction effect was significant when the two studies were combined. Inhibitory control disrupts healthy appetite regulation among ruminators. These findings suggest the need for caution in interventions that rely on inhibitory control, especially among samples with compulsive thought tendencies. © 2017 Wiley Periodicals, Inc.

Effects of homeopathic medications Eupatorium perfoliatum and Arsenicum album on parasitemia of Plasmodium berghei-infected mice.

PubMed

Lira-Salazar, G; Marines-Montiel, E; Torres-Monzón, J; Hernández-Hernández, F; Salas-Benito, J S

2006-10-01

Malaria is one of the most important parasitic diseases in the world and a major public health problem because of emerging drug-resistant strains of Plasmodium. A number of synthetic and natural compounds are now being analysed to develop more effective antimalarial drugs. We investigated the effect of homeopathic preparations of Eupatorium perfoliatum and Arsenicum album on parasitemia using a rodent malaria model. We found significant inhibitory effect on parasite multiplication with both medications with a level of 60% for Eupatorium perfoliatum at a 30 CH potency. Arsenicum album 0/6 gave 70% inhibition but this was less stable than Eupatorium perfoliatum. The number of schizonts was higher in animals treated with homeopathic medications. Although the mechanism of action is unknown, these agents would be good candidates as alternative or complementary medications in the treatment of malaria.

Food-drug interactions: grapefruit juice.

PubMed

Diaconu, Camelia Harapu; Cuciureanu, Magdalena; Vlase, L; Cuciureanu, Rodica

2011-01-01

Food-drug interactions are increasingly recognized as important clinical events which may change significantly the bioavailability of oral administrated drugs. Grapefruit juice (GFJ) demonstrated multiple interactions with drugs leading to loss of the therapeutic effects or increased side-effects. GFJ decreases pre-systemic metabolism through a) competitive or mechanism-based inhibition of gut wall CYP3A4 isoenzymes and b) P-glycoprotein (P-gp), c) multidrug resistance protein-2 (MRP2) or d) organic anion-transporting polypeptide (OATP) inhibition. Although, GFJ presents high amounts of flavonoids (e.g. naringin, naringenin), furanocoumarins (e.g. 6',7'-dihydroxybergamottin, bergamottin) are the main chemicals involved in the pharmacokinetic interactions. As compounds of GFJ show additive or synergistic effects, all the major furanocoumarins are necessary for the maximal inhibitory effect. Also, related citrus fruits (sweeties, pummelo and sour orange) or various plants containing furanocoumarins may present pharmacological interactions, yet to be discovered.

Inhibitory effect of D3 dopamine receptors on neuropeptide Y‑induced migration in vascular smooth muscle cells.

PubMed

Xia, Xue-Wei; Zhou, Yong-Qiao; Luo, Hao; Zeng, Chunyu

2017-10-01

Abnormal migration of vascular smooth muscle cells (VSMCs) serves an important role in hypertension, atherosclerosis and restenosis following angioplasty, which is regulated numerous hormonal and humoral factors, including neuropeptide Y (NPY) and dopamine. Dopamine and NPY are both sympathetic neurotransmitters, and a previous study reported that NPY increased VSMC proliferation, while dopamine receptor inhibited it. Therefore, the authors wondered whether or not there is an inhibitory effect of dopamine receptor on NPY‑mediated VSMC migration. The present study demonstrated that stimulation with NPY dose‑dependence (10‑10‑10‑7M, 24 h) increased VSMC migration, the stimulatory effect of NPY was via the Y1 receptor. This is because, in the presence of the Y1 receptor antagonist, BIBP3226 (10‑7 M), the stimulatory effect of NPY on VSMC migration was blocked. Activation of the D3 receptor by PD128907 dose‑dependence (10‑11‑10‑8 M) reduced the stimulatory effect of NPY on VSMC migration. The effect of PD128907 was via the D3 receptor, because the inhibitory effect of PD128907 on NPY‑mediated migration was blocked by the D3 receptor antagonist, U99194. The authors' further study suggested that the inhibitory effect of the D3 receptor was via the PKA signaling pathway, in the presence of the PKA inhibitor, 14‑22 (10‑6 M), the inhibitory effect of PD128907 on VSMC migration was blocked. Moreover, the inhibitory effect of PD128907 was imitated by PKA activator, Sp‑cAMP [S], in the presence of Sp‑cAMP [S], the NPY‑mediated stimulatory effect on VSMC migration was abolished. The present study indicated that activation of the D3 receptor inhibits NPY Y1‑mediated migration on VSMCs, PKA is involved in the signaling pathway.

Effect of clavulanic acid on minimal inhibitory concentrations of 16 antimicrobial agents tested against Legionella pneumophila.

PubMed Central

Pohlod, D J; Saravolatz, L D; Quinn, E L; Somerville, M M

1980-01-01

A total of 15 Legionella pneumophilia isolated were tested against 16 antimicrobial agents used singly and in combination with clavulanic acid. When combined with clavulanic acid, 4 of the 16 antimicrobial agents produced no enhanced effect. However, the minimal inhibitory concentrations of 12 of the antimicrobial agents were reduced by one-half to one-third when in combination with clavulanic acid. These reductions reflected only a one-dilution decrease, however, in the original minimal inhibitory concentrations. Thus, clavulanic acid combinations appear to be only nominally effective beta-lactamase inhibitors against L. pneumophilia. PMID:6969575

Enzyme inhibitory and radical scavenging effects of some antidiabetic plants of Turkey

PubMed Central

Orhan, Nilüfer; Hoçbaç, Sanem; Orhan, Didem Deliorman; Asian, Mustafa; Ergun, Fatma

2014-01-01

Objective(s): Ethnopharmacological field surveys demonstrated that many plants, such as Gentiana olivieri, Helichrysum graveolens, Helichrysum plicatum ssp. plicatum, Juniperus oxycedrus ssp. oxycedrus, Juniperus communis var. saxatilis, Viscum album (ssp. album, ssp. austriacum), are used as traditional medicine for diabetes in different regions of Anatolia. The present study was designed to evaluate the in vitro antidiabetic effects of some selected plants, tested in animal models recently. Materials and Methods: α-glucosidase and α-amylase enzyme inhibitory effects of the plant extracts were investigated and Acarbose was used as a reference drug. Additionally, radical scavenging capacities were determined using 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) ABTS radical cation scavenging assay and total phenolic content of the extracts were evaluated using Folin Ciocalteu method. Results: H. graveolens ethanol extract exhibited the highest inhibitory activity (55.7 % ± 2.2) on α-amylase enzyme. Additionally, J. oxycedrus hydro-alcoholic leaf extract had potent α-amylase inhibitory effect, while the hydro-alcoholic extract of J. communis fruit showed the highest α-glucosidase inhibitory activity (IC50: 4.4 μg/ml). Conclusion: Results indicated that, antidiabetic effect of hydro-alcoholic extracts of H. graveolens capitulums, J. communis fruit and J. oxycedrus leaf might arise from inhibition of digestive enzymes. PMID:25140204

Reward Improves Cancellation and Restraint Inhibition Across Childhood and Adolescence

PubMed Central

Sinopoli, Katia J.; Schachar, Russell; Dennis, Maureen

2011-01-01

Inhibitory control allows for the regulation of thought and action, and interacts with motivational variables, such as reward, to modify behavior adaptively as environments change. We examined the effects of reward on two distinct forms of inhibitory control, cancellation and restraint. Typically developing children and adolescents completed two versions of the stop signal task (cancellation and restraint) under three reward conditions (neutral, low reward, and high reward), where rewards were earned for successful inhibitory control. Rewards improved both cancellation and restraint inhibition, with similar effects of reward on each form of inhibitory control. Rewards did not alter the speed of response execution in either task, suggesting that rewards specifically altered inhibition processes without influencing processes related to response execution. Adolescents were faster and less variable than children when executing and inhibiting their responses. There were similar developmental effects of reward on the speed of inhibitory control, but group differences were found in terms of accuracy of inhibition in the restraint task. These results clarify how reward modulates two different forms of regulatory behavior in children and adolescents. PMID:21744952

Phytochemical composition and antibacterial activity of the essential oils from different parts of sea buckthorn (Hippophae rhamnoides L.).

PubMed

Yue, Xuan-Feng; Shang, Xiao; Zhang, Zhi-Juan; Zhang, Yan-Ni

2017-04-01

Essential oils from the seed, pulp, and leaf of sea buckthorn were obtained with hydrodistillation, and their phytochemical composition was analyzed through gas chromatography-mass spectrometry. Furthermore, the antibacterial activity of the oils was tested on five food-borne bacteria by spectrometry and evaluated in terms of minimum inhibitory concentration. The results indicate that the composition of all essential oils is dominated by free fatty acids, esters, and alkanes. Minimum inhibitory concentration values on each bacterium were obtained for oils from different parts. The oils from different parts exhibited nearly equal inhibitory effect on Staphylococcus aureus. The pulp oil was found to be the most effective for the rest of bacteria tested except Escherichia coli, on which seed oil shows twice the inhibitory effect to that of leaf or pulp oil. Three natural inhibitory examples were found comparable with or even better than the positive control: pulp oil on Bacillus subtilis, and pulp oil and leaf oil on Bacillus coagulans. Copyright © 2016. Published by Elsevier B.V.

Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells.

PubMed

Noyan, Kajsa; Nguyen, Son; Betts, Michael R; Sönnerborg, Anders; Buggert, Marcus

2018-01-01

Human immunodeficiency virus type-1 (HIV-1) elite controllers (ELCs) represent a unique population that control viral replication in the absence of antiretroviral therapy (cART). It is well established that expression of multiple inhibitory receptors on CD8+ T cells is associated with HIV-1 disease progression. However, whether reduced co-expression of inhibitory receptors on CD4+ T cells is linked to natural viral control and slow HIV-1 disease progression remains undefined. Here, we report on the expression pattern of numerous measurable inhibitory receptors, associated with T cell exhaustion (programmed cell death-1, CTLA-4, and TIGIT), on different CD4+ T cell memory populations in ELCs and HIV-infected subjects with or without long-term cART. We found that the co-expression pattern of inhibitory receptors was significantly reduced in ELCs compared with HIV-1 cART-treated and viremic subjects, and similar to healthy controls. Markers associated with T cell exhaustion varied among different memory CD4+ T cell subsets and highest levels were found mainly on transitional memory T cells. CD4+ T cells co-expressing all inhibitory markers were positively correlated to T cell activation (CD38+ HLA-DR+) as well as the transcription factors Helios and FoxP3. Finally, clinical parameters such as CD4 count, HIV-1 viral load, and the CD4/CD8 ratio all showed significant associations with CD4+ T cell exhaustion. We demonstrate that ELCs are able to maintain lower levels of CD4+ T cell exhaustion despite years of ongoing viral replication compared with successfully cART-treated subjects. Our findings suggest that ELCs harbor a "healthy" state of inhibitory receptor expression on CD4+ T cells that might play part in maintenance of their control status.

The inhibitory avoidance discrimination task to investigate accuracy of memory.

PubMed

Atucha, Erika; Roozendaal, Benno

2015-01-01

The present study was aimed at developing a new inhibitory avoidance task, based on training and/or testing rats in multiple contexts, to investigate accuracy of memory. In the first experiment, male Sprague-Dawley rats were given footshock in an inhibitory avoidance apparatus and, 48 h later, retention latencies of each rat were assessed in the training apparatus (Shock box) as well as in a novel, contextually modified, apparatus. Retention latencies in the Shock box were significantly longer than those in the Novel box, indicating accurate memory of the training context. When the noradrenergic stimulant yohimbine (0.3 mg/kg, sc) was administered after the training, 48-h retention latencies in the Shock box, but not Novel box, were increased, indicating that the noradrenergic activation enhanced memory of the training experience without reducing memory accuracy. In the second experiment, rats were trained on an inhibitory avoidance discrimination task: They were first trained in an inhibitory avoidance apparatus without footshock (Non-Shock box), followed 1 min later by footshock training in a contextually modified apparatus (Shock box). Forty-eight-hour retention latencies in the Shock and Non-Shock boxes did not differ from each other but were both significantly longer than those in a Novel box, indicating that rats remembered the two training contexts but did not have episodic-like memory of the association of footshock with the correct training context. When the interval between the two training episodes was increased to 2 min, rats showed accurate memory of the association of footshock with the training context. Yohimbine administered after the training also enhanced rats' ability to remember in which training context they had received actual footshock. These findings indicate that the inhibitory avoidance discrimination task is a novel variant of the well-established inhibitory avoidance task suitable to investigate accuracy of memory.

Inhibitory control and the onset of combustible cigarette, e-cigarette, and hookah use in early adolescence: The moderating role of socioeconomic status.

PubMed

Riggs, Nathaniel R; Pentz, Mary Ann

2016-01-01

The purpose of the study was to test the moderating influence of socioeconomic status (SES) on the associations between inhibitory control and the onset of combustible cigarette, electronic (e-) cigarette, and hookah use in early adolescence. A total of 407 adolescents self-reported nicotine use, inhibitory control, and SES. The hypothesis that inhibitory control would be significantly associated with nicotine use onset (i.e., combustible cigarettes, e-cigarettes, and hookah) only under the condition of low SES was tested. Direct associations were found for inhibitory control on "ever use" of all three nicotine use variables. A moderating effect was also found whereby low inhibitory control was significantly associated with nicotine use onset when participants were from low, but not high, SES families. Findings illustrate one contextual condition under which inhibitory control is associated with early onset of nicotine use.

Study on Medicinal Plant Active Substances Extraction and Antibacterial Activity of Houttuynia Cordata

NASA Astrophysics Data System (ADS)

Yubin, Ji; Junjun, Yang; Miao, Yu; Yue, Cao; Shizhen, Guo; Anna, Qiao

2017-12-01

This study was about the effective component extraction from Houttuynia cordata by steam distillation and antibacterial effect on Escherichia coli, Staphylococcus aureus and Bacillus subtilis. The extraction of Herba Houttuyniae extract of Escherichia coli, Staphylococcus aureus and Bacillus subtilis were certain inhibitory effect of, which inhibitory effect on Staphylococcus aureus the most obvious.

Stimulatory and inhibitory effects of PKC isozymes are mediated by serine/threonine PKC sites of the Cav2.3α1 subunits.

PubMed

Rajagopal, Senthilkumar; Burton, Brittney K; Fields, Blanche L; El, India O; Kamatchi, Ganesan L

2017-05-01

Protein kinase C (PKC) isozymes modulate voltage-gated calcium (Ca v ) currents through Ca v 2.2 and Ca v 2.3 channels by targeting serine/threonine (Ser/Thr) phosphorylation sites of Ca v α 1 subunits. Stimulatory (Thr-422, Ser-2108 and Ser-2132) and inhibitory (Ser-425) sites were identified in the Ca v 2.2α 1 subunits to PKCs βII and ε. In the current study, we investigated if the homologous sites of Ca v 2.3α 1 subunits (stimulatory: Thr-365, Ser-1995 and Ser-2011; inhibitory: Ser-369) behaved in similar manner. Several Ala and Asp mutants were constructed in Ca v 2.3α 1 subunits in such a way that the Ser/Thr sites can be examined in isolation. These mutants or WT Ca v 2.3α 1 along with auxiliary β 1b and α 2 /δ subunits were expressed in Xenopus oocytes and the effects of PKCs βII and ε studied on the barium current (I Ba ). Among these sites, stimulatory Thr-365 and Ser-1995 and inhibitory Ser-369 behaved similar to their homologs in Ca v 2.2α 1 subunits. Furthermore PKCs produced neither stimulation nor inhibition when stimulatory Thr-365 or Ser-1995 and inhibitory Ser-369 were present together. However, the PKCs potentiated the I Ba when two stimulatory sites, Thr-365 and Ser-1995 were present together, thus overcoming the inhibitory effect of Ser-369. Taken together net PKC effect may be the difference between the responses of the stimulatory and inhibitory sites. Copyright © 2017 Elsevier Inc. All rights reserved.

Bilingual Contexts Modulate the Inhibitory Control Network

PubMed Central

Yang, Jing; Ye, Jianqiao; Wang, Ruiming; Zhou, Ke; Wu, Yan Jing

2018-01-01

The present functional magnetic resonance imaging (fMRI) study investigated influences of language contexts on inhibitory control and the underlying neural processes. Thirty Cantonese–Mandarin–English trilingual speakers, who were highly proficient in Cantonese (L1) and Mandarin (L2), and moderately proficient in English (L3), performed a picture-naming task in three dual-language contexts (L1-L2, L2-L3, and L1-L3). After each of the three naming tasks, participants performed a flanker task, measuring contextual effects on the inhibitory control system. Behavioral results showed a typical flanker effect in the L2-L3 and L1-L3 condition, but not in the L1-L2 condition, which indicates contextual facilitation on inhibitory control performance by the L1-L2 context. Whole brain analysis of the fMRI data acquired during the flanker tasks showed more neural activations in the right prefrontal cortex and subcortical areas in the L2-L3 and L1-L3 condition on one hand as compared to the L1-L2 condition on the other hand, suggesting greater involvement of the cognitive control areas when participants were performing the flanker task in L2-L3 and L1-L3 contexts. Effective connectivity analyses displayed a cortical-subcortical-cerebellar circuitry for inhibitory control in the trilinguals. However, contrary to the right-lateralized network in the L1-L2 condition, functional networks for inhibitory control in the L2-L3 and L1-L3 condition are less integrated and more left-lateralized. These findings provide a novel perspective for investigating the interaction between bilingualism (multilingualism) and inhibitory control by demonstrating instant behavioral effects and neural plasticity as a function of changes in global language contexts. PMID:29636713

Bilingual Contexts Modulate the Inhibitory Control Network.

PubMed

Yang, Jing; Ye, Jianqiao; Wang, Ruiming; Zhou, Ke; Wu, Yan Jing

2018-01-01

The present functional magnetic resonance imaging (fMRI) study investigated influences of language contexts on inhibitory control and the underlying neural processes. Thirty Cantonese-Mandarin-English trilingual speakers, who were highly proficient in Cantonese (L1) and Mandarin (L2), and moderately proficient in English (L3), performed a picture-naming task in three dual-language contexts (L1-L2, L2-L3, and L1-L3). After each of the three naming tasks, participants performed a flanker task, measuring contextual effects on the inhibitory control system. Behavioral results showed a typical flanker effect in the L2-L3 and L1-L3 condition, but not in the L1-L2 condition, which indicates contextual facilitation on inhibitory control performance by the L1-L2 context. Whole brain analysis of the fMRI data acquired during the flanker tasks showed more neural activations in the right prefrontal cortex and subcortical areas in the L2-L3 and L1-L3 condition on one hand as compared to the L1-L2 condition on the other hand, suggesting greater involvement of the cognitive control areas when participants were performing the flanker task in L2-L3 and L1-L3 contexts. Effective connectivity analyses displayed a cortical-subcortical-cerebellar circuitry for inhibitory control in the trilinguals. However, contrary to the right-lateralized network in the L1-L2 condition, functional networks for inhibitory control in the L2-L3 and L1-L3 condition are less integrated and more left-lateralized. These findings provide a novel perspective for investigating the interaction between bilingualism (multilingualism) and inhibitory control by demonstrating instant behavioral effects and neural plasticity as a function of changes in global language contexts.

Aging, subjective experience, and cognitive control: dramatic false remembering by older adults.

PubMed

Jacoby, Larry L; Bishara, Anthony J; Hessels, Sandra; Toth, Jeffrey P

2005-05-01

Recent research suggests that older adults are more susceptible to interference effects than are young adults; however, that research has failed to equate differences in original learning. In 4 experiments, the authors show that older adults are more susceptible to interference effects produced by a misleading prime. Even when original learning was equated, older adults were 10 times as likely to falsely remember misleading information and were much less likely to increase their accuracy by opting not to answer under conditions of free responding. The results are well described by a multinomial model that postulates multiple modes of cognitive control. According to that model, older adults are likely to be captured by misleading information, a form of goal neglect or deficit in inhibitory functions. Copyright 2005 APA, all rights reserved.

Anticholinesterase activity of 7-methoxyflavones isolated from Kaempferia parviflora.

PubMed

Sawasdee, Pattara; Sabphon, Chalisa; Sitthiwongwanit, Duangporn; Kokpol, Udom

2009-12-01

The rhizome of Kaempferia parviflora or kra-chai-dum (in Thai) is used traditionally as a folk medicine. The preliminary cholinesterase inhibitory screening of this plant extract exhibited significant acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Thirteen known methoxyflavones (1-13) were isolated and their structures were completely elucidated based on NMR analysis and compared with literature reports. Minor compounds 12-13 were reported for the first time from this species. The cholinesterase inhibitory test results showed that the highest potential inhibitors toward AChE and BChE were 5,7,4'-trimethoxyflavone (6) and 5,7-dimethoxyflavone (7), respectively, with the percentage inhibitory activity varying over 43-85%. The structure-activity relationship study led to the conclusion that compounds bearing 5,7-dimethoxy groups and a free substituent at C-3 had a significant inhibitory effect at a concentration of 0.1 mg/mL, but those bearing a 5-hydroxyl group reduced the inhibitory potency. On the other hand, flavones bearing a 3'- or 5'-methoxy group did not influence the inhibitory effect. Interestingly, 5,7-dimethoxyflavone (7) exhibited strong selectivity for BChE over AChE which may be of great interest to modify as a treatment agent for Alzheimer's disease. Copyright (c) 2009 John Wiley & Sons, Ltd.

Effect of inhibitory feedback on correlated firing of spiking neural network.

PubMed

Xie, Jinli; Wang, Zhijie

2013-08-01

Understanding the properties and mechanisms that generate different forms of correlation is critical for determining their role in cortical processing. Researches on retina, visual cortex, sensory cortex, and computational model have suggested that fast correlation with high temporal precision appears consistent with common input, and correlation on a slow time scale likely involves feedback. Based on feedback spiking neural network model, we investigate the role of inhibitory feedback in shaping correlations on a time scale of 100 ms. Notably, the relationship between the correlation coefficient and inhibitory feedback strength is non-monotonic. Further, computational simulations show how firing rate and oscillatory activity form the basis of the mechanisms underlying this relationship. When the mean firing rate holds unvaried, the correlation coefficient increases monotonically with inhibitory feedback, but the correlation coefficient keeps decreasing when the network has no oscillatory activity. Our findings reveal that two opposing effects of the inhibitory feedback on the firing activity of the network contribute to the non-monotonic relationship between the correlation coefficient and the strength of the inhibitory feedback. The inhibitory feedback affects the correlated firing activity by modulating the intensity and regularity of the spike trains. Finally, the non-monotonic relationship is replicated with varying transmission delay and different spatial network structure, demonstrating the universality of the results.

Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca2+ release

PubMed Central

Lamoral-Theys, Delphine; Wauthoz, Nathalie; Heffeter, Petra; Mathieu, Véronique; Jungwirth, Utte; Lefranc, Florence; Nève, Jean; Dubois, Jacques; Dufrasne, François; Amighi, Karim; Berger, Walter; Gailly, Philippe; Kiss, Robert

2012-01-01

Abstract Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC50in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs. PMID:21810170

The spatial extent of excitatory and inhibitory zones in the receptive field of superficial layer hypercomplex cells

PubMed Central

Sillito, A. M.

1977-01-01

1. An investigation has been made of the extent of inhibitory and excitatory components in the receptive field of superficial layer hypercomplex cells in the cat's striate cortex and the relation of the components to the length preference exhibited by these cells. 2. Maximal responses were produced by an optimal length stimulus moving through a restricted region of the receptive field. The length of this receptive field region was less than the total length of the excitatory zone as mapped with a very short slit. Slits of similar length to the excitatory zone produced a smaller response than an optimal length slit. 3. An increase of slit length so that it passed over receptive field regions either side of the excitatory zone resulted in an elimination of the response. When background discharge levels were increased by the iontophoretic application of D, L-homocysteic acid slits of this length were observed to produce a suppression of the resting discharge as they passed over the receptive field. They did not modify the resting discharge level when it was induced by the iontophoretic application of the GABA antagonist bicuculline. This data is taken to indicate that long slits activate a powerful post-synaptic inhibitory input to the cell. 4. Maximal inhibitory effects were only observed if the testing slit passed over the receptive field centre. That is slits with a gap positioned midway along their length so as to exclude the optimal excitatory response region surprisingly tended to produce excitatory effects rather than the expected inhibitory effects. It appears that simultaneous stimulation of the receptive field centre is a precondition for the inhibitory effect of stimulation of regions either side of the excitatory zone to be activated. 5. It is suggested that the interneurones mediating the inhibitory input to the superficial layer hypercomplex cells are driven both by cells in adjacent hypercolumns with receptive fields spatially displaced to either side of the excitatory zone and by cells in the same column, optimal inhibitory effects only being achieved when both sets of input to the interneurone are activated. PMID:604459

[Inhibition effects of Houttuynia cordata Thunb. on Microcystis aeruginosa].

PubMed

Liu, Lu; Li, Cheng; Xia, Wentong; Yang, Xiaohui; Zhang, Tingting

2014-05-01

To research the inhibitory effect of Houttuynia cordata Thunb. on Microcystis aeruginosa. M. aeruginosat were treated respectively by H. cordata leaching solution or H. cordata extracts. H. cordata leaching solution extracted by water and the H. cordata extracts extracted by organic solvent (acetone, ethyl acetate, petroleum ether and ethanol, respectively). The inhibition ratios were calculated according to the M. aeruginosa densities, and the allelochemicals of the extract that had the best inhibitiory effect on M. aeruginosa were identified by GC-MS analysis. It was proved that leaching solution of H. cordata and four crude extracts had good inhibitory effect on M. aeruginosa. The inhibitory effects of the four crude extracts were the fraction extracted by ethyl acetate, the fraction extracted by ethanol, the fraction extracted by acetone and the fraction extracted by petroleum ether form strong to weak in turn. Then, the allelochemicals of the fraction extracted by ethyl acetate were indentified, mainly including acetonyldimethylcarbinol, 2,2-dimethyl-3-hexanone, 6-chlorohexanoic and 4-cyanophenyl ester. H. cordata has strong inhibitory effect on water-blooming cyanobacteria and the potential to develop into an ecological M. aeruginosa inhibiting agent.

Combat veterans with comorbid PTSD and mild TBI exhibit a greater inhibitory processing ERP from the dorsal anterior cingulate cortex.

PubMed

Shu, I-Wei; Onton, Julie A; O'Connell, Ryan M; Simmons, Alan N; Matthews, Scott C

2014-10-30

Posttraumatic stress disorder (PTSD) is common among combat personnel with mild traumatic brain injury (mTBI). While patients with either PTSD or mTBI share abnormal activation of multiple frontal brain areas, anterior cingulate cortex (ACC) activity during inhibitory processing may be particularly affected by PTSD. To further test this hypothesis, we recorded electroencephalography from 32 combat veterans with mTBI-17 of whom were also comorbid for PTSD (mTBI+PTSD) and 15 without PTSD (mTBI-only). Subjects performed the Stop Task, a validated inhibitory control task requiring inhibition of initiated motor responses. We observed a larger inhibitory processing eventrelated potential (ERP) in veterans with mTBI+PTSD, including greater N200 negativity. Furthermore, greater N200 negativity correlated with greater PTSD severity. This correlation was most dependent on contributions from the dorsal ACC. Support vector machine analysis demonstrated that N200 and P300 amplitudes objectively classified veterans into mTBI-only or mTBI+PTSD groups with 79.4% accuracy. Our results support a model where, in combat veterans with mTBI, larger ERPs from cingulate areas are associated with greater PTSD severity and likely related to difficulty controlling ongoing brain processes, including trauma-related thoughts and feelings. Published by Elsevier Ireland Ltd.

Fast voltage-sensitive dye imaging of excitatory and inhibitory synaptic transmission in the rat granular retrosplenial cortex.

PubMed

Nixima, Ken'ichi; Okanoya, Kazuo; Ichinohe, Noritaka; Kurotani, Tohru

2017-09-01

Rodent granular retrosplenial cortex (GRS) has dense connections between the anterior thalamic nuclei (ATN) and hippocampal formation. GRS superficial pyramidal neurons exhibit distinctive late spiking (LS) firing property and form patchy clusters with prominent apical dendritic bundles. The aim of this study was to investigate spatiotemporal dynamics of signal transduction in the GRS induced by ATN afferent stimulation by using fast voltage-sensitive dye imaging in rat brain slices. In coronal slices, layer 1a stimulation, which presumably activated thalamic fibers, evoked propagation of excitatory synaptic signals from layers 2-4 to layers 5-6 in a direction perpendicular to the layer axis, followed by transverse signal propagation within each layer. In the presence of ionotropic glutamate receptor antagonists, inhibitory responses were observed in superficial layers, induced by direct activation of inhibitory interneurons in layer 1. In horizontal slices, excitatory signals in deep layers propagated transversely mainly from posterior to anterior via superficial layers. Cortical inhibitory responses upon layer 1a stimulation in horizontal slices were weaker than those in the coronal slices. Observed differences between coronal and horizontal planes suggest anisotropy of the intracortical circuitry. In conclusion, ATN inputs are processed differently in coronal and horizontal planes of the GRS and then conveyed to other cortical areas. In both planes, GRS superficial layers play an important role in signal propagation, which suggests that superficial neuronal cascade is crucial in the integration of multiple information sources. NEW & NOTEWORTHY Superficial neurons in the rat granular retrosplenial cortex (GRS) show distinctive late-spiking (LS) firing property. However, little is known about spatiotemporal dynamics of signal transduction in the GRS. We demonstrated LS neuron network relaying thalamic inputs to deep layers and anisotropic distribution of inhibition between coronal and horizontal planes. Since deep layers of the GRS receive inputs from the subiculum, GRS circuits may work as an integrator of multiple sources such as sensory and memory information. Copyright © 2017 the American Physiological Society.

No Retrieval-Induced Forgetting Using Item-Specific Independent Cues: Evidence against a General Inhibitory Account

ERIC Educational Resources Information Center

Camp, Gino; Pecher, Diane; Schmidt, Henk G.

2007-01-01

Retrieval practice with particular items from memory can impair the recall of related items on a later memory test. This retrieval-induced forgetting effect has been ascribed to inhibitory processes (M. C. Anderson & B. A. Spellman, 1995). A critical finding that distinguishes inhibitory from interference explanations is that forgetting is found…

The Effect of Inhibitory Control on General Mathematics Achievement and Fraction Comparison in Middle School Children

ERIC Educational Resources Information Center

Gómez, David Maximiliano; Jiménez, Abelino; Bobadilla, Roberto; Reyes, Cristián; Dartnell, Pablo

2015-01-01

Individual differences in inhibitory control have been shown to relate to general mathematics achievement, but whether this relation varies for specific areas within mathematics is a question that remains open. Here, we evaluate if inhibitory processes play a specific role in the particular case of fraction comparison, where learners must ignore…

Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing.

PubMed

Le Foll, Christelle; Irani, Boman G; Magnan, Christophe; Dunn-Meynell, Ambrose A; Levin, Barry E

2009-09-01

We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca(2+)) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC(50)) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC(50)) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K(+) channel activity or activation of uncoupling protein 2 (UCP2) accounted for only approximately 20% of OA's excitatory effects and approximately 40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such "metabolic sensing" neurons can respond to differences in the metabolic states associated with fasting and feeding.

Antitubercular activity and inhibitory effect on Epstein-Barr virus activation of sterols and polyisoprenepolyols from an edible mushroom, Hypsizigus marmoreus.

PubMed

Akihisa, Toshihiro; Franzblau, Scott Gary; Tokuda, Harukuni; Tagata, Masaaki; Ukiya, Motohiko; Matsuzawa, Tsunetomo; Metori, Koichi; Kimura, Yumiko; Suzuki, Takashi; Yasukawa, Ken

2005-06-01

Seven sterols (1-7) and eight polyisoprenepolyols (8-15), isolated from the non-saponifiable lipid fraction of the dichloromethane extract of an edible mushroom, Hypsizigus marmoreus (Buna-shimeji), were tested for their antitubercular activity against Mycobacterium tuberculosis strain H37Rv using the Microplate Alamar Blue Assay (MABA). Six sterols (2-7) and two polyisoprenepolyols (8, 12) showed a minimum inhibitory concentration (MIC) in the range of 1-51 microg/ml, while the others (1, 9-11, 13-15) were inactive (MIC>128 microg/ml). The seven sterols (1-7) and three polyisoprenepolyols (8, 10, 12) were further evaluated for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Sterols 6 and 7 showed potent inhibitory effects while preserving the high viability of Raji cells.

Influence of baking enzymes on antimicrobial activity of five bacteriocin-like inhibitory substances produced by lactic acid bacteria isolated from Lithuanian sourdoughs.

PubMed

Narbutaite, V; Fernandez, A; Horn, N; Juodeikiene, G; Narbad, A

2008-12-01

To evaluate the effect of four different baking enzymes on the inhibitory activity of five bacteriocin-like inhibitory substances (BLIS) produced by lactic acid bacteria (LAB) isolated from Lithuanian sourdoughs. The overlay assay and the Bioscreen methods revealed that the five BLIS exhibited an inhibitory effect against spore germination and vegetative outgrowth of Bacillus subtilis, the predominant species causing ropiness in bread. The possibility that the observed antibacterial activity of BLIS might be lost after treatment with enzymes used for baking purposes was also examined. The enzymes tested; hemicellulase, lipase, amyloglucosidase and amylase had little or no effect on the majority of the antimicrobial activities associated with the five BLIS studied. This study suggests a potential application in the sourdough baking industry for these antimicrobial producing LAB strains in the control of B. subtilis spore germination and vegetative outgrowth.

Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC.

PubMed

Piddock, Rachel E; Marlein, Christopher R; Abdul-Aziz, Amina; Shafat, Manar S; Auger, Martin J; Bowles, Kristian M; Rushworth, Stuart A

2018-05-16

Multiple myeloma (MM) remains an incurable malignancy despite the recent advancements in its treatment. The protective effects of the niche in which it develops has been well documented; however, little has been done to investigate the MM cell's ability to 're-program' cells within its environment to benefit disease progression. Here, we show that MM-derived macrophage migratory inhibitory factor (MIF) stimulates bone marrow stromal cells to produce the disease critical cytokines IL-6 and IL-8, prior to any cell-cell contact. Furthermore, we provide evidence that this IL-6/8 production is mediated by the transcription factor cMYC. Pharmacological inhibition of cMYC in vivo using JQ1 led to significantly decreased levels of serum IL-6-a highly positive prognostic marker in MM patients. Our presented findings show that MM-derived MIF causes BMSC secretion of IL-6 and IL-8 via BMSC cMYC. Furthermore, we show that the cMYC inhibitor JQ1 can reduce BMSC secreted IL-6 in vivo, irrespective of tumor burden. These data provide evidence for the clinical evaluation of both MIF and cMYC inhibitors in the treatment of MM.

Effect of Aconitum coreanum polysaccharide and its sulphated derivative on the migration of human breast cancer MDA-MB-435s cell.

PubMed

Zhang, Yandong; Wu, Wei; Kang, Lihua; Yu, Dehai; Liu, Chunshui

2017-10-01

Polysaccharides extracted from medicinal plants possess multiple functions. However, the inhibitory capacity of polysaccharides on the metastasis of breast cancer remains unclear. In the present study, we investigated the inhibitory activity of Aconitum coreanum polysaccharide (ACP1) and its sulphated derivative ACP1-s on migratory behaviour of human breast cancer cells MDA-MB-435s and evaluated the underlying molecular mechanism. The data from Transwell assay indicated that ACP1 and ACP1-s caused a significant inhibition of MDA-MB-435s cell migration in vitro. ACP1 and ACP1-s significantly impaired MDA-MB-435s cell migratory behaviour, and the accumulated distance and average velocity of ACP1- and ACP1-s-treated cells were reduced markedly. We also found ACP1 and ACP1-s treatment could affect dynamic remodeling of actin cytoskeleton, and suppress phosphorylation and activation of signalling molecules, attributing to anti-metastatic role of ACP1 and ACP1-s. These findings reveal a novel therapeutic potential of A. coreanum polysaccharide and its sulphated derivative for breast cancer metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural requirements for inhibitory effects of bisphenols on the activity of the sarco/endoplasmic reticulum calcium ATPase

PubMed Central

Woeste, Matthew; Steller, Jeffrey; Hofmann, Emily; Kidd, Taylor; Patel, Rahul; Connolly, Kevin; Jayasinghe, Manori; Paula, Stefan

2013-01-01

Bisphenols (BPs) are a class of small organic compounds with widespread industrial applications. Previous studies have identified several BPs that interfere with the activity of the ion-translocating enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). In order to define the molecular determinants of BP-mediated SERCA inhibition, we conducted enzyme activity assays with rabbit SERCA to determine the inhibitory potencies of 27 commercially available BPs, which were the basis for structure-activity relationships. The most potent BPs inhibited SERCA at low micromolar concentrations and carried at their two phenyl rings multiple non-polar substituents, such as small alkyl groups or halides. Furthermore, the presence of methyl groups or a cyclohexyl group at the central carbon atom connecting the two phenyl moieties correlated with good potencies. For a characterization and visualization of inhibitor/enzyme interactions, molecular docking was performed, which suggested that hydrogen bonding with Asp254 and hydrophobic interactions were the major driving forces for BP binding to SERCA. Calcium imaging studies with a selection of BPs showed that these inhibitors were able to increase intracellular calcium levels in living human cells, a behavior consistent with that of a SERCA inhibitor. PMID:23643898

4-allylanisole as an inhibitor of bark beetle (Coleoptera: Scolytidae) aggregation

Treesearch

Jane L. Hayes; Brian L. Strom

1994-01-01

To assess the extent of inhibitory activity of the host compound 4-allylanisole, we conducted field studies with three scolytid species.These species are geographically widespread and economically important.Trials were completed with Dendroctonus brevicomis LeConte (California), D. ponderosae Hopkins (Oregon), and Ips pini (Say) (Wisconsin) by using multiple-funnel...

INHIBITORY EFFECTS OF VOLATILE ORGANIC COMPOUNDS ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS.

EPA Science Inventory

INHIBITORY EFFECTS OF VOLATILE ORGANIC COMPOUNDS ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS.
A.S. Bale*; P.J. Bushnell; C.A. Meacham; T.J. Shafer
Neurotoxicology Division, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC, USA
Toluene (TOL...

Inhibitory effect of corn silk on skin pigmentation.

PubMed

Choi, Sang Yoon; Lee, Yeonmi; Kim, Sung Soo; Ju, Hyun Min; Baek, Ji Hwoon; Park, Chul-Soo; Lee, Dong-Hyuk

2014-03-03

In this study, the inhibitory effect of corn silk on melanin production was evaluated. This study was performed to investigate the inhibitory effect of corn silk on melanin production in Melan-A cells by measuring melanin production and protein expression. The corn silk extract applied on Melan-A cells at a concentration of 100 ppm decreased melanin production by 37.2% without cytotoxicity. This was a better result than arbutin, a positive whitening agent, which exhibited a 26.8% melanin production inhibitory effect at the same concentration. The corn silk extract did not suppress tyrosinase activity but greatly reduced the expression of tyrosinase in Melan-A cells. In addition, corn silk extract was applied to the human face with hyperpigmentation, and skin color was measured to examine the degree of skin pigment reduction. The application of corn silk extract on faces with hyperpigmentation significantly reduced skin pigmentation without abnormal reactions. Based on the results above, corn silk has good prospects for use as a material for suppressing skin pigmentation.

Inhibitory Effect of Waste Glass Powder on ASR Expansion Induced by Waste Glass Aggregate

PubMed Central

Liu, Shuhua; Wang, Shu; Tang, Wan; Hu, Ningning; Wei, Jianpeng

2015-01-01

Detailed research is carried out to ascertain the inhibitory effect of waste glass powder (WGP) on alkali-silica reaction (ASR) expansion induced by waste glass aggregate in this paper. The alkali reactivity of waste glass aggregate is examined by two methods in accordance with the China Test Code SL352-2006. The potential of WGP to control the ASR expansion is determined in terms of mean diameter, specific surface area, content of WGP and curing temperature. Two mathematical models are developed to estimate the inhibitory efficiency of WGP. These studies show that there is ASR risk with an ASR expansion rate over 0.2% when the sand contains more than 30% glass aggregate. However, WGP can effectively control the ASR expansion and inhibit the expansion rate induced by the glass aggregate to be under 0.1%. The two mathematical models have good simulation results, which can be used to evaluate the inhibitory effect of WGP on ASR risk. PMID:28793603

Propofol inhibits carbachol-induced chloride secretion by directly targeting the basolateral K+ channel in rat ileum epithelium.

PubMed

Tang, S-H; Wang, H-Y; Sun, H; An, N; Xiao, L; Sun, Q; Zhao, D-B

2017-02-01

Propofol is a widely used intravenous general anesthetic. Acetylcholine (ACh) is critical in controlling epithelial ion transport. This study was to investigate the effects of propofol on ACh-evoked secretion in rat ileum epithelium. The Ussing chamber technique was used to investigate the effects of propofol on carbachol (CCh)-evoked short-circuit currents (Isc). Propofol (10 -2 -10 -6  mol/L) attenuated CCh-evoked Isc of rat ileum mucosa in a dose-dependent manner. The inhibitory effect of propofol was only evident after application to the serosal side. Pretreatment with tetrodotoxin (TTX, 0.3 μmol/L, n=5) had no effect on propofol-induced inhibitory effect, whereas serosal application of K + channel inhibitor, glibenclamide, but not, an ATP-sensitive K + channel inhibitor, largely reduced the inhibitory effect of propofol. In addition, pretreatment with either hexamethonium bromide (HB, nicotinic nACh receptor antagonist) or Cl - channel blockers niflumic acid and cystic fibrosis transmembrane conductance regulator (inh)-172 did not produce any effect on the propofol-induced inhibitory effect. Propofol inhibits CCh-induced intestinal secretion by directly targeting basolateral K + channels. © 2016 John Wiley & Sons Ltd.

Antibacterial effect of mango (Mangifera indica Linn.) leaf extract against antibiotic sensitive and multi-drug resistant Salmonella typhi.

PubMed

Hannan, Abdul; Asghar, Samra; Naeem, Tahir; Ikram Ullah, Muhammad; Ahmed, Ijaz; Aneela, Syeda; Hussain, Shabbir

2013-07-01

Alternative herbal medicine has been used to treat various infections from centuries. Natural plants contain phytoconstituents having similar chemical properties as of synthetic antibiotics. Typhoid fever is a serious infection and failure of its treatment emerged multi-drug resistant (MDR) bugs of Salmonella typhi. Due to multiple and repeated issues with antibiotics efficacy, it became essential to evaluate biological properties of plants from different geographical origins. Mango leaves have been Reported for various medicinal effects like antioxidant, antimicrobial, antihelminthic, antidiabetic and antiallergic etc. Objective of present study was to investigate anti-typhoid properties of acetone mango leaf extract (AMLE) against antibiotic sensitive and MDR S. typhi isolates. A total of 50 isolates of S. typhi including MDR (n=30) and antibiotic sensitive (n=20) were investigated. Staphylococcus aureus (ATCC 25923) and Salmonella typhimurium (ATCC14028) were used as quality control strains. AMLE was prepared and its antibacterial activity was evaluated by agar well diffusion screening method and minimum inhibitory concentration (MIC), by agar dilution technique. Zone of inhibition (mm) of AMLE against MDR and antibiotic sensitive isolates was 18±1.5mm (Mean±S.D). Zone of S. aureus (ATCC 25923) and S. typhimurium (ATCC14028) was 20±1.5mm (Mean±S.D). MIC of AMLE was Reported in range from 10-50 mg/ml. The present study described the inhibitory effects of mango leaves against S. typhi.

Musical training, bilingualism, and executive function: working memory and inhibitory control.

PubMed

D'Souza, Annalise A; Moradzadeh, Linda; Wiseheart, Melody

2018-01-01

The current study investigated whether long-term experience in music or a second language is associated with enhanced cognitive functioning. Early studies suggested the possibility of a cognitive advantage from musical training and bilingualism but have failed to be replicated by recent findings. Further, each form of expertise has been independently investigated leaving it unclear whether any benefits are specifically caused by each skill or are a result of skill learning in general. To assess whether cognitive benefits from training exist, and how unique they are to each training domain, the current study compared musicians and bilinguals to each other, plus to individuals who had expertise in both skills, or neither. Young adults ( n = 153) were categorized into one of four groups: monolingual musician; bilingual musician; bilingual non-musician; and monolingual non-musician. Multiple tasks per cognitive ability were used to examine the coherency of any training effects. Results revealed that musically trained individuals, but not bilinguals, had enhanced working memory. Neither skill had enhanced inhibitory control. The findings confirm previous associations between musicians and improved cognition and extend existing evidence to show that benefits are narrower than expected but can be uniquely attributed to music compared to another specialized auditory skill domain. The null bilingual effect despite a music effect in the same group of individuals challenges the proposition that young adults are at a performance ceiling and adds to increasing evidence on the lack of a bilingual advantage on cognition.

Eye Gaze and Aging: Selective and Combined Effects of Working Memory and Inhibitory Control.

PubMed

Crawford, Trevor J; Smith, Eleanor S; Berry, Donna M

2017-01-01

Eye-tracking is increasingly studied as a cognitive and biological marker for the early signs of neuropsychological and psychiatric disorders. However, in order to make further progress, a more comprehensive understanding of the age-related effects on eye-tracking is essential. The antisaccade task requires participants to make saccadic eye movements away from a prepotent stimulus. Speculation on the cause of the observed age-related differences in the antisaccade task largely centers around two sources of cognitive dysfunction: inhibitory control (IC) and working memory (WM). The IC account views cognitive slowing and task errors as a direct result of the decline of inhibitory cognitive mechanisms. An alternative theory considers that a deterioration of WM is the cause of these age-related effects on behavior. The current study assessed IC and WM processes underpinning saccadic eye movements in young and older participants. This was achieved with three experimental conditions that systematically varied the extent to which WM and IC were taxed in the antisaccade task: a memory-guided task was used to explore the effect of increasing the WM load; a Go/No-Go task was used to explore the effect of increasing the inhibitory load; a 'standard' antisaccade task retained the standard WM and inhibitory loads. Saccadic eye movements were also examined in a control condition: the standard prosaccade task where the load of WM and IC were minimal or absent. Saccade latencies, error rates and the spatial accuracy of saccades of older participants were compared to the same measures in healthy young controls across the conditions. The results revealed that aging is associated with changes in both IC and WM. Increasing the inhibitory load was associated with increased reaction times in the older group, while the increased WM load and the inhibitory load contributed to an increase in the antisaccade errors. These results reveal that aging is associated with changes in both IC and WM.

Effects of Neuromodulation on Excitatory-Inhibitory Neural Network Dynamics Depend on Network Connectivity Structure

NASA Astrophysics Data System (ADS)

Rich, Scott; Zochowski, Michal; Booth, Victoria

2018-01-01

Acetylcholine (ACh), one of the brain's most potent neuromodulators, can affect intrinsic neuron properties through blockade of an M-type potassium current. The effect of ACh on excitatory and inhibitory cells with this potassium channel modulates their membrane excitability, which in turn affects their tendency to synchronize in networks. Here, we study the resulting changes in dynamics in networks with inter-connected excitatory and inhibitory populations (E-I networks), which are ubiquitous in the brain. Utilizing biophysical models of E-I networks, we analyze how the network connectivity structure in terms of synaptic connectivity alters the influence of ACh on the generation of synchronous excitatory bursting. We investigate networks containing all combinations of excitatory and inhibitory cells with high (Type I properties) or low (Type II properties) modulatory tone. To vary network connectivity structure, we focus on the effects of the strengths of inter-connections between excitatory and inhibitory cells (E-I synapses and I-E synapses), and the strengths of intra-connections among excitatory cells (E-E synapses) and among inhibitory cells (I-I synapses). We show that the presence of ACh may or may not affect the generation of network synchrony depending on the network connectivity. Specifically, strong network inter-connectivity induces synchronous excitatory bursting regardless of the cellular propensity for synchronization, which aligns with predictions of the PING model. However, when a network's intra-connectivity dominates its inter-connectivity, the propensity for synchrony of either inhibitory or excitatory cells can determine the generation of network-wide bursting.

Inhibitory activities of the alkaloids from Coptidis Rhizoma against aldose reductase.

PubMed

Jung, Hyun Ah; Yoon, Na Young; Bae, Hyun Ju; Min, Byung-Sun; Choi, Jae Sue

2008-11-01

As part of our ongoing search of natural sources for therapeutic and preventive agents for diabetic complications, the rat lens aldose reductase (RLAR) inhibitory effect of Coptidis Rhizoma (the rhizome of Coptis chinensis Franch) was evaluated. Its extract and fractions exhibited broad and moderate RLAR inhibitory activities of 38.9 approximately 67.5 microg/mL. In an attempt to identify bioactive components, six quaternary protoberberine-type alkaloids (berberine, palmatine, jateorrhizine, epiberberine, coptisine, and groenlandicine) and one quaternary aporphine-type alkaloid (magnoflorine) were isolated from the most active n-BuOH fraction, and the chemical structures therein were elucidated on the basis of spectroscopic evidence and comparison with published data. The anti-diabetic complications capacities of seven C. chinensis-derived alkaloids were evaluated via RLAR and human recombinant AR (HRAR) inhibitory assays. Although berberine and palmatine were previously reported as prime contributors to AR inhibition, these two major components exhibited no AR inhibitory effects at a higher concentration of 50 microg/ml in the present study. Conversely, epiberberine, coptisine, and groenlandicine exhibited moderate inhibitory effects with IC(50) values of 100.1, 118.4, 140.1 microM for RLAR and 168.1, 187.3, 154.2 microM for HRAR. The results clearly indicated that the presence of the dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring were partly responsible for the AR inhibitory activities of protoberberine-type alkaloids. Therefore, Coptidis Rhizoma, and the alkaloids contained therein, would clearly have beneficial uses in the development of therapeutic and preventive agents for diabetic complications and diabetes mellitus.

Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM)

PubMed Central

Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L.; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

2016-01-01

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment. PMID:27706074

Cue response dissociates inhibitory processes: task identity information is related to backward inhibition but not to competitor rule suppression.

PubMed

Regev, Shirley; Meiran, Nachshon

2017-01-01

In task switching, a conflict between competing task-sets is resolved by inhibiting the interfering task-set. Recent models have proposed a framework of the task-set as composed of two hierarchical components: abstract task identity (e.g., respond to quantity) and more concrete task rules (e.g., category-response rules mapping the categories "one" and "three" to the left and right keys, respectively). The present study explored whether task-set inhibition is the outcome of a general control process or whether it reflects multiple inhibitory processes, each targeting a different component of the competing task-set. To this end, two effects of task-set inhibition were examined: backward inhibition (BI), reflecting the suppression of a just-performed task-set that is no longer relevant; and, competitor rule suppression (CRS), reflecting the suppression of an irrelevant task-set that generates a response conflict. In two task switching experiments, each involving three tasks, we asked participants to make two responses: a cue response, indicating the identity of the relevant task (e.g., "Color"), and a target response requiring the implementation of the task rule (e.g., "Red"). The results demonstrate that BI, but not CRS, appears in cue responses, and thus, suggests that BI reflects inhibition that influences representations related to abstract task identity, rather than (just) competing responses or response rules. These results support a dissociation between inhibitory processes in task switching. The current findings also provide further evidence for a multi-component conceptualization of task-set and task-set inhibition.

Acute fasting increases somatodendritic dopamine release in the ventral tegmental area

PubMed Central

2015-01-01

Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. PMID:26084913

Aging and inhibitory control of action: cortico-subthalamic connection strength predicts stopping performance.

PubMed

Coxon, James P; Van Impe, Annouchka; Wenderoth, Nicole; Swinnen, Stephan P

2012-06-13

Diffusion weighted imaging (DWI) studies in humans have shown that seniors exhibit reduced white matter integrity compared with young adults, with the most pronounced change occurring in frontal white matter. It is generally assumed that this structural deterioration underlies inhibitory control deficits in old age, but specific evidence from a structural neuroscience perspective is lacking. Cognitive action control is thought to rely on an interconnected network consisting of right inferior frontal cortex (r-IFC), pre-supplementary motor area (preSMA), and the subthalamic nucleus (STN). Here we performed probabilistic DWI tractography to delineate this cognitive control network and had the same individuals (20 young, 20 older adults) perform a task probing both response inhibition and action reprogramming. We hypothesized that structural integrity (fractional anisotropy) and connection strength within this network would be predictive of individual and age-related differences in task performance. We show that the integrity of r-IFC white matter is an age-independent predictor of stop-signal reaction time (SSRT). We further provide evidence that the integrity of white matter projecting to STN predicts both outright stopping (SSRT) and transient braking of response initiation to buy time for action reprogramming (stopping interference effects). These associations remain even after controlling for Go task performance, demonstrating specificity to the Stop component of this task. Finally, a multiple regression analysis reveals bilateral preSMA-STN tract strength as a significant predictor of SSRT in older adults. Our data link age-related decline in inhibitory control with structural decline of STN projections.

In vivo evidence for the involvement of tachykinin NK3 receptors in the hexamethonium-resistant inhibitory transmission in the rat colon.

PubMed

Lecci, A; Giuliani, S; Tramontana, M; Meini, S; De Giorgio, R; Maggi, C A

1996-05-01

In urethane-anaesthetized rats, moderate colonic distention (0.5 ml) induced reflex rhythmic contractions (5 mm Hg amplitude and 1.1 cycles/min frequency). Senktide (1-10 nmol/kg, i.v.), a tachykinin NK3 receptor selective agonist, transiently suppressed distension-induced contractions. SR 142,801 (1-10 mumol/kg i.v.), a non-peptide tachykinin NK3 receptor antagonist, had no effect on distension-induced contractions but prevented the inhibitory effect of senktide. Infusion of N-omega-nitro-1-arginine methyl esther hydrochloride (L-NAME, 20 mumol/ml/h, i.v) increased the amplitude of colonic contractions and decreased the inhibitory effect of senktide. Hexamethonium (15 mumol/ml/h, i.v.) or atropine (1 mumol/ml/h, i.v.) inhibited the distension-induced contractions. In hexamethonium- or atropine-treated rats, senktide (10 nmol/kg) transiently and selectively enhanced the amplitude of contractions. Also SR 142,801 (10 mumol/kg), but not its inactive enantiomer SR 142,806, increased both amplitude and frequency of contractions. During continuous infusion of L-NAME and hexamethonium or atropine both frequency and amplitude of distension-induced colonic contractions were higher than when in hexamethonium or atropine only. Senktide (10 nmol/kg) had no effect and SR 142,801 (10 mumol/kg) produced a slight enhancement of colonic contractions. Infusion of sodium nitroprusside (3 mumol/ml/h, i.v.) decreased amplitude and frequency of distension-induced contractions. SR 142,801 had no effect in the presence of the nitric oxide (NO) donor. We conclude that tachykinins acting through NK3 receptors exert at least four different actions on colonic motility activated by distension: 1) a hexamethonium-resistant, NO-dependent, suppressant effect on contractions; 2) a hexamethonium-sensitive, NO-independent inhibitory effect on the amplitude of contractions; 3) a hexamethonium-resistant, NO-independent inhibitory effect on the amplitude of contractions and 4) a hexamethonium resistant and L-NAME-sensitive excitatory effect on amplitude of contractions. The prevalent inhibitory effect evoked in normal conditions along with the excitatory activity induced by SR 142,801 on hexamethonium-resistant colonic motility indicates that tachykinins, acting through neuronal NK3 receptors, activate NO-dependent and NO-independent inhibitory neurotransmission in the rat colon.

Pituitary adenylate cyclase-activating polypeptide is a potent inhibitor of the growth of light chain-secreting human multiple myeloma cells.

PubMed

Li, Min; Cortez, Shirley; Nakamachi, Tomoya; Batuman, Vecihi; Arimura, Akira

2006-09-01

Multiple myeloma represents a malignant proliferation of plasma cells in the bone marrow, which often overproduces immunoglobulin light chains. We have shown previously that pituitary adenylate cyclase-activating polypeptide (PACAP) markedly suppresses the release of proinflammatory cytokines from light chain-stimulated human renal proximal tubule epithelial cells and prevents the resulting tubule cell injury. In this study, we have shown that PACAP suppresses the proliferation of human kappa and lambda light chain-secreting multiple myeloma-derived cells. The addition of PACAP suppressed light chain-producing myeloma cell-stimulated interleukin 6 (IL-6) secretion by the bone marrow stromal cells (BMSCs). A specific antagonist to either the human PACAP-specific receptor or the vasoactive intestinal peptide receptor attenuated the suppressive effect of PACAP on IL-6 production in the adhesion of human multiple myeloma cells to BMSCs. The secretion of IL-6 by BMSCs was completely inhibited by 10(-9) mol/L PACAP, which also attenuated the phosphorylation of both p42/44 and p38 mitogen-activated protein kinases (MAPK) as well as nuclear factor-kappaB (NF-kappaB) activation in response to the adhesion of multiple myeloma cells to BMSCs, whereas the inhibition of p42/44 MAPK signaling attenuated PACAP action. The signaling cascades involved in the inhibitory effect of PACAP on IL-6-mediated paracrine stimulation of light chain-secreting myeloma cell growth was mediated through the suppression of p38 MAPK as well as modulation of activation of transcription factor NF-kappaB. These findings suggest that PACAP may be a new antitumor agent that directly suppresses light chain-secreting myeloma cell growth and indirectly affects tumor cell growth by modifying the bone marrow milieu of the multiple myeloma.

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

PubMed Central

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50–555 nmol/ear. PMID:24734106

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis.

PubMed

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50-555 nmol/ear.

GMP reverses the facilitatory effect of glutamate on inhibitory avoidance task in rats.

PubMed

Rubin, M A; Jurach, A; da Costa Júnior, E M; Lima, T T; Jiménez-Bernal, R E; Begnini, J; Souza, D O; de Mello, C F

1996-09-02

Previous studies have demonstrated that post-training intrahippocampal glutamate administration improves inhibitory avoidance task performance in rats. Antagonism of the agonist actions of glutamate by guanine nucleotides has been shown at the molecular and behavioural level. In the present investigation we demonstrate that intrahippocampal co-administration of GMP (guanosine 5'-monophosphate) reverses the facilitatory effect of glutamate on the inhibitory avoidance learning paradigm and inhibits [3H]glutamate binding in hippocampal synaptic plasma membranes. These results suggest that guanine nucleotides may modulate glutamate actions.

Short communication: Effect of casein haplotype on angiotensin-converting enzyme inhibitory and antioxidant capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes.

PubMed

Perna, Annamaria; Simonetti, Amalia; Gambacorta, Emilio

2016-09-01

The aim of this work was to investigate the effect of casein haplotype (αS1, β, and κ) on antioxidative and angiotensin-converting enzyme (ACE) inhibitory capacities of milk casein from Italian Holstein cows before and following in vitro digestion with gastrointestinal enzymes. The antioxidant capacity was measured using 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid and ferric-reducing antioxidant power assays, whereas ACE inhibition was determined by ACE-inhibitory assay. The ACE-inhibitory and antioxidant capacities of milk casein increased during in vitro gastrointestinal digestion. Casein haplotype significantly influenced the antioxidative and ACE-inhibitory capacities of digested casein. In particular, BB-A(2)A(1)-AA casein and BB-A(1)A(1)-AA casein showed the highest ACE-inhibitory capacity, BB-A(2)A(2)-AA casein showed the highest antioxidant capacity, whereas BB-A(2)A(2)-BB casein showed the lowest biological capacity. To date, few studies have been done on the effect of casein haplotype on biological capacity of milk casein, thus the present study sets the basis for a new knowledge that could lead to the production of milk with better nutraceutical properties. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Comparison of the acute effects of high-intensity interval training and continuous aerobic walking on inhibitory control.

PubMed

Kao, Shih-Chun; Westfall, Daniel R; Soneson, Jack; Gurd, Brendon; Hillman, Charles H

2017-09-01

The purpose of this study was to investigate the effects of a single bout of high-intensity interval training (HIIT) and continuous aerobic exercise (CAE) on inhibitory control. The P3 component of the stimulus-locked ERP was collected in 64 young adults during a modified flanker task following 20 min of seated rest, 20 min of CAE, and 9 min of HIIT on separate days in counterbalanced order. Participants exhibited shorter overall reaction time following CAE and HIIT compared to seated rest. Response accuracy improved following HIIT in the task condition requiring greater inhibitory control compared to seated rest and CAE. P3 amplitude was larger following CAE compared to seated rest and HIIT. Decreased P3 amplitude and latency were observed following HIIT compared to seated rest. The current results replicated previous findings indicating the beneficial effect of acute CAE on behavioral and neuroelectric indices of inhibitory control. With a smaller duration and volume of exercise, a single bout of HIIT resulted in additional improvements in inhibitory control, paralleled by a smaller and more efficient P3 component. In sum, the current study demonstrated that CAE and HIIT differentially facilitate inhibitory control and its underlying neuroelectric activation, and that HIIT may be a time-efficient approach for enhancing cognitive health. © 2017 Society for Psychophysiological Research.

Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

PubMed

Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

2018-01-01

Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Curcumin, an antibiotic resistance breaker against a multiresistant clinical isolate of Mycobacterium abscessus.

PubMed

Marini, Emanuela; Di Giulio, Mara; Magi, Gloria; Di Lodovico, Silvia; Cimarelli, Maria Enrica; Brenciani, Andrea; Nostro, Antonia; Cellini, Luigina; Facinelli, Bruna

2018-03-01

Curcumin, a phenolic compound extracted from Curcuma longa, exerts multiple pharmacological effects, including an antimicrobial action. Mycobacterium abscessus, an environmental, nontuberculous, rapidly growing mycobacterium, is an emerging human pathogen causing serious lung infections and one of the most difficult to treat, due to its multidrug resistance and biofilm-forming ability. We wanted to evaluate the antimicrobial and antivirulence activity of curcumin and its ability to synergize with antibiotics against a clinical M. abscessus strain (29904), isolated from the bronchoaspirate of a 66-year-old woman admitted to hospital for suspected tuberculosis. Curcumin [minimum inhibitory concentrations (MIC) = 128 mg/L] was synergic (fractional inhibitory concentration index ≤0.5) with amikacin, clarithromycin, ciprofloxacin, and linezolid, to which strain 29904 showed resistance/intermediate susceptibility. Curcumin at 1/8 × MIC significantly reduced motility, whereas at 4 × MIC, it completely inhibited 4- and 8-day mature biofilms. Synergistic combinations of curcumin and amikacin induced a general reduction in microbial aggregates and substantial loss in cell viability. Disruption of 4- and 8-day biofilms was the main effect detected when curcumin was the predominant compound. The present findings support previous evidence that curcumin is a potential antibiotic resistance breaker. Curcumin, either alone or combined with antibiotics, could provide a novel strategy to combat antibiotic resistance and virulence of M. abscessus. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacological characterization of [trans-5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate (JTT-553), a novel acyl CoA:diacylglycerol transferase (DGAT) 1 inhibitor.

PubMed

Tomimoto, Daisuke; Okuma, Chihiro; Ishii, Yukihito; Akiyama, Yoshiyuki; Ohta, Takeshi; Kakutani, Makoto; Ohkuma, Yoshiaki; Ogawa, Nobuya

2015-01-01

Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the final step in triglyceride (TG) synthesis. This enzyme is considered to be a potential therapeutic target for obesity and diabetes. Here, results of an investigation of the pharmacological effects of JTT-553 [trans-5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate, a novel DGAT1 inhibitor, are reported. To measure the inhibitory activity of JTT-553 against DGAT1, TG synthesis using [(14)C]-labeled oleoyl-CoA was evaluated. Similarly, the inhibitory activity of JTT-553 against DGAT2, an isozyme of DGAT1, and acyl-CoA cholesterol acyltransferase (ACAT) 1, which is highly homologous to DGAT1, were evaluated. JTT-553 selectively inhibited human DGAT1 and showed comparable inhibitory effects on the activity of human, rat, and mouse DGAT. In vivo, JTT-553 suppressed plasma TG and chylomicron TG levels after olive oil loading in Sprague-Dawley (SD) rats. JTT-553 also inhibited TG synthesis in epididymal fat after [(14)C] oleic acid injection in C57BL/6J mice. Food intake was evaluated in SD rats fed 3.1%, 13%, or 35% (w/w) fat diets. In rats fed the 35% fat diet, JTT-553 reduced food intake. This reduction of food intake was observed 2 h after feeding, lasted for 24 h, and correlated with dietary fat content. Furthermore, JTT-553 reduced daily food intake and body weight gain in diet-induced obese rats after 4-week repeated administration. JTT-553 exerted multiple effects on intestinal fat absorption, adipose fat synthesis, and food intake, and consequently induced body weight reduction. Therefore, JTT-553 is expected to be an effective novel therapeutic agent for the treatment of obesity.

Dynamics of excitatory and inhibitory networks are differentially altered by selective attention.

PubMed

Snyder, Adam C; Morais, Michael J; Smith, Matthew A

2016-10-01

Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. Copyright © 2016 the American Physiological Society.

Dynamics of excitatory and inhibitory networks are differentially altered by selective attention

PubMed Central

Snyder, Adam C.; Morais, Michael J.

2016-01-01

Inhibition and excitation form two fundamental modes of neuronal interaction, yet we understand relatively little about their distinct roles in service of perceptual and cognitive processes. We developed a multidimensional waveform analysis to identify fast-spiking (putative inhibitory) and regular-spiking (putative excitatory) neurons in vivo and used this method to analyze how attention affects these two cell classes in visual area V4 of the extrastriate cortex of rhesus macaques. We found that putative inhibitory neurons had both greater increases in firing rate and decreases in correlated variability with attention compared with putative excitatory neurons. Moreover, the time course of attention effects for putative inhibitory neurons more closely tracked the temporal statistics of target probability in our task. Finally, the session-to-session variability in a behavioral measure of attention covaried with the magnitude of this effect. Together, these results suggest that selective targeting of inhibitory neurons and networks is a critical mechanism for attentional modulation. PMID:27466133

Effect of inhibitory firing pattern on coherence resonance in random neural networks

NASA Astrophysics Data System (ADS)

Yu, Haitao; Zhang, Lianghao; Guo, Xinmeng; Wang, Jiang; Cao, Yibin; Liu, Jing

2018-01-01

The effect of inhibitory firing patterns on coherence resonance (CR) in random neuronal network is systematically studied. Spiking and bursting are two main types of firing pattern considered in this work. Numerical results show that, irrespective of the inhibitory firing patterns, the regularity of network is maximized by an optimal intensity of external noise, indicating the occurrence of coherence resonance. Moreover, the firing pattern of inhibitory neuron indeed has a significant influence on coherence resonance, but the efficacy is determined by network property. In the network with strong coupling strength but weak inhibition, bursting neurons largely increase the amplitude of resonance, while they can decrease the noise intensity that induced coherence resonance within the neural system of strong inhibition. Different temporal windows of inhibition induced by different inhibitory neurons may account for the above observations. The network structure also plays a constructive role in the coherence resonance. There exists an optimal network topology to maximize the regularity of the neural systems.

Improvement of ACE inhibitory activity of casein hydrolysate by Maillard reaction with xylose.

PubMed

Hong, Xu; Meng, Jun; Lu, Rong-Rong

2015-01-01

The Maillard reaction is widely used to improve the functional properties or biological activities of food. The purpose of this study was to investigate the effect of the Maillard reaction on angiotensin I converting enzyme (ACE) inhibitory activity in a casein hydrolysate-xylose system. Two-step hydrolysis was used to prepare casein ACE inhibitory peptides. Maillard reaction products (MRPs) were prepared by heating hydrolyzed casein with xylose at pH 8.0, 110 °C for up to 16 h. The results showed that the content of free amino group decreased (P < 0.05); however, browning intensity and absorbance at 294 nm increased because of the Maillard reaction (P < 0.05). The ACE inhibitory activity improved greatly within 2 h (from 63.48% to 90.23%), which was mainly due to carbonyl ammonia condensation reaction in the MRPs. The study shows that the Maillard reaction under appropriate conditions can improve the ACE inhibitory activity of casein hydrolysate effectively. © 2014 Society of Chemical Industry.

Structural Basis for the Effective Myostatin Inhibition of the Mouse Myostatin Prodomain-Derived Minimum Peptide.

PubMed

Asari, Tomo; Takayama, Kentaro; Nakamura, Akari; Shimada, Takahiro; Taguchi, Akihiro; Hayashi, Yoshio

2017-01-12

Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent-specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue. Subsequently, we designed five Pro-substituted peptides and examined the relationship between secondary structure and inhibitory activity. As a result, we found that Pro-substitutions of Ala or Gln residues around the center of 1 significantly decreased both α-helicity and inhibitory activity. These results suggested that an α-helical structure possessing hydrophobic faces formed around the C-terminus is important for inhibitory activity.

Potent Inhibitory Effect of Chinese Dietary Spices on Fatty Acid Synthase.

PubMed

Jiang, Bing; Liang, Yan; Sun, Xuebing; Liu, Xiaoxin; Tian, Weixi; Ma, Xiaofeng

2015-09-01

Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC(50)) values ranging from 1.72 to 810.7 μg/ml. Among them, seven spices showed strong inhibitory effect with IC(50) values lower than 10 μg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases.

Associative plasticity in intracortical inhibitory circuits in human motor cortex.

PubMed

Russmann, Heike; Lamy, Jean-Charles; Shamim, Ejaz A; Meunier, Sabine; Hallett, Mark

2009-06-01

Paired associative stimulation (PAS) is a transcranial magnetic stimulation technique inducing Hebbian-like synaptic plasticity in the human motor cortex (M1). PAS is produced by repetitive pairing of a peripheral nerve shock and a transcranial magnetic stimulus (TMS). Its effect is assessed by a change in size of a motor evoked response (MEP). MEP size results from excitatory and inhibitory influences exerted on cortical pyramidal cells, but no robust effects on inhibitory networks have been demonstrated so far. In 38 healthy volunteers, we assessed whether a PAS intervention influences three intracortical inhibitory circuits: short (SICI) and long (LICI) intracortical inhibitions reflecting activity of GABA(A) and GABA(B) interneurons, respectively, and long afferent inhibition (LAI) reflecting activity of somatosensory inputs. After PAS, MEP sizes, LICI and LAI levels were significantly changed while changes of SICI were inconsistent. The changes in LICI and LAI lasted 45 min after PAS. Their direction depended on the delay between the arrival time of the afferent volley at the cortex and the TMS-induced cortical activation during the PAS. PAS influences inhibitory circuits in M1. PAS paradigms can demonstrate Hebbian-like plasticity at selected inhibitory networks as well as excitatory networks.

Inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism.

PubMed

Zhang, Xia; Chen, Yingping; Zhang, Ting; Zhang, Yaming

2015-03-01

Da Huang (Radix et Rhizoma Rhei) is the dried root or rhizome of Rheum palmatum L., Rheum tanguticum Maxim ex Balf. or Rheum officinale Braill of family Polygonaceae. It has heat clearing, damp drying, fire purging and toxin removing effects. Because of its definite curative efficacy, it has been widely applied in clinical settings. To study the inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism. MTT assay, flow cytometry and electron microscopy were used to investigate the inhibitory effect of different concentrations of emodin on human hepatoma cell line SMMC-7721. 12 h, 24 h and 48 h after the action of 20, 40 and 80 umol/L emodin on SMMC-7721 cells, the proliferation of human hepatoma SMMC-7721 cells was inhibited; the inhibitory effects showed time-and concentration-dependence. 48 h after the action of different concentrations of emodin on SMMC-7721 cells, cells in G2/M phase increased significantly, while the proportion of S phase cells gradually declined. Emodin can inhibit human hepatoma cell line SMMC-7721.

Inhibitory effect of strychnine on acetylcholine receptor activation in bovine adrenal medullary chromaffin cells.

PubMed Central

Kuijpers, G A; Vergara, L A; Calvo, S; Yadid, G

1994-01-01

1. Strychnine, which is known as a potent and selective antagonist of the inhibitory glycine receptor in the central nervous system, inhibits the nicotinic stimulation of catecholamine release from bovine cultured adrenal chromaffin cells in a concentration-dependent (1-100 microM) manner. At 10 microM nicotine, the IC50 value for strychnine is approximately 30 microM. Strychnine also inhibits the nicotine-induced membrane depolarization and increase in intracellular Ca2+ concentration. 2. The inhibitory action of strychnine is reversible and is selective for nicotinic stimulation, with no effect observed on secretion elicited by a high external K+ concentration, histamine or angiotensin II. 3. Strychnine competes with nicotine in its effect, but not modify the apparent positive cooperatively of the nicotine binding sites. In the absence of nicotine, strychnine has no effect on catecholamine release. Glycine does not affect catecholamine release nor the inhibitory action of strychnine on this release. 4. These results suggest that strychnine interacts with the agonist binding site of the nicotinic acetylcholine receptor in chromaffin cells, thus exerting a pharmacological effect independently of the glycine receptor. PMID:7834198

In vitro inhibitory effects of pulvinic acid derivatives isolated from Chinese edible mushrooms, Boletus calopus and Suillus bovinus, on cytochrome P450 activity.

PubMed

Huang, Yu-Ting; Onose, Jun-ichi; Abe, Naoki; Yoshikawa, Kunie

2009-04-23

Increasing attention has been focused on food-drug interactions. We have investigated the inhibitory effect of Chinese edible mushrooms, Boletus calopus and Suillus bovinus, on cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4, the main drug-metabolizing enzymes. Three pulvinic acid derivatives, atromentic acid (1), variegatic acid (2), and xerocomic acid (3), isolated from Boletus calopus and Suillus bovinus, revealed nonspecific inhibitory effects on all four CYPs. Using these compounds, the maximum IC50 values obtained with CYP3A4 in vitro were atromentic acid (1), 65.1+/-3.9 microM; variegatic acid (2), 2.2+/-0.1 microM; and xerocomic acid (3), 2.4+/-0.1 microM. Variegatic acid (2) and xerocomic acid (3) were effective inhibitors, comparable to cimetidine, dicoumarol, erythromycin, safrole, and uniconazole. Variegatic acid (2) and xerocomic acid (3) efficiently reduced ferryl myoglobin in CYPs. Reduction of ferryl heme to ferric heme is likely the mechanism of the nonspecific inhibitory effects of these compounds on CYPs.

The effect of the anodal transcranial direct current stimulation over the cerebellum on the motor cortex excitability.

PubMed

Ates, Mehlika Panpalli; Alaydin, Halil Can; Cengiz, Bulent

2018-04-25

This study was designed to investigate whether the cerebellum has an inhibitory effect on motor cortical excitability. Sixteen healthy adults (age range, 25-50 years, five female) participated in the study. Anodal cerebellar transcranial direct current stimulation (a-cTDCS) was used to modulate cerebellar excitability. A-cTDCS was given for 20 min at 1 mA intensity. The automatic threshold tracking method was used to investigate cortical excitability. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), intracortical facilitation (ICF), and the input output curve (I-O curve) were motor cortical excitability parameters. a-cTDCS caused a reduction in overall SICI and the reduced SICF for interstimulus intervals (ISIs) to 2.4-4.4 ms. a-cTDCS has no effect on ICF, RMT, and the I-O curve. There were no significant changes in any of these cortical excitability parameters after sham cTDCS. Results of the study indicate that a-cTDCS has a dual (both inhibitory and excitatory) effect on motor cortical excitability, rather than a simple inhibitory effect. The cerebellum modulates both the inhibitory and facilitatory activities of motor cortex (M1) and suggest that cerebello-cerebral motor connectivity is more complex than solely inhibitory or facilitatory connections. Copyright © 2018 Elsevier Inc. All rights reserved.

Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons

PubMed Central

2010-01-01

Background The molecular targets for the promising gaseous anaesthetic xenon are still under investigation. Most studies identify N-methyl-D-aspartate (NMDA) receptors as the primary molecular target for xenon, but the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid (AMPA) receptors is less clear. In this study we evaluated the effect of xenon on excitatory and inhibitory synaptic transmission in the superficial dorsal horn of the spinal cord using in vitro patch-clamp recordings from rat spinal cord slices. We further evaluated the effects of xenon on innocuous and noxious stimuli using in vivo patch-clamp method. Results In vitro, xenon decreased the amplitude and area under the curve of currents induced by exogenous NMDA and AMPA and inhibited dorsal root stimulation-evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There was no discernible effect on miniature or evoked inhibitory postsynaptic currents or on the current induced by inhibitory neurotransmitters. In vivo, xenon inhibited responses to tactile and painful stimuli even in the presence of NMDA receptor antagonist. Conclusions Xenon inhibits glutamatergic excitatory transmission in the superficial dorsal horn via a postsynaptic mechanism. There is no substantial effect on inhibitory synaptic transmission at the concentration we used. The blunting of excitation in the dorsal horn lamina II neurons could underlie the analgesic effect of xenon. PMID:20444263

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users.

PubMed

Strickland, Justin C; Bolin, B Levi; Romanelli, Michael R; Rush, Craig R; Stoops, William W

2017-01-01

Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions. Copyright © 2017 John Wiley & Sons, Ltd.

Medicinal Plants and Their Inhibitory Activities against Pancreatic Lipase: A Review

PubMed Central

Seyedan, Atefehalsadat; Alshawsh, Mohammed Abdullah; Alshagga, Mustafa Ahmed; Koosha, Sanaz

2015-01-01

Obesity is recognized as a major life style disorder especially in developing countries and it is prevailing at an alarming speed in new world countries due to fast food intake, industrialization, and reduction of physical activity. Furthermore, it is associated with a vast number of chronic diseases and disabilities. To date, relatively effective drugs, from either natural or synthetic sources, are generally associated with serious side effects, often leading to cessation of clinical trials or even withdrawal from the market. In order to find new compounds which are more effective or with less adverse effects compared to orlistat, the drug that has been approved for obesity, new compounds isolated from natural products are being identified and screened for antiobesity effects, in particular, for their pancreatic lipase inhibitory effect. Pancreatic lipase inhibitory activity has been extensively used for the determination of potential efficacy of natural products as antiobesity agents. In attempts to identify natural products for overcoming obesity, more researches have been focused on the identification of newer pancreatic lipase inhibitors with less unpleasant adverse effects. In this review, we consider the potential role of plants that have been investigated for their pancreatic lipase inhibitory activity. PMID:26640503

Discovery of new class of methoxy carrying isoxazole derivatives as COX-II inhibitors: Investigation of a detailed molecular dynamics study

NASA Astrophysics Data System (ADS)

Joy, Monu; Elrashedy, Ahmed A.; Mathew, Bijo; Pillay, Ashona Singh; Mathews, Annie; Dev, Sanal; Soliman, Mahmoud E. S.; Sudarsanakumar, C.

2018-04-01

Two novel isoxazole derivatives were synthesized and characterized by NMR and single crystal X-ray crystallography techniques. The methoxy and dimethoxy functionalized variants of isoxazole were screened for its anti-inflammatory profile using cyclooxygenase fluorescent inhibitor screening assay methods along with standard drugs, Celecoxib and Diclofenac. The potent and selective nature of the two isoxazole derivatives on COX-II isoenzyme with a greater magnitude of inhibitory concentration, as compared to the standard drugs and further exploited through molecular dynamics (MD) simulation. Classical, accelerated and multiple MD simulations were performed to investigate the actual binding mode of the two non-steroidal anti-inflammatory drug candidates and addressed their functional selectivity towards COX-II enzyme inhibitory nature.

Chromenylchalcones with inhibitory effects on monoamine oxidase B.

PubMed

Jo, Geunhyeong; Ahn, Seunghyun; Kim, Bong-Gyu; Park, Hye Ri; Kim, Young Hwa; Choo, Hyun Ah; Koh, Dongsoo; Chong, Youhoon; Ahn, Joong-Hoon; Lim, Yoongho

2013-12-15

Structure-activity relationship (SAR) calculations were used to find monoamine oxidase-B (MAO-B) inhibitors by identifying pharmacophores exhibiting high inhibitory activities. Several such chromenylchalcones were designed and synthesized accordingly. Their inhibitory effects on MAO-B were determined using an HPLC-based method and an MAO-B enzyme assay kit. (E)-3-(6-Methoxy-2H-chromen-3-yl)-1-(2-methoxyphenyl)prop-2-en-1-one exhibited a half-maximal inhibitory concentration of 320 nM. Its molecular-level binding mode with the three-dimensional structure of MAO-B was elucidated using an in silico docking study. The chromenylchalcone scaffold, which is derived from natural products including isoflavonoids and chalcones, had not been previously reported as an MAO-B inhibitor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ultraviolet-Visible (UV-Vis) and Fluorescence Spectroscopic Investigation of the Interactions of Ionic Liquids and Catalase.

PubMed

Dong, Xing; Fan, Yunchang; Yang, Peng; Kong, Jichuan; Li, Dandan; Miao, Juan; Hua, Shaofeng; Hu, Chaobing

2016-11-01

The inhibitory effects of nine ionic liquids (ILs) on the catalase activity were investigated using fluorescence, absorption ultraviolet-visible spectroscopy. The interactions of ILs and catalase on the molecular level were studied. The experimental results indicated that ILs could inhibit the catalase activity and their inhibitory abilities depended on their chemical structures. Fluorescence experiments showed that hydrogen bonding played an important role in the interaction process. The inhibitory abilities of ILs on catalase activity could be simply described by their hydrophobicity and hydrogen bonding abilities. Unexpected less inhibitory effects of trifluoromethanesulfonate (TfO - ) might be ascribed to its larger size, which makes it difficult to go through the substrate channel of catalase to the active site. © The Author(s) 2016.

[The influence of mitomycin C and paclitaxel on the proliferation and apoptosis of human pulmonary fibroblast].

PubMed

Chen, Nan; Zhang, Jie; Xu, Min; Wang, Ting; Wang, Yu-ling; Pei, Ying-hua

2013-09-01

To observe the inhibitory effect and potential mechanism of mitomycin C and paclitaxel on the proliferation of Human Pulmonary Fibroblast in vitro. So as to providing an experimental reference for the design of drug eluting airway stents. Cell viability was measured by MTT assay after different concentrations of mitomycin C or paclitaxel varying from 10(-1)1 mol/L to 10(-4) mol/L had been applied to the fibroblasts for 24, 48 or 72 h, respectively. Cell apoptosis was assessed by flow cytometry using dual staining with annexin V-FITC and propidium iodide 48 h after administering mitomycin C or paclitaxel at a concentration of 5×10(-6), 10(-5), 5×10(-5), 10(-4), 2×10(-4) mol/L, respectively. And the morphological character of cell apoptosis was observed by Hoechst 33342 fluorescent staining. The results of MTT revealed that cell proliferation were inhibited by mitomycin C and paclitaxel at all concentrations and exposure times. Among them, the inhibitory effect of mitomycin C were weak when the concentrations were between 10(-1)1 mol/L to 10(-8) mol/L. And within this context, the inhibitory ratio didn't correspond to the elevation of the concentration or the prolongation of the exposure times.However, when the concentration were between 10(-7) mol/L to 10(-4) mol/L, the inhibitory ratio rise progressively as the elevation of the concentration at all exposure times. The inhibitory ratio were 53.52%, 60.23%, 89.81% and 96.47% respectively when cells were treated by 10(-7), 10(-6), 10(-5) mol/L and 10(-4) mol/L mitomycin C for 72 h. An apparent "threshold dose effect" was observed in the paclitaxel treated groups.It's worth noting that the inhibitory ratio was only 48.22% when the cells had already been treated by 10(-5) mol/L paclitaxel for 72 h.However, when the concentration had reached 10(-4) mol/L, the inhibitory ratio sharply climbed to 93.38% even the cells had only been treated for 24 h. And the inhibitory ratio continued to rise as time prolonged. The results of cell apoptosis were consistent with MTT.When a significant inhibitory effect were detected by MTT, remarkable cell apoptosis could be observed by flow cytometry, and typical apoptotic cell could be identified by Hoechst 33342 fluorescent staining. A certain concentration of mitomycin C or paclitaxel can inhibit Human Pulmonary Fibroblast proliferation in vitro. Both of these two drugs have potential value for the preparation of drug eluting airway stents. In order to ensure the inhibitory effect, the eluting concentration of mitomycin C and paclitaxel should not be less than 10(-7) mol/L and 10(-5) mol/L. But the eluting concentration of these two drugs should not exceed 10(-4) mol/L when both of the inhibitory ratio of these two drugs were higher than 95%.On this basis, elevating the drug concentration has little significance for improving the inhibitory effect, but increase the risk of systemic toxicity. Inducing cell apoptosis is one of the potential mechanisms of mitomycin C and paclitaxel in inhibiting cell proliferation.

Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings.

PubMed

Pan, Chih-Ming; Wang, Mong-Lien; Chiou, Shih-Hwa; Chen, Hsiao-Yun; Wu, Cheng-Wen

2016-09-13

Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM-mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1-dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells.

Inhibitory effect of BCG cell-wall skeletons (BCG-CWS) emulsified in squalane on tumor growth and metastasis in mice.

PubMed

Yoo, Yung Choon; Hata, Katsusuke; Lee, Kyung Bok; Azuma, Ichiro

2002-08-01

The antimetastatic effect of BCG-CWS, which was emulsified in an oil-in-water form with either Drakeol 6VR mineral oil (BCG-CWS/DK) or squalane (BCG-CWS/SQA), on lung metastasis produced by highly metastatic murine tumor cells, Colon26-M3.1 carcinoma cells and B16-BL6 melanoma cells, was investigated in syngeneic mice. An intravenous (i.v.) administration of BCG-CWS (100 mg/mouse) 1 day after tumor inoculation significantly inhibited tumor metastasis of both Colon26-M3.1 carcinoma and B16-BL6 melanoma cells in experimental lung metastasis models. No differences in the antitumor activity of the two oil-based formulations (BCG-CWS/DK and BCG-CWS/SQA) were obverved. However, BCG-CWS/SQA administered through subcutaneous (s.c.) route was shown to be effective only when it was consecutively injected (3 times) after tumor inoculation. An in vivo analysis for tumor-induced angiogenesis showed that a single i.v. administration of BCG-CWS/SQA inhibited the number of tumor-induced blood vessels and suppressed tumor growth. Furthermore, the multiple administration of BCG-CWS/SQA given at on week intervals led to a significant reduction in spontaneous lung metastasis of B16-BL6 melanoma cells in a spontaneous metastasis model. These results suggest that BCG-CWS emulsified with squalane is a potent inhibitory agent of lung metastasis, and that the antimetastatic effect of BCG-CWS is related to the suppression of tumor growth and the inhibition of tumor-induced angiogenesis.

SESN2/sestrin 2 induction-mediated autophagy and inhibitory effect of isorhapontigenin (ISO) on human bladder cancers.

PubMed

Liang, Yuguang; Zhu, Junlan; Huang, Haishan; Xiang, Daimin; Li, Yang; Zhang, Dongyun; Li, Jingxia; Wang, Yulei; Jin, Honglei; Jiang, Guosong; Liu, Zeyuan; Huang, Chuanshu

2016-08-02

Isorhapontigenin (ISO) is a new derivative of stilbene isolated from the Chinese herb Gnetum cleistostachyum. Our recent studies have revealed that ISO treatment at doses ranging from 20 to 80 μM triggers apoptosis in multiple human cancer cell lines. In the present study, we evaluated the potential effect of ISO on autophagy induction. We found that ISO treatment at sublethal doses induced autophagy effectively in human bladder cancer cells, which contributed to the inhibition of anchorage-independent growth of cancer cells. In addition, our studies revealed that ISO-mediated autophagy induction occurred in a SESN2 (sestrin 2)-dependent and BECN1 (Beclin 1, autophagy related)-independent manner. Furthermore, we identified that ISO treatment induced SESN2 expression via a MAPK8/JNK1 (mitogen-activated protein kinase 8)/JUN-dependent mechanism, in which ISO triggered MAPK8-dependent JUN activation and facilitated the binding of JUN to a consensus AP-1 binding site in the SESN2 promoter region, thereby led to a significant transcriptional induction of SESN2. Importantly, we found that SESN2 expression was dramatically downregulated or even lost in human bladder cancer tissues as compared to their paired adjacent normal tissues. Collectively, our results demonstrate that ISO treatment induces autophagy and inhibits bladder cancer growth through MAPK8-JUN-dependent transcriptional induction of SESN2, which provides a novel mechanistic insight into understanding the inhibitory effect of ISO on bladder cancers and suggests that ISO might act as a promising preventive and/or therapeutic drug against human bladder cancer.

Botulinum toxin in spinal cord injury patients with neurogenic detrusor overactivity

PubMed Central

Cho, Young Sam; Kim, Khae Hawn

2016-01-01

Evidence for the efficacy and safety of intravesical onabotulinum toxin A (onabotA) injections has led to them being licensed in many countries, including Korea, for the treatment of patients with urinary incontinence due to neurogenic detrusor overactivity (NDO) resulting from spinal cord injury or multiple sclerosis who are refractory or intolerant to anticholinergic medications. OnabotA injections have an inhibitory effect on acetylcholine release for up to 10 months, with a recommended dose of 200 U. OnabotA treatment has a beneficial effect not only on urinary symptoms, but also on quality of life. Several clinical studies have shown onabotA to have better effects than placebo in achieving continence, reducing incontinence episodes, improving urodynamic parameters, and improving health-related quality of life. Urinary tract infections and postvoid residual volume are the most prevalent side effects. In patients with residual volume, clean intermittent catheterization may be necessary. In patients with spinal cord injury or multiple sclerosis, it is recommended to evaluate physical and cognitive function before intravesical onabotA injection to ensure that the patient and caregiver are able to perform catheterization if necessary. Further controlled trials should assess the optimal dose, injection technique, long-term safety of repeated injections, and optimal timing of onabotA treatment in the treatment of NDO. PMID:28119887

Reproduction and the renin-angiotensin system

NASA Technical Reports Server (NTRS)

Ganong, W. F.

1995-01-01

A unique aspect of the circulating renin-angiotensin system and the many independent tissue renin-angiotensin systems is their interactions at multiple levels with reproduction. These interactions, which have received relatively little attention, include effects of estrogens and possibly androgens on hepatic and renal angiotensinogen mRNA; effects of androgens on the Ren-2 gene and salivary renin in mice; the prorenin surge that occurs with but outlasts the LH surge during the menstrual cycle; the inhibitory effects of estrogens on thirst and water intake; the tissue renin-angiotensin systems in the brain, the anterior pituitary, and the ovaries and testes, that is, in all the components of the hypothalamo-pituitary-gonadal axis; the presence of some components of the renin-angiotensin system in the uterus and the fetoplacental unit; and the possible relation of renin and angiotensin to ovulation and fetal well-being. These interactions are described and their significance considered in this short review.

Role of F1C fimbriae, flagella, and secreted bacterial components in the inhibitory effect of probiotic Escherichia coli Nissle 1917 on atypical enteropathogenic E. coli infection.

PubMed

Kleta, Sylvia; Nordhoff, Marcel; Tedin, Karsten; Wieler, Lothar H; Kolenda, Rafal; Oswald, Sibylle; Oelschlaeger, Tobias A; Bleiss, Wilfried; Schierack, Peter

2014-05-01

Enteropathogenic Escherichia coli (EPEC) is recognized as an important intestinal pathogen that frequently causes acute and persistent diarrhea in humans and animals. The use of probiotic bacteria to prevent diarrhea is gaining increasing interest. The probiotic E. coli strain Nissle 1917 (EcN) is known to be effective in the treatment of several gastrointestinal disorders. While both in vitro and in vivo studies have described strong inhibitory effects of EcN on enteropathogenic bacteria, including pathogenic E. coli, the underlying molecular mechanisms remain largely unknown. In this study, we examined the inhibitory effect of EcN on infections of porcine intestinal epithelial cells with atypical enteropathogenic E. coli (aEPEC) with respect to single infection steps, including adhesion, microcolony formation, and the attaching and effacing phenotype. We show that EcN drastically reduced the infection efficiencies of aEPEC by inhibiting bacterial adhesion and growth of microcolonies, but not the attaching and effacing of adherent bacteria. The inhibitory effect correlated with EcN adhesion capacities and was predominantly mediated by F1C fimbriae, but also by H1 flagella, which served as bridges between EcN cells. Furthermore, EcN seemed to interfere with the initial adhesion of aEPEC to host cells by secretion of inhibitory components. These components do not appear to be specific to EcN, but we propose that the strong adhesion capacities enable EcN to secrete sufficient local concentrations of the inhibitory factors. The results of this study are consistent with a mode of action whereby EcN inhibits secretion of virulence-associated proteins of EPEC, but not their expression.

Evaluation of the tannic acid inhibitory effect against the NorA efflux pump of Staphylococcus aureus.

PubMed

Tintino, Saulo R; Oliveira-Tintino, Cícera D M; Campina, Fábia F; Silva, Raimundo L P; Costa, Maria do S; Menezes, Irwin R A; Calixto-Júnior, João T; Siqueira-Junior, José P; Coutinho, Henrique D M; Leal-Balbino, Tereza C; Balbino, Valdir Q

2016-08-01

During the early periods of antibiotic usage, bacterial infections were considered tamed. However, widespread antibiotic use has promoted the emergence of antibiotic-resistant pathogens, including multidrug resistant strains. Active efflux is a mechanism for bacterial resistance to inhibitory substances, known simply as drug efflux pumps. The bacterium Staphylococcus aureus is an important pathogenic bacterium responsible for an array of infections. The NorA efflux pump has been shown to be responsible for moderate fluoroquinolone resistance of S. aureus. The inhibition of the efflux pump was assayed using a sub-inhibitory concentration of standard efflux pump inhibitors and tannic acid (MIC/8), where its capacity to decrease the MIC of Ethidium bromide (EtBr) and antibiotics due to the possible inhibitory effect of these substances was observed. The MICs of EtBr and antibiotics were significantly reduced in the presence of tannic acid, indicating the inhibitory effect of this agent against the efflux pumps of both strains causing a three-fold reduction of the MIC when compared with the control. These results indicate the possible usage of tannic acid as an adjuvant in antibiotic therapy against multidrug resistant bacteria (MDR). Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibitory Effects of Polyacetylene Compounds from Panax ginseng on Neurotrophin Receptor-Mediated Hair Growth.

PubMed

Suzuki, Aoi; Matsuura, Daisuke; Kanatani, Hirotoshi; Yano, Shingo; Tsunakawa, Mitsuo; Matsuyama, Shigeru; Shigemori, Hideyuki

2017-01-01

Neurotrophins play an important role in the control of the hair growth cycle. Therefore, neurotrophin receptor antagonists have therapeutic potential for the treatment of hair growth disorders. In this study, we investigated the inhibitory effect of Panax ginseng, a medicinal plant commonly used to treat alopecia, on the binding of neurotrophins to their receptors. In addition, we isolated and characterized the bioactive compounds of P. ginseng extracts. P. ginseng hexane extracts strongly inhibited brain-derived neurotrophic factor (BDNF)-TrkB and β-nerve growth factor (β-NGF)-p75 neurotrophin receptor (p75NTR) binding. Furthermore, we identified the following 6 polyacetylene compounds as the bioactive components in P. ginseng hexane extract: panaxynol (1), panaxydol (2), panaxydol chlorohydrin (3), 1,8-heptadecadiene-4,6-diyne-3,10-diol (4), panaxytriol (5), and dihydropanaxacol (6). In particular, compounds 4, 5, and 6 significantly inhibited BDNF-TrkB binding in a dose-dependent manner. To identify the structural component mediating the inhibitory effect, we investigated the effects of the hydroxyl moiety in these compounds. We found that the inhibitory effect of panaxytriol (5) was strong, whereas the inhibitory effect of Ac-panaxytriol (7) was relatively weak. Our findings suggest that P. ginseng-derived polyacetylenes with a hydroxyl moiety might provide therapeutic benefits to patients with hair growth disorders such as alopecia by inhibiting the binding of neurotrophins to their receptors. Although saponins have been proposed to be the primary mediators of the effects of P. ginseng on hair growth, this study revealed that polyacetylene compounds exert similar effects.

Investigations of the inhibitory effects of tocopherol (vitamin E) on free radical deterioration of cellular membranes

NASA Technical Reports Server (NTRS)

Richardson, D.

1975-01-01

The inhibitory effects are investigated of d,1-alpha-tocopherol and d,1-alpha-tocopheryl acetate on the free radical deterioration of cellular membranes. The level of toxicity of d,1-alpha-tocopherol and d,1-alpha-tocopheryl acetate in mice is determined.

Developmental Effects of Incentives on Response Inhibition

ERIC Educational Resources Information Center

Geier, Charles F.; Luna, Beatriz

2012-01-01

Inhibitory control and incentive processes underlie decision making, yet few studies have explicitly examined their interaction across development. Here, the effects of potential rewards and losses on inhibitory control in 64 adolescents (13- to 17-year-olds) and 42 young adults (18- to 29-year-olds) were examined using an incentivized antisaccade…

Growth regulation of the mammalian ocular lens by vitreous humor.

PubMed

Banerjee, A; Parafina, J; Bagchi, M

1992-05-01

Experiments were performed in our laboratory to study the effects of a mammalian 8 kD vitreous humor (VH) factor on the DNA synthesis and mitosis of the epithelial cells of organ cultured rabbit lens. The 8 kD polypeptide factor was purified from mature rabbit vitreous humor by liquid chromatography. Proliferative activities of the epithelial cells of organ cultured lenses were stimulated by 3% rabbit serum. The data from our experiments depicted that the 8 kD VH factor effectively inhibits DNA synthesis and mitosis by the epithelial cells of the organ cultured lens. Our experiments also showed that this 8 kD VH factor can maintain its growth inhibitory activity even when heated for 3 min at 95 degrees C. The growth inhibitory effect of the 8 kD VH factor was dose dependent. Using iodinated vitreal proteins it was demonstrated that the VH proteins are able to enter or bind to lens epithelial cells. The growth inhibitory effect of the 8 kD VH factor was also tested on tissue cultured lens epithelial cells. These experiments showed that the 8 kD VH factor has no growth inhibitory effect on the tissue cultured lens epithelial cells. This experiment has been repeated many times using different concentrations of the factor. These observations suggest that the 8 kD VH factor may have receptors in the lens capsular material (extracellular matrix) and the factor-receptor binding is essential for the growth inhibitory effect.

Novel whey-derived peptides with inhibitory effect against angiotensin-converting enzyme: in vitro effect and stability to gastrointestinal enzymes.

PubMed

Tavares, Tânia; Contreras, Maria Del Mar; Amorim, Manuela; Pintado, Manuela; Recio, Isidra; Malcata, F Xavier

2011-05-01

Whey protein concentrate (WPC) was subjected to enzymatic hydrolysis by proteases from the flowers of Cynara cardunculus, and the resulting angiotensin-converting enzyme (ACE)-inhibitory effect was monitored. The whole WPC hydrolysate exhibited an IC(50) value of 52.9 ± 2.9 μg/mL, whereas the associated peptide fraction with molecular weight below 3 kDa scored 23.6 ± 1.1 μg/mL. The latter fraction was submitted to RP-HPLC, and 6 fractions were resolved that exhibited ACE-inhibitory effects. Among the various peptides found, a total of 14 were identified via sequencing with an ion-trap mass spectrometer. Eleven of these peptides were synthesized de novo--to validate their ACE-inhibitory effect, and also to ascertain their stability when exposed to simulated gastrointestinal digestion. Among them, three novel, highly potent peptides were found, corresponding to α-lactalbumin f(16-26)--with the sequence KGYGGVSLPEW, α-lactalbumin f(97-104) with DKVGINYW, and β-lactoglobulin f(33-42) with DAQSAPLRVY; their IC(50) values were as low as 0.80 ± 0.1, 25.2 ± 1.0 and 13.0 ± 1.0 μg/mL, respectively. None of them remained stable in the presence of gastrointestinal enzymes: they were partially, or even totally hydrolyzed to smaller peptides--yet the observed ACE-inhibitory effects were not severely affected for two of those peptides. Copyright © 2011 Elsevier Inc. All rights reserved.

Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi

PubMed Central

Thomas, María Carmen; Carrilero, Bartolomé; González, John Mario; Cuéllar, Adriana; Segovia, Manuel; Puerta, Concepción Judith

2017-01-01

Congenital T. cruzi infections involve multiple factors in which complex interactions between the parasite and the immune system of pregnant women play important roles. In this study, we used an experimental murine model of chronic infection with T. cruzi to evaluate the changes in the expression of inhibitory receptors and the polyfunctionality of T cells during gestation and their association with congenital transmission rate of T. cruzi infection. The results showed that pregnant naïve mice had a higher percentage of CD4+ and CD8+ T cells that expressed inhibitory receptors than cells from non-pregnant naïve mice. However, in mice chronically infected with T. cruzi, gestation induced a significant decrease in the frequency of T cells that expressed or co-expressed inhibitory receptors, as well as an increase in the frequency of polyfunctional CD4+ and CD8+ T cells. This different behavior may be due to the breakdown in the infected mice of the gestation-induced immune homeostasis, probably to control the parasite load. Remarkably, it was observed that the mothers that transmitted the parasite had a higher frequency of T cells that expressed and co-expressed inhibitory receptors as well as a lower frequency of polyfunctional parasite-specific T cells than those that did not transmit it, even though the parasitemia load was similar in both groups. All together these data suggest that the maternal immune profile of the CD4+ and CD8+ T cells could be a determining factor in the congenital transmission of T. cruzi. PMID:28598971

Dual inhibition of nitric oxide and prostaglandin E2 production by polysubstituted 2-aminopyrimidines.

PubMed

Zídek, Zdeněk; Kverka, Miloslav; Dusilová, Adéla; Kmoníčková, Eva; Jansa, Petr

2016-07-01

The present in vitro experiments demonstrate inhibitory effects of polysubstituted 2-aminopyrimidines on high output production of nitric oxide (NO) and prostaglandin E2 (PGE2) stimulated by interferon-γ and lipopolysaccharide (LPS) in peritoneal macrophages of mouse and rat origin. PGE2 production was inhibited also in LPS-activated human peripheral blood mononuclear cells. A tight dependence of the suppressive activities on chemical structure of pyrimidines was observed. Derivatives containing hydroxyl groups at the C-4 and C-6 positions of pyrimidine ring were devoid of any influence on NO and PGE2. Remarkable inhibitory potential was acquired by the replacement of hydroxyl groups with chlorine, the 4,6-dichloro derivatives being more effective than the monochloro analogues. The effects were further intensified by modification of the amino group at the C-2 position, changing it to the (N,N-dimethylamino)methyleneamino or the formamido ones. There was no substantial difference in the expression of NO-inhibitory effects among derivatives containing distinct types of substituents at the C-5 position (hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl). In contrast to NO, larger substituents then methyl were required to inhibit PGE2 production. Overall, no significant correlation between the extent of NO and PGE2 suppression was observed. The IC50s of derivatives with the strongest effects on both NO and PGE2 were within the range of 2-10 μM. Their NO-inhibitory potential of pyrimidines was stronger than that of non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin. The PGE2-inhibitory effectiveness of pyrimidines was about the same as that of aspirin, but weaker as compared to indomethacin. The NO- and PGE2-inhibitory activity of tested pyrimidines has been found associated with decreased expression of iNOS mRNA and COX-2 mRNA, respectively, and with post-translation interactions. Selected NO-/PGE2-inhibitory derivatives decreased severity of intestinal inflammation in murine model of ulcerative colitis. Copyright © 2016 Elsevier Inc. All rights reserved.

A cross-cultural investigation of inhibitory control, generative fluency, and anxiety symptoms in Romanian and Russian preschoolers.

PubMed

Cheie, Lavinia; Veraksa, Aleksander; Zinchenko, Yuri; Gorovaya, Alexandra; Visu-Petra, Laura

2015-01-01

The current study focused on the early development of inhibitory control in 5- to 7-year-old children attending kindergarten in two Eastern-European countries, Romania and Russia. These two countries share many aspects of child-rearing and educational practices, previously documented to influence the development of inhibitory control. Using the Lurian-based developmental approach offered by the Developmental Neuropsychological Assessment battery, the study aimed to contribute to cross-cultural developmental neuropsychology by exploring (a) early interrelationships between subcomponents of inhibitory control (response suppression and attention control) and generative fluency (verbal and figural) in these two cultures, as well as (b) the predictive value of external factors (culture and maternal education) and individual differences (age, gender, nonverbal intelligence, trait anxiety) on inhibitory control and fluency outcomes in children from both countries. First, findings in both culture samples suggest that even at this young age, the construct of inhibitory control cannot be considered a unitary entity. Second, differences in maternal education were not predictive of either inhibitory control or fluency scores. However, children's attention control performance varied as a function of culture, and the direction of these cultural effects differed by whether the target outcome involved performance accuracy versus efficiency as an output. Findings also confirmed the previously documented intensive developmental improvement in preschoolers' inhibitory control during this period, influencing measures of response suppression and particularly attention control. Finally, the results further stress the importance of individual differences effects in trait anxiety on attention control efficiency across cultures.

The neural circuit and synaptic dynamics underlying perceptual decision-making

NASA Astrophysics Data System (ADS)

Liu, Feng

2015-03-01

Decision-making with several choice options is central to cognition. To elucidate the neural mechanisms of multiple-choice motion discrimination, we built a continuous recurrent network model to represent a local circuit in the lateral intraparietal area (LIP). The network is composed of pyramidal cells and interneurons, which are directionally tuned. All neurons are reciprocally connected, and the synaptic connectivity strength is heterogeneous. Specifically, we assume two types of inhibitory connectivity to pyramidal cells: opposite-feature and similar-feature inhibition. The model accounted for both physiological and behavioral data from monkey experiments. The network is endowed with slow excitatory reverberation, which subserves the buildup and maintenance of persistent neural activity, and predominant feedback inhibition, which underlies the winner-take-all competition and attractor dynamics. The opposite-feature and opposite-feature inhibition have different effects on decision-making, and only their combination allows for a categorical choice among 12 alternatives. Together, our work highlights the importance of structured synaptic inhibition in multiple-choice decision-making processes.

[Killing effect of icotinib combined with CIK on human lung adenocarcinoma cells in vitro].

PubMed

Yao, B Q; Jia, Y; Guo, J Q; Zhao, Q; Sun, H; Zhang, J P

2017-08-23

Objective: To explore the inhibitory effect of icotinib combined with cytokine induced killer (CIK) on various human lung adenocarcinoma cell lines in vitro. Methods: The inhibitory effect of icotinib alone or icotinib combined with CIK on HCC827 and A549 cells was detected by cell counting kit-8(CCK-8). The apoptosis was detected by flow cytometry via Annexin V/PI staining. The effect of icotinib on CIK phenotype was detected by flow cytometry. Results: The inhibitory rates of HCC827 cells treated with 1.5, 3, 6, 12 μmol/L icotinib were (5.64±0.05)%, (8.62±0.45)%, (14.57±0.65)% and (18.52±0.91)%, respectively. The inhibitory rates of A549 cells were (1.64±0.48)%, (2.09±0.28)%, (3.69±0.45)%, (4.41±0.58)%, respectively. At the same concentration, the inhibitory rate of HCC827 cells with icotinib treatment was significantly higher than that of A549 cells ( P <0.05). When the effector/target ratio was 10∶1, 20∶1 or 40∶1, the inhibitory rates of HCC827 cells co-cultured with CIK were (15.17±2.33)%, (42.59±7.18)%, (62.59±8.95)%, respectively, and the inhibitory rates of A549 were(16.99±2.81)%, (46.31±1.89)%, (58.24±4.23)%, respectively. The inhibitory rate of HCC827 cells co-cultured with CIK was not significantly different from that of A549 cells at the same effector/target ratio ( P (10∶1)=0.299, P (20∶1)=0.318, P (40∶1)=0.366). When the effector/target ratio of CIK combined with 6 μmol/L icotinib was 10∶1, 20∶1 or 40∶1, the inhibitory rates of HCC827 cells were (37.07±3.50)%, (76.03±6.55)%, (80.34±10.69)%, respectively, and the inhibitory rates of A549 cells were(25.72±1.41)%, (52.76±3.82)%, (62.26±1.94)%, respectively. The inhibitory rates of 6 μmol/L icotinib combined with CIK were significantly higher than those of icotinib group and CIK group alone at the same effector/target ratio ( P <0.05), except for the effector/target ratio at 40︰1 on A549 cells ( P =0.089). Moreover, all of the combination index (CI) of combined group were <1 ( P <0.05). The apoptotic rates of HCC827 and A549 cells induced by icotinib combined with CIK were significantly higher than those of icotinib group and blank control group ( P <0.05), especially the proportion of late apoptotic or necrotic cells.Increasing effector/target ratio of CIK contributed to stronger inhibition( P <0.05). The expressional rate of CIK phenotype with or without icotinib treatment was not significantly different from each other( P >0.05). Conclusions: EGFR mutant lung adenocarcinoma cells are more sensitive to icotinib, while the EGFR mutation status has no effect on the killing effect of CIK cells. icotinib combined with CIK has a synergistic effect on the inhibition of tumor growth, and icotinib has no any impact on the phenotype of CIK cells.

[Investigation on Inhibitory Capacities of Seventeen Herbal Extracts on Oxidative Stress using Ultraviolet and Fluorescence Spectroscopy].

PubMed

Hou, Guang-yue; Zheng, Zhong; Song, Feng-rui; Liu, Zhi-qiang; Zhao, Bing

2015-03-01

Diabetic patients usually suffer from complications and the long-term secondary complications are the main cause of morbidity and mortality. The hyperglycemia-induced oxidative stress is one of the important pathogenesis of diabetic complications, while the oxidative stress is associated with the lipid peroxidation reaction and the formation of advanced glycation end products (AGEs). Our study was focus on the pathogenesis of diabetic complications and based on the oxidative stress reaction. In this research, the oxidative stress inhibiting effects of seventeen herbal extracts were studied based on spectroscopic methodology. The capacities of herbal extracts against the lipid peroxidation reaction of rat liver in vitro were investigated using spectrophotometric method. It showed that the inhibitory activity of Radix Scutellariae and Flos Sophorae Immaturus were better than other herbal extracts. Additionally, the herbal extracts rich in flavonoids, alkaloids and lignanoids showed good inhibitory activities on the lipid peroxidation reaction. On the contrary, the saponin-rich herbal extracts possessed weak inhibitory effects. We applied the BSA/glucose (fructose) system combined with fluorescent spectroscopy to determine the inhibitory activities of herbal extracts in glycation model reactions. The results showed that the AGEs formation inhibitory activity of Flos Sophorae Immaturus, Radix Scutellariae and Rhizoma Anemarrhenae were better than others in the BSA/glucose (fructose) system by fluorescene analysis. The results demonstrated that the herbal extracts rich in flavonoids were found to be more effective than that of those herbal extracts as alkaloids and terpenoids class in inhibiting oxidative stress, while the saponin-rich herbal extracts showed weak inhibitory activities against oxidative stress. The Flos Sophorae Immaturus and Radix Scutellariae extracts had better inhibitory activity to the oxidative stress, so their pharmacological activity could be explored in further investigations. These results demonstrated in this assay could provide a reference for the study of pharmacological activity, and thus lays the foundation for the further study of the application of natural products in the prevention and treatment of diabetic complications.

A pilot investigation of acute inhibitory control training in cocaine users.

PubMed

Alcorn, Joseph L; Pike, Erika; Stoops, William S; Lile, Joshua A; Rush, Craig R

2017-05-01

Disrupted response inhibition and presence of drug-cue attentional bias in cocaine-using individuals have predicted poor treatment outcomes. Inhibitory control training could help improve treatment outcomes by strengthening cognitive control. This pilot study assessed the effects of acute inhibitory control training to drug- and non-drug-related cues on response inhibition performance and cocaine-cue attentional bias in cocaine-using individuals. Participants who met criteria for a cocaine-use disorder underwent five sessions of inhibitory control training to either non-drug-related cues (i.e., rectangles) or cocaine cues (n=10/condition) in a single day. Response inhibition and attentional bias were assessed prior to and following training using the stop-signal task and visual-probe task with eye tracking, respectively. Training condition groups did not differ on demographics, inhibitory control training performance, response inhibition, or cocaine-cue attentional bias. Response inhibition performance improved as a function of inhibitory control training in both conditions. Cocaine-cue attentional bias was observed, but did not change as a function of inhibitory control training in either condition. Response inhibition in cocaine-using individuals was augmented by acute inhibitory control training, which may improve treatment outcomes through better behavioral inhibition. Future studies should investigate longer-term implementation of inhibitory control training, as well as combining inhibitory control training with other treatment modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

Is the structural diversity of tripeptides sufficient for developing functional food additives with satisfactory multiple bioactivities?

NASA Astrophysics Data System (ADS)

Wang, Jian-Hui; Liu, Yong-Le; Ning, Jing-Heng; Yu, Jian; Li, Xiang-Hong; Wang, Fa-Xiang

2013-05-01

Multifunctional peptides have attracted increasing attention in the food science community because of their therapeutic potential, low toxicity and rapid intestinal absorption. However, previous study demonstrated that the limited structural variations make it difficult to optimize dipeptide molecules in a good balance between desirable and undesirable properties (F. Tian, P. Zhou, F. Lv, R. Song, Z. Li, J. Pept. Sci. 13 (2007) 549-566). In the present work, we attempt to answer whether the structural diversity is sufficient for a tripeptide to have satisfactory multiple bioactivities. Statistical test, structural examination and energetic analysis confirm that peptides of three amino acids long can bind tightly to human angiotensin converting enzyme (ACE) and thus exert significant antihypertensive efficacy. Further quantitative structure-activity relationship (QSAR) modeling and prediction of all 8000 possible tripeptides reveal that their ACE-inhibitory potency exhibits a good (positive) relationship to antioxidative activity, but has only a quite modest correlation with bitterness. This means that it is possible to find certain tripeptide entities possessing the optimal combination of strong ACE-inhibitory potency, high antioxidative activity and weak bitter taste, which are the promising candidates for developing multifunctional food additives with satisfactory multiple bioactivities. The marked difference between dipeptide and tripeptide can be attributed to the fact that the structural diversity of peptides increases dramatically with a slight change in sequence length.

Selective Memories: Infants' Encoding Is Enhanced in Selection via Suppression

ERIC Educational Resources Information Center

Markant, Julie; Amso, Dima

2013-01-01

The present study examined the hypothesis that inhibitory visual selection mechanisms play a vital role in memory by limiting distractor interference during item encoding. In Experiment 1a we used a modified spatial cueing task in which 9-month-old infants encoded multiple category exemplars in the contexts of an attention orienting mechanism…

Lateral Orbitofrontal Cortical Modulation on the Medial Prefrontal Cortex-Amygdala Pathway: Differential Regulation of Intra-Amygdala GABAA and GABAB Receptors.

PubMed

Chang, Chun-Hui

2017-07-01

The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex and lateral orbitofrontal cortex. Earlier studies have shown that lateral orbitofrontal cortex activation exerts an inhibitory gating on medial prefrontal cortex-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to medial prefrontal cortex activation, tested lateral orbitofrontal cortex gating at different delays (lateral orbitofrontal cortex-medial prefrontal cortex delays: 25, 50, 100, 250, 500, and 1000 milliseconds), and examined differential contribution of GABAA and GABAB receptors with iontophoresis. Relative to baseline, lateral orbitofrontal cortex stimulation exerted an inhibitory modulatory gating on the medial prefrontal cortex-amygdala pathway and was effective up to a long delay of 500 ms (long-delay latencies at 100, 250, and 500 milliseconds). Moreover, blockade of intra-amygdala GABAA receptors with bicuculline abolished the lateral orbitofrontal cortex inhibitory gating at both short- (25 milliseconds) and long-delay (100 milliseconds) intervals, while blockade of GABAB receptors with saclofen reversed the inhibitory gating at long delay (100 milliseconds) only. Among the majority of the neurons examined (8 of 9), inactivation of either GABAA or GABAB receptors during baseline did not change evoked probability per se, suggesting that local feed-forward inhibitory mechanism is pathway specific. Our results suggest that the effect of lateral orbitofrontal cortex inhibitory modulatory gating was effective up to 500 milliseconds and that intra-amygdala GABAA and GABAB receptors differentially modulate the short- and long-delay lateral orbitofrontal cortex inhibitory gating on the medial prefrontal cortex-amygdala pathway. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Fear Conditioning Selectively Disrupts Noradrenergic Facilitation of GABAergic Inhibition in the Basolateral Amygdala

PubMed Central

Skelly, M. J.; Ariwodola, O. J.; Weiner, J. L.

2016-01-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1- and β3-AR agonists (1μM A61603 and 10μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. PMID:27720769

Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

PubMed

Skelly, M J; Ariwodola, O J; Weiner, J L

2017-02-01

Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline. Copyright © 2016 Elsevier Ltd. All rights reserved.

THE MECHANISM OF THE INHIBITION OF HEMOLYSIS

PubMed Central

Ponder, Eric

1945-01-01

This paper contains a description of some of the inhibitory, and occasionally acceleratory, effects of sols of lecithins, cholesterol, and proteins in hemolytic systems containing simple lysins, together with investigations on the nature of the reactions by means of which the effects are brought about. The principal conclusions are: A. As regards sols of lecithins. 1. In lysin-inhibitor-cell systems, distearyl lecithin is an inhibitor of saponin and digitonin hemolysis, part of the effect being the result of a reaction with the components of the red cell surface and part being the result of a reaction with lysin in the bulk phase of the system. Lecithin ab ovo (Merck) is an accelerator of saponin hemolysis and either an accelerator or an inhibitor of digitonin hemolysis according to the initial concentration of lysin present in the system. Soybean lecithin is an inhibitor of both saponin and digitonin hemolysis, but both soybean lecithin and lecithin ab ovo contain also a hemolytic, or acceleratory, component. 2. The inhibitory effects depend on the order in which the components of the hemolytic system are mixed together. Distearyl lecithin is about 5 times more inhibitory in cell-inhibitor-lysin systems than in lysin-inhibitor-cell systems containing saponin, digitonin, or taurocholate. Lecithin ab ovo is more inhibitory in cell-inhibitor-lysin systems when the time of contact between cells and inhibitor is short, but when it is long, the hemolytic properties of the lecithin offset its inhibitory properties. A similar state of affairs is observed with soybean lecithin. 3. An increase in temperature decreases the inhibitory effect of distearyl lecithin in systems containing saponin or digitonin. B. As regards sols of cholesterol. 4. The quantity of lysin Δ apparently inhibited by a quantity Q of cholesterol sol is dependent on both the type of red cell and the number of red cells added to the system. 5. Δ is a non-linear function of Q and of c 1, the initial quantity of lysin present in the hemolytic system, Δ generally increasing as c 1 increases. 6. The inhibitory effect of cholesterol sols is essentially due to a reaction between the cholesterol and the lysin in the bulk phase of the system, modified by what appear to be redistribution effects which depend on the kind and number of red cells added to complete the hemolytic system. 7. The value of Δ depends on the temperature and on the length of time during which the cholesterol and the lysin remain in contact before the addition of the cells. 8. Distearyl lecithin considerably enhances the inhibitory effects of cholesterol sols. C. As regards the proteins. 9. Freshly prepared serum globulin is inhibitory in systems containing saponin, digitonin, taurocholate, and oleate, and the effect is due to reactions in the bulk phase of the system, modified by redistribution effects. 10. Serum albumin either accelerates or inhibits lysis by saponin, depending on the initial concentration of lysin, and the inhibition depends on such factors as the type of red cell used and the time of contact. In the case of sodium taurocholate, the inhibition has a very marked pH dependence. D. As regards plasma. 11. The way in which the inhibitory effect depends on the length of time during which inhibitor and lysin are in contact before the addition of the cells is not the same when plasma is used as an inhibitor as when a cholesterol sol is used as the inhibitor. The amount of cholesterol sol which is equal in inhibitory power to a given amount of plasma accordingly varies according to the length of the time of contact which is selected. 12. The inhibitory effect in systems containing saponin, plasma, and red cells can be shown to depend on the order in which the components are mixed, when the concentration of the plasma is small. 13. The question as to how much of the inhibitory power of plasma can be accounted for by the contained cholesterol (total or free) is one which can be answered only if the experimental conditions are defined with respect to initial concentration of lysin, time of contact, and several other variables. Very roughly, about 50 per cent of the total inhibition of plasma, or a little more, can be attributed to the cholesterol fraction. 14. Since the inhibitory effects of plasma are the result of reactions in the bulk phase of the system, complicated by redistributions among the phases, of reactions between some of its components and components of the red cell surface, and of enhancing effects of its components upon each other, it is not surprising that nothing better than an empirical expression should have been found to describe the inhibition quantitatively. PMID:19873439

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans.

PubMed

Mills, Holly; Wragg, Rachel; Hapiak, Vera; Castelletto, Michelle; Zahratka, Jeffrey; Harris, Gareth; Summers, Philip; Korchnak, Amanda; Law, Wenjing; Bamber, Bruce; Komuniecki, Richard

2012-02-01

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α(2)-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gα(o). In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of 'inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α(2)-adrenoreceptors on afferent nociceptors and stimulatory α(1)-receptors on inhibitory peptidergic interneurons.

Monoamines and neuropeptides interact to inhibit aversive behaviour in Caenorhabditis elegans

PubMed Central

Mills, Holly; Wragg, Rachel; Hapiak, Vera; Castelletto, Michelle; Zahratka, Jeffrey; Harris, Gareth; Summers, Philip; Korchnak, Amanda; Law, Wenjing; Bamber, Bruce; Komuniecki, Richard

2012-01-01

Pain modulation is complex, but noradrenergic signalling promotes anti-nociception, with α2-adrenergic agonists used clinically. To better understand the noradrenergic/peptidergic modulation of nociception, we examined the octopaminergic inhibition of aversive behaviour initiated by the Caenorhabditis elegans nociceptive ASH sensory neurons. Octopamine (OA), the invertebrate counterpart of norepinephrine, modulates sensory-mediated reversal through three α-adrenergic-like OA receptors. OCTR-1 and SER-3 antagonistically modulate ASH signalling directly, with OCTR-1 signalling mediated by Gαo. In contrast, SER-6 inhibits aversive responses by stimulating the release of an array of ‘inhibitory' neuropeptides that activate receptors on sensory neurons mediating attraction or repulsion, suggesting that peptidergic signalling may integrate multiple sensory inputs to modulate locomotory transitions. These studies highlight the complexity of octopaminergic/peptidergic interactions, the role of OA in activating global peptidergic signalling cascades and the similarities of this modulatory network to the noradrenergic inhibition of nociception in mammals, where norepinephrine suppresses chronic pain through inhibitory α2-adrenoreceptors on afferent nociceptors and stimulatory α1-receptors on inhibitory peptidergic interneurons. PMID:22124329

Role of Microglia Disturbances and Immune-Related Marker Abnormalities in Cortical Circuitry Dysfunction in Schizophrenia

PubMed Central

Volk, David W.

2017-01-01

Studies of genetics, serum cytokines, and autoimmune illnesses suggest that immune-related abnormalities are involved in the disease process of schizophrenia. Furthermore, direct evidence of cortical immune activation, including markedly elevated levels of many immune-related markers, have been reported in the prefrontal cortex in multiple cohorts of schizophrenia subjects. Within the prefrontal cortex in schizophrenia, deficits in the basilar dendritic spines of layer 3 pyramidal neurons and disturbances in inhibitory inputs to pyramidal neurons have also been commonly reported. Interestingly, microglia, the resident immune-related cells of the brain, also regulate excitatory and inhibitory input to pyramidal neurons. Consequently, in this review, we describe the cytological and molecular evidence of immune activation that has been reported in the brains of individuals with schizophrenia and the potential links between these immune-related disturbances with previously reported disturbances in pyramidal and inhibitory neurons in the disorder. Finally, we discuss the role that activated microglia may play in connecting these observations and as potential therapeutic treatment targets in schizophrenia. PMID:28007586

Distinct kinetics of inhibitory currents in thalamocortical neurons that arise from dendritic or axonal origin.

PubMed

Yang, Sunggu; Govindaiah, Gubbi; Lee, Sang-Hun; Yang, Sungchil; Cox, Charles L

2017-01-01

Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) transfer visual information from retina to primary visual cortex. This information is modulated by inhibitory input arising from local interneurons and thalamic reticular nucleus (TRN) neurons, leading to alterations of receptive field properties of thalamocortical neurons. Local GABAergic interneurons provide two distinct synaptic outputs: axonal (F1 terminals) and dendritic (F2 terminals) onto dLGN thalamocortical neurons. By contrast, TRN neurons provide only axonal output (F1 terminals) onto dLGN thalamocortical neurons. It is unclear if GABAA receptor-mediated currents originating from F1 and F2 terminals have different characteristics. In the present study, we examined multiple characteristics (rise time, slope, halfwidth and decay τ) of GABAA receptor-mediated miniature inhibitory postsynaptic synaptic currents (mIPSCs) originating from F1 and F2 terminals. The mIPSCs arising from F2 terminals showed slower kinetics relative to those from F1 terminals. Such differential kinetics of GABAAR-mediated responses could be an important role in temporal coding of visual signals.

A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing.

PubMed

Kumar, Priyadarsini; Walsh, Donal A

2002-03-15

We have previously shown that the protein kinase inhibitor beta (PKIbeta) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. Chem. 272, 20011-20020]. We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garige, Mamatha; Walters, Eric, E-mail: ewalters@howard.edu

The molecular basis for nutraceutical properties of the polyphenol curcumin (Curcuma longa, Turmeric) is complex, affecting multiple factors that regulate cell signaling and homeostasis. Here, we report the effect of curcumin on cellular and developmental mechanisms in the eukaryotic model, Dictyostelium discoideum. Dictyostelium proliferation was inhibited in the presence of curcumin, which also suppressed the prestarvation marker, discoidin I, members of the yakA-mediated developmental signaling pathway, and expression of the extracellular matrix/cell adhesion proteins (DdCAD and csA). This resulted in delayed chemotaxis, adhesion, and development of the organism. In contrast to the inhibitory effects on developmental genes, curcumin induced gstAmore » gene expression, overall GST activity, and generated production of reactive oxygen species. These studies expand our knowledge of developmental and biochemical signaling influenced by curcumin, and lends greater consideration of GST enzyme function in eukaryotic cell signaling, development, and differentiation.« less

GONADOTROPIN RELEASING HORMONE (GNRH) PARTIALLY REVERSES THE INHIBITORY EFFECT OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ON OVULATION IN THE IMMATURE GONADOTROPIN-TREATED RAT. (R826132)

EPA Science Inventory

Abstract

Several studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inhibitory effects on ovulation. This action may be the result of either direct effect(s) of TCDD on ovarian function or via altered secretion of pituitary luteinizing hormon...

Activation of Phosphoinositide Metabolism by Cholinergic Agents.

DTIC Science & Technology

1990-12-16

acid significantly inhibited NE-induced [3H]IP1 production in slices that had been prelabelled with [3H]inositol and baclofen , a specific GABAB...agonist, was as effective as GABA in enhancing the response to NE (Figure 15). Neither GABA nor baclofen significantly blocked the inhibitory effect of...quisqualate, but baclofen reduced the inhibitory effect of arachidonic acid. Effects of NMDA receptor antagonists on phosphoinositide hydrolysis MK-801 is

[Peptidergic modulation of the hippocampus synaptic activity].

PubMed

Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

2011-11-01

Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent.

Research progress on the anticancer effects of vitamin K2.

PubMed

Xv, Fan; Chen, Jiepeng; Duan, Lili; Li, Shuzhuang

2018-06-01

Despite the availability of multiple therapeutic methods for patients with cancer, the long-term prognosis is not satisfactory in a number of different cancer types. Vitamin K2 (VK2), which exerts anticancer effects on a number of cancer cell lines, is considered to be a prospective novel agent for the treatment of cancer. The present review aims to summarize the results of studies in which VK2 was administered either to patients with cancer or animals inoculated with cancerous cells, particularly investigating the inhibitory effects of VK2 on cancerous cells, primarily involving cell-cycle arrest, cell differentiation, apoptosis, autophagy and invasion. The present review summarizes evidence stating that treatment with VK2 could positively inhibit the growth of cancer cells, making it a potentially useful approach for the prevention and clinical treatment of cancer. Additionally, the combination treatment of VK2 and established chemotherapeutics may achieve better results, with fewer side effects. Therefore, more attention should be paid to the effects of micronutrients on tumors.

Joint toxicity of methamidophos and cadmium acting on Abelmoschus manihot.

PubMed

Wang, Xiao-Fei; Zhou, Qi-Xing

2005-01-01

Joint toxicity of methamidophos and cadmium (Cd) on the ornamental Abelmoschus manihot was firstly examined and compared with single-factor effects of the two pollutants using ecotoxicological indexes including the inhibitory rate of seed germination, root elongation and inhibitory concentration 50% (IC50). The results indicated that methamidophos and Cd had unobvious( p > 0.05) effects on seed germination of the ornamental. There were significant( p < 0.05) inhibitory effects of Cd on root elongation of the tested plant. When the concentration of added Cd was low( < 20 mg/L), significant antagonistic effects on root elongation were observed. And synergic effects were observed when Cd was added in high dose( > 20 mg/L). However, the analysis of joint effects indicated that there were antagonistic effects between Cd and methamidophos under all the treatments. At the high concentration of Cd, joint toxicity of methamidophos and Cd was more dependent on concentration of Cd.

Selective Attention and Inhibitory Deficits in ADHD: Does Subtype or Comorbidity Modulate Negative Priming Effects?

ERIC Educational Resources Information Center

Pritchard, Verena E.; Neumann, Ewald; Rucklidge, Julia J.

2008-01-01

Selective attention has durable consequences for behavior and neural activation. Negative priming (NP) effects are assumed to reflect a critical inhibitory component of selective attention. The performance of adolescents with Attention Deficit/Hyperactivity Disorder (ADHD) was assessed across two conceptually based NP tasks within a selective…

Inhibitory Effect of Autoclaving Whey-Based Medium on Propionic Acid Production by Propionibacterium shermanii.

PubMed

Anderson, T M; Bodie, E A; Goodman, N; Schwartz, R D

1986-02-01

Propionic acid production by Propionibacterium shermanii was compared in pasteurized and autoclaved whey-based media. Propionic acid production decreased with increasing whey concentration in autoclaved media but not in pasteurized media. Increasing the yeast extract concentration from 5 to 10 g/liter greatly reduced the inhibitory effect of autoclaving.

Evaluation of human D-amino acid oxidase inhibition by anti-psychotic drugs in vitro.

PubMed

Shishikura, Miho; Hakariya, Hitomi; Iwasa, Sumiko; Yoshio, Takashi; Ichiba, Hideaki; Yorita, Kazuko; Fukui, Kiyoshi; Fukushima, Takeshi

2014-06-01

It is of importance to determine whether antipsychotic drugs currently prescribed for schizophrenia exert D-amino acid oxidase (DAO)-inhibitory effects. We first investigated whether human (h)DAO can metabolize D-kynurenine (D-KYN) to produce the fluorescent compound kynurenic acid (KYNA) by using high-performance liquid chromatography with mass spectrometry, and fluorescence spectrometry. After confirmation of KYNA production from D-KYN by hDAO, 8 first- and second-generation antipsychotic drugs, and 6 drugs often prescribed concomitantly, were assayed for hDAO-inhibitory effects by using in vitro fluorometric methods with D-KYN as the substrate. DAO inhibitors 3-methylpyrazole-5-carboxylic acid and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid inhibited KYNA production in a dose-dependent manner. Similarly, the second-generation antipsychotics blonanserin and risperidone were found to possess relatively strong hDAO-inhibitory effects in vitro (5.29 ± 0.47 μM and 4.70 ± 0.17 μM, respectively). With regard to blonanserin and risperidone, DAO-inhibitory effects should be taken into consideration in the context of their in vivo pharmacotherapeutic efficacy.

Inhibitory effects of toxic compounds on nitrification process for cokes wastewater treatment.

PubMed

Kim, Young Mo; Park, Donghee; Lee, Dae Sung; Park, Jong Moon

2008-04-15

Cokes wastewater is one of the most toxic industrial effluents since it contains high concentrations of toxic compounds such as phenols, cyanides and thiocyanate. Although activated sludge process has been adapted to treat this wastewater, nitrification process has been occasionally upset by serious inhibitory effects of toxic compounds. In this study, therefore, we examined inhibitory effects of ammonia, thiocyanate, free cyanide, ferric cyanide, phenol and p-cresol on nitrification in an activated sludge system, and then correlated their threshold concentrations with the full-scale pre-denitrification process for treating cokes wastewater. Ammonia below 350 mg/L did not cause substrate inhibition for nitrifying bacteria. Thiocyanate above 200mg/L seemed to inhibit nitrification, but it was due to the increased loading of ammonia produced from its biodegradation. Free cyanide above 0.2mg/L seriously inhibited nitrification, but ferric cyanide below 100mg/L did not. Phenol and p-cresol significantly inhibited nitrification above 200 mg/L and 100mg/L, respectively. Meantime, activated carbon was added to reduce inhibitory effects of phenol and free cyanide.

Effects of leukemia inhibitory factor and basic fibroblast growth factor on free radicals and endogenous stem cell proliferation in a mouse model of cerebral infarction.

PubMed

Huang, Weihui; Li, Yadan; Lin, Yufeng; Ye, Xue; Zang, Dawei

2012-07-05

The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion, and monitored the effect of 25 μg/kg leukemia inhibitory factor and (or) basic fibroblast growth factor administration 2 hours after model establishment. Results showed that following administration, the number of endogenous neural stem cells in the infarct area significantly increased, malondialdehyde content in brain tissue homogenates significantly decreased, nitric oxide content, glutathione peroxidase and superoxide dismutase activity significantly elevated, and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests. In particular, the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant. Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels, improving the quantity of endogenous neural stem cells, and promoting neurological function of mice with cerebral infarction.

Chemo-enzymatic synthesis of vinyl and l-ascorbyl phenolates and their inhibitory effects on advanced glycation end products.

PubMed

Hwang, Seung Hwan; Wang, Zhiqiang; Lim, Soon Sung

2017-01-01

This study successfully established the feasibility of a two-step chemo-enzymatic synthesis of l-ascorbyl phenolates. Intermediate vinyl phenolates were first chemically produced and then underwent trans-esterification with l-ascorbic acid in the presence of Novozyme 435® (Candida Antarctica lipase B) as a catalyst. Twenty vinyl phenolates and 11 ascorbyl phenolates were subjected to in vitro bioassays to investigate their inhibitory activity against advanced glycation end products (AGEs). Among them, vinyl 4-hydroxycinnamate (17VP), vinyl 4-hydroxy-3-methoxycinnamate (18VP), vinyl 4-hydroxy-3,5-dimethoxycinnamate (20VP), ascorbyl 4-hydroxy-3-methoxycinnamate (18AP) and ascorbyl 3,4-dimethoxycinnamate (19AP) showed 2-10 times stronger inhibitory activities than positive control (aminoguanidine and its precursors). These results indicated that chemo-enzymatically synthesized compounds have AGE inhibitory effect and thus are effective in either preventing or retarding glycation protein formation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Inhibitory effect of selective cyclooxygenase-2 inhibitor etoricoxib on human organic anion transporter 3 (hOAT3).

PubMed

Honjo, Hiroaki; Uwai, Yuichi; Iwamoto, Kikuo

2011-04-01

It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) delay the elimination of methotrexate. One of the mechanisms is thought to be inhibition of methotrexate uptake via human organic anion transporter 3 (hOAT3, SLC22A8) in the renal proximal tubule by NSAIDs. In this study, we evaluated the inhibitory effects of selective cyclooxygenase-2 inhibitor etoricoxib on hOAT3 by uptake experiments using Xenopus laevis oocytes. The injection of hOAT3 cRNA stimulated the uptake of methotrexate into the oocytes, and its transport was inhibited by etoricoxib. Etoricoxib inhibited estrone sulfate uptake by hOAT3 dose dependently, and the 50% inhibitory concentration was estimated to be 9.8 µM. Eadie-Hofstee plot analysis showed that etoricoxib inhibited hOAT3 in a competitive manner. These findings show that etoricoxib has inhibitory effect on hOAT3, and that the potential is comparable to that of traditional NSAIDs. ©2011 Bentham Science Publishers Ltd.

Extract from Nandina domestica inhibits lipopolysaccharide-induced cyclooxygenase-2 expression in human pulmonary epithelial A549 cells.

PubMed

Ueki, Takuro; Akaishi, Tatsuhiro; Okumura, Hidenobu; Abe, Kazuho

2012-01-01

Extract from fruits of Nandina domestica THUNBERG (NDE) has been used to improve cough and breathing difficulty in Japan for many years. To explore whether NDE may alleviate respiratory inflammation, we investigated its effect on expression of cyclooxygenase-2 (COX-2) and production of prostaglandin E₂ (PGE₂) in human pulmonary epithelial A549 cells in culture. Treatment with lipopolysaccharide (LPS; 6 µg/mL) resulted in an increase of COX-2 expression and PGE₂ production in A549 cells. Both the LPS-induced COX-2 expression and PGE₂ production were significantly inhibited by NDE (1-10 µg/mL) in a concentration-dependent manner. NDE did not affect COX-1 expression nor COX activity. These results suggest that NDE downregulates LPS-induced COX-2 expression and inhibits PGE₂ production in pulmonary epithelial cells. Furthermore, higenamine and nantenine, two major constituents responsible for tracheal relaxing effect of NDE, did not mimic the inhibitory effect of NDE on LPS-induced COX-2 expression in A549 cells. To identify active constituent(s) of NDE responsible for the anti-inflammatory effect, NDE was introduced in a polyaromatic absorbent resin column and stepwise eluted to yield water fraction, 20% methanol fraction, 40% methanol fraction, 99.8% methanol fraction, and 99.5% acetone fraction. However, none of these five fractions alone inhibited LPS-induced COX-2 expression. On the other hand, exclusion of water fraction from NDE abolished the inhibitory effect of NDE on LPS-induced COX-2 expression. These results suggest that constituent(s) present in water fraction is required but not sufficient for the anti-inflammatory activity of NDE, which may result from interactions among multiple constituents.

Comparable effects of low-intensity electromagnetic irradiation at the frequency of 51.8 and 53 GHz and antibiotic ceftazidime on Lactobacillus acidophilus growth and survival.

PubMed

Soghomonyan, Diana; Trchounian, Armen

2013-01-01

The effects of low-intensity electromagnetic irradiation (EMI) with the frequencies of 51.8 and 53 GHz on Lactobacillus acidophilus growth and survival were revealed. These effects were compared with antibacterial effects of antibiotic ceftazidime. Decrease in bacterial growth rate by EMI was comparable with the inhibitory effect of ceftazidime (minimal inhibitory concentration-16 μM) and no enhanced action was observed with combined effects of EMI and the antibiotic. However, EMI-enhanced antibiotic inhibitory effect on bacterial survival. The kinetics of the bacterial suspension oxidation-reduction potential up to 24 h of the growth was changed by EMI and ceftazidime. The changes were more strongly expressed by combined effects of EMI and antibiotic especially up to 12 h. Moreover, EMI did not change overall energy (glucose)-dependent H(+) efflux across the membrane but it increased N,N'-dicyclohexylcarbodiimide (DCCD)-inhibited H(+) efflux. In contrast, this EMI in combination with ceftazidime decreased DCCD-sensitive H(+) efflux. Low-intensity EMI had inhibitory effect on L. acidophilus bacterial growth and survival. The effect on bacterial survival was more significant in the combination with ceftazidime. The H(+)-translocating F 0 F 1-ATPase, for which DCCD is specific inhibitor, might be a target for EMI and ceftazidime. The revealed bactericide effects on L. acidophilus can be applied in biotechnology, food producing and safety technology.

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses

PubMed Central

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-01-01

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage. PMID:27021285

Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses.

PubMed

Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

2016-03-29

γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage.

An event-related potential investigation of the acute effects of aerobic and coordinative exercise on inhibitory control in children with ADHD.

PubMed

Ludyga, Sebastian; Brand, Serge; Gerber, Markus; Weber, Peter; Brotzmann, Mark; Habibifar, Fahimeh; Pühse, Uwe

2017-12-01

The current body of evidence suggests that an aerobic exercise session has a beneficial effect on inhibitory control, whereas the impact of coordinative exercise on this executive function has not yet been examined in children with ADHD. Therefore, the present study aims to investigate the acute effects of aerobic and coordinative exercise on behavioral performance and the allocation of attentional resources in an inhibitory control task. Using a cross-over design, children with ADHD-combined type and healthy comparisons completed a Flanker task before and after 20min moderately-intense cycling exercise, coordinative exercise and an inactive control condition. During the task, stimulus-locked event-related potentials were recorded with electroencephalography. Both groups showed an increase of P300 amplitude and decrease of reaction time after exercise compared to the control condition. Investigating the effect of exercise modality, aerobic exercise led to greater increases of P300 amplitude and reductions in reaction time than coordinative exercise in children with ADHD. The findings suggest that a single exercise bout improves inhibitory control and the allocation of attentional resources. There were some indications that an aerobic exercise session seems to be more efficient than coordinative exercise in reducing the inhibitory control deficits that persist in children with ADHD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics.

PubMed

Harris, Kenneth D; Hochgerner, Hannah; Skene, Nathan G; Magno, Lorenza; Katona, Linda; Bengtsson Gonzales, Carolina; Somogyi, Peter; Kessaris, Nicoletta; Linnarsson, Sten; Hjerling-Leffler, Jens

2018-06-18

Understanding any brain circuit will require a categorization of its constituent neurons. In hippocampal area CA1, at least 23 classes of GABAergic neuron have been proposed to date. However, this list may be incomplete; additionally, it is unclear whether discrete classes are sufficient to describe the diversity of cortical inhibitory neurons or whether continuous modes of variability are also required. We studied the transcriptomes of 3,663 CA1 inhibitory cells, revealing 10 major GABAergic groups that divided into 49 fine-scale clusters. All previously described and several novel cell classes were identified, with three previously described classes unexpectedly found to be identical. A division into discrete classes, however, was not sufficient to describe the diversity of these cells, as continuous variation also occurred between and within classes. Latent factor analysis revealed that a single continuous variable could predict the expression levels of several genes, which correlated similarly with it across multiple cell types. Analysis of the genes correlating with this variable suggested it reflects a range from metabolically highly active faster-spiking cells that proximally target pyramidal cells to slower-spiking cells targeting distal dendrites or interneurons. These results elucidate the complexity of inhibitory neurons in one of the simplest cortical structures and show that characterizing these cells requires continuous modes of variation as well as discrete cell classes.

Hunger, inhibitory control and distress-induced emotional eating.

PubMed

van Strien, Tatjana; Ouwens, Machteld A; Engel, Carmen; de Weerth, Carolina

2014-08-01

Self-reported emotional eating has been found to significantly moderate distress-induced food intake, with low emotional eaters eating less after a stress task than after a control task and high emotional eaters eating more. The aim of the present study was to explore possible underlying mechanisms by assessing possible associations with (1) ability to experience the typical post-stress reduction of hunger and (2) inhibitory control. We studied these effects in 54 female students who were preselected on the basis of extremely high or low scores on an emotional eating questionnaire. Using a within subject design we measured the difference of actual food or snack intake after a control or a stress task (Trier Social Stress Test). As expected, the moderator effect of emotional eating on distress-induced food intake was found to be only present in females with a failure to report the typical reduction of hunger immediately after a stress task (an a-typical hunger stress response). Contrary to our expectations, this moderator effect of emotional eating was also found to be only present in females with high ability to stop motor impulses (high inhibitory control). These findings suggest that an a-typical hunger stress response but not poor inhibitory control may underlie the moderator effect of emotional eating on distress-induced food intake. However, inhibitory control may play a role whether or not there is a moderator effect of self-reported emotional eating on distress-induced food intake. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of Heterogeneity on Decorrelation Mechanisms in Spiking Neural Networks: A Neuromorphic-Hardware Study

NASA Astrophysics Data System (ADS)

Pfeil, Thomas; Jordan, Jakob; Tetzlaff, Tom; Grübl, Andreas; Schemmel, Johannes; Diesmann, Markus; Meier, Karlheinz

2016-04-01

High-level brain function, such as memory, classification, or reasoning, can be realized by means of recurrent networks of simplified model neurons. Analog neuromorphic hardware constitutes a fast and energy-efficient substrate for the implementation of such neural computing architectures in technical applications and neuroscientific research. The functional performance of neural networks is often critically dependent on the level of correlations in the neural activity. In finite networks, correlations are typically inevitable due to shared presynaptic input. Recent theoretical studies have shown that inhibitory feedback, abundant in biological neural networks, can actively suppress these shared-input correlations and thereby enable neurons to fire nearly independently. For networks of spiking neurons, the decorrelating effect of inhibitory feedback has so far been explicitly demonstrated only for homogeneous networks of neurons with linear subthreshold dynamics. Theory, however, suggests that the effect is a general phenomenon, present in any system with sufficient inhibitory feedback, irrespective of the details of the network structure or the neuronal and synaptic properties. Here, we investigate the effect of network heterogeneity on correlations in sparse, random networks of inhibitory neurons with nonlinear, conductance-based synapses. Emulations of these networks on the analog neuromorphic-hardware system Spikey allow us to test the efficiency of decorrelation by inhibitory feedback in the presence of hardware-specific heterogeneities. The configurability of the hardware substrate enables us to modulate the extent of heterogeneity in a systematic manner. We selectively study the effects of shared input and recurrent connections on correlations in membrane potentials and spike trains. Our results confirm that shared-input correlations are actively suppressed by inhibitory feedback also in highly heterogeneous networks exhibiting broad, heavy-tailed firing-rate distributions. In line with former studies, cell heterogeneities reduce shared-input correlations. Overall, however, correlations in the recurrent system can increase with the level of heterogeneity as a consequence of diminished effective negative feedback.

Membrane vesicles shed by oligodendroglioma cells induce neuronal apoptosis.

PubMed

D'Agostino, Stefania; Salamone, Monica; Di Liegro, Italia; Vittorelli, M Letizia

2006-11-01

In order to investigate the mechanism by which oligodendrogliomas cause neuronal damage, media conditioned by G26/24 oligodendroglioma cells, were fractionated into shed vesicles and vesicle-free supernatants, and added to primary cultures of rat fetal cortical neurons. After one night treatment with vesicles, a reproducible, dose-dependent, inhibitory effect on neurite outgrowth was already induced and, after 48-72 h of incubation, neuronal apoptosis was evident. Vesicle-free supernatants and vesicles shed by NIH-3T3 cells had no inhibitory effects on neurons. Western blot analyses showed that treated neurons expressed a decreased amount of neurofilament (NF), growth-associated protein (GAP-43) and microtubule-associated protein (MAP-2). Moreover procaspase-3 and -8 were activated while Bcl-2 expression was reduced. Vesicles were found positive for the proapoptotic molecule, Fas-ligand (Fas-L), and for the B isoform of Nogo protein, a myelin component with inhibitory effects on neurons. Nogo B involvement in the vesicle effects was analyzed both by testing the neutralizing capability of anti-Nogo antibodies and by removing the Nogo receptor from neurons by phospholipase C digestion. These treatments did not revert the vesicle effects. To test the role of Fas-L, vesicles were treated with functional anti-Fas-L monoclonals. Vesicle inhibitory and proapoptotic effects were reduced. Vesicles shed by ovarian carcinoma cells (OvCa), which are known to vehicle biologically active Fas-L, had similar effects on neurons to those of oligodendroglioma vesicles, and their inhibitory effects were also reduced by anti Fas-L antibodies. We therefore conclude that vesicles shed by G26/24 cells induce neuronal apoptosis at least partially by a Fas-L mediated mechanism.

Effects of Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) on contractile activity of circular smooth muscle of the rat distal colon.

PubMed

Kito, Yoshihiko; Teramoto, Noriyoshi

2012-11-01

The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 μM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility.

Beta-interferon inhibits cell infection by Trypanosoma cruzi

NASA Technical Reports Server (NTRS)

Kierszenbaum, F.; Sonnenfeld, G.

1984-01-01

Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

Essential Oils from Ugandan Aromatic Medicinal Plants: Chemical Composition and Growth Inhibitory Effects on Oral Pathogens

PubMed Central

Ocheng, Francis; Bwanga, Freddie; Joloba, Moses; Softrata, Abier; Azeem, Muhammad; Pütsep, Katrin; Borg-Karlson, Anna-Karin; Obua, Celestino; Gustafsson, Anders

2015-01-01

The study assessed the growth inhibitory effects of essential oils extracted from ten Ugandan medicinal plants (Bidens pilosa, Helichrysum odoratissimum, Vernonia amygdalina, Hoslundia opposita, Ocimum gratissimum, Cymbopogon citratus, Cymbopogon nardus, Teclea nobilis, Zanthoxylum chalybeum, and Lantana trifolia) used traditionally in the management of oral diseases against oral pathogens. Chemical compositions of the oils were explored by GC-MS. Inhibitory effects of the oils were assessed on periodontopathic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans and cariogenic Streptococcus mutans and Lactobacillus acidophilus using broth dilution methods at concentrations of 1%, 0.1%, and 0.01%. The most sensitive organism was A. actinomycetemcomitans. Its growth was markedly inhibited by six of the oils at all the concentrations tested. Essential oil from C. nardus exhibited the highest activity with complete growth inhibition of A. actinomycetemcomitans and P. gingivalis at all the three concentrations tested, the major constituents in the oil being mainly oxygenated sesquiterpenes. Most of the oils exhibited limited effects on L. acidophilus. We conclude that essential oils from the studied plants show marked growth inhibitory effects on periodontopathic A. actinomycetemcomitans and P. gingivalis, moderate effects on cariogenic S. mutans, and the least effect on L. acidophilus. The present study constitutes a basis for further investigations and development of certain oils into alternative antiplaque agents. PMID:26170872

What Do We Really Know about Cognitive Inhibition? Task Demands and Inhibitory Effects across a Range of Memory and Behavioural Tasks

PubMed Central

Noreen, Saima; MacLeod, Malcolm D.

2015-01-01

Our study explores inhibitory control across a range of widely recognised memory and behavioural tasks. Eighty-seven never-depressed participants completed a series of tasks designed to measure inhibitory control in memory and behaviour. Specifically, a variant of the selective retrieval-practice and the Think/No-Think tasks were employed as measures of memory inhibition. The Stroop-Colour Naming and the Go/No-Go tasks were used as measures of behavioural inhibition. Participants completed all 4 tasks. Task presentation order was counterbalanced across 3 separate testing sessions for each participant. Standard inhibitory forgetting effects emerged on both memory tasks but the extent of forgetting across these tasks was not correlated. Furthermore, there was no relationship between memory inhibition tasks and either of the main behavioural inhibition measures. At a time when cognitive inhibition continues to gain acceptance as an explanatory mechanism, our study raises fundamental questions about what we actually know about inhibition and how it is affected by the processing demands of particular inhibitory tasks. PMID:26270470

High-disinhibition restrained eaters are disinhibited by self-regulatory depletion in the food-related inhibitory control.

PubMed

Zhou, Yizhou; Gao, Xiao; Chen, Hong; Kong, Fanchang

2017-08-01

Restrained eating for weight control and loss is becoming highly prevalent in many affluent societies, while most of the restrained eaters are rather unsuccessful in the long term. According to the strength model of self-control, the disinhibition effect of restrained eaters may occur after the depletion of self-control resources. However, no work has examined the direct impact of self-control resources on inhibitory control ability of restrained eaters. This study investigated the influences of self-control resources on the food-related inhibitory control among high-restraint/low-disinhibition restrained eaters, high-restraint/high-disinhibition restrained eaters and unrestrained eaters using stop signal task. Results reveal that there's no difference of food-related inhibitory control between three groups when the self-control resources are non-depleted, while high-restraint/high-disinhibition restrained eaters showing a decrease of food-related inhibitory control after ego-depletion. This disinhibition effect only seems to occur in samples of restrained eaters with a high tendency toward overeating. Copyright © 2017 Elsevier Ltd. All rights reserved.

What Do We Really Know about Cognitive Inhibition? Task Demands and Inhibitory Effects across a Range of Memory and Behavioural Tasks.

PubMed

Noreen, Saima; MacLeod, Malcolm D

2015-01-01

Our study explores inhibitory control across a range of widely recognised memory and behavioural tasks. Eighty-seven never-depressed participants completed a series of tasks designed to measure inhibitory control in memory and behaviour. Specifically, a variant of the selective retrieval-practice and the Think/No-Think tasks were employed as measures of memory inhibition. The Stroop-Colour Naming and the Go/No-Go tasks were used as measures of behavioural inhibition. Participants completed all 4 tasks. Task presentation order was counterbalanced across 3 separate testing sessions for each participant. Standard inhibitory forgetting effects emerged on both memory tasks but the extent of forgetting across these tasks was not correlated. Furthermore, there was no relationship between memory inhibition tasks and either of the main behavioural inhibition measures. At a time when cognitive inhibition continues to gain acceptance as an explanatory mechanism, our study raises fundamental questions about what we actually know about inhibition and how it is affected by the processing demands of particular inhibitory tasks.

Dieckol, a phlorotannin isolated from a brown seaweed, Ecklonia cava, inhibits adipogenesis through AMP-activated protein kinase (AMPK) activation in 3T3-L1 preadipocytes.

PubMed

Ko, Seok-Chun; Lee, Myoungsook; Lee, Ji-Hyeok; Lee, Seung-Hong; Lim, Yunsook; Jeon, You-Jin

2013-11-01

In this study, we assessed the potential inhibitory effect of 5 species of brown seaweeds on adipogenesis the differentiation of 3T3-L1 preadipocytes into mature adipocytes by measuring Oil-Red O staining. The Ecklonia cava extract tested herein evidenced profound adipogenesis inhibitory effect, compared to that exhibited by the other four brown seaweed extracts. Thus, E. cava was selected for isolation of active compounds and finally the three polyphenol compounds of phlorotannins were obtained and their inhibitory effect on adipogenesis was observed. Among the phlorotannins, dieckol exhibited greatest potential adipogenesis inhibition and down-regulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding proteins (C/EBPα), sterol regulatory element-binding protein 1 (SREBP1) and fatty acid binding protein 4 (FABP4) in a dose-dependent manner. The specific mechanism mediating the effects of dieckol was confirmed by AMP-activated protein kinase (AMPK) activation. These results demonstrate inhibitory effect of dieckol compound on adipogenesis through the activation of the AMPK signal pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Antioxidant effects of 14 Chinese traditional medicinal herbs against human low-density lipoprotein oxidation.

PubMed

Lin, Hsin-Hung; Charles, Albert Linton; Hsieh, Chang-Wei; Lee, Ya-Chi; Ciou, Jhih-Ying

2015-01-01

The relationship between the antioxidant activities and inhibitory effect of 14 Chinese medicinal herbs against oxidized low-density lipoprotein (LDL) formation was evaluated. Prolongation of the lag phase of LDL oxidation depended on the concentration of the herbs. The concentration of each herb that was able to prolong the lag time by about two-fold was calculated and expressed as doubling-time concentration. The lower the doubling-time concentration, the stronger the inhibitory effect exhibited toward LDL oxidation. Among them, Chrysanthemi Flos (Chrysanthemum morifolium ramat; gān jú huā), Crataegi Fructus (Crataegus pinnatifida Bge. var. major N.E.Br.; shān zhā), and Roselle (Hibiscus sabdariffa Linn.; luò shén) showed significant inhibitory effects. Correlation coefficients between doubling-time concentration and radical-scavenging activities were high; the total phenolic content was also high. In conclusion, phenolic compounds contributed not only to antioxidant activities, but also to the inhibitory effect against LDL oxidation. Chrysanthemi Flos, Crataegi Fructus, and H. sabdariffa, with lower doubling-time concentrations, could be potent phytochemical agents to reduce LDL oxidation and prevent the progression of atherosclerosis.

Spice phenolics inhibit human PMNL 5-lipoxygenase.

PubMed

Prasad, N Satya; Raghavendra, R; Lokesh, B R; Naidu, K Akhilender

2004-06-01

A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.

The inhibitory effect of the various seed coating substances against rice seed borne fungi and their shelf-life during storage.

PubMed

Thobunluepop, Pitipong

2009-08-15

Presently, chemical seed treatments are in discussion due to their directly or indirectly impacts on human health or other living organisms. They may also negatively affect the ecosystem and the food chain. In rice seeds, chemicals may cause phytotoxic effects including seed degradation. Eugenol is the main component of clove (Eugenia caryophillis) oil, which was proved to act simultaneously as bactericide, virocide and especially fungicide. The in vitro study was aimed to compare the inhibitory effect of the following seed treatment substances against seed borne fungi and their shelf-life during 12 months of storage; conventional captan (CA), chitosan-lignosulphonate polymer (CL), eugenol incorporated into chitosan-lignosulphonate polymer (E+CL) and control (CO). The obtained results of fungi inhibition were classified in three groups, which showed at first that CA treatment led to a better, i.e., longer, inhibitory effect on Alternaria padwickii, Rhizoctonia solani, Curvularia sp., Aspergillus flavus and Aspergillus niger than E+CL. Secondly, E+CL coating polymer showed the longest inhibitory effect against Bipolaris oryzae and Nigrospora oryzae compared to CA and CL coating polymer. Finally, both CA and E+CL coating polymer had non-significant difference inhibitory effect on Fusarium moniliforme. The variant of CL coating polymer for seed coating was only during the first 6 months of storage able to inhibit all species of the observed seed borne fungi, whereas CA and E+CL coating polymer were capable to inhibit most of the fungi until 9 months of storage.

Effects of chalcone derivatives on lipoxygenase and cyclooxygenase activities of mouse epidermis.

PubMed

Nakadate, T; Aizu, E; Yamamoto, S; Kato, R

1985-09-01

The effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis were investigated. The chalcone derivatives which have 3,4-dihydroxycinnamoyl structure in the molecule, such as 3,4-dihydroxychalcone, 3,4,2'-trihydroxychalcone, 3,4,4'-trihydroxychalcone and 3,4,2'4'-tetrahydroxychalcone, potently inhibited epidermal 12-lipoxygenase activity. Although some of them also inhibited cyclooxygenase activity at relatively high concentrations, the inhibitory effects of these chalcone derivatives on 12-lipoxygenase were 10 times or more potent than their effects on cyclooxygenase. The chalcone derivatives which have cinnamoyl or 4-hydroxycinnamoyl structure, instead of 3,4-dihydroxycinnamoyl structure, in the molecule, showed little or no inhibitory effects on either 12-lipoxygenase or cyclooxygenase activities. The inhibitory effects of chalcone derivatives on 12-lipoxygenase and cyclooxygenase of mouse epidermis are dependent on the particular structure, i.e. 3,4-dihydroxycinnamoyl structure, of the chalcone derivatives.

Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund's adjuvant (CFA).

PubMed

Lin, C-R; Cheng, J-K; Wu, C-H; Chen, K-H; Liu, C-K

2017-02-01

Multiple mechanisms contribute to the stimulus-evoked pain hypersensitivity that may be experienced after peripheral inflammation. Persistent pathological stimuli in many pain conditions affect the expression of certain genes through epigenetic alternations. The main purpose of our study was to investigate the role of epigenetic modification on potassium-chloride co-transporter 2 (KCC2) gene expression in the persistence of inflammatory pain. Persistent inflammatory pain was induced through the injection of complete Freund's adjuvant (CFA) in the left hind paw of rats. Acetyl-histone H3 and H4 level was determined by chromatin immunoprecipitation in the spinal dorsal horn. Pain behaviour and inhibitory synaptic function of spinal cord were determined before and after CFA injection. KCC2 expression was determined by real time RT-PCR and Western blot. Intrathecal KCC2 siRNA (2 μg per 10 μL per rat) or HDAC inhibitor (10 μg per 10 μL per rat) was injected once daily for 3 days before CFA injection. Persistent inflammatory pain epigenetically suppressed KCC2 expression through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in decreased inhibitory signalling efficacy. KCC2 knock-down caused by intrathecal administration of KCC2 siRNA in naïve rats reduced KCC2 expression in the spinal cord, leading to sensitized pain behaviours and impaired inhibitory synaptic transmission in their spinal cords. Moreover, intrathecal HDAC inhibitor injection in CFA rats increased KCC2 expression, partially restoring the spinal inhibitory synaptic transmission and relieving the sensitized pain behaviour. These findings suggest that the transcription of spinal KCC2 is regulated by histone acetylation epigenetically following CFA. Persistent pain suppresses KCC2 expression through HDAC-mediated histone hypoacetylation and consequently impairs the inhibitory function of inhibitory interneurons. Drugs such as HDAC inhibitors that suppress the influences of persistent pain on the expression of KCC2 may serve as a novel analgesic. © 2016 European Pain Federation - EFIC®.

Constituents of PG201 (Layla(®)), a multi-component phytopharmaceutical, with inhibitory activity on LPS-induced nitric oxide and prostaglandin E2 productions in macrophages.

PubMed

Kim, Hyun Ji; Kim, Hye Mi; Ryu, Byeol; Lee, Woo-Seok; Shin, Ji-Sun; Lee, Kyung-Tae; Jang, Dae Sik

2016-02-01

Fourteen compounds, coumarin (1), demethylsuberosin (2), xanthotoxin (3), psoralen (4), decursinol (5), decursin (6), decursinol angelate (7), chikusetsusaponin IVa (8), chikusetsusaponin IVa methyl ester (9), ethyl caffeate (10), syringaresinol (11), cnidilide (12), farnesol (13), and linoleic acid (14), were isolated from phytopharmaceutical PG201 (Layla(®)) by activity-guided fractionation utilizing inhibitory activity on nitric oxide (NO) production in vitro. The isolates 1-14 were evaluated for their inhibitory activity on LPS-induced NO and prostaglandin E2 (PGE2) productions in RAW 264.7 cells. All the compounds except 14 displayed suppressive effects on LPS-induced NO and PGE2 production with IC50 values ranging from 8 to 60 μM. Among these, compound 10 showed the most potent inhibitory effect on NO production from RAW 264.7 cells with an IC50 value of 8.25 μM. Compounds 2, 9, and 10 exhibited high inhibitory effects on PGE2 production with the IC50 values of 9.42, 7.51, and 6.49 μM, respectively. These findings suggest that compounds 2, 9, and 10 are the potential anti-inflammatory active constituents of PG201 and further study may be needed to explain their mechanism of action.

A cyclohexanecarboxamide derivative with inhibitory effects on Schistosoma mansoni cercarial serine protease and penetration of mice skin by the parasite.

PubMed

Bahgat, Mahmoud; Aboul-Enein, Mohamed N; El Azzouny, Aida A; Maghraby, Amany; Ruppel, Andreas; Soliman, Wael M

2009-01-01

A cyclohexanecarboxamide derivative, N-phenyl-N-[1-(piperidine-1-carbonyl)cyclohexyl] benzamide (MNRC-5), was evaluated for its inhibitory effects on Schistosoma mansoni cercarial serine protease activity and cercarial penetration. MNRC-5 exerted an inhibitory effect on S. mansoni cercarial serine protease at serial concentrations of the specific chromogenic substrate Boc-Val-Leu-Gly-Arg-PNA for such enzyme family and the inhibitory coefficient (Ki) value was deduced. Moreover, topical treatment of mice tails with the most potent inhibitory concentration of MNRC-5 formulated in jojoba oil successfully blocked cercarial penetration as demonstrated by a significant reduction (75%; p < 0.05) in the recovered S. mansoni worms from treated mice in comparison to control ones whose tails were painted with jojoba oil base containing no MNRC-5. In addition, the IgM and IgG reactivities to crude S. mansoni cercarial, worm and egg antigens were generally lower in sera from treated infected mice than untreated infected mice. In conclusion, we report on a new serine protease inhibitor capable for blocking penetration of host skin by S. mansoni cercariae as measured by lowering worm burden and decrease in the levels of both IgM and IgG towards different bilharzial antigens upon topical treatment.

Cholinesterase inhibitory effects of Rhizophora lamarckii, Avicennia officinalis, Sesuvium portulacastrum and Suaeda monica: Mangroves inhabiting an Indian coastal area (Vellar Estuary).

PubMed

Suganthy, Natarajan; Pandian, Shanmugiahthevar Karutha; Devi, Kasi Pandima

2009-06-01

Alzheimer's disease is a progressive neurodegenerative illness accounting for approximately 50% of all types of dementia in elderly people. The only symptomatic treatment proven effective to date is the use of cholinesterase inhibitors to augment surviving cholinergic activity. The purpose of this study is to investigate cholinesterase inhibitory activity of mangroves as an alternative medicine for the treatment of Alzheimer's disease. About nine mangrove plants, which were used as folk medicine in tropical countries, were collected from Parangipettai, Vellar estuary, Tamilnadu, India. Nile Tilapia muscle homogenate was used as source of enzyme. Inhibitory effect of methanolic leaf extract was assessed under in vitro condition by incubating various concentration of the extract with total cholinesterase and butyryl cholinesterase and assessing their residual activities by Ellman's colorimetric method. The results showed that of the nine plants screened Rhizophora lamarckii, Suaeda monica, Avicennia officinalis and Sesuvium portulacastrum showed 50% inhibitory activity to both TChE and BChE at concentrations less than 2 mg/mL when compared to other plant extracts, which was comparable to the standard drug Donepezil. Phytochemical analysis showed the presence of alkaloids in high concentration which might be correlated to its cholinesterase inhibitory activity.

Acute effect of vigorous aerobic exercise on the inhibitory control in adolescents

PubMed Central

Browne, Rodrigo Alberto Vieira; Costa, Eduardo Caldas; Sales, Marcelo Magalhães; Fonteles, André Igor; de Moraes, José Fernando Vila Nova; Barros, Jônatas de França

2016-01-01

Abstract Objective: To assess the acute effect of vigorous aerobic exercise on the inhibitory control in adolescents. Methods: Controlled, randomized study with crossover design. Twenty pubertal individuals underwent two 30-minute sessions: (1) aerobic exercise session performed between 65% and 75% of heart rate reserve, divided into 5 min of warm-up, 20 min at the target intensity and 5 min of cool down; and (2) control session watching a cartoon. Before and after the sessions, the computerized Stroop test-Testinpacs™ was applied to evaluate the inhibitory control. Reaction time (ms) and errors (n) were recorded. Results: The control session reaction time showed no significant difference. On the other hand, the reaction time of the exercise session decreased after the intervention (p<0.001). The number of errors made at the exercise session were lower than in the control session (p=0.011). Additionally, there was a positive association between reaction time (Δ) of the exercise session and age (r 2=0.404, p=0.003). Conclusions: Vigorous aerobic exercise seems to promote acute improvement in the inhibitory control in adolescents. The effect of exercise on the inhibitory control performance was associated with age, showing that it was reduced at older age ranges. PMID:26564328

Aversive and non-aversive memory impairment in the mucopolysaccharidosis II mouse model.

PubMed

Azambuja, Amanda Stapenhorst; Correa, Lilian; Gabiatti, Bernardo Pappi; Martins, Giselle Renata; de Oliveira Franco, Álvaro; Ribeiro, Maria Flávia Marques; Baldo, Guilherme

2018-02-01

Hunter syndrome (MPS II, OMIM 309900) is a lysosomal storage disorder due to deficient iduronate sulphatase activity. Patients present multiple cognitive alterations, and the aim of this work was to verify if MPS II mice also present some progressive cognitive alterations. For that, MPS II mice from 2 to 6 months of age were submitted to repeated open field and inhibitory avoidance tests to evaluate memory parameters. MPS II mice presented impaired memory at 6 months evaluated by open field test. They also performed poorly in the inhibitory avoidance test from 4 months. We conclude that MPS II mice develop cognitive alterations as the disease progresses. These tests can be used in the future to study the efficacy of therapeutic approaches in the central nervous system.

New Chimeric Antigen Receptor Design for Solid Tumors

PubMed Central

Wang, Yuedi; Luo, Feifei; Yang, Jiao; Zhao, Chujun; Chu, Yiwei

2017-01-01

In recent years, chimeric antigen receptor (CAR) T-cell therapy has become popular in immunotherapy, particularly after its tremendous success in the treatment of lineage-restricted hematologic cancers. However, the application of CAR T-cell therapy for solid tumors has not reached its full potential because of the lack of specific tumor antigens and inhibitory factors in suppressive tumor microenvironment (TME) (e.g., programmed death ligand-1, myeloid-derived suppressor cells, and transforming growth factor-β). In this review, we include some limitations in CAR design, such as tumor heterogeneity, indefinite spatial distance between CAR T-cell and its target cell, and suppressive TME. We also summarize some new approaches to overcome these hurdles, including targeting neoantigens and/or multiple antigens at once and depleting some inhibitory factors. PMID:29312360

Nicotine depresses the functions of multiple cardiac potassium channels.

PubMed

Wang, H; Shi, H; Wang, Z

1999-01-01

Nicotine is the main constituent of tobacco smoke responsible for the elevated risk of the cardiovascular disease and sudden coronary death associated with smoking, presumably by provoking cardiac arrhythmias. The cellular mechanisms may be related to the ability of nicotine to prolong action potentials and to depolarize membrane potential. However, the underlying ionic mechanisms remained unknown. We showed here that nicotine blocked multiple types of K+ currents, including the native currents in canine ventricular myocytes and the cloned channels expressed in Xenopus oocytes: A-type K+ currents (I(to)/Kv4.3), delayed rectifier K+ currents (I(Kr)/HERG) and inward rectifier K+ currents (I(K1)/Kir2.1). Most noticeably, nicotine at a concentration as low as of 10 nM significantly suppressed I(to) and Kv4.3 by approximately 20%. The effects of nicotine were independent of nicotinic receptor simulation or catecholamine release. Our results indicate that nicotine is a non-specific blocker of K+ channels and the inhibitory effects are the consequence of direct interactions between nicotine molecules and the channel proteins. Our study provided for the first time the evidence for the direct inhibition of cardiac K+ channels by nicotine and established a novel aspect of nicotine pharmacology.

Bombesin administration impairs memory and does not reverse memory deficit caused by sleep deprivation.

PubMed

Ferreira, L B T; Oliveira, S L B; Raya, J; Esumi, L A; Hipolide, D C

2017-07-28

Sleep deprivation impairs performance in emotional memory tasks, however this effect on memory is not completely understood. Possible mechanisms may involve an alteration in neurotransmission systems, as shown by the fact that many drugs that modulate neural pathways can prevent memory impairment by sleep loss. Gastrin releasing peptide (GRP) is a neuropeptide that emerged as a regulatory molecule of emotional memory through the modulation of other neurotransmission systems. Thus, the present study addressed the effect of intraperitoneal (IP) administration of bombesin (BB) (2.5, 5.0 and 10.0μg/kg), a GRP agonist, on the performance of Wistar rats in a multiple trail inhibitory avoidance (MTIA) task, after sleep deprivation, using the modified multiple platforms method (MMPM). Sleep deprived animals exhibited acquisition and retention impairment that was not prevented by BB injection. In addition, non-sleep deprived animals treated with BB before and after the training session, but not before the test, have shown a retention deficit. In summary, BB did not improve the memory impairment by sleep loss and, under normal conditions, produced a memory consolidation deficit. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: comparison between RU486 and a new 21-substituted-19-nor-progestin.

PubMed

Wiehle, Ronald D; Christov, Konstantin; Mehta, Rajendra

2007-07-01

In this report, we evaluate the effects of a 21-substituted-19-nor-progestin, CDB-4124, on 7,12,-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats in comparison with RU486. Sprague-Dawley female rats were treated with DMBA at 50 days of age in order to induce mammary tumors. When the tumors reached the size of 10-12 mm, the animals were treated for 28 days with the vehicle, RU486, progesterone, CDB-4124 at various doses, or CDB-4124 plus progesterone. Anti-progestins resulted in the regression in the size of the existing tumors, and in the suppressed development of new tumors and tumor multiplicity. Progesterone treatment, however, increased the size and multiplicity. Progesterone rendered an increased number of growing tumors as compared to the regression in the anti-progesterone treatment groups. The combination of CDB-4124 and high doses of progesterone opposed the efficacy of CDB-4124. The growth inhibitory effects of the anti-progestins were correlated with increased apoptosis and reduced cell proliferation. These results indicate that anti-progestins should be developed for the chemoprevention and treatment of hormone-responsive breast cancer.

Bacillus species (BT42) isolated from Coffea arabica L. rhizosphere antagonizes Colletotrichum gloeosporioides and Fusarium oxysporum and also exhibits multiple plant growth promoting activity.

PubMed

Kejela, Tekalign; Thakkar, Vasudev R; Thakor, Parth

2016-11-18

Colletotrichum and Fusarium species are among pathogenic fungi widely affecting Coffea arabica L., resulting in major yield loss. In the present study, we aimed to isolate bacteria from root rhizosphere of the same plant that is capable of antagonizing Colletotrichum gloeosporioides and Fusarium oxysporum as well as promotes plant growth. A total of 42 Bacillus species were isolated, one of the isolates named BT42 showed maximum radial mycelial growth inhibition against Colletotrichum gloeosporioides (78%) and Fusarium oxysporum (86%). BT42 increased germination of Coffee arabica L. seeds by 38.89%, decreased disease incidence due to infection of Colletotrichum gloeosporioides to 2.77% and due to infection of Fusarium oxysporum to 0 (p < 0.001). The isolate BT42 showed multiple growth-promoting traits. The isolate showed maximum similarity with Bacillus amyloliquefaciens. Bacillus species (BT42), isolated in the present work was found to be capable of antagonizing the pathogenic effects of Colletotrichum gloeosporioides and Fusarium oxysporum. The mechanism of action of inhibition of the pathogenic fungi found to be synergistic effects of secondary metabolites, lytic enzymes, and siderophores. The major inhibitory secondary metabolite identified as harmine (β-carboline alkaloids).

Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase

PubMed Central

Liu, Binbin; Banavali, Nilesh K.; Jones, Susan A.; Zhang, Jing; Li, Zhong; Kramer, Laura D.; Li, Hongmin

2015-01-01

The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2’-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition. PMID:26098995

Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2010-08-01

The ubiquitin-proteasome system plays a critical role in selective protein degradation and regulates almost all cellular events such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control, development, and neuronal function. The recent approval of bortezomib, a synthetic proteasome inhibitor, for the treatment of relapsed multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and ubiquitinating and deubiquitinating enzymes as well as the delivery system. To date, various synthetic and natural products have been reported to inhibit the components of the ubiquitin-proteasome system. Here, we review natural products targeting the ubiquitin-proteasome system as well as synthetic compounds with potent inhibitory effects. Georg Thieme Verlag KG Stuttgart-New York.

No Evidence for True Training and Transfer Effects after Inhibitory Control Training in Young Healthy Adults

ERIC Educational Resources Information Center

Enge, Sören; Behnke, Alexander; Fleischhauer, Monika; Küttler, Lena; Kliegel, Matthias; Strobel, Alexander

2014-01-01

Recent studies reported that training of working memory may improve performance in the trained function and beyond. Other executive functions, however, have been rarely or not yet systematically examined. The aim of this study was to test the effectiveness of inhibitory control (IC) training to produce true training-related function improvements…

Inhibitory Effect of Autoclaving Whey-Based Medium on Propionic Acid Production by Propionibacterium shermanii

PubMed Central

Anderson, Thomas M.; Bodie, Elizabeth A.; Goodman, Nelson; Schwartz, Robert D.

1986-01-01

Propionic acid production by Propionibacterium shermanii was compared in pasteurized and autoclaved whey-based media. Propionic acid production decreased with increasing whey concentration in autoclaved media but not in pasteurized media. Increasing the yeast extract concentration from 5 to 10 g/liter greatly reduced the inhibitory effect of autoclaving. PMID:16346998

Isolation, structural elucidation, MS profiling, and evaluation of triglyceride accumulation inhibitory effects of benzophenone C-glucosides from leaves of Mangifera indica L.

PubMed

Zhang, Yi; Han, Lifeng; Ge, Dandan; Liu, Xuefeng; Liu, Erwei; Wu, Chunhua; Gao, Xiumei; Wang, Tao

2013-02-27

Seventy percent ethanol-water extract from the leaves of Mangifera indica L. (Anacardiaceae) was found to show an inhibitory effect on triglyceride (TG) accumulation in 3T3-L1 cells. From the active fraction, six new benzophenone C-glucosides, foliamangiferosides A(3) (1), A(4) (2), C(4) (3), C(5) (4), C(6) (5), and C(7) (6) together with 11 known benzophenone C-glucosides (7-17) were obtained. In this paper, isolation, structure elucidation (1-6), and MS fragment cleavage pathways of all 17 isolates were studied. 1-6 showed inhibitory effects on TG and free fatty acid accumulation in 3T3-L1 cells at 10 μM.

Developmental Effects of Incentives on Response Inhibition

PubMed Central

Geier, Charles F.; Luna, Beatriz

2012-01-01

Inhibitory control and incentive processes underlie decision-making, yet few studies have explicitly examined their interaction across development. Here, the effects of potential rewards and losses on inhibitory control in sixty-four adolescents (13-17-year-olds) and forty-two young adults (18-29-year-olds) were examined using an incentivized antisaccade task. Notably, measures were implemented to minimize age-related differences in reward valuation and potentially confounding motivation effects. Incentives affected antisaccade metrics differently across the age groups. Younger adolescents generated more errors than adults on reward trials, but all groups performed well on loss trials. Adolescent saccade latencies also differed from adults across the range of reward trials. Overall, results suggest persistent immaturities in the integration of reward and inhibitory control processes across adolescence. PMID:22540668

Cocaine improves inhibitory control in a human model of response conflict.

PubMed

Fillmore, Mark T; Rush, Craig R; Hays, Lon

2005-11-01

The present study was designed to test the acute effects of cocaine on behavioral control in the presence and absence of motivational conflict. Adults (N = 14) with a history of stimulant use received oral cocaine hydrogen chloride (0, 100, 200, and 300 mg) and performed a cue-dependent go/no-go task to measure inhibitory and activational mechanisms of behavioral control either with or without motivated conflict between the inhibition and the activation of responses. Cocaine improved response inhibition in both conflict conditions, as evident by a decrease in inhibitory failures following active doses. The current study provides a useful model to investigate the effects of other drugs reported to have performance-enhancing effects. Copyright 2005 APA, all rights reserved.

The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways.

PubMed

Youns, Mаhmoud; Abdel Halim Hegazy, Wael

2017-01-01

Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.

The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

PubMed Central

Youns, Mаhmoud; Abdel Halim Hegazy, Wael

2017-01-01

Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes. PMID:28052097

The effect of several crude oils and some petroleum distillation fractions on intestinal absorption in ducklings (Anas platyhynchos).

PubMed

Crocker, A D; Cronshaw, J; Holmes, W N

1975-01-01

Ducklings given hypertonic saline drinking water show significant increases in the rates of Na+ and water transfer across the intestinal mucosa. These increased rates of transfer are maintained as long as the birds are fed dypertonic saline. Oral administration of a single small dose of crude oil had no effect on the basal rate of mucosal transfer in freshwater-maintained ducklings but the adaptive response of the mucosa is suppressed in birds given hypertonic saline. When crude oils from eight different geographical locations were tested, the degree of inhibition varied between them; the greatest and smallest degrees of inhibition being observed following administration of Kuwait and North Slope, Alaska, crude oils respectively. The effects of distallation fractions derived from two chemically different crude oils were also examined. The volume of each distallation fraction administered corresponded to its relative abundance in the crude oil from which it was derived. The inhibitory effect was not associated exclusively with the same distallation fractions from each oil. A highly naphthenic crude oil from the San Joaquin Valley, California, showed the greatest inhibitory activity in the least abundant (2%), low boiling point (smaller than 245 degrees C) fraction and the least inhibitory activity in the highest boiling point (greater than 482 degrees C) most abundant (47%) fraction. In contrast, a highly paraffinic crude oil from Paradox Basin, Utah, showed the greatest inhibitory effect with the highest boiling point fraction and a minimal effect with the lowest boiling point fraction; the relative abundances of these two fractions in the crude oil represented 27 and 28% respectively. Water-soluble extracts of both crude oils also had inhibitory effects on mucosal transfer rates and these roughly proportionate to the inhibitory potency of the low boiling point fraction of each oil. Weathered samples of San Joaquin Valley, California, and the Paradox Basin, Utah, oils showed greater effects than corresponding samples of unweathered oils even though most of the low molecular weight material from both oils was either evaporated or solubilized in the underlying water during the 36-h weathering period.

Cellulase retention and sugar removal by membrane ultrafiltration during lignocellulosic biomass hydrolysis.

PubMed

Knutsen, Jeffrey S; Davis, Robert H

2004-01-01

Technologies suitable for the separation and reuse of cellulase enzymes during the enzymatic saccharification of pretreated corn stover are investigated to examine the economic and technical viability of processes that promote cellulase reuse while removing inhibitory reaction products such as glucose and cellobiose. The simplest and most suitable separation is a filter with relatively large pores on the order of 20-25 mm that retains residual corn stover solids while passing reaction products such as glucose and cellobiose to form a sugar stream for a variety of end uses. Such a simple separation is effective because cellulase remains bound to the residual solids. Ultrafiltration using 50-kDa polyethersulfone membranes to recover cellulase enzymes in solution was shown not to enhance further the saccharification rate or overall conversion. Instead, it appears that the necessary cellulase enzymes, including beta-glucosidase, are tightly bound to the substrate; when fresh corn stover is contacted with highly washed residual solids, without the addition of fresh enzymes, glucose is generated at a high rate. When filtration was applied multiple times, the concentration of inhibitory reaction products such as glucose and cellobiose was reduced from 70 to 10 g/L. However, an enhanced saccharification performance was not observed, most likely because the concentration of the inhibitory products remained too high. Further reduction in the product concentration was not investigated, because it would make the reaction unnecessarily complex and result in a product stream that is much too dilute to be useful. Finally, an economic analysis shows that reuse of cellulase can reduce glucose production costs, especially when the enzyme price is high. The most economic performance is shown to occur when the cellulase enzyme is reused and a small amount of fresh enzyme is added after each separation step to replace lost or deactivated enzyme.

No retrieval-induced forgetting using item-specific independent cues: evidence against a general inhibitory account.

PubMed

Camp, Gino; Pecher, Diane; Schmidt, Henk G

2007-09-01

Retrieval practice with particular items from memory can impair the recall of related items on a later memory test. This retrieval-induced forgetting effect has been ascribed to inhibitory processes (M. C. Anderson & B. A. Spellman, 1995). A critical finding that distinguishes inhibitory from interference explanations is that forgetting is found with independent (or extralist) cues. In 4 experiments, the authors tested whether the forgetting effect is cue-independent. Forgetting was investigated for both studied and unstudied semantically related items. Retrieval-induced forgetting was not found using item-specific independent cues for either studied or unstudied items. However, forgetting was found for both item types when studied categories were used as cues. These results are not in line with a general inhibitory account, because this account predicts retrieval-induced forgetting with independent cues. Interference and context-specific inhibition are discussed as possible explanations for the data. 2007 APA

Training Attentional Control Improves Cognitive and Motor Task Performance.

PubMed

Ducrocq, Emmanuel; Wilson, Mark; Vine, Sam; Derakshan, Nazanin

2016-10-01

Attentional control is a necessary function for the regulation of goal-directed behavior. In three experiments we investigated whether training inhibitory control using a visual search task could improve task-specific measures of attentional control and performance. In Experiment 1 results revealed that training elicited a near-transfer effect, improving performance on a cognitive (antisaccade) task assessing inhibitory control. In Experiment 2 an initial far-transfer effect of training was observed on an index of attentional control validated for tennis. The principal aim of Experiment 3 was to expand on these findings by assessing objective gaze measures of inhibitory control during the performance of a tennis task. Training improved inhibitory control and performance when pressure was elevated, confirming the mechanisms by which cognitive anxiety impacts performance. These results suggest that attentional control training can improve inhibition and reduce taskspecific distractibility with promise of transfer to more efficient sporting performance in competitive contexts.

Analysis of glycation induced protein cross-linking inhibitory effects of some antidiabetic plants and spices.

PubMed

Perera, Handunge Kumudu Irani; Handuwalage, Charith Sandaruwan

2015-06-09

Protein cross-linking which occurs towards the latter part of protein glycation is implicated in the development of chronic diabetic complications. Glycation induced protein cross-linking inhibitory effects of nine antidiabetic plants and three spices were evaluated in this study using a novel, simple, electrophoresis based method. Methanol extracts of thirteen plants including nine antidiabetic plants and three spices were used. Lysozyme and fructose were incubated at 37 °C in the presence or absence of different concentrations of plant extracts up to 31 days. Standard glycation inhibitor aminoguanidine and other appropriate controls were included. A recently established sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE) method was used to detect the products of protein cross-linking in the incubation mixtures. High molecular weight protein products representing the dimer, trimer and tetramer of lysozyme were detected in the presence of fructose. Among the nine antidiabetic plants, seven showed glycation induced protein cross-linking inhibitory effects namely Ficus racemosa (FR) stem bark, Gymnema sylvestre (GS) leaves, Musa paradisiaca (MP) yam, Phyllanthus debilis (PD) whole plant, Phyllanthus emblica (PE) fruit, Pterocarpus marsupium (PM) latex and Tinospora cordifolia (TC) leaves. Inhibition observed with Coccinia grandis (CG) leaves and Strychnos potatorum (SP) seeds were much low. Leaves of Gymnema lactiferum (GL), the plant without known antidiabetic effects showed the lowest inhibition. All three spices namely Coriandrum sativum (CS) seeds, Cinnamomum zeylanicum (CZ) bark and Syzygium aromaticum (SA) flower buds showed cross-link inhibitory effects with higher effects in CS and SA. PD, PE, PM, CS and SA showed almost complete inhibition on the formation of cross-linking with 25 μg/ml extracts. Methanol extracts of PD, PE, PM, CS and SA have shown promising inhibitory effects on glycation induced protein cross-linking.

Curcumin (Diferuloylmethane) Inhibits Cell Proliferation, Induces Apoptosis, and Decreases Hormone Levels and Secretion in Pituitary Tumor Cells

PubMed Central

Miller, Matthew; Chen, Shenglin; Woodliff, Jeffrey; Kansra, Sanjay

2008-01-01

Prolactinomas are the most prevalent functional pituitary adenomas. Dopamine D2 receptor (D2R) agonists, such as bromocriptine are the first line of therapy; however, drug intolerance/resistance to D2R agonists exists. Apart from D2R agonists, there is no established medical therapy for prolactinomas; therefore, identifying novel therapeutics is warranted. Curcumin, a commonly used food additive in South Asian cooking, inhibits proliferation of several tumor cell lines; however, its effect on pituitary tumor cell proliferation has not been determined. Our objectives were to: 1) determine whether curcumin inhibits proliferation of pituitary tumor cell lines; 2) identify the signaling intermediaries that mediate the effect of curcumin; 3) examine whether curcumin inhibited pituitary hormone production and release; and 4) examine whether curcumin could enhance the growth-inhibitory effect of bromocriptine. Using rat lactotroph cell lines, GH3 and MMQ cells, we report that curcumin had a robust dose and time-dependent inhibitory effect on GH3 and MMQ cell proliferation. Inhibitory effects of curcumin persisted, even on removal of curcumin, and curcumin also blocked colony formation ability of pituitary tumor cells. The growth-inhibitory effect of curcumin was accompanied by decreased expression of cyclin D3 and ser 780 phosphorylation of retinoblastoma protein. In addition, curcumin also induced apoptosis in both GH3 and MMQ cells. Furthermore, curcumin suppresses intracellular levels and release of both prolactin and GH. Finally, we show that low concentrations of curcumin enhanced the growth-inhibitory effect of bromocriptine on MMQ cell proliferation. Taken together we demonstrate that curcumin inhibits pituitary tumor cell proliferation, induces apoptosis, and decreases hormone production and release, and thus, we propose developing curcumin as a novel therapeutic tool in the management of prolactinomas. PMID:18450960

Curcumin (diferuloylmethane) inhibits cell proliferation, induces apoptosis, and decreases hormone levels and secretion in pituitary tumor cells.

PubMed

Miller, Matthew; Chen, Shenglin; Woodliff, Jeffrey; Kansra, Sanjay

2008-08-01

Prolactinomas are the most prevalent functional pituitary adenomas. Dopamine D2 receptor (D2R) agonists, such as bromocriptine are the first line of therapy; however, drug intolerance/resistance to D2R agonists exists. Apart from D2R agonists, there is no established medical therapy for prolactinomas; therefore, identifying novel therapeutics is warranted. Curcumin, a commonly used food additive in South Asian cooking, inhibits proliferation of several tumor cell lines; however, its effect on pituitary tumor cell proliferation has not been determined. Our objectives were to: 1) determine whether curcumin inhibits proliferation of pituitary tumor cell lines; 2) identify the signaling intermediaries that mediate the effect of curcumin; 3) examine whether curcumin inhibited pituitary hormone production and release; and 4) examine whether curcumin could enhance the growth-inhibitory effect of bromocriptine. Using rat lactotroph cell lines, GH3 and MMQ cells, we report that curcumin had a robust dose and time-dependent inhibitory effect on GH3 and MMQ cell proliferation. Inhibitory effects of curcumin persisted, even on removal of curcumin, and curcumin also blocked colony formation ability of pituitary tumor cells. The growth-inhibitory effect of curcumin was accompanied by decreased expression of cyclin D3 and ser 780 phosphorylation of retinoblastoma protein. In addition, curcumin also induced apoptosis in both GH3 and MMQ cells. Furthermore, curcumin suppresses intracellular levels and release of both prolactin and GH. Finally, we show that low concentrations of curcumin enhanced the growth-inhibitory effect of bromocriptine on MMQ cell proliferation. Taken together we demonstrate that curcumin inhibits pituitary tumor cell proliferation, induces apoptosis, and decreases hormone production and release, and thus, we propose developing curcumin as a novel therapeutic tool in the management of prolactinomas.

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

PubMed

Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

2015-07-21

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

Interaction of divalent metal ions with Zn(2+)-glycerophosphocholine cholinephosphodiesterase from ox brain.

PubMed

Lee, K J; Kim, M R; Kim, Y B; Myung, P K; Sok, D E

1997-12-01

The effect of divalent metal ions on the activity of glycerophosphocholine cholinephosphodiesterse from ox brain was examined. Zn(2+)- and Co(2+)-glycerophosphocholine cholinephosphodiesterases were prepared from the exposure of apoenzyme to Zn2+ and Co2+, respectively, and the properties of two metallo-phosphodiesterases were compared to those of native phosphodiesterase. Although two metallo-enzymes were similar in expressing Km value, optimum pH or sensitivity to Cu2+, they differed in the susceptibility to the inhibition by thiocholine or tellurite; while Co(2+)-phosphodiesterase was more sensitive to tellurites, Zn(2+)-phosphodiesterase was more susceptible to inhibition by thiocholine. In addition, Zn(2+)-phosphodiesterase was more thermo-stable than Co2+ enzyme. Separately, when properties of native phosphodiesterase were compared to those of each metallo-phosphodiesterase, native phosphodiesterase was found to be quite similar to Zn(2+)-phosphodiesterase in many respects. Even in thermo-stability, native enzyme resembled Zn(2+)-phosphodiesterase rather than Co(2+)-enzyme. Consistent with this, the stability of native phosphodiesterase was maintained in the presence of Zn2+, but not Co2+, Mn2+ was also as effective as Zn2+ in the stabilization of the enzyme. Noteworthy, the native enzyme was found to be inhibited competitively by Cu2+ with a Ki value of 20 microM, and its inhibitory action was antagonized effectively by Zn2+ or Co2+. Also, choline, another competitive inhibitor of the enzyme, appeared to antagonize the inhibitory action of Cu2+. Taken together, it is suggested that there may be multiple binding sites for divalent metal ions in the molecule of glycerophosphocholine cholinephosphodiesterase.

SUMO expression shortens the lag phase of Saccharomyces cerevisiae yeast growth caused by complex interactive effects of major mixed fermentation inhibitors found in hot-compressed water-treated lignocellulosic hydrolysate.

PubMed

Jayakody, Lahiru N; Kadowaki, Masafumi; Tsuge, Keisuke; Horie, Kenta; Suzuki, Akihiro; Hayashi, Nobuyuki; Kitagaki, Hiroshi

2015-01-01

The complex inhibitory effects of inhibitors present in lignocellulose hydrolysate suppress the ethanol fermentation of Saccharomyces cerevisiae. Although the interactive inhibitory effects play important roles in the actual hydrolysate, few studies have investigated glycolaldehyde, the key inhibitor of hot-compressed water-treated lignocellulose hydrolysate. Given this challenge, we investigated the interactive effects of mixed fermentation inhibitors, including glycolaldehyde. First, we confirmed that glycolaldehyde was the most potent inhibitor in the hydrolysate and exerted interactive inhibitory effects in combination with major inhibitors. Next, through genome-wide analysis and megavariate data modeling, we identified SUMOylation as a novel potential mechanism to overcome the combinational inhibitory effects of fermentation inhibitors. Indeed, overall SUMOylation was increased and Pgk1, which produces an ATP molecule in glycolysis by substrate-level phosphorylation, was SUMOylated and degraded in response to glycolaldehyde. Augmenting the SUMO-dependent ubiquitin system in the ADH1-expressing strain significantly shortened the lag phase of growth, released cells from G2/M arrest, and improved energy status and glucose uptake in the inhibitor-containing medium. In summary, our study was the first to establish SUMOylation as a novel platform for regulating the lag phase caused by complex fermentation inhibitors.

Comparison of the effects of omeprazole and rabeprazole on ticlopidine metabolism in vitro.

PubMed

Kinoshita, Yuichi; Matsumoto, Naoki; Watanabe, Minoru; Takeba, Yuko; Yoshida, Yutoku; Ohba, Keiichiro; Suzuki, Satoshi; Itoh, Fumio; Kumai, Toshio; Kobayashi, Shinichi

2011-01-01

The thienopyridine derivative ticlopidine (TCL) is an inhibitor of adenosine diphosphate-induced platelet aggregation. Combination therapy with a thienopyridine derivative and aspirin is standard after coronary stenting, although more hemorrhagic complications occur with the combination therapy than with aspirin alone. A proton pump inhibitor (PPI) is required for prevention or treatment of upper gastrointestinal bleeding in such cases. We examined the effects of PPIs [omeprazole (OPZ) and rabeprazole (RPZ)] on TCL metabolism using pooled human liver microsomes prepared from various human liver blocks and 12 individual human liver microsomes. We calculated the K(i) values of each PPI for TCL metabolic activity and compared the inhibitory effect of each PPI on TCL metabolism. The K(i) values of OPZ and RPZ were 1.4 and 12.7 µM, respectively. The inhibitory effect of OPZ (78.6 ± 0.05%) was significantly greater than that of RPZ (24.2 ± 0.05%) (P < 0.001). Interestingly, a negative correlation existed between the inhibitory effect of OPZ and CYP2C19 activity (r = -0.909, P < 0.001). These results suggest that the inhibitory effect of OPZ is more potent than that of RPZ in vitro. In conclusion, RPZ appears preferable when administering TCL, aspirin, and a PPI in combination.

A study on isolation of chemical constituents from Sophora flavescens Ait. and their anti-glioma effects.

PubMed

Zheng, Kebin; Li, Chunhui; Shan, Xiaosong; Liu, Haipeng; Fan, Wufang; Wang, Zhenshan

2014-01-01

Sophora flavescens Ait. is a traditional Chinese medicine with a long history in China. It is mainly used in the treatment of heat dysentery and similar ailments in the clinical. The objective of this paper was to isolate, purify and identify alkaloids from Sophora flavescens Ait. and to explore their inhibitory effects on C6 glioma cells. Column chromatography, extraction and NMR spectroscopy were used to structurally identify the isolated compounds. MTT assay and flow cytometry were used to detect the inhibitory effect of matrine on C6 cells. Three compounds were isolated from Sophora flavescens Ait., namely matrine, oxymatrine and lupeol. Different concentrations of matrine solution all had inhibitory effects on growth of C6 cell lines, which showed apparent dose-effect relationship. Compared with the control group, proportion of G0/G1 phase cells increased in each matrine concentration group to a maximum of 79.8%; proportion of S phase cells reduced, and proportion of G2/M phase cells declined slightly to a minimum of 6.3%, suggesting that after the action of matrine proliferation of C6 cells was significantly inhibited and the cells were arrested in the G1 phase. We concluded that Sophora flavescens Ait. has an inhibitory effect on C6 cell proliferation.

Mobility of multiple heavy metalloids in contaminated soil under various redox conditions: Effects of iron sulfide presence and phosphate competition.

PubMed

Park, Ji-Hyun; Kim, So-Jeong; Ahn, Joo Sung; Lim, Dong-Hee; Han, Young-Soo

2018-04-01

The mobility of heavy metalloids including As, Sb, Mo, W, and Cr in soil was investigated under both reducing and oxidizing conditions. The effects of soil mineralogy and the presence of competitive anions were studied as important factors affecting the mobility of these contaminants. Batch experiments conducted with the addition of oxidized and fresh FeS exhibited enhanced sorption rates for As and W under oxidizing conditions, and for Mo under reducing conditions. The inhibitory effect of phosphate on the sorption rates was most apparent for As and Mo under both oxidizing and reducing conditions, while only a small phosphate effect was observed for Sb and W. For Sb and W mobility, pH was determined to be the most important controlling factor. The results of long-term batch experiments revealed that differences in the mobility of metalloids, particularly As, were also influenced by microbial activity in the oxidizing and reducing conditions. Copyright © 2018 Elsevier Ltd. All rights reserved.

Production, optimisation and characterisation of angiotensin converting enzyme inhibitory peptides from sea cucumber (Stichopus japonicus) gonad.

PubMed

Zhong, Chan; Sun, Le-Chang; Yan, Long-Jie; Lin, Yi-Chen; Liu, Guang-Ming; Cao, Min-Jie

2018-01-24

In this study, production of bioactive peptides with angiotensin converting enzyme (ACE) inhibitory activity from sea cucumber (Stichopus japonicus) gonad using commercial protamex was optimised by response surface methodology (RSM). As a result, the optimal condition to achieve the highest ACE inhibitory activity in sea cucumber gonad hydrolysate (SCGH) was hydrolysis for 1.95 h and E/S of 0.75%. For further characterisation, three individual peptides (EIYR, LF and NAPHMR) were purified and identified. The peptide NAPHMR showed the highest ACE inhibitory activity with IC 50 of 260.22 ± 3.71 μM. NAPHMR was stable against simulated gastrointestinal digestion and revealed no significant cytotoxicity toward Caco-2 cells. Molecular docking study suggested that Arg, His and Asn residues in NAPHMR interact with the S2 pocket or Zn 2+ binding motifs of ACE via hydrogen or π-bonds, potentially contributing to ACE inhibitory effect. Sea cucumber gonad is thus a potential resource to produce ACE inhibitory peptides for preparation of functional foods.

Neural networks with excitatory and inhibitory components: Direct and inverse problems by a mean-field approach

NASA Astrophysics Data System (ADS)

di Volo, Matteo; Burioni, Raffaella; Casartelli, Mario; Livi, Roberto; Vezzani, Alessandro

2016-01-01

We study the dynamics of networks with inhibitory and excitatory leak-integrate-and-fire neurons with short-term synaptic plasticity in the presence of depressive and facilitating mechanisms. The dynamics is analyzed by a heterogeneous mean-field approximation, which allows us to keep track of the effects of structural disorder in the network. We describe the complex behavior of different classes of excitatory and inhibitory components, which give rise to a rich dynamical phase diagram as a function of the fraction of inhibitory neurons. Using the same mean-field approach, we study and solve a global inverse problem: reconstructing the degree probability distributions of the inhibitory and excitatory components and the fraction of inhibitory neurons from the knowledge of the average synaptic activity field. This approach unveils new perspectives on the numerical study of neural network dynamics and the possibility of using these models as a test bed for the analysis of experimental data.

The role of cardiac vagal tone and inhibitory control in pre-schoolers' listening comprehension.

PubMed

Scrimin, Sara; Patron, Elisabetta; Florit, Elena; Palomba, Daniela; Mason, Lucia

2017-12-01

This study investigated the role of basal cardiac activity and inhibitory control at the beginning of the school year in predicting oral comprehension at the end of the year in pre-schoolers. Forty-three, 4-year-olds participated in the study. At the beginning of the school year children's electrocardiogram at rest was registered followed by the assessment of inhibitory control as well as verbal working memory and verbal ability. At the end of the year all children were administered a listening comprehension ability measure. A stepwise regression showed a significant effect of basal cardiac vagal tone in predicting listening comprehension together with inhibitory control and verbal ability. These results are among the first to show the predictive role of basal cardiac vagal tone and inhibitory control in pre-schoolers' oral text comprehension, and offer new insight into the association between autonomic regulation of the heart, inhibitory control, and cognitive activity at a young age. © 2017 Wiley Periodicals, Inc.

2',5'-Dihydroxychalcone as a potent chemical mediator and cyclooxygenase inhibitor.

PubMed

Lin, C N; Lee, T H; Hsu, M F; Wang, J P; Ko, F N; Teng, C M

1997-05-01

Eleven chalcone derivatives have been tested for their inhibitory effects on platelet aggregation in rabbit platelet suspension and the activation of mast cells and neutrophils. Arachidonic acid-induced platelet aggregation was potently inhibited by almost all the compounds and some also had a potent inhibitory effect on collagen-induced platelet aggregation and cyclooxygenase. Some hydroxychalcone derivatives showed strong inhibitory effects on the release of beta-glucuronidase and lysozyme, and on superoxide formation by rat neutrophils stimulated with the peptide fMet-Leu-Phe (fMLP). We found that the anti-inflammatory effect of 2',5'-dihydroxychalcone was greater than that of trifluoperazine. 2'5'-Dihydroxy and 2',3,4,5'-tetrahydroxyl chalcones, even at low concentration (50 microM), tested in platelet-rich plasma from man almost completely inhibited secondary aggregation induced by adrenaline. These results suggest that the anti-platelet effects of the chalcones are mainly a result of inhibition of thromboxane formation.

Sociodemographic risk, parenting, and inhibitory control in early childhood: the role of respiratory sinus arrhythmia.

PubMed

Holochwost, Steven J; Volpe, Vanessa V; Gueron-Sela, Noa; Propper, Cathi B; Mills-Koonce, W Roger

2018-03-13

Deficits of inhibitory control in early childhood are linked to externalizing behaviors and attention problems. While environmental factors and physiological processes are associated with its etiology, few studies have examined how these factors jointly predict inhibitory control. This study examined whether respiratory sinus arrhythmia (RSA) functioned as a mediator or moderator of both cumulative sociodemographic risk and parenting behaviors on inhibitory control during early childhood. The sample included 206 children and their biological mothers. At 24, 30, and 36 months of child age dyads participated in a series of laboratory visits in which sociodemographic, parenting, and baseline RSA (RSAB) data were collected. Inhibitory control was assessed at 36 months using a gift-wrap delay task. A series of structural equation models yielded no evidence that RSAB mediated the relations of risk or parenting and inhibitory control. RSAB moderated the effects of risk, such that high-risk children with low RSAB performed more poorly on tasks of inhibitory control, while high-risk children with high RSAB did not. These results suggest that higher levels of RSAB may mitigate the influence of environmental risk on the development of inhibitory control early childhood. © 2018 Association for Child and Adolescent Mental Health.

Promotion and computation of inhibitory effect on tyrosinase activity of herbal cream by incorporating indigenous medicinal plants.

PubMed

Sahu, Ram Kumar; Roy, Amit; Dwivedi, Jaya; Jha, Arvind Kumar

2014-01-01

Herbal cream imparts a chief role in regulating melanin production of skin. The phytoconstituents present in herbal cream impact biological functions of skin and contribute nutrients required for the healthy skin. In the present study, it was envisaged to prepare three batches of herbal cream (HC1, HC2 and HC3) containing ethanol extracts of Emblica officinalis (fruits), Daucus carota (root), Mangifera indica (leaves), Mentha arvensis (leaves), Terminalia arjuna (bark) and Cucumis sativus (fruits) and investigated the prepared cream for inhibitory effect on tyrosinase activity. The herbal cream was formulated by incorporating different ratio of extracts, by using cream base. Each formulation HC1, HC2 and HC3 were segregated into three different formulations (HC1.1, HC1.2, HC1.3, HC2.1, HC2.2, HC2.3, HC3.1, HC3.2 and HC3.3) by incorporating increasing ratio of extract in formulation. The HC3.2 cream produces highest tyrosinase inhibitory effect 65.23 +/- 0.07%, while the HC2.1 exhibited minimum tyrosinase inhibitory effect 26.19 +/- 0.08% compared to other prepared cream. Comparison of the inhibitory activity of the formulations demonstrated that the rank order was HC3.2 > HC3.3 > HC1.2 > HC1.3 > HC3.1 > HC1.1 > HC2.3 > HC2.2 > HC2.1. It has been observed from the result that the formulations of antityrosinase activity were not concentrate dependent. This finding suggests that decrease in antityrosinase activity of HC1 and HC3 might be considering that the incompatibility of the higher extract content with the base of cream. The HC3 produce the maximum inhibitory effects on tyrosinase activity might be due to higher level of polyphenol and flavonoids present in extracts.

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1.

PubMed Central

Arruda, E; Crump, C E; Marlin, S D; Merluzzi, V J; Hayden, F G

1992-01-01

We studied the in vitro antirhinovirus activity of a soluble form of intercellular adhesion molecule-1 (sICAM-1). sICAM-1 inhibited the cytopathic effect of 10 representative human rhinovirus (HRV) serotypes of the major receptor group with, 50% effective concentrations (EC50s) of 0.1 to 7.9 micrograms/ml. Cell type-dependent variation in the inhibitory activity of sICAM-1 was observed for two major receptor group serotypes in HeLa cells (EC50, greater than 32 micrograms/ml), and no inhibitory effect was observed for two serotypes which use different cell receptors. Yield reduction assays showed that sICAM-1 inhibited the replication of HRV serotype 39 (HRV-39) in human adenoid explants in a concentration-dependent manner. No direct inactivation of infectivity of HRV-39 (EC50, 0.5 microgram/ml) was observed after incubation with sICAM-1 (32 micrograms/ml) for up to 24 h. Single-cycle-of-replication experiments with the addition of sICAM-1 at 10 micrograms/ml at different times showed that the inhibitory effect occurs only when sICAM-1 is added within 30 min after infection. In experiments in which absorption was carried out at 4 degrees C and then a single cycle of replication incubation was carried out at 33 degrees C, it was found that sICAM-1 at 10 micrograms/ml was inhibitory only when it was present during the absorption period. Our data show that sICAM-1 is inhibitory for representative major receptor group serotypes of HRV in two cell lines and human respiratory epithelium, that the interaction of sICAM-1 with HRV is readily reversible by dilution, and that the inhibitory effect of sICAM-1 on virus replication is present early in the infection cycle. PMID:1358025

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

PubMed Central

Hoyt, Laura R.; Ather, Jennifer L.; Randall, Matthew J.; DePuccio, Daniel P.; Landry, Christopher C.; Wewers, Mark D.; Gavrilin, Mikhail A.; Poynter, Matthew E.

2016-01-01

Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished ASC speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow derived dendritic cells, mouse neutrophils, and human PBMCs. The inhibitory effects on the Nlrp3 inflammasome were independent of GABAA receptor activation or NMDA receptor inhibition, but was associated with decreased oxidant production. Ethanol treatment markedly decreased cellular tyrosine phosphorylation, while administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored tyrosine phosphorylation and IL-1β secretion subsequent to ATP stimulation. Furthermore, sodium orthovanadate-induced phosphorylation of ASC Y144, necessary and sufficient for Nlrp3 inflammasome activation, and secretion of phosphorylated ASC, were inhibited by ethanol. Finally, multiple alcohol-containing organic compounds exerted inhibitory effects on the Nlrp3 inflammasome, whereas 2-methylbutane (isopentane), the analogous alkane of the potent inhibitor isoamyl alcohol (isopentanol), did not. Our results demonstrate that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation through the stimulation of protein tyrosine phosphatases, an effect shared by other short-chain alcohols. PMID:27421477

Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation.

PubMed

Hoyt, Laura R; Ather, Jennifer L; Randall, Matthew J; DePuccio, Daniel P; Landry, Christopher C; Wewers, Mark D; Gavrilin, Mikhail A; Poynter, Matthew E

2016-08-15

Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multiprotein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the proinflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol, and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow-derived dendritic cells, mouse neutrophils, and human PBMCs. The inhibitory effects on the Nlrp3 inflammasome were independent of γ-aminobutyric acid A receptor activation or N-methyl-d-asparate receptor inhibition but were associated with decreased oxidant production. Ethanol treatment markedly decreased cellular tyrosine phosphorylation, whereas administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored tyrosine phosphorylation and IL-1β secretion subsequent to ATP stimulation. Furthermore, sodium orthovanadate-induced phosphorylation of ASC Y144, necessary and sufficient for Nlrp3 inflammasome activation, and secretion of phosphorylated ASC were inhibited by ethanol. Finally, multiple alcohol-containing organic compounds exerted inhibitory effects on the Nlrp3 inflammasome, whereas 2-methylbutane (isopentane), the analogous alkane of the potent inhibitor isoamyl alcohol (isopentanol), did not. Our results demonstrate that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation through the stimulation of protein tyrosine phosphatases, an effect shared by other short-chain alcohols. Copyright © 2016 by The American Association of Immunologists, Inc.

PTAP motif duplication in the p6 Gag protein confers a replication advantage on HIV-1 subtype C.

PubMed

Sharma, Shilpee; Arunachalam, Prabhu S; Menon, Malini; Ragupathy, Viswanath; Satya, Ravi Vijaya; Jebaraj, Joshua; Ganeshappa Aralaguppe, Shambhu; Rao, Chaitra; Pal, Sreshtha; Saravanan, Shanmugam; Murugavel, Kailapuri G; Balakrishnan, Pachamuthu; Solomon, Suniti; Hewlett, Indira; Ranga, Udaykumar

2018-05-17

HIV-1 subtype C (HIV-1C) may duplicate longer amino acid stretches in the p6 Gag protein, leading to the creation of an additional Pro-Thr/Ser-Ala-Pro (PTAP) motif necessary for viral packaging. However, the biological significance of a duplication of the PTAP motif for HIV-1 replication and pathogenesis has not been experimentally validated. In a longitudinal study of two different clinical cohorts of select HIV-1 seropositive, drug-naive individuals from India, we found that 8 of 50 of these individuals harbored a mixed infection of viral strains discordant for the PTAP duplication. Conventional and next-generation sequencing of six primary viral quasispecies at multiple time points disclosed that in a mixed infection, the viral strains containing the PTAP duplication dominated the infection. The dominance of the double-PTAP viral strains over a genetically similar single-PTAP viral clone was confirmed in viral proliferation and pairwise competition assays. Of note, in the proximity ligation assay, double-PTAP Gag proteins exhibited a significantly enhanced interaction with the host protein tumor susceptibility gene 101 (Tsg101). Moreover, Tsg101 overexpression resulted in a biphasic effect on HIV-1C proliferation - an enhanced effect at low concentration and an inhibitory effect only at higher concentrations - unlike a uniformly inhibitory effect on subtype B strains. In summary, our results indicate that the duplication of the PTAP motif in the p6 Gag protein enhances the replication fitness of HIV-1C by engaging the Tsg101 host protein with a higher affinity. Our results have implications for HIV-1 pathogenesis, especially of HIV-1C. Copyright © 2018, The American Society for Biochemistry and Molecular Biology.

Cognitive Effects of Androgen Deprivation Therapy in Men With Advanced Prostate Cancer.

PubMed

Gunlusoy, Bulent; Ceylan, Yasin; Koskderelioglu, Aslı; Gedizlioglu, Muhtesem; Degirmenci, Tansu; Ortan, Pınar; Kozacioglu, Zafer

2017-05-01

To evaluate the prostate cancer effects of androgen deprivation therapy (ADT) by using a systematic set of methods to calculate specific cognitive functions in men with locally advanced or metastatic prostate cancer. From April 2014 to February 2016, a prospective, comparative study was done to evaluate the cognitive effects of hormone therapy. Group 1 consisted of 78 patients with locally advanced or metastatic prostate cancer who received complete ADT treatment continuously for 12 months and group 2 (control group) consisted of 78 patients who underwent radical prostatectomy without any additional treatment. The Montreal Cognitive Assessment (MoCA) test and the Frontal Assessment Battery (FAB) test with Turkish language version were used to evaluate multiple domains of cognitive function. Post-treatment results of both tests revealed that patients in group 1 achieved lower mean total scores than group 2. In MoCA test, the deficits were especially prominent in the areas of language ability and short-term memory capacity (P < .05 and P < .05). No significant differences could be identified between groups in respect to attention, executive functions, visuospatial abilities, abstract thinking, calculating abilities, and orientation. In FAB test, the deficits were especially prominent in the areas of mental flexibility and inhibitory control (P < .05 and P < .05). No significant differences could be identified between groups in conceptualization, motor series, conflicting instructions, and environmental autonomy. ADT affects cognitive functions such as language ability, short-term memory capacity, mental flexibility, and inhibitory control. Urologists should keep in mind these side effects and inform the patients and their families for the early symptoms of cognitive dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

The different roles of opioid receptors in the inhibitory effects induced by sacral dorsal root ganglion stimulation on nociceptive and nonnociceptive conditions in cats.

PubMed

Wang, Zhaoxia; Liao, Limin; Deng, Han; Li, Xing; Chen, Guoqing; Liao, Xiwen

2018-06-04

To examine the roles of opioid receptors in the inhibition of nociceptive and nonnociceptive bladder reflexes by sacral dorsal root ganglion (DRG) stimulation in cats. Hook electrodes were placed in the right S1 and S2 DRG of cats. The bladders were infused with physiologic saline or 0.25% acetic acid (AA). Naloxone (0.1, 0.3, and 1 mg/kg), an opioid receptor antagonist, was administered intravenously. S1 or S2 DRG stimulation was applied before and after administering the drug. Multiple cystometrograms were performed to determine the effects of DRG stimulation and opioid receptors on the micturition reflex under nociceptive and non-nociceptive conditions. AA significantly (P < 0.01) reduced bladder capacity (BC). DRG stimulation at threshold (T) and 1.5 T significantly increased BC of the saline control under nociceptive and non-nociceptive conditions. When saline was infused, naloxone (0.1-1 mg/kg) significantly (P < 0.01) reduced BC; however, naloxone did not change BC during AA irritation. During saline infusion, naloxone (0.3 and 1 mg/kg) partly blocked S1 DRG stimulation-induced inhibition but had only a slight effect on S2 DRG stimulation. During AA infusion, naloxone (0.3 and 1 mg/kg) only partially blocked S1 DRG stimulation at T intensity but not during 1.5 T stimulation. However, no doses of naloxone significantly affected S2 DRG stimulation. Opioid receptors play a role in sacral DRG stimulation on non-nociceptive condition but are not involved in the inhibitory effect of stimulation in nociceptive conditions. © 2018 Wiley Periodicals, Inc.

Bilateral theta-burst magnetic stimulation influence on event-related brain potentials.

PubMed

Pinto, Nuno; Duarte, Marta; Gonçalves, Helena; Silva, Ricardo; Gama, Jorge; Pato, Maria Vaz

2018-01-01

Theta-burst stimulation (TBS) can be a non-invasive technique to modulate cognitive functions, with promising therapeutic potential, but with some contradictory results. Event related potentials are used as a marker of brain deterioration and can be used to evaluate TBS-related cognitive performance, but its use remains scant. This study aimed to study bilateral inhibitory and excitatory TBS effects upon neurocognitive performance of young healthy volunteers, using the auditory P300' results. Using a double-blind sham-controlled study, 51 healthy volunteers were randomly assigned to five different groups, two submitted to either excitatory (iTBS) or inhibitory (cTBS) stimulation over the left dorsolateral pre-frontal cortex (DLPFC), two other actively stimulated the right DLPFC and finally a sham stimulation group. An oddball based auditory P300 was performed just before a single session of iTBS, cTBS or sham stimulation and repeated immediately after. P300 mean latency comparison between the pre- and post-TBS stimulation stages revealed significantly faster post stimulation latencies only when iTBS was performed on the left hemisphere (p = 0.003). Right and left hemisphere cTBS significantly delayed P300 latency (right p = 0.026; left p = 0.000). Multiple comparisons for N200 showed slower latencies after iTBS over the right hemisphere. No significant difference was found in amplitude variation. TBS appears to effectively influence neural networking involved in P300 formation, but effects seem distinct for iTBS vs cTBS and for the right or the left hemisphere. P300 evoked potentials can be an effective and practical tool to evaluate transcranial magnetic stimulation related outcomes.

In vitro antibiofilm efficacy of Piper betle against quorum sensing mediated biofilm formation of luminescent Vibrio harveyi.

PubMed

Srinivasan, Ramanathan; Santhakumari, Sivasubramanian; Ravi, Arumugam Veera

2017-09-01

Vibrio harveyi is a potent biofilm former, which confers resistance to multiple antimicrobials, disinfectants, chemicals and biocides. The prevalence of biofilm mediated antibiotic resistance among aquatic bacterial pathogens stresses the search for novel alternative approach to treat vibriosis in aquaculture. Exploring suitable therapeutics from natural resources could be a novel area of research. Therefore, this work was executed to evaluate the inhibitory effect of Piper betle ethyl acetate extract (PBE) on bioluminescence production and biofilm formation of V. harveyi. Minimal inhibitory concentration (MIC) of PBE against planktonic V. harveyi was found to be 1600 μg ml -1 ; furthermore, PBE inhibited the quorum sensing (QS) mediated bioluminescence production and biofilm formation in V. harveyi upto 98 and 74% respectively, at its sub-MIC concentration of 400 μg ml -1 without affecting their cell viability. Similar results were obtained for exopolysaccharides production and swimming motility related to biofilm formation of V. harveyi, where PBE reduced EPS production upto 64%. Light and confocal laser scanning microscopic analyses further confirmed that the PBE effectively prevented the initial attachment as well as microcolonies formation of V. harveyi biofilm, when compared to their untreated controls. This study demonstrates the promising antibiofilm activity of PBE and confirms the ethnopharmacological potential of this plant against V. harveyi infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

Screening of plants used in the European traditional medicine to treat memory disorders for acetylcholinesterase inhibitory activity and anti amyloidogenic activity.

PubMed

Lobbens, Eva S B; Vissing, Karina J; Jorgensen, Lene; van de Weert, Marco; Jäger, Anna K

2017-03-22

Plants used in the traditional medicine of Europe to treat memory dysfunction and/or to enhance memory were investigated for activity against the underlying mechanisms of Alzheimer's disease. To investigate 35 ethanolic extracts of plants, selected using an ethnopharmacological approach, for anti-amyloidogenic activity as well as an ability to inhibit the enzymatic activity of acetylcholinesterase. The anti-amyloidogenic activity of the extracts against amyloid beta was investigated by Thioflavin T fibrillation assays and the ability to inhibit the enzymatic activity of acetylcholinesterase was evaluated monitoring the hydrolysis of acetylthiocholine RESULTS: Under the experimental conditions investigated, extracts of two plants, Carum carvi and Olea sylvestris, inhibited amyloid beta fibrillation considerably, eight plant extracts inhibited amyloid beta fibrillation to some extent, 16 plant extracts had no effect on amyloid beta fibrillation and nine extracts accelerated fibrillation of amyloid beta. Furthermore, five plant extracts from Corydalis species inhibited the enzymatic activity of acetylcholinesterase considerably, one plant extract inhibited the enzymatic activity of acetylcholinesterase to some extent and 29 plant extract had no effect on the enzymatic activity of acetylcholinesterase. An optimal extract in this study would possess acetylcholinesterase inhibitory activity as well as anti-amyloidogenic activity in order to address multiple facets of Alzheimer's disease, until the molecular origin of the disease is unraveled. Unfortunately no such extract was found. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Endophytic fungi from mangrove inhibit lung cancer cell growth and angiogenesis in vitro.

PubMed

Liu, Xin; Wu, Xin; Ma, Yuefan; Zhang, Wenzhang; Hu, Liang; Feng, Xiaowei; Li, Xiangyong; Tang, Xudong

2017-03-01

The secondary metabolites of mangrove-derived endophytic fungi contain multiple substances with novel structures and biological activities. In the present study, three types of mangrove plants, namely Kandelia candel, Rhizophora stylosa and Rhizophoraceae from Zhanjiang region including the leaves, roots and stems were collected, and endophytic fungi were isolated, purified and identified from these mangrove plants. MTT assay was used to observe the effects of the isolated endophytic fungi on the growth of A549 and NCI-H460 lung cancer cells. The effect of the endophytic fungi on lung cancer angiogenesis in vitro induced by the HPV-16 E7 oncoprotein was observed. Our results showed that 28 strains of endophytic fungi were isolated, purified and identified from the three types of mangrove plants. Ten strains of endophytic fungi significantly suppressed the growth of A549 and NCI-H460 cells. The average inhibitory rates in the A549 cells were 64.4, 59.5, 81.9, 43.9, 58.3, 56.2, 48.3, 42.4, 93.0 and 49.7%, respectively. The average inhibitory rates in the NCI-H460 cells were 41.2, 49.3, 82.7, 40.7, 53.9, 52.6, 56.8, 64.3, 91.0 and 45.6%, respectively. Particularly, three strains of endophytic fungi markedly inhibited HPV-16 E7 oncoprotein‑induced lung cancer angiogenesis in vitro. These findings contribute to the further screening of potential chemotherapeutic agents from mangrove-derived endophytic fungi.

[Neurology of laughter and humour: pathological laughing and crying].

PubMed

Arias, Manuel

2011-10-01

Laughter, which is usually a healthy biological phenomenon, may be also a symptom of several severe brain pathologies. To review the neurobiological bases of laughter and humour, as well as those of pathological laughing and crying syndrome. At the mesencephalic-pontine junction there is a central coordinator of the nuclei that innervate the muscles involved in laughter (facial expression, respiratory and phonatory). This centre receives connections from three systems: inhibitory (pre-motor and motor cortex), excitatory (temporal cortex, amygdala, hypothalamus) and modulator (cerebellum). Humour is a complex phenomenon with a range of components: the perception of the unexpected incongruence (occipitotemporal area, prefrontal cortex), emotional (reward circuit) and volitional (temporal and frontal cortex). Functional magnetic resonance imaging studies do not reveal a markedly prominent role of the right frontal lobe in processing humour, as had been suggested in the classical studies. The causes of pathological laughing and crying syndrome can be classified in two groups: altered behaviour with unmotivated happiness (Angelman syndrome, schizophrenia, manias, dementia) and interference with the inhibitory/excitatory mechanisms (gelastic epilepsy, fou rire prodromique in strokes, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease and Parkinson-plus, traumatic injuries, tumours). Serotonin and noradrenalin reuptake inhibitors, levodopa, lamotrigine and the association of dextromethorphan/quinidine can be effective in certain cases of pathological laughing and crying. As human neurobiological phenomena, laughter and humour also belong to the field of clinical neurology; their processing is affected in a number of different diseases and, in certain cases, effective treatment can be established.

A simple robust method for synthesis of metallic copper nanoparticles of high antibacterial potency against E. coli

NASA Astrophysics Data System (ADS)

Chatterjee, Arijit Kumar; Sarkar, Raj Kumar; Prasun Chattopadhyay, Asoke; Aich, Pulakesh; Chakraborty, Ruchira; Basu, Tarakdas

2012-03-01

A method for preparation of copper nanoparticles (Cu-NPs) was developed by simple reduction of CuCl2 in the presence of gelatin as a stabilizer and without applying stringent conditions like purging with nitrogen. The NPs were characterized by spectrophotometry, dynamic light scattering, x-ray diffraction, transmission electron microscopy, atomic force microscopy and x-ray photoelectron spectroscopy. The particles were about 50-60 nm in size and highly stable. The antibacterial activity of this Cu-NP on Gram-negative Escherichia coli was demonstrated by the methods of agar plating, flow cytometry and phase contrast microscopy. The minimum inhibitory concentration (3.0 µg ml-1), minimum bactericidal concentration (7.5 µg ml-1) and susceptibility constant (0.92) showed that this Cu-NP is highly effective against E. coli at a much lower concentration than that reported previously. Treatment with Cu-NPs made E. coli cells filamentous. The higher the concentration of Cu-NPs, the greater the population of filamentous cells; average filament size varied from 7 to 20 µm compared to the normal cell size of ˜2.5 µm. Both filamentation and killing of cells by Cu-NPs (7.5 µg ml-1) also occurred in an E. coli strain resistant to multiple antibiotics. Moreover, an antibacterial effect of Cu-NPs was also observed in Gram-positive Bacillus subtilis and Staphylococcus aureus, for which the values of minimum inhibitory concentration and minimum bactericidal concentration were close to that for E. coli.

Polysulfonate suramin inhibits Zika virus infection.

PubMed

Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

2017-07-01

Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

Ciclopirox delivery into the human nail plate using novel lipid diffusion enhancers.

PubMed

Hafeez, Farhaan; Hui, Xiaoying; Selner, Marc; Rosenthal, Bert; Maibach, Howard

2014-06-01

Onychomycosis is a common fungal infection of the nail plate and bed that affects up to 14% of the population and can have a substantial impact on the quality of life of those affected. This study compared the onychopharmacokinetics, nail absorption, nail distribution, and nail penetration of [(14)C]-ciclopirox dissolved in novel lipid diffusion enhancers with that of a commercial ciclopirox nail lacquer using the in vitro finite dose model. The penetration rate of ciclopirox was determined by applying doses of topical formulation twice daily to human nail plates for 11 d. Drug absorption was then measured by monitoring its rate of appearance in each nail layer and in the cotton pad/nail supporting bed. After a multiple day treatment, cumulative concentrations of ciclopirox formulated with lipid enhancers in the deep nail layer and the nail bed were significantly greater than cumulative concentrations of the commercial ciclopirox lacquer (p < 0.001) as well as several orders of magnitude greater than the minimal inhibitory concentration (MIC) deemed necessary to inhibit the growth of the causative dermatophyte species. When formulated with lipid enhancers, the amount of ciclopirox in the ventral/intermediate layer and supporting bed dramatically exceed the inhibitory concentration of ciclopirox for the most common onychomycosis organisms. These results suggest that topical ciclopirox with lipid enhancers has the potential to be an effective topical treatment for onychomycosis, and the lipidic pathway of the nail can be utilized as a means of effective transungual delivery.

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex

PubMed Central

McGarry, Laura M.

2016-01-01

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. PMID:27605614

Inhibitory Gating of Basolateral Amygdala Inputs to the Prefrontal Cortex.

PubMed

McGarry, Laura M; Carter, Adam G

2016-09-07

Interactions between the prefrontal cortex (PFC) and basolateral amygdala (BLA) regulate emotional behaviors. However, a circuit-level understanding of functional connections between these brain regions remains incomplete. The BLA sends prominent glutamatergic projections to the PFC, but the overall influence of these inputs is predominantly inhibitory. Here we combine targeted recordings and optogenetics to examine the synaptic underpinnings of this inhibition in the mouse infralimbic PFC. We find that BLA inputs preferentially target layer 2 corticoamygdala over neighboring corticostriatal neurons. However, these inputs make even stronger connections onto neighboring parvalbumin and somatostatin expressing interneurons. Inhibitory connections from these two populations of interneurons are also much stronger onto corticoamygdala neurons. Consequently, BLA inputs are able to drive robust feedforward inhibition via two parallel interneuron pathways. Moreover, the contributions of these interneurons shift during repetitive activity, due to differences in short-term synaptic dynamics. Thus, parvalbumin interneurons are activated at the start of stimulus trains, whereas somatostatin interneuron activation builds during these trains. Together, these results reveal how the BLA impacts the PFC through a complex interplay of direct excitation and feedforward inhibition. They also highlight the roles of targeted connections onto multiple projection neurons and interneurons in this cortical circuit. Our findings provide a mechanistic understanding for how the BLA can influence the PFC circuit, with important implications for how this circuit participates in the regulation of emotion. The prefrontal cortex (PFC) and basolateral amygdala (BLA) interact to control emotional behaviors. Here we show that BLA inputs elicit direct excitation and feedforward inhibition of layer 2 projection neurons in infralimbic PFC. BLA inputs are much stronger at corticoamygdala neurons compared with nearby corticostriatal neurons. However, these inputs are even more powerful at parvalbumin and somatostatin expressing interneurons. BLA inputs thus activate two parallel inhibitory networks, whose contributions change during repetitive activity. Finally, connections from these interneurons are also more powerful at corticoamygdala neurons compared with corticostriatal neurons. Together, our results demonstrate how the BLA predominantly inhibits the PFC via a complex sequence involving multiple cell-type and input-specific connections. Copyright © 2016 the authors 0270-6474/16/369391-16$15.00/0.

Inhibitory effect of resin composite containing S-PRG filler on Streptococcus mutans glucose metabolism.

PubMed

Kitagawa, Haruaki; Miki-Oka, Saeki; Mayanagi, Gen; Abiko, Yuki; Takahashi, Nobuhiro; Imazato, Satoshi

2018-03-01

Resin composites containing surface pre-reacted glass-ionomer (S-PRG) fillers have been reported to inhibit Streptococcus mutans growth on their surfaces, and their inhibitory effects were attributed to BO 3 3- and F - ions. The aim of this study was to evaluate S. mutans acid production through glucose metabolism on resin composite containing S-PRG fillers and assess inhibitory effects of BO 3 3- and F - on S. mutans metabolic activities. The pH change through S. mutans acid production on experimental resin composite was periodically measured after the addition of glucose. Inhibitory effects of BO 3 3- or F - solutions on S. mutans metabolism were evaluated by XTT assays and measurement of the acid production rate. The pH of experimental resin containing S-PRG fillers was significantly higher than that of control resin containing silica fillers (p < 0.05). OD 450 values by XTT assays and S. mutans acid production rates significantly decreased in the presence of BO 3 3- and F - compared with the absence of these ions (p < 0.05). pH reduction by S. mutans acid production was inhibited on resin composite containing S-PRG fillers. Moreover, S. mutans glucose metabolism and acid production were inhibited in the presence of low concentrations of BO 3 3- or F - . BO 3 3- or F - released from resin composite containing S-PRG fillers exhibits inhibitory effects on S. mutans metabolism at concentrations lower than those which inhibit bacterial growth. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo

PubMed Central

Zeng, Yun; Liu, Gang; Zhou, Li-Ming

2009-01-01

AIM: To investigate the inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 and its mechanism. METHODS: MTT assay was used to assess the inhibitory effect of acetylshikonin on proliferation of SGC-7901 cells. Apoptosis-inducing effect was determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling with Hoechst staining. Expression of mRNA and protein in Bcl-2 and Bax was analyzed by reverse transcription-polymerase chain reaction and Western blot. Antitumor effect of acetylshikonin on a mouse SGC-7901 model was also determined. RESULTS: Forty-eight hours after treatment with acetylshikonin, MTT assay showed that acetylshikonin inhibited the proliferation of SGC-7901 cells in a dose-dependent manner. The half maximal inhibitory concentration of acetylshikonin to SGC-7901 cells was 0.428 ± 0.07 mg/L. Cell shrinkage, nuclear pyknosis and chromatin condensation, which are the characteristics of cell apoptosis, were observed in treated SGC-7901 cells and the percentage of apoptosis increased in a dose-dependent manner. Acetylshikonin down-regulated the expression of Bcl-2 and up-regulated the expression of Bax in the treated SGC-7901 cells compared with the controls. The experiment in vivo showed that 0.5, 1, and 2 mg/kg of acetylshikonin significantly inhibited the growth of tumor in the mouse SGC-7901 model, with an inhibitory rate of 25.00%-55.76%. CONCLUSION: Acetylshikonin inhibits the growth of SGC-7901 cells in vitro and in vivo by inducing cell apoptosis. PMID:19370777

Inhibitory effect of essential oils against herpes simplex virus type 2.

PubMed

Koch, C; Reichling, J; Schneele, J; Schnitzler, P

2008-01-01

Essential oils from anise, hyssop, thyme, ginger, camomile and sandalwood were screened for their inhibitory effect against herpes simplex virus type 2 (HSV-2) in vitro on RC-37 cells using a plaque reduction assay. Genital herpes is a chronic, persistent infection spreading efficiently and silently as sexually transmitted disease through the population. Antiviral agents currently applied for the treatment of herpesvirus infections include acyclovir and its derivatives. The inhibitory concentrations (IC50) were determined at 0.016%, 0.0075%, 0.007%, 0.004%, 0.003% and 0.0015% for anise oil, hyssop oil, thyme oil, ginger oil, camomile oil and sandalwood oil, respectively. A clearly dose-dependent virucidal activity against HSV-2 could be demonstrated for all essential oils tested. In order to determine the mode of the inhibitory effect, essential oils were added at different stages during the viral infection cycle. At maximum noncytotoxic concentrations of the essential oils, plaque formation was significantly reduced by more than 90% when HSV-2 was preincubated with hyssop oil, thyme oil or ginger oil. However, no inhibitory effect could be observed when the essential oils were added to the cells prior to infection with HSV-2 or after the adsorption period. These results indicate that essential oils affected HSV-2 mainly before adsorption probably by interacting with the viral envelope. Camomile oil exhibited a high selectivity index and seems to be a promising candidate for topical therapeutic application as virucidal agents for treatment of herpes genitalis.

Tannic Acid as a Potential Modulator of Norfloxacin Resistance in Staphylococcus Aureus Overexpressing norA.

PubMed

Diniz-Silva, Helena Taina; Cirino, Isis Caroline da Silva; Falcão-Silva, Vivyanne Dos Santos; Magnani, Marciane; de Souza, Evandro Leite; Siqueira-Júnior, José P

2016-01-01

Tannins have shown inhibitory effects against pathogenic bacteria, and these properties make tannins potential modifying agents in bacterial resistance. The minimum inhibitory concentration (MIC) of tannic acid (TA), gallic acid (GA) and norfloxacin (Nor) against Staphylococcus aureus SA-1119 (NorA-effluxing strain) was determined using broth microdilution tests. To assess the modulation of antibiotic resistance, the MIC of Nor was determined in growth media with or without TA or GA at a subinhibitory concentration (1/4 MIC). The checkerboard method was performed to obtain the fractional inhibitory concentration index (FICI) for the combined application of TA and Nor. TA displayed a weak inhibitory effect (MIC 512 μg/ml) against S. aureus SA-1119, while no inhibitory effect was displayed by GA (MIC >512 μg/ml). However, when TA was tested at a subinhibitory concentration in combination with Nor, the MIC of Nor against S. aureus SA-1119 decreased from 128 to 4 μg/ml (32-fold); this effect was not observed for GA. In the checkerboard assay, the MIC of TA and Nor decreased from 512 to 128 μg/ml (4-fold) and from 128 to 8 μg/ml (16-fold), respectively. The combination of TA and Nor presented an FICI as low as 0.31, which indicates a synergistic interaction. TA is a potential agent for increasing the clinical efficacy of Nor to control resistant S. aureus. © 2016 S. Karger AG, Basel.

Inhibitory Effects of Urothelium-related Factors.

PubMed

Guan, Na N; Gustafsson, Lars E; Svennersten, Karl

2017-10-01

The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor and cyclooxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD 2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD 2 was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the out-flow region. An altered release of excitatory and inhibitory factors is likely to play an important part in bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Developmental regulation of inhibitory synaptic currents in the dorsal motor nucleus of the vagus in the rat

PubMed Central

Anselmi, Laura; Travagli, R. Alberto

2016-01-01

Prior immunohistochemical studies have demonstrated that at early postnatal time points, central vagal neurons receive both glycinergic and GABAergic inhibitory inputs. Functional studies have demonstrated, however, that adult vagal efferent motoneurons receive only inhibitory GABAergic synaptic inputs, suggesting loss of glycinergic inhibitory neurotransmission during postnatal development. The purpose of the present study was to test the hypothesis that the loss of glycinergic inhibitory synapses occurs in the immediate postnatal period. Whole cell patch-clamp recordings were made from dorsal motor nucleus of the vagus (DMV) neurons from postnatal days 1–30, and the effects of the GABAA receptor antagonist bicuculline (1–10 μM) and the glycine receptor antagonist strychnine (1 μM) on miniature inhibitory postsynaptic current (mIPSC) properties were examined. While the baseline frequency of mIPSCs was not altered by maturation, perfusion with bicuculline either abolished mIPSCs altogether or decreased mIPSC frequency and decay constant in the majority of neurons at all time points. In contrast, while strychnine had no effect on mIPSC frequency, its actions to increase current decay time declined during postnatal maturation. These data suggest that in early postnatal development, DMV neurons receive both GABAergic and glycinergic synaptic inputs. Glycinergic neurotransmission appears to decline by the second postnatal week, and adult neurons receive principally GABAergic inhibitory inputs. Disruption of this developmental switch from GABA-glycine to purely GABAergic transmission in response to early life events may, therefore, lead to adverse consequences in vagal efferent control of visceral functions. PMID:27440241

Inhibitory Effects of Megakaryocytes in Prostate Cancer Bone Metastasis

DTIC Science & Technology

2010-04-01

meeting, Feb. 2010, Seattle, WA) 3. Inhibitory effects of megakaryocytes in prostate cancer bone metastasis. (Oral presentation and Young ...cancer bone metastasis. (Oral presentation and ASBMR-Harold M. Frost Young Investigator Award, Aug. 2009, Sun Valley, ID) 5. Career development...valuable new scientific information and also provided critical career development support for an a spiring young scientist. References Please refer

Anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol and lupeol isolated from Diospyros lotus L.

PubMed

Rauf, Abdur; Uddin, Ghias; Khan, Haroon; Raza, Muslim; Zafar, Muhammad; Tokuda, Harukuni

2016-01-01

In this study, the anti-tumour-promoting and thermal-induced protein denaturation inhibitory activities of β-sitosterol (1) and lupeol (2), isolated from Diospyros lotus L., were explored. Compound 1 showed a marked concentration-dependent inhibition against 12-O-tetradecanoylphorbol-13-acetate (20 ng/32 pmol)-induced Epstein-Barr virus early antigen activation in Raji cells with IC50 of 270 μg/ml, without significant toxicity (70% viability). Compound 2 showed significant anti-tumour-promoting effect with IC50 of 412 μg/ml, without significant toxicity (60% viability). In heat-induced protein denaturation assay, compound 1 exhibited a concentration-dependent attenuation with a maximum effect of 73.5% at 500 μg/ml with EC50 of 117 μg/ml, while compound 2 exhibited a maximum effect of 59.2% at 500 μg/ml with EC50 of 355 μg/ml. Moreover, in silico docking studies against the phosphoinositide 3-kinase enzyme also show the inhibitory potency of these compounds. In short, both the compounds exhibited a marked anti-tumour-promoting and potent inhibitory effect on thermal-induced protein denaturation.

Virucidal activity of Colombian Lippia essential oils on dengue virus replication in vitro.

PubMed

Ocazionez, Raquel Elvira; Meneses, Rocio; Torres, Flor Angela; Stashenko, Elena

2010-05-01

The inhibitory effect of Lippia alba and Lippia citriodora essential oils on dengue virus serotypes replication in vitro was investigated. The cytotoxicity (CC50) was evaluated by the MTT assay and the mode of viral inhibitory effect was investigated with a plaque reduction assay. The virus was treated with the essential oil for 2 h at 37 masculineC before cell adsorption and experiments were conducted to evaluate inhibition of untreated-virus replication in the presence of oil. Antiviral activity was defined as the concentration of essential oil that caused 50% reduction of the virus plaque number (IC50). L. alba oil resulted in less cytotoxicity than L. citriodora oil (CC50: 139.5 vs. 57.6 microg/mL). Virus plaque reduction for all four dengue serotypes was observed by treatment of the virus before adsorption on cell. The IC50 values for L. alba oil were between 0.4-32.6 microg/mL and between 1.9-33.7 microg/mL for L. citriodora oil. No viral inhibitory effect was observed by addition of the essential oil after virus adsorption. The inhibitory effect of the essential oil seems to cause direct virus inactivation before adsorption on host cell.

Influence of gas-liquid two-phase flow on angiotensin-I converting enzyme inhibitory peptides separation by ultra-filtration.

PubMed

Charoenphun, Narin; Youravong, Wirote

2017-01-01

Membrane fouling is a major problem in ultra-filtration systems and two-phase flow is a promising technique for permeate flux enhancement. The objective of this research was to study the use of an ultra-filtration (UF) system to enrich angiotensin-I converting enzyme (ACE) inhibitory peptides from tilapia protein hydrolysate. To select the most appropriate membrane and operating condition, the effects of membrane molecular weight cut-off (MWCO), transmembrane pressure (TMP) and cross-flow velocity (CFV) on permeate flux and ACE inhibitory peptide separation were studied. Additionally, the gas-liquid two-phase flow technique was applied to investigate its effect on the process capability. The results showed that the highest ACE inhibitory activity was obtained from permeate of the 1 kDa membrane. In terms of TMP and CFV, the permeate flux tended to increase with TMP and CFV. The use of gas-liquid two-phase flow as indicated by shear stress number could reduce membrane fouling and increase the permeate flux up to 42%, depending on shear stress number. Moreover, the use of a shear stress number of 0.039 led to an augmentation in ACE inhibitory activity of permeates. Operating conditions using a shear stress number of 0.039 were recommended for enrichment of ACE inhibitory peptides. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Adolescents with and without gestational cocaine exposure: Longitudinal analysis of inhibitory control, memory and receptive language.

PubMed

Betancourt, Laura M; Yang, Wei; Brodsky, Nancy L; Gallagher, Paul R; Malmud, Elsa K; Giannetta, Joan M; Farah, Martha J; Hurt, Hallam

2011-01-01

Preclinical studies of gestational cocaine exposure (GCE) show evidence of changes in brain function at the anatomical, physiological, and behavioral levels, to include effects on developing dopaminergic systems. In contrast, human studies have produced less consistent results, with most showing small effects or no effects on developmental outcomes. Important changes in brain structure and function occur through adolescence, therefore it is possible that prenatal cocaine exposure has latent effects on neurocognitive (NC) outcome that do not manifest until adolescence or young adulthood. We examined NC function using a set of 5 tasks designed to tap 4 different systems: inhibitory control, working memory, receptive language, and incidental memory. For each NC task, data were collected longitudinally at ages 12, 14.5 and 17 years and examined using generalized estimating equations. One hundred and nine children completed at least two of the three evaluations. Covariates included in the final model were assessment number, gender, participant age at first assessment, caregiver depression, and two composites from the Home Observation for Measurement of the Environment (HOME), Environmental Stimulation and Parental Nurturance. We found no cocaine effects on inhibitory control, working memory, or receptive language (p=0.18). GCE effects were observed on incidental face memory task (p=0.055), and GCE by assessment number interaction effects were seen on the incidental word memory task (p=0.031). Participant performance on inhibitory control, working memory, and receptive language tasks improved over time. HOME Environmental Stimulation composite was associated with better receptive language functioning. With a larger sample size smaller differences between groups may have been detected. This report shows no evidence of latent effects of GCE on inhibitory control, working memory, or receptive language. GCE effects were observed on the incidental face memory task, and GCE by assessment number interaction effects was seen on the incidental word memory task. Copyright © 2010 Elsevier Inc. All rights reserved.

Subliminal unconscious conflict alpha power inhibits supraliminal conscious symptom experience.

PubMed

Shevrin, Howard; Snodgrass, Michael; Brakel, Linda A W; Kushwaha, Ramesh; Kalaida, Natalia L; Bazan, Ariane

2013-01-01

Our approach is based on a tri-partite method of integrating psychodynamic hypotheses, cognitive subliminal processes, and psychophysiological alpha power measures. We present ten social phobic subjects with three individually selected groups of words representing unconscious conflict, conscious symptom experience, and Osgood Semantic negative valence words used as a control word group. The unconscious conflict and conscious symptom words, presented subliminally and supraliminally, act as primes preceding the conscious symptom and control words presented as supraliminal targets. With alpha power as a marker of inhibitory brain activity, we show that unconscious conflict primes, only when presented subliminally, have a unique inhibitory effect on conscious symptom targets. This effect is absent when the unconscious conflict primes are presented supraliminally, or when the target is the control words. Unconscious conflict prime effects were found to correlate with a measure of repressiveness in a similar previous study (Shevrin et al., 1992, 1996). Conscious symptom primes have no inhibitory effect when presented subliminally. Inhibitory effects with conscious symptom primes are present, but only when the primes are supraliminal, and they did not correlate with repressiveness in a previous study (Shevrin et al., 1992, 1996). We conclude that while the inhibition following supraliminal conscious symptom primes is due to conscious threat bias, the inhibition following subliminal unconscious conflict primes provides a neurological blueprint for dynamic repression: it is only activated subliminally by an individual's unconscious conflict and has an inhibitory effect specific only to the conscious symptom. These novel findings constitute neuroscientific evidence for the psychoanalytic concepts of unconscious conflict and repression, while extending neuroscience theory and methods into the realm of personal, psychological meaning.

Subliminal unconscious conflict alpha power inhibits supraliminal conscious symptom experience

PubMed Central

Shevrin, Howard; Snodgrass, Michael; Brakel, Linda A. W.; Kushwaha, Ramesh; Kalaida, Natalia L.; Bazan, Ariane

2013-01-01

Our approach is based on a tri-partite method of integrating psychodynamic hypotheses, cognitive subliminal processes, and psychophysiological alpha power measures. We present ten social phobic subjects with three individually selected groups of words representing unconscious conflict, conscious symptom experience, and Osgood Semantic negative valence words used as a control word group. The unconscious conflict and conscious symptom words, presented subliminally and supraliminally, act as primes preceding the conscious symptom and control words presented as supraliminal targets. With alpha power as a marker of inhibitory brain activity, we show that unconscious conflict primes, only when presented subliminally, have a unique inhibitory effect on conscious symptom targets. This effect is absent when the unconscious conflict primes are presented supraliminally, or when the target is the control words. Unconscious conflict prime effects were found to correlate with a measure of repressiveness in a similar previous study (Shevrin et al., 1992, 1996). Conscious symptom primes have no inhibitory effect when presented subliminally. Inhibitory effects with conscious symptom primes are present, but only when the primes are supraliminal, and they did not correlate with repressiveness in a previous study (Shevrin et al., 1992, 1996). We conclude that while the inhibition following supraliminal conscious symptom primes is due to conscious threat bias, the inhibition following subliminal unconscious conflict primes provides a neurological blueprint for dynamic repression: it is only activated subliminally by an individual's unconscious conflict and has an inhibitory effect specific only to the conscious symptom. These novel findings constitute neuroscientific evidence for the psychoanalytic concepts of unconscious conflict and repression, while extending neuroscience theory and methods into the realm of personal, psychological meaning. PMID:24046743

Effect of Essential Oils on Germination and Growth of Some Pathogenic and Spoilage Spore-Forming Bacteria.

PubMed

Voundi, Stève Olugu; Nyegue, Maximilienne; Lazar, Iuliana; Raducanu, Dumitra; Ndoye, Florentine Foe; Marius, Stamate; Etoa, François-Xavier

2015-06-01

The use of essential oils as a food preservative has increased due to their capacity to inhibit vegetative growth of some bacteria. However, only limited data are available on their effect on bacterial spores. The aim of the present study was to evaluate the effect of some essential oils on the growth and germination of three Bacillus species and Geobacillus stearothermophilus. Essential oils were chemically analyzed using gas chromatography and gas chromatography coupled to mass spectrometry. The minimal inhibitory and bactericidal concentrations of vegetative growth and spore germination were assessed using the macrodilution method. Germination inhibitory effect of treated spores with essential oils was evaluated on solid medium, while kinetic growth was followed using spectrophotometry in the presence of essential oils. Essential oil from Drypetes gossweileri mainly composed of benzyl isothiocyanate (86.7%) was the most potent, with minimal inhibitory concentrations ranging from 0.0048 to 0.0097 mg/mL on vegetative cells and 0.001 to 0.002 mg/mL on spore germination. Furthermore, essential oil from D. gossweileri reduced 50% of spore germination after treatment at 1.25 mg/mL, and its combination with other oils improved both bacteriostatic and bactericidal activities with additive or synergistic effects. Concerning the other essential oils, the minimal inhibitory concentration ranged from 5 to 0.63 mg/mL on vegetative growth and from 0.75 to 0.09 mg/mL on the germination of spores. Spectrophotometric evaluation showed an inhibitory effect of essential oils on both germination and outgrowth. From these results, it is concluded that some of the essential oils tested might be a valuable tool for bacteriological control in food industries. Therefore, further research regarding their use as food preservatives should be carried out.

Flavonoids of Cynara scolymus possess potent xanthinoxidase inhibitory activity in vitro but are devoid of hypouricemic effects in rats after oral application.

PubMed

Sarawek, Sasiporn; Feistel, Bjoern; Pischel, Ivo; Butterweck, Veronika

2008-02-01

Artichoke (Cynara scolymus L.) leaves have been historically used for the treatment of hyperuricemia and gout, however whether artichoke is truly efficacious for this indication, is still a matter of debate. Thus, the goal of the present study was first to examine the xanthine oxidase (XO) inhibitory activity of an artichoke leaf extract (ALE) and some of its main compounds in vitro and then further test potentially active substances for possible hypouricemic effects using an in vivo rat model. The in vitro study showed that ALE inhibited XO with only minimal inhibitory action (< 5 %) at 100 microg/mL. However, when selected compounds were tested, the caffeic acid derivatives revealed a weak XO inhibitory effect with IC (50) > 100 microM. From the tested flavones the aglycone luteolin potently inhibited XO with an IC (50) value of 1.49 microM. Luteolin 7-O-glucoside and luteolin 7-O-glucuronide showed lower XO inhibition activities with IC (50) values of 19.90 microM and 20.24 microM, respectively. However, oral administration of an aqueous ALE, luteolin, and luteolin 7-O-glucoside did not produce any observable hypouricemic effects after acute oral treatment in potassium oxonate-treated rats. After intraperitoneal injection of luteolin a decrease in uric acid levels was detected suggesting that the hypouricemic effects of luteolin are due to its original form rather than its metabolites produced by the gut flora. In conclusion, an aqueous ALE, caffeic acid derivatives and flavones exerted XO inhibitory effects in vitro but a hypouricemic activity could not be confirmed after oral administration.

A novel diarylheptanoid-bearing sesquiterpene moiety from the rhizomes of Alpinia officinarum.

PubMed

Wei, Na; Zhou, Zhonglin; Wei, Qing; Wang, Yong; Jiang, Jun; Zhang, Junqing; Wu, Lixiang; Dai, Shuiping; Li, Youbin

2016-10-01

A new diarylheptanoid analogue-bearing sesquiterpene moiety, named Alpinisin A, was isolated from the rhizomes of Alpinia officinarum Hance. The new structure was determined by various spectroscopic techniques (1)H-nuclear magnetic resonance ((1)H NMR), (13)C-attached proton test ((13)C-APT), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC), (1)H-(1)H correlation spectroscopy ((1)H-(1)HCOSY), nuclear overhauser effect spectroscopy (NOESY) and high resolution electrospray ionization mass spectrometry (HR-ESI-MS). The compound was tested for cytotoxic activity in vitro against human tumour cell lines (gastric carcinoma cell -7901 (SGC-7901), Michigan Cancer Foundation-7 (MCF-7) and Caski), which showed significant inhibitory effects with IC50 levels of 11.42, 15.14 and 14.78 μM, respectively. The novel chemical structure characterised with a diarylheptanoid linked to a chain-like sesquiterpenoid should be highlighted.

Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity

NASA Astrophysics Data System (ADS)

Lim, Seng Koon; Sandén, Camilla; Selegård, Robert; Liedberg, Bo; Aili, Daniel

2016-02-01

Membrane active peptides are of large interest for development of drug delivery vehicles and therapeutics for treatment of multiple drug resistant infections. Lack of specificity can be detrimental and finding routes to tune specificity and activity of membrane active peptides is vital for improving their therapeutic efficacy and minimize harmful side effects. We describe a de novo designed membrane active peptide that partition into lipid membranes only when specifically and covalently anchored to the membrane, resulting in pore-formation. Dimerization with a complementary peptide efficiently inhibits formation of pores. The effect can be regulated by proteolytic digestion of the inhibitory peptide by the matrix metalloproteinase MMP-7, an enzyme upregulated in many malignant tumors. This system thus provides a precise and specific route for tuning the permeability of lipid membranes and a novel strategy for development of recognition based membrane active peptides and indirect enzymatically controlled release of liposomal cargo.

Killing of Serratia marcescens biofilms with chloramphenicol.

PubMed

Ray, Christopher; Shenoy, Anukul T; Orihuela, Carlos J; González-Juarbe, Norberto

2017-03-29

Serratia marcescens is a Gram-negative bacterium with proven resistance to multiple antibiotics and causative of catheter-associated infections. Bacterial colonization of catheters mainly involves the formation of biofilm. The objectives of this study were to explore the susceptibility of S. marcescens biofilms to high doses of common antibiotics and non-antimicrobial agents. Biofilms formed by a clinical isolate of S. marcescens were treated with ceftriaxone, kanamycin, gentamicin, and chloramphenicol at doses corresponding to 10, 100 and 1000 times their planktonic minimum inhibitory concentration. In addition, biofilms were also treated with chemical compounds such as polysorbate-80 and ursolic acid. S. marcescens demonstrated susceptibility to ceftriaxone, kanamycin, gentamicin, and chloramphenicol in its planktonic form, however, only chloramphenicol reduced both biofilm biomass and biofilm viability. Polysorbate-80 and ursolic acid had minimal to no effect on either planktonic and biofilm grown S. marcescens. Our results suggest that supratherapeutic doses of chloramphenicol can be used effectively against established S. marcescens biofilms.

Repetitive Transcranial Magnetic Stimulation of the Primary Somatosensory Cortex Modulates Perception of the Tendon Vibration Illusion.

PubMed

Huh, D C; Lee, J M; Oh, S M; Lee, J-H; Van Donkelaar, P; Lee, D H

2016-10-01

The effect of repetitive transcranial magnetic stimulation on kinesthetic perception, when applied to the somatosensory cortex, was examined. Further, the facilitatory and inhibitory effects of repetitive transcranial magnetic stimulation using different stimulation frequencies were tested. Six female (M age = 32.0 years, SD = 6.7) and nine male (M age = 32.9 years, SD = 6.6) participants were asked to perceive the tendon vibration illusion of the left wrist joint and to replicate the illusion with their right hand. When comparing changes in the corresponding movement amplitude and velocity after three different repetitive transcranial magnetic stimulation protocols (sham, 1 Hz inhibitory, and 5 Hz facilitatory repetitive transcranial magnetic stimulation), the movement amplitude was found to decrease with the inhibitory repetitive transcranial magnetic stimulation, while the movement velocity respectively increased and decreased with the facilitatory and inhibitory repetitive transcranial magnetic stimulation. These results confirmed the modulating effects of repetitive transcranial magnetic stimulation on kinesthetic perception in a single experimental paradigm. © The Author(s) 2016.

Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.

PubMed

Arnadottir, M; Nilsson-Ehle, P

1994-01-01

The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions.

Discovery of SMP-304, a novel benzylpiperidine derivative with serotonin transporter inhibitory activity and 5-HT1A weak partial agonistic activity showing the antidepressant-like effect.

PubMed

Yoshinaga, Hidefumi; Masumoto, Shuji; Koyama, Koji; Kinomura, Naoya; Matsumoto, Yuji; Kato, Taro; Baba, Satoko; Matsumoto, Kenji; Horisawa, Tomoko; Oki, Hitomi; Yabuuchi, Kazuki; Kodo, Toru

2017-01-01

We report the discovery of a novel benzylpiperidine derivative with serotonin transporter (SERT) inhibitory activity and 5-HT 1A receptor weak partial agonistic activity showing the antidepressant-like effect. The 3-methoxyphenyl group and the phenethyl group of compound 1, which has weak SERT binding activity, but potent 5-HT 1A binding activity, were optimized, leading to compound 35 with potent and balanced dual SERT and 5-HT 1A binding activity, but also potent CYP2D6 inhibitory activity. Replacement of the methoxy group in the left part of compound 35 with a larger alkoxy group, such as ethoxy, isopropoxy or methoxy-ethoxy group ameliorated CYP2D6 inhibition, giving SMP-304 as a candidate. SMP-304 with serotonin uptake inhibitory activity and 5-HT 1A weak partial agonistic activity, which could work as a 5-HT 1A antagonist, displayed faster onset of antidepressant-like effect than a representative SSRI paroxetine in an animal model. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

DTIC Science & Technology

2016-10-01

effectiveness on cell growth with potent toxicity. Second, we set to advance a Siah inhibitory peptide that we recently developed in parallel, as...Siah1/2 inhibitors to the ubiquitin ligase Siah1/2 has been advanced by the ability to develop a Siah1/2 inhibitory peptide that effectively inhibits...Siah1/2 activity, which was found to effectively attenuate the growth of prostate cancer tumors in vivo when transplanted subcutaneously or

Intervention of Prostate Cancer by a Flavonoid Antioxidant Silymarin

DTIC Science & Technology

2001-04-01

effect of silymarin on PCA tumor growth in nude mice. Treatment of LNCaP and DUl45 human prostate carcinoma cells with silibinin (the pure form of...dimerization. These inhibitory effects of silibinin also corroborate with its inhibitory effect on both cellular and released expression of TGFalpha in...these two cell lines. In cytoplasmic signaling, silibinin showed strong decrease in ERKl/2 phosphorylation in both LNCaP and DUl45 cells and inhibition in

Stimulus control in pigeons after extended discriminative training

NASA Technical Reports Server (NTRS)

Yarczower, M.

1972-01-01

The effects of amount of training on conditioned inhibition and on the degree of stimulus control were studied using pigeons. The ability of an S- associated with non-reinforcement of suppress positive reinforced behavior was acquired very rapidly during discriminative training. Increased S+, S- training appeared to weaken this conditioned inhibitory effect while at the same time more S+ training apparently increased the amount of external inhibition (non-conditioned inhibition) of positively reinforced behavior by a novel stimulus. Behavioral contrast and incremental generalization gradients along the S- dimension (inhibitory dimensional control) were absent at all stages of training. Behavioral contrast and inhibitory dimensional control are therefore not necessary concomitants of conditioned inhibition by an S-. A new method of assessing the suppressive effects of stimuli during generalization tests was described.

Inhibitory Effects of Palmultang on Inflammatory Mediator Production Related to Suppression of NF-κB and MAPK Pathways and Induction of HO-1 Expression in Macrophages

PubMed Central

Oh, You-Chang; Jeong, Yun Hee; Cho, Won-Kyung; Gu, Min-Jung; Ma, Jin Yeul

2014-01-01

Palmultang (PM) is an herbal decoction that has been used to treat anorexia, anemia, general prostration, and weakness due to chronic illness since medieval times in Korea, China, and Japan. The present study focused on the inhibitory effects of PM on the production of inflammatory factors and on the activation of mechanisms in murine macrophages. PM suppressed the expression of nitric oxide (NO), inflammatory cytokines and inflammatory proteins by inhibiting nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways and by inducing heme oxygenase (HO)-1 expression. Collectively, our results explain the anti-inflammatory effect and inhibitory mechanism of PM in macrophages stimulated with lipopolysaccharide (LPS). PMID:24828204

[The characteristics of the cholinoreceptors on the identified TAN neuron of the giant African snail Achatina fulica].

PubMed

Stepanov, I I; Losev, N A

1999-04-01

Acetylcholine, nicotine, a selective agonist of N-cholinoreceptors suberildicholine dibromide, as well as a selective agonist of M-cholinoreceptors 5-methylfurmethide inhibited spike discharges in a dose-dependent manner up to a complete ceasing of the firing in cholinoreceptors situated on the identified neurone TAN of African giant snail Achatina fulica. M-cholinoblocker metamizylum completely prevented the inhibitory effect of methylfurmethide. Central cholinoblocker aetherophen completely prevented the inhibitory effect of suberildicholine dibromide. Metamizylum or aetherophen used alone were only able to decrease the inhibitory effect of acetylcholine, whereas a mixture of these agents suppressed completely the acetylcholine-induced inhibition. The findings suggest that, on the TAN membrane, nicotinic and muscarinic cholinoreceptors co-exist and function in one and the same direction.

Identification and the molecular mechanism of a novel myosin-derived ACE inhibitory peptide.

PubMed

Yu, Zhipeng; Wu, Sijia; Zhao, Wenzhu; Ding, Long; Shiuan, David; Chen, Feng; Li, Jianrong; Liu, Jingbo

2018-01-24

The objective of this work was to identify a novel ACE inhibitory peptide from myosin using a number of in silico methods. Myosin was evaluated as a substrate for use in the generation of ACE inhibitory peptides using BIOPEP and ExPASy PeptideCutter. Then the ACE inhibitory activity prediction of peptides in silico was evaluated using the program peptide ranker, following the database search of known and unknown peptides using the program BIOPEP. In addition, the interaction mechanisms of the peptide and ACE were evaluated by DS. All of the tripeptides were predicted to be nontoxic. Results suggested that the tripeptide NCW exerted potent ACE inhibitory activity with an IC 50 value of 35.5 μM. Furthermore, the results suggested that the peptide NCW comes into contact with Zn 701, Tyr 523, His 383, Glu 384, Glu 411, and His 387. The potential molecular mechanism of the NCW/ACE interaction was investigated. Results confirmed that the higher inhibitory potency of NCW might be attributed to the formation of more hydrogen bonds with the ACE's active site. Therefore, the in silico method is effective to predict and identify novel ACE inhibitory peptides from protein hydrolysates.

Effects of Ganodermanondiol, a New Melanogenesis Inhibitor from the Medicinal Mushroom Ganoderma lucidum

PubMed Central

Kim, Ji-Woong; Kim, Hong-Il; Kim, Jong-Hyeon; Kwon, O-Chul; Son, Eun-Suk; Lee, Chang-Soo; Park, Young-Jin

2016-01-01

Ganoderma lucidum, a species of the Basidiomycetes class, has been attracting international attention owing to its wide variety of biological activities and great potential as an ingredient in skin care cosmetics including “skin-whitening” products. However, there is little information available on its inhibitory effect against tyrosinase activity. Therefore, the objectives of this study were to investigate the chemical composition of G. lucidum and its inhibitory effects on melanogenesis. We isolated the active compound from G. lucidum using ethanol extraction and ethyl acetate fractionation. In addition, we assayed its inhibitory effects on tyrosinase activity and melanin biosynthesis in B16F10 melanoma cells. In this study, we identified a bioactive compound, ganodermanondiol, which inhibits the activity and expression of cellular tyrosinase and the expression of tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), thereby decreasing melanin production. Furthermore, ganodermanondiol also affected the mitogen-activated protein kinase (MAPK) cascade and cyclic adenosine monophosphate (cAMP)-dependent signaling pathway, which are involved in the melanogenesis of B16F10 melanoma cells. The finding that ganodermanondiol from G. lucidum exerts an inhibitory effect on tyrosinase will contribute to the use of this mushroom in the preparation of skin care products in the future. PMID:27801787

Graphene oxide significantly inhibits cell growth at sublethal concentrations by causing extracellular iron deficiency.

PubMed

Yu, Qilin; Zhang, Bing; Li, Jianrong; Du, Tingting; Yi, Xiao; Li, Mingchun; Chen, Wei; Alvarez, Pedro J J

Graphene oxide (GO)-based materials are increasingly being used in medical materials and consumer products. However, their sublethal effects on biological systems are poorly understood. Here, we report that GO (at 10 to 160 mg/L) induced significant inhibitory effects on the growth of different unicellular organisms, including eukaryotes (i.e. Saccharomyces cerevisiae, Candida albicans, and Komagataella pastoris) and prokaryotes (Pseudomonas fluorescens). Growth inhibition could not be explained by commonly reported cytotoxicity mechanisms such as plasma membrane damage or oxidative stress. Based on transcriptomic analysis and measurement of extra- and intracellular iron concentrations, we show that the inhibitory effect of GO was mainly attributable to iron deficiency caused by binding to the O-functional groups of GO, which sequestered iron and disrupted iron-related physiological and metabolic processes. This inhibitory mechanism was corroborated with supplementary experiments, where adding bathophenanthroline disulfonate-an iron chelating agent-to the culture medium exerted similar inhibition, whereas removing surface O-functional groups of GO decreased iron sequestration and significantly alleviated the inhibitory effect. These findings highlight a potential indirect detrimental effect of nanomaterials (i.e. scavenging of critical nutrients), and encourage research on potential biomedical applications of GO-based materials to sequester iron and enhance treatment of iron-dependent diseases such as cancer and some pathogenic infections.

Effects of Ganodermanondiol, a New Melanogenesis Inhibitor from the Medicinal Mushroom Ganoderma lucidum.

PubMed

Kim, Ji-Woong; Kim, Hong-Il; Kim, Jong-Hyeon; Kwon, O-Chul; Son, Eun-Suk; Lee, Chang-Soo; Park, Young-Jin

2016-10-27

Ganoderma lucidum , a species of the Basidiomycetes class, has been attracting international attention owing to its wide variety of biological activities and great potential as an ingredient in skin care cosmetics including "skin-whitening" products. However, there is little information available on its inhibitory effect against tyrosinase activity. Therefore, the objectives of this study were to investigate the chemical composition of G. lucidum and its inhibitory effects on melanogenesis. We isolated the active compound from G. lucidum using ethanol extraction and ethyl acetate fractionation. In addition, we assayed its inhibitory effects on tyrosinase activity and melanin biosynthesis in B16F10 melanoma cells. In this study, we identified a bioactive compound, ganodermanondiol, which inhibits the activity and expression of cellular tyrosinase and the expression of tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor (MITF), thereby decreasing melanin production. Furthermore, ganodermanondiol also affected the mitogen-activated protein kinase (MAPK) cascade and cyclic adenosine monophosphate (cAMP)-dependent signaling pathway, which are involved in the melanogenesis of B16F10 melanoma cells. The finding that ganodermanondiol from G. lucidum exerts an inhibitory effect on tyrosinase will contribute to the use of this mushroom in the preparation of skin care products in the future.

Physiologically based pharmacokinetics model predicts the lack of inhibition by repaglinide on the metabolism of pioglitazone.

PubMed

Xiao, Qingqing; Tang, Liling; Xu, Ruijuan; Qian, Wei; Yang, Jin

2015-12-01

Repaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study was to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro, in silico and in vivo. In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE-PBPK linked model was built with Simcyp®. Then, a randomized, 2-phase cross-over clinical study was conducted in 12 healthy volunteers. Repaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki  = 0.0757 µm), [I]/Ki  > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of pioglitazone in clinical trials showed no significant difference between these two treatment groups (p > 0.05). Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo, which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and to the high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. Copyright © 2015 John Wiley & Sons, Ltd.

Multiparameter analysis of activated sludge inhibition by nickel, cadmium, and cobalt.

PubMed

Hernandez-Martinez, Gabriel R; Ortiz-Alvarez, Daniela; Perez-Roa, Michael; Urbina-Suarez, Nestor Andres; Thalasso, Frederic

2018-06-05

Activated sludge processes are often inhibited by nickel, cadmium, and cobalt. The inhibitory effect of these heavy metals on a synthetic wastewater treatment process was tested through pulse microrespirometry; i.e., pulse of substrate injected in a microreactor system. The inhibitory effect was tested under different conditions including the heavy metals, substrate and biomass concentrations, and exposure time. The inhibitory effect was quantified by the percentage of inhibition, half saturation constant (K S ), inhibition constant (K I ), and maximum oxygen uptake rate (OUR max ). The results indicated that, in a range of concentration from 0 to 40 mg L -1 , the three heavy metals exerted an uncompetitive and incomplete inhibitory effect, with a maximum inhibition of 67, 57, and 53% for Ni, Co, and Cd, respectively. An increase of the biomass concentration by 620% resulted in a decrease of the inhibition by 47 and 69% for Co and Cd, respectively, while no effect was observed on Ni inhibition. An increase of the substrate concentration by 87% resulted in an increase of the inhibition by 24, 70, and 47% for Ni, Co and Cd, respectively. In the case of nickel and cadmium, an increase in the exposure time to the heavy metals also increased the inhibition. Copyright © 2018 Elsevier B.V. All rights reserved.

Circuit variability interacts with excitatory-inhibitory diversity of interneurons to regulate network encoding capacity.

PubMed

Tsai, Kuo-Ting; Hu, Chin-Kun; Li, Kuan-Wei; Hwang, Wen-Liang; Chou, Ya-Hui

2018-05-23

Local interneurons (LNs) in the Drosophila olfactory system exhibit neuronal diversity and variability, yet it is still unknown how these features impact information encoding capacity and reliability in a complex LN network. We employed two strategies to construct a diverse excitatory-inhibitory neural network beginning with a ring network structure and then introduced distinct types of inhibitory interneurons and circuit variability to the simulated network. The continuity of activity within the node ensemble (oscillation pattern) was used as a readout to describe the temporal dynamics of network activity. We found that inhibitory interneurons enhance the encoding capacity by protecting the network from extremely short activation periods when the network wiring complexity is very high. In addition, distinct types of interneurons have differential effects on encoding capacity and reliability. Circuit variability may enhance the encoding reliability, with or without compromising encoding capacity. Therefore, we have described how circuit variability of interneurons may interact with excitatory-inhibitory diversity to enhance the encoding capacity and distinguishability of neural networks. In this work, we evaluate the effects of different types and degrees of connection diversity on a ring model, which may simulate interneuron networks in the Drosophila olfactory system or other biological systems.

Improving the acetylcholinesterase inhibitory effect of Illigera henryi by solid-state fermentation with Clonostachys rogersoniana.

PubMed

Li, Xue-Jiao; Dong, Jian-Wei; Cai, Le; Mei, Rui-Feng; Ding, Zhong-Tao

2017-11-01

Illigera henryi, an endemic traditional Chinese medicine, contains abundant aporphine alkaloids that possess various bioactivities. In the present study, tubers of I. henryi were fermented by several fungi, and the acetylcholinesterase (AChE) inhibitory activities of non-fermented and fermented I. henryi were measured. The results showed that the fermentation of I. henryi with Clonostachys rogersoniana 828H2 is effective for improving the AChE inhibitory activity. A key biotransformation was found during the C. rogersoniana fermentation for clarifying the improvement of the AChE inhibitory activity of I. henryi: (S)-actinodaphnine (1) was converted to a new 4-hydroxyaporphine alkaloid (4R,6aS)-4-hydroxyactinodaphnine (2) that possessed a stronger AChE inhibitory activity, with an IC 50 value of 17.66±0.06 μM. This paper is the first to report that the pure strain fermentation processing of I. henryi and indicated C. rogersoniana fermentation might be a potential processing method for I. henryi. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

In Vitro Growth Inhibitory Activities of Natural Products from Irciniid Sponges against Cancer Cells: A Comparative Study

PubMed Central

BenRedjem Romdhane, Yosr; Elbour, Monia; Carbone, Marianna; Ciavatta, Maria Letizia; Gavagnin, Margherita; Mathieu, Véronique; Lefranc, Florence; Ktari, Leila; Ben Mustapha, Karim; Boudabous, Abdellatif; Kiss, Robert

2016-01-01

Marine sponges of the Irciniidae family contain both bioactive furanosesterterpene tetronic acids (FTAs) and prenylated hydroquinones (PHQs). Both classes of compounds are known for their anti-inflammatory, antioxidant, and antimicrobial properties and known to display growth inhibitory effects against various human tumor cell lines. However, the different experimental conditions of the reported in vitro bioassays, carried out on different cancer cell lines within separate studies, prevent realistic actual discrimination between the two classes of compounds from being carried out in terms of growth inhibitory effects. In the present work, a chemical investigation of irciniid sponges from Tunisian coasts led to the purification of three known FTAs and three known PHQs. The in vitro growth inhibitory properties of the six purified compounds have been evaluated in the same experiment in a panel of five human and one murine cancer cell lines displaying various levels of sensitivity to proapoptotic stimuli. Surprisingly, FTAs and PHQs elicited distinct profiles of growth inhibitory-responses, differing by one to two orders of magnitude in favor of the PHQs in all cell lines. The obtained comparative results are discussed in the light of a better selection of drug candidates from natural sources. PMID:27597966

Plant growth inhibitory activity of p-hydroxyacetophenones and tremetones from Chilean endemic Baccharis species and some analogous: a comparative study.

PubMed

Céspedes, Carlos L; Uchoa, Adjaci; Salazar, Juan R; Perich, Fernando; Pardo, Fernando

2002-04-10

Plant growth inhibitory effects of acetophenones 1-6, tremetones 7-12, and MeOH and CH(2)Cl(2) extracts from the aerial parts of Baccharis linnearis, Baccharis magellanica, and Baccharis umbelliformis collected in Chile were assayed as growth inhibitory activity in ranges of 10-500 microM and 0.1-150 ppm, respectively. The effects on seedling growth, germination, and respiration of ryegrass, lettuce, green tomato, and red clover weedy target species were measured. In addition to the inhibitory activity on bleaching of crocin induced by alkoxyl radicals, these compounds also demonstrated scavenging properties toward 2,2-diphenyl-1-picrylhydrazyl in thin-layer chromatography autographic and spectrophotometric assays. In addition, acetophenones and tremetones also showed inhibition of H(+) uptake and oxygen uptake respiration in isolated chloroplasts and mitochondria, respectively. Our results indicate that 1, 4, 7-12, and CH(2)Cl(2) extracts interfere with the dicot preemergence properties, mainly energy metabolism of the seeds at the level of respiration. These compounds appear to have selective effects on the radicle more than shoot growth of dicot seeds. Also, the levels of radicle inhibition obtained with some compounds on Physalis ixocarpa and Trifolium pratense are totally comparable to those of ovatifolin, a known natural growth inhibitor. This behavior might be responsible for its plant growth inhibitory properties and its possible role as an allelopathic agent.

1,8-cineole inhibits both proliferation and elongation of BY-2 cultured tobacco cells.

PubMed

Yoshimura, Hiroko; Sawai, Yu; Tamotsu, Satoshi; Sakai, Atsushi

2011-03-01

Volatile monoterpenes such as 1,8-cineole inhibit the growth of Brassica campestris seedlings in a dose-dependent manner, and the growth-inhibitory effects are more severe for roots than hypocotyls. The preferential inhibition of root growth may be explained if the compounds inhibit cell proliferation more severely than cell elongation because root growth requires both elongation and proliferation of the constituent cells, whereas hypocotyl growth depends exclusively on elongation of existing cells. In order to examine this possibility, BY-2 suspension-cultured tobacco (Nicotiana tabacum) cells were treated with 1,8-cineole, and the inhibitory effects on cell proliferation and on cell elongation were assessed quantitatively. Treatment with 1,8-cineole lowered both the mitotic index and elongation of the cells in a dose-dependent manner, and the half-maximal inhibitory concentration (IC₅₀) for cell elongation was lower than that for cell proliferation. Moreover, 1,8-cineole also inhibited starch synthesis, with IC₅₀ lower than that for cell proliferation. Thus, the inhibitory effects of 1,8-cineole were not specific to cell proliferation; rather, 1,8-cineole seemed inhibitory to a variety of physiological activities when it was in direct contact with target cells. Based on these results, possible mechanisms for the mode of action of 1,8-cineole and for its preferential inhibition on root growth are discussed.

The Recurrent Case for the Renshaw Cell

PubMed Central

Bhumbra, Gardave S.; Bannatyne, B. Anne; Watanabe, Masahiko; Todd, Andrew J.

2014-01-01

Although Renshaw cells (RCs) were discovered over half a century ago, their precise role in recurrent inhibition and ability to modulate motoneuron excitability have yet to be established. Indirect measurements of recurrent inhibition have suggested only a weak modulatory effect but are limited by the lack of observed motoneuron responses to inputs from single RCs. Here we present dual recordings between connected RC–motoneuron pairs, performed on mouse spinal cord. Motoneuron responses demonstrated that Renshaw synapses elicit large inhibitory conductances and show short-term potentiation. Anatomical reconstruction, combined with a novel method of quantal analysis, showed that the strong inhibitory input from RCs results from the large number of synaptic contacts that they make onto individual motoneurons. We used the NEURON simulation environment to construct realistic electrotonic models, which showed that inhibitory conductances from Renshaw inputs exert considerable shunting effects in motoneurons and reduce the frequency of spikes generated by excitatory inputs. This was confirmed experimentally by showing that excitation of a single RC or selective activation of the recurrent inhibitory pathway to generate equivalent inhibitory conductances both suppress motoneuron firing. We conclude that recurrent inhibition is remarkably effective, in that a single action potential from one RC is sufficient to silence a motoneuron. Although our results may differ from previous indirect observations, they underline a need for a reevaluation of the role that RCs perform in one of the first neuronal circuits to be discovered. PMID:25232126

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

PubMed Central

Chen, Chun; Li, Peng; Li, Ye; Yao, Guan; Xu, Jian-Hua

2016-01-01

Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC50) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle. PMID:27900038

Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins.

PubMed

Zhang, Mingce; Robinson, Tanya O; Duverger, Alexandra; Kutsch, Olaf; Heath, Sonya L; Cron, Randy Q

2018-03-01

During chronic HIV-1 infection, regulatory CD4 T cells (Tregs) frequently represent the largest subpopulation of CD4 T cell subsets, implying relative resistant to HIV-1. When HIV-1 infection of CD4 T cells was explored in vitro and ex vivo from patient samples, Tregs possessed lower levels of HIV-1 DNA and RNA in comparison with conventional effector and memory CD4 T cells. Moreover, Tregs suppressed HIV-1 expression in other CD4 T cells in an in vitro co-culture system. This suppression was mediated in part via multiple inhibitory surface proteins expressed on Tregs. Antibody blockade of CTLA-4, PD-1, and GARP on Tregs resulted in increased HIV-1 DNA integration and mRNA expression in neighboring CD4 T cells. Moreover, antibody blockade of Tregs inhibitory proteins resulted in increased HIV-1 LTR transcription in co-cultured CD4 T cells. Thus, Tregs inhibit HIV-1 infection of other CD4 T cell subsets via interactions with inhibitory cell surface proteins. Copyright © 2018 Elsevier Inc. All rights reserved.

Roles of macrophage migration inhibitory factor in Guillain-Barré syndrome and experimental autoimmune neuritis: beneficial or harmful?

PubMed

Shen, Donghui; Lang, Yue; Chu, Fengna; Wu, Xiujuan; Wang, Ying; Zheng, Xiangyu; Zhang, Hong-Liang; Zhu, Jie; Liu, Kangding

2018-06-11

Macrophage migration inhibitory factor (MIF) plays an important role in the pathogenesis of Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN), which may offer an opportunity for the development of the novel therapeutic strategies for GBS. Areas covered: 'macrophage migration inhibitory factor' and 'Guillain-Barré syndrome' were used as keywords to search for related publications on Pub-Med, National Center for Biotechnology Information (NCBI), USA. MIF is involved in the etiology of various inflammatory and autoimmune disorders. However, the roles of MIF in GBS and EAN have not been summarized in the publications we identified. Therefore, in this review, we described and analyzed the major roles of MIF in GBS/EAN. Primarily, this molecule aggravates the inflammatory responses in this disorder. However, multiple studies indicated a protective role of MIF in GBS. The potential of MIF as a therapeutic target in GBS has been recently demonstrated in experimental and clinical studies, although clinical trials have been unavailable to date. Expert opinion: MIF plays a critical role in the initiation and progression of GBS and EAN, and it may represent a potential therapeutic target for GBS.

Northeast Parallel Architectures Center (NPAC)

DTIC Science & Technology

1992-07-01

Computational Techniques: Mapping receptor units to processors , using NEWS communication to model interaction in the inhibitory field Goal of the Research...algorithms for classical problems to take advantage of multiple processors . Experiments in probability that have been too time consuming on serial...machine and achieved speedups of 4 to 5 times with 11 processors . It is believed that a slightly better speedup is achievable. In the case of stuck

Contrast Gain Control Model Fits Masking Data

NASA Technical Reports Server (NTRS)

Watson, Andrew B.; Solomon, Joshua A.; Null, Cynthia H. (Technical Monitor)

1994-01-01

We studied the fit of a contrast gain control model to data of Foley (JOSA 1994), consisting of thresholds for a Gabor patch masked by gratings of various orientations, or by compounds of two orientations. Our general model includes models of Foley and Teo & Heeger (IEEE 1994). Our specific model used a bank of Gabor filters with octave bandwidths at 8 orientations. Excitatory and inhibitory nonlinearities were power functions with exponents of 2.4 and 2. Inhibitory pooling was broad in orientation, but narrow in spatial frequency and space. Minkowski pooling used an exponent of 4. All of the data for observer KMF were well fit by the model. We have developed a contrast gain control model that fits masking data. Unlike Foley's, our model accepts images as inputs. Unlike Teo & Heeger's, our model did not require multiple channels for different dynamic ranges.

Selective inhibition of Zn(2+)-glycerophosphocholine cholinephosphodiesterase by tellurium tetrachloride.

PubMed Central

Sok, D E; Kim, M R

1992-01-01

A Zn(2+)-glycerophosphocholine cholinephosphodiesterase (EC 3.1.4.38) purified from mouse brain was found to be reversibly inhibited by tellurium tetrachloride. This effect was characterized by a competitive pattern of inhibition, with apparent Ki values of 0.7 microM and 1.5 microM for the hydrolysis of p-nitrophenylphosphocholine and glycerophosphocholine respectively. Interestingly, the inhibitory effect of tellurium tetrachloride was found to be greatly potentiated by tetramethylammonium salt, indicative of a synergistic interaction between the two compounds. Additionally, it was observed that the effect of tellurium tetrachloride was not affected by a number of other metal ions, and was more pronounced at neutral pH, suggesting that the inhibitory role of the tellurium tetrachloride may be of importance under physiological conditions. Thus Zn(2+)-glycerophosphocholine cholinephosphodiesterase is proposed to be one of the target enzymes which is susceptible to the inhibitory effect of tellurium tetrachloride. PMID:1320372

Sex-specific effect of the anabolic steroid, 17α-methyltestosterone, on inhibitory avoidance learning in periadolescent rats

PubMed Central

Ramos-Pratts, Keyla; Rosa-González, Dariana; Pérez-Acevedo, Nivia L.; Cintrón-López, Dahima; Barreto-Estrada, Jennifer L.

2013-01-01

The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17α-methyltestosterone; 17α-meT-7.5 mg/kg) in male and female periadolescent rats. A single injection of 17α-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17α-meT during periadolescence exerts sex-specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. PMID:23792034

Antibacterial Activity of Cinoxacin In Vitro

PubMed Central

Giamarellou, Helen; Jackson, George G.

1975-01-01

Cinoxacin is a new synthetic compound similar chemically and in antimicrobial activity to oxolonic acid and nalidixic acid. It is most effective against Escherichia coli and Proteus mirabilis, but at concentrations expected in the urine it is inhibitory for all species of Enterobacteriaceae. Relative to nalidixic acid, cinoxacin has slightly greater inhibitory and bactericidal activity, less inoculum effect probably due to less heterogeneity in the susceptibility of bacterial cells, and less inhibition by high concentrations of serum protein. Both drugs are more active in an acid than an alkaline medium. Glucose can specifically antagonize the inhibitory effect against P. mirabilis. In urine the bactericidal rate and effect are decreased. Resistance to cinoxacin can be developed quickly by serial transfers in vitro. Some nonresistant organisms remained viable in bactericidal drug concentrations. The in vivo importance of the favorable features of cinoxacin must be determined by clinical trials. PMID:1096811

Inhibitory effect of propolis on the development of AA amyloidosis.

PubMed

Harata, Daichi; Tsuchiya, Yuya; Miyoshi, Tomoyuki; Yanai, Tokuma; Suzuki, Kazuhiko; Murakami, Tomoaki

2018-04-01

In the several types of amyloidoses, participation of oxidative stresses in the pathogenesis and the effect of antioxidants on amyloidosis have been reported. Meanwhile, the relationship between oxidative stresses and pathogenesis of amyloid A (AA) amyloidosis is still unclear. In this study, we used an antioxidant, Brazilian propolis, to investigate the inhibitory effects on AA amyloidosis. The results showed that AA deposition was inhibited by administration of propolis. Increased expression of antioxidant markers was detected in molecular biological examinations of mice treated with propolis. Although serum amyloid A (SAA) levels were strongly correlated with the immunoreactive area of AA deposits in the control group, the correlation was weaker in the propolis-treated groups. In addition, there were no changes in SAA levels between the control group and the propolis-treated groups. The results indicate that propolis, an antioxidant, may induce inhibitory effects against AA amyloidosis.

Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules.

PubMed

Gardner, Joanne K; Mamotte, Cyril D S; Jackaman, Connie; Nelson, Delia J

2017-09-01

Dendritic cells (DCs) undergo continuous changes throughout life, and there is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour immune responses in elderly people with cancer. Changes in checkpoint inhibitory molecules/pathways during aging may be one mechanism that impairs the ability of elderly DCs to activate T cells. However, little is currently known regarding the combined effects of aging and cancer on DC and T cell inhibitory molecules/pathways. In this review, we discuss our current understanding of the influence of aging and cancer on key DC and T cell inhibitory molecules/pathways, the potential underlying cellular and molecular mechanisms contributing to their modulation, and the possibility of therapeutically targeting inhibitory molecules in elderly cancer patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessment of the inhibitory effects of pyrethroids against human carboxylesterases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lei, Wei

Pyrethroids are broad-spectrum insecticides that widely used in many countries, while humans may be exposed to these toxins by drinking or eating pesticide-contaminated foods. This study aimed to investigate the inhibitory effects of six commonly used pyrethroids against two major human carboxylesterases (CES) including CES1 and CES2. Three optical probe substrates for CES1 (DME, BMBT and DMCB) and a fluorescent probe substrate for CES2 (DDAB) were used to characterize the inhibitory effects of these pyrethroids. The results demonstrated that most of the tested pyrethroids showed moderate to weak inhibitory effects against both CES1 and CES2, but deltamethrin displayed strong inhibitionmore » towards CES1. The IC{sub 50} values of deltamethrin against CES1-mediated BMBT, DME, and DMCB hydrolysis were determined as 1.58 μM, 2.39 μM, and 3.3 μM, respectively. Moreover, deltamethrin was cell membrane permeable and capable of inhibition endogenous CES1 in living cells. Further investigation revealed that deltamethrin inhibited CES1-mediated BMBT hydrolysis via competitive manner but noncompetitively inhibited DME or DMCB hydrolysis. The inhibition behaviors of deltamethrin against CES1 were also studied by molecular docking simulation. The results demonstrated that CES1 had at least two different ligand-binding sites, one was the DME site and another was the BMBT site which was identical to the binding site of deltamethrin. In summary, deltamethrin was a strong reversible inhibitor against CES1 and it could tightly bind on CES1 at the same ligand-binding site as BMBT. These findings are helpful for the deep understanding of the interactions between xenobiotics and CES1. - Highlights: • The inhibitory effects of six commonly used pyrethroids on human carboxylesterases were investigated. • Deltamethrin displayed strong inhibitory effects against human carboxylesterase 1 (CES1). • Deltamethrin was cell membrane permeable and could inhibit intracellular CES1 in living cells. • Both experimental and docking studies demonstrated that CES1 had at least two different ligand-binding sites.« less

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

PubMed Central

Merino-Ramos, Teresa; Vázquez-Calvo, Ángela; Casas, Josefina; Sobrino, Francisco; Saiz, Juan-Carlos

2015-01-01

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses. PMID:26503654

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication.

PubMed

Merino-Ramos, Teresa; Vázquez-Calvo, Ángela; Casas, Josefina; Sobrino, Francisco; Saiz, Juan-Carlos; Martín-Acebes, Miguel A

2016-01-01

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bite of mosquitoes that causes meningitis and encephalitis in humans, horses, and birds. Several studies have highlighted that flavivirus infection is highly dependent on cellular lipids for virus replication and infectious particle biogenesis. The first steps of lipid synthesis involve the carboxylation of acetyl coenzyme A (acetyl-CoA) to malonyl-CoA that is catalyzed by the acetyl-CoA carboxylase (ACC). This makes ACC a key enzyme of lipid synthesis that is currently being evaluated as a therapeutic target for different disorders, including cancers, obesity, diabetes, and viral infections. We have analyzed the effect of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) on infection by WNV. Lipidomic analysis of TOFA-treated cells confirmed that this drug reduced the cellular content of multiple lipids, including those directly implicated in the flavivirus life cycle (glycerophospholipids, sphingolipids, and cholesterol). Treatment with TOFA significantly inhibited the multiplication of WNV in a dose-dependent manner. Further analysis of the antiviral effect of this drug showed that the inhibitory effect was related to a reduction of viral replication. Furthermore, treatment with another ACC inhibitor, 3,3,14,14-tetramethylhexadecanedioic acid (MEDICA 16), also inhibited WNV infection. Interestingly, TOFA and MEDICA 16 also reduced the multiplication of Usutu virus (USUV), a WNV-related flavivirus. These results point to the ACC as a druggable cellular target suitable for antiviral development against WNV and other flaviviruses. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Melanogenesis inhibitory activity of a 7-O-9'-linked neolignan from Alpinia galanga fruit.

PubMed

Manse, Yoshiaki; Ninomiya, Kiyofumi; Nishi, Ryosuke; Kamei, Iyori; Katsuyama, Yushi; Imagawa, Takahito; Chaipech, Saowanee; Muraoka, Osamu; Morikawa, Toshio

2016-12-01

An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC 50 =7.3μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9'-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2-15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC 50 =2.5μM), 1'S-1'-acetoxychavicol acetate (2, 5.0μM), and 1'S-1'-acetoxyeugenol acetate (3, 5.6μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1'-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9'-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1' (IC 50 =1.9μM) and 2' (4.5μM)] and racemic mixtures [(±)-1 (2.2μM) and (±)-2 (4.4μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1-3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Strong inhibitory effect of furanoses and sugar lactones on beta-galactosidase Escherichia coli.

PubMed

Huber, R E; Brockbank, R L

1987-03-24

Various sugars and their lactones were tested for their inhibition of beta-galactosidase (Escherichia coli). L-Ribose, which in the furanose form has a hydroxyl configuration similar to that of D-galactose at positions equivalent to the 3- and 4-positions of D-galactose, was a very strong inhibitor, and D-lyxose, which in the furanose form also resembles D-galactose, was a much better inhibitor than expected. Structural comparisons prelude the pyranose forms of these sugars from being significant contributors to the inhibition, and inhibition at different temperatures (at which there are different furanose concentrations) strongly supported the conclusion that the furanose form is inhibitory. Studies with sugar derivatives that can only be in the furanose form also supported the conclusion. This is the first report of the inhibitory effect of furanose on beta-galactosidase. Lactones were also inhibitory. Every lactone tested was much more inhibitory than was its parent sugar. D-Galactonolactone was especially good. Experiments indicated that it was D-galactono-1,5-lactone rather than D-galactono-1,4-lactone which was inhibitory. Inhibition of beta-galactosidases from mammalian sources by lactones has been reported previously, but this is the first report of the effect of beta-galactosidase from E. coli. Since furanoses in the envelope form are analogous (in some ways) to half-chair or sofa conformations and since lactones with six-membered rings probably have half-chair or sofa conformations, the results indicate that beta-galactosidase probably destabilizes its substrate into a planar conformation of some type and that the galactose in the transition state may, therefore, also be quite planar.(ABSTRACT TRUNCATED AT 250 WORDS)

Protection by naringin and some other flavonoids of hepatocytic autophagy and endocytosis against inhibition by okadaic acid.

PubMed

Gordon, P B; Holen, I; Seglen, P O

1995-03-17

In isolated rat hepatocytes, the protein phosphatase inhibitor okadaic acid exerts a strong inhibitory effect on autophagy, which can be partially overcome by certain protein kinase inhibitors like the isoflavone genistein. To see if other, more specific okadaic acid antagonists could be found among the flavonoids, 55 different flavonoids were tested for their effect on okadaic acid-inhibited autophagy, measured as the sequestration of electroinjected [3H]raffinose. Naringin (naringenin 7-hesperidoside) and several other flavanone and flavone glycosides (prunin, neoeriocitrin, neohesperidin, apiin, rhoifolin, kaempferol 3-rutinoside) offered virtually complete protection against the autophagy-inhibitory effect of okadaic acid. Unlike genistein, these compounds had little or no autophagy-inhibitory effect of their own. Their innocuousness appeared to be related to glycosylation, because the corresponding aglycones (naringenin, eriodictyol, hesperetin, apigenin, kaempferol) were all inhibitory, in particular apigenin (80% inhibition at 100 microM). Naringin, the most potent okadaic acid-antagonistic flavonoid, gave half-maximal protection at 5 microM and maximal effect at 100 microM. Naringin also prevented the okadaic acid-induced inhibition of endogenous, autophagic lysosomal protein degradation and of receptor-mediated asialoglycoprotein uptake and degradation. Naringin and other okadaic acid-antagonistic flavonoids may be useful tools in the study of intracellular protein phosphorylation and could have potential therapeutic value as protectants against pathological hyperphosphorylations, environmental toxins, or side effects of chemotherapeutic drugs.

Comparative evaluation of 12 immature citrus fruit extracts for the inhibition of cytochrome P450 isoform activities.

PubMed

Fujita, Tadashi; Kawase, Atsushi; Niwa, Toshiro; Tomohiro, Norimichi; Masuda, Megumi; Matsuda, Hideaki; Iwaki, Masahiro

2008-05-01

In a previous study we found that 50% ethanol extracts of immature fruits of Citrus unshiu (satsuma mandarin) have anti-allergic effects against the Type I, II and IV allergic reactions. However, many adverse interactions between citrus fruit, especially grapefruit juice, and drugs have been reported due to the inhibition of cytochrome P450 (CYP) activities. The purpose of this study was to examine the competitive inhibitory effects of extracts from immature citrus fruit on CYP activity. Extracts were prepared from 12 citrus species or cultivars, and were tested against three kinds of major CYPs, CYP2C9, CYP2D6 and CYP3A4, in human liver microsomes. We also estimated the amounts of flavonoids (narirutin, hesperidin, naringin and neohesperidin) and furanocoumarins (bergapten, 6',7'-dihydroxybergamottin and bergamottin) in each extract using HPLC. Citrus paradisi (grapefruit) showed the greatest inhibition of CYP activities, while Citrus unshiu which has an antiallergic effect, showed relatively weak inhibitory effects. Extracts having relatively strong inhibitory effects for CYP3A4 tended to contain higher amounts of naringin, bergamottin and 6',7'-dihydroxybergamottin. These results, providing comparative information on the inhibitory effects of citrus extracts on CYP isoforms, suggest that citrus extracts containing high levels of narirutin and hesperidin and lower levels of furanocoumarins such as C. unshiu are favorable as antiallergic functional ingredients.

Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling.

PubMed

Patel, Dhaval D; Anderson, Bradley D

2014-05-05

This study quantitatively explores the mechanisms underpinning the effects of model pharmaceutical polymeric precipitation inhibitors (PPIs) on the crystal growth and, in turn, maintenance of supersaturation of indomethacin, a model poorly water-soluble drug. A recently developed second-derivative UV spectroscopy method and a first-order empirical crystal growth model were used to determine indomethacin crystal growth rates in the presence of model PPIs. All three model PPIs including HP-β-CD, PVP, and HPMC inhibited indomethacin crystal growth at both high and low degrees of supersaturation (S). The bulk viscosity changes in the presence of model PPIs could not explain their crystal growth inhibitory effects. At 0.05% w/w, PVP (133-fold) and HPMC (28-fold) were better crystal growth inhibitors than HP-β-CD at high S. The inhibitory effect of HP-β-CD on the bulk diffusion-controlled indomethacin crystal growth at high S was successfully modeled using reactive diffusion layer theory, which assumes reversible complexation in the diffusion layer. Although HP-β-CD only modestly inhibited indomethacin crystal growth at either high S (∼15%) or low S (∼2-fold), the crystal growth inhibitory effects of PVP and HPMC were more dramatic, particularly at high S (0.05% w/w). The superior crystal growth inhibitory effects of PVP and HPMC as compared with HP-β-CD at high S were attributed to a change in the indomethacin crystal growth rate-limiting step from bulk diffusion to surface integration. Indomethacin crystal growth inhibitory effects of all three model PPIs at low S were attributed to retardation of the rate of surface integration of indomethacin, a phenomenon that may reflect the adsorption of PPIs onto the growing crystal surface. The quantitative approaches outlined in this study should be useful in future studies to develop tools to predict supersaturation maintenance effects of PPIs.

Phosphate Changes Effect of Humic Acids on TiO2 Photocatalysis: From Inhibition to Mitigation of Electron-Hole Recombination.

PubMed

Long, Mingce; Brame, Jonathon; Qin, Fan; Bao, Jiming; Li, Qilin; Alvarez, Pedro J J

2017-01-03

A major challenge for photocatalytic water purification with TiO 2 is the strong inhibitory effect of natural organic matter (NOM), which can scavenge photogenerated holes and radicals and occlude ROS generation sites upon adsorption. This study shows that phosphate counteracts the inhibitory effect of humic acids (HA) by decreasing HA adsorption and mitigating electron-hole recombination. As a measure of the inhibitory effect of HA, the ratios of first-order reaction rate constants between photocatalytic phenol degradation in the absence versus presence of HA were calculated. This ratio was very high, up to 5.72 at 30 mg/L HA and pH 4.8 without phosphate, but was decreased to 0.76 (5 mg/L HA, pH 8.4) with 2 mM phosphate. The latter ratio indicates a surprising favorable effect of HA on TiO 2 photocatalysis. FTIR analyses suggest that this favorable effect is likely due to a change in the conformation of adsorbed HA, from a multiligand exchange arrangement to a complexation predominantly between COOH groups in HA and the TiO 2 surface in the presence of phosphate. This configuration can reduce hole consumption and facilitate electron transfer to O 2 by the adsorbed HA (indicated by linear sweep voltammetry), which mitigates electron-hole recombination and enhances contaminant degradation. A decrease in HA surface adsorption and hole scavenging (the predominant inhibitory mechanisms of HA) by phosphate (2 mM) was indicated by a 50% decrease in the photocatalytic degradation rate of HA and 80% decrease in the decay rate coefficient of interfacial-related photooxidation in photocurrent transients. These results, which were validated with other compounds (FFA and cimetidine), indicate that anchoring phosphate - or anions that exert similar effects on the TiO 2 surface - might be a feasible strategy to counteract the inhibitory effect of NOM during photocatalytic water treatment.

Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan.

PubMed

Onoda, Toshihisa; Li, Wei; Sasaki, Tatsunori; Miyake, Megumi; Higai, Koji; Koike, Kazuo

2016-06-20

Masiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan. Bioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway. From Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3μM, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway. Magnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Anti-cancer, anti-inflammatory and anti-microbial activities of plant extracts used against hematological tumors in traditional medicine of Jordan.

PubMed

Assaf, Areej M; Haddadin, Randa N; Aldouri, Nedhal A; Alabbassi, Reem; Mashallah, Sundus; Mohammad, Mohammad; Bustanji, Yasser

2013-02-13

Mercurialis annua L., Bongardia chrysogonum L., and Viscum cruciatum Sieb have been traditionally used by local herbalists in Jordan for the treatment of hematopoietic neoplasms. To determine the anti-cancer, anti-inflammatory and anti-microbial potentials of the three extracts against two of the most common hematopoietic malignancies in the Jordanian populations; Burkitt's lymphoma and Multiple myeloma. The anti-cancer activity was tested against the two cell lines (BJAB Burkitt's lymphoma and U266 multiple myeloma) using the MTT and trypan blue assays. The agar dilution assay was used to study the anti-microbial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria and yeast. The pro-inflammatory cytokines interleukin (IL) -1β, IL-8 and tumor necrosis factor-α (TNF-α) were measured in the pretreated cell lines using ELISA assay to determine the anti-inflammatory activity of Viscum cruciatum Sieb against the two cell lines. The results show no evidence of stimulation of tumor growth by any of the three extracts comprising cell lines from hematological malignancies, but Viscum cruciatum Sieb showed a selective anticancer activity against BJAB cells, with IC(50) value of 14.21μg/ml. The antimicrobial effect was only noticed with Viscum cruciatum extract by inhibiting Staphylococcus aureus, Candida albicans and Propionibacterium acne, but not Pseudomonas aeruginosa at MIC of 1.25, 1.25, 0.625 and <5mg/ml, respectively. The highest activity was against the anaerobic bacteria Propionibacterium acne. Viscum cruciatum Sieb extract showed an inhibitory effect on the pro-inflammatory cytokine IL-8, but it increased TNF-α and IL-1β secretions in BJAB cells. Whereas, it had an inhibitory effect on TNF-α and IL-1β cytokines while it enhanced IL-8 secretions in U266 cells. Among the three tested herbal extracts used in the traditional medicine in Jordan, only Viscum cruciatum Sieb showed high anti-cancer and anti-microbial potentials. They also had an anti-inflammatory effect. These observations raise the prospects of using Viscum cruciatum Sieb for treatment of diseases associated with some bacterial and fungal infections, for imbalanced cytokine production and for enhancing cancer and other immunotherapies. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

PubMed Central

Goodin, Burel; Kindler, Lindsay L.; Caudle, Robert M.; Edwards, Robert R.; Gravenstein, Nikolaus; Riley, Joseph L.; Fillingim, Roger B.

2013-01-01

The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain. PMID:22534819

Effect of ketamine on endogenous pain modulation in healthy volunteers.

PubMed

Niesters, Marieke; Dahan, Albert; Swartjes, Maarten; Noppers, Ingeborg; Fillingim, Roger B; Aarts, Leon; Sarton, Elise Y

2011-03-01

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Inhibitory Effect of Phragmanthera Incana (Schum.) Harvested from Cocoa (Theobroma Cacao) and Kolanut (Cola Nitida) Trees on Fe2+ induced Lipid Oxidative Stress in Some Rat Tissues - In Vitro

PubMed Central

Ogunmefun, O. T.; Fasola, T. R.; Saba, A. B.; Akinyemi, A. J.

2015-01-01

Evidence in both experimental and clinical studies has shown the participation of oxidative stress in the development and progression of diabetes mellitus. This study therefore, sought to investigate the inhibitory effect of methanolic extract of Phragmanthera incana leaves, a mistletoe species harvested from Cocoa (Theobroma cacao) and Kolanut (Cola nitida) on FeSO4 induced lipid peroxidation in rat pancreas, liver, kidney, heart and brain in vitro. The methanolic extract was prepared with 90% methanol (v/v); subsequently, the antioxidant properties and inhibitory effect of the extract on Fe2+ induced lipid peroxidation in some rat tissues were determined in vitro. Incubation of the different rat tissues homogenate in the presence of Fe caused a significant increase in the malondialdehyde (MDA) contents of the tissues. However, the methanolic extracts of Phragmanthera incana leaves harvested from both Cocoa and Kolanut trees caused a significant decrease in the MDA contents of all the tissues tested in a dose-dependent manner. However, the extract of Phragmanthera incana leaves harvested from kolanut trees had a better inhibitory effect on Fe2+- induced lipid peroxidation in the rat tissues homogenates than that of Phragmanthera incana leaves harvested from cocoa trees. This higher inhibitory effect could be attributed to its significantly higher antioxidant properties as typified by their phenolic content, DPPH radical scavenging ability and reducing power. Therefore, oxidative stress associated with diabetes and its other complications could be potentially managed/prevented by harnessing Phragmanthera incana leaves as cheap nutraceuticals. However, Phragmanthera incana leaves harvested from kolanut trees exhibited better antioxidant properties.

Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons.

PubMed

Kubota, Shinji; Hirano, Masato; Morishita, Takuya; Uehara, Kazumasa; Funase, Kozo

2015-03-25

Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Kinetics of α-amylase and α-glucosidase inhibitory potential of Zea mays Linnaeus (Poaceae), Stigma maydis aqueous extract: An in vitro assessment.

PubMed

Sabiu, S; O'Neill, F H; Ashafa, A O T

2016-05-13

Corn silk (Zea mays L., Stigma maydis) is an important herb used traditionally in many parts of the world to treat array of diseases including diabetes mellitus. Inhibitors of α-amylase and α-glucosidase offer an effective strategy to modulate levels of post prandial hyperglycaemia via control of starch metabolism. This study evaluated α-amylase and α-glucosidase inhibitory potentials of corn silk aqueous extract. Active principles and antioxidant attributes of the extract were also analysed. The α-amylase inhibitory potential of the extract was investigated by reacting its different concentrations with α-amylase and starch solution, while α-glucosidase inhibition was determined by pre-incubating α-glucosidase with different concentrations of the extract followed by addition of p-nitrophenylglucopyranoside. The mode(s) of inhibition of the enzymes were determined using Lineweaver-Burke plot. In vitro analysis of the extract showed that it exhibited potent and moderate inhibitory potential against α-amylase and α-glucosidase, respectively. The inhibition was concentration-dependent with respective half-maximal inhibitory concentration (IC50) values of 5.89 and 0.93mg/mL. Phytochemical analyses revealed the presence of alkaloids, flavonoids, phenols, saponins, tannins and phytosterols as probable inhibitory constituents. Furthermore, the extract remarkably scavenges reactive oxygen species like DPPH and nitric oxide radicals, elicited good reducing power and a significant metal chelating attributes. Overall, the non-competitive and uncompetitive mechanism of action of corn silk extract is due to its inhibitory effects on α-amylase and α-glucosidase, respectively. Consequently, this will reduce the rate of starch hydrolysis, enhance palliated glucose levels, and thus, lending credence to hypoglycaemic candidature of corn silk. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.