Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor.

Science.gov (United States)

Sharma, Mamta; Saravolatz, Louis D

2013-02-01

Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class.

Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation

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Amal Abdussalam Ali A. Hmaid

2018-03-01

Full Text Available Structural changes affecting cardiomyocyte function may contribute to the pathophysiological remodeling underlying cardiac function impairment. Recent reports have shown that endogenous nitric oxide (NO plays an important role in this process. In order to examine the role of NO in cardiomyocyte remodeling, male rats were acclimated to room temperature (22 ± 1 °C or cold (4 ± 1 °C and treated with 2.25% l-arginine·HCl or 0.01% l-NAME (Nω-nitro-l-arginine methyl ester·HCl for 45 days. Untreated groups served as controls. Right heart ventricles were routinely prepared for light microscopic examination. Stereological estimations of volume densities of cardiomyocytes, surrounding blood vessels and connective tissue, as well as the morphometric measurements of cardiomyocyte diameters were performed. Tissue sections were also analyzed for structural alterations. We observed that both l-arginine and l-NAME supplementation induced cardiomyocyte hypertrophy, regardless of ambient temperature. However, cardiomyocyte hypertrophy was associated with fibrosis and extra collagen deposition only in the l-NAME treated group. Taken together, our results suggest that NO has a modulatory role in right heart ventricle remodeling by coordinating hypertrophy of cardiomyocytes and fibrous tissue preventing cardiac fibrosis. Keywords: Cardiomyocyte, Cardiac hypertrophy, l-Arginine, l-NAME, Myocardium

Extraribosomal l13a is a specific innate immune factor for antiviral defense.

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Mazumder, Barsanjit; Poddar, Darshana; Basu, Abhijit; Kour, Ravinder; Verbovetskaya, Valentina; Barik, Sailen

2014-08-01

We report a novel extraribosomal innate immune function of mammalian ribosomal protein L13a, whereby it acts as an antiviral agent. We found that L13a is released from the 60S ribosomal subunit in response to infection by respiratory syncytial virus (RSV), an RNA virus of the Pneumovirus genus and a serious lung pathogen. Unexpectedly, the growth of RSV was highly enhanced in L13a-knocked-down cells of various lineages as well as in L13a knockout macrophages from mice. In all L13a-deficient cells tested, translation of RSV matrix (M) protein was specifically stimulated, as judged by a greater abundance of M protein and greater association of the M mRNA with polyribosomes, while general translation was unaffected. In silico RNA folding analysis and translational reporter assays revealed a putative hairpin in the 3'untranslated region (UTR) of M mRNA with significant structural similarity to the cellular GAIT (gamma-activated inhibitor of translation) RNA hairpin, previously shown to be responsible for assembling a large, L13a-containing ribonucleoprotein complex that promoted translational silencing in gamma interferon (IFN-γ)-activated myeloid cells. However, RNA-protein interaction studies revealed that this complex, which we named VAIT (respiratory syncytial virus-activated inhibitor of translation) is functionally different from the GAIT complex. VAIT is the first report of an extraribosomal L13a-mediated, IFN-γ-independent innate antiviral complex triggered in response to virus infection. We provide a model in which the VAIT complex strongly hinders RSV replication by inhibiting the translation of the rate-limiting viral M protein, which is a new paradigm in antiviral defense. The innate immune mechanisms of host cells are diverse in nature and act as a broad-spectrum cellular defense against viruses. Here, we report a novel innate immune mechanism functioning against respiratory syncytial virus (RSV), in which the cellular ribosomal protein L13a is released

Arbutus unedo prevents cardiovascular and morphological alterations in L-NAME-induced hypertensive rats Part I: cardiovascular and renal hemodynamic effects of Arbutus unedo in L-NAME-induced hypertensive rats.

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Afkir, Saida; Nguelefack, Telesphore Benoit; Aziz, Mohamed; Zoheir, Johar; Cuisinaud, Guy; Bnouham, Mohamed; Mekhfi, Hassane; Legssyer, Abdelkhaleq; Lahlou, Saad; Ziyyat, Abderrahim

2008-03-05

Hypertension induced by nitric oxide synthase inhibition is associated with functional abnormalities of the heart and kidney. The aim of the present study was to investigate whether chronic treatment with Arbutus unedo leaf (AuL) or root (AuR) aqueous extracts can prevent these alterations. Six groups of rats were used: control group received tap water; N(G)-nitro-l-arginine methyl-ester (L-NAME) group treated with L-NAME at 40 mg/kg/day; AuL and AuR groups received simultaneously L-NAME (40 mg/kg/day) and Au leaves or roots extract at the same concentration 250 mg/kg/day; l-arginine and enalapril groups received simultaneously L-NAME (40 mg/kg/day) and l-arginine at 50mg/kg/day or enalapril at 15 mg/kg/day. Treatment of rats during 4 weeks with L-NAME caused an increase of the systolic blood pressure (SBP) accompanied by a ventricular hypertrophy, an impairment of endothelium-dependent vasorelaxation, an increase of the cardiac baroreflex sensitivity and a decrease of water, sodium and potassium excretion. The co-administration of AuL or AuR extracts with L-NAME reduces the development of increased SBP, ameliorates the vascular reactivity as well as the baroreflex sensitivity and normalizes the renal function. AuR reduces the ventricular hypertrophy but AuL do not. Enalapril associated with L-NAME reverses the majority of alterations induced by L-NAME while l-arginine only lightly ameliorates the vascular reactivity. These results show that chronic treatment with Arbutus extract regress the development of hypertension and ameliorate cardiovascular and renal functions in NO deficient hypertension.

Potential Inhibitors for Isocitrate Lyase of Mycobacterium tuberculosis and Non-M. tuberculosis: A Summary

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Yie-Vern Lee

2015-01-01

Full Text Available Isocitrate lyase (ICL is the first enzyme involved in glyoxylate cycle. Many plants and microorganisms are relying on glyoxylate cycle enzymes to survive upon downregulation of tricarboxylic acid cycle (TCA cycle, especially Mycobacterium tuberculosis (MTB. In fact, ICL is a potential drug target for MTB in dormancy. With the urge for new antitubercular drug to overcome tuberculosis treat such as multidrug resistant strain and HIV-coinfection, the pace of drug discovery has to be increased. There are many approaches to discovering potential inhibitor for MTB ICL and we hereby review the updated list of them. The potential inhibitors can be either a natural compound or synthetic compound. Moreover, these compounds are not necessary to be discovered only from MTB ICL, as it can also be discovered by a non-MTB ICL. Our review is categorized into four sections, namely, (a MTB ICL with natural compounds; (b MTB ICL with synthetic compounds; (c non-MTB ICL with natural compounds; and (d non-MTB ICL with synthetic compounds. Each of the approaches is capable of overcoming different challenges of inhibitor discovery. We hope that this paper will benefit the discovery of better inhibitor for ICL.

77 FR 3636 - Federal Acquisition Regulation; Brand-Name Specifications; Correction

Science.gov (United States)

2012-01-25

... 26] RIN 9000-AK55 Federal Acquisition Regulation; Brand-Name Specifications; Correction AGENCY... Regulation (FAR) to implement the Office of Management and Budget memoranda on brand-name specifications, FAR Case 2005-037, Brand-Name Specifications, which published in the Federal Register at 77 FR 189 on...

The correct name for a subspecies of Oenothera fruticosa L. (Onagraceae).

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Wagner, Warren L

2014-01-01

In 1978 when Straley adopted the name Oenothera fruticosa L. subsp. glauca (Michx.) Straley for one of the two recognized subspecies of O. fruticosa it was the correct name for this taxon; however, since that time the botanical code has changed so that now an autonym is treated as having priority over the name or names of the same date and rank that established it. This change means that since 1981 O. fruticosa subsp. glauca was no longer the correct name. The appropriate combination for it is made here as O. fruticosa L. subsp. tetragona (Roth) W.L. Wagner. Original material for the basionym, O. tetragona, is no longer extant so a neotype is designated.

The effect of pre-eclampsia-like syndrome induced by L-NAME on learning and memory and hippocampal glucocorticoid receptor expression: A rat model.

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Zhu, Hao; Zhu, Weimin; Hu, Rong; Wang, Huijun; Ma, Duan; Li, Xiaotian

2017-02-01

We aimed to study the impacts of pre-eclampsia on the cognitive and learning capabilities of adolescent rat offspring and to explore the possible underlying mechanisms at the molecular level. Pregnant rats were subcutaneously injected with saline solution (control) (n = 16) or NG-nitro-L-arginine methyl ester (L-NAME) (n = 16) from the 13th day of gestation until parturition. The brain tissues from fetal rats delivered by cesarean section were examined in both groups with hematoxylin and eosin (H&E) staining. Rats born vaginally in both groups were subjected to the Morris water maze test when 8-week-old and their hippocampi were analyzed for glucocorticoid receptor (GR) expression. A pre-eclampsia-like model was successfully built in pregnant rats by infusion of the NO synthase inhibitor L-NAME, including phenotypes as maternal hypertension and proteinuria, high stillbirth rate, and fetal growth retardation. Neuroepithelial cell proliferation was found in the hippocampus of fetal rats in the L-NAME group. Grown to 8-week-old, the L-NAME group showed significantly longer escape latency than the control group in the beginning as well as in the end of navigation trials. At the same time, the swimming distance achieved by the L-NAME group was significantly longer than that of the control group. Such differences in cognitive and learning capabilities between the two groups were not gender dependent. Besides, the 8-week-old rats in the L-NAME group had increased GR expression in the hippocampus than the control group. Pre-eclampsia would impair cognitive and learning capabilities in adolescent offspring, and the upregulated expression of hippocampal GR may be involved in the underlying mechanisms.

The correct name for a subspecies of Oenothera fruticosa L. (Onagraceae

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Warren Wagner

2014-01-01

Full Text Available In 1978 when Straley adopted the name Oenothera fruticosa L. subsp. glauca (Michx. Straley for one of the two recognized subspecies of O. fruticosa it was the correct name for this taxon; however, since that time the botanical code has changed so that now an autonym is treated aspriority over the name or names of the same date and rank that established it. This change means that since 1981 O. fruticosa subsp. glauca was no longer the correct name. The appropriate combination for it is made here as O. fruticosa L. subsp. tetragona (Roth W.L. Wagner. Original material for the basionym, O. tetragona, is no longer extant so a neotype is designated.

Structural alterations in rat myocardium induced by chronic l-arginine and l-NAME supplementation.

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Hmaid, Amal Abdussalam Ali A; Markelic, Milica; Otasevic, Vesna; Masovic, Sava; Jankovic, Aleksandra; Korac, Bato; Korac, Aleksandra

2018-03-01

Structural changes affecting cardiomyocyte function may contribute to the pathophysiological remodeling underlying cardiac function impairment. Recent reports have shown that endogenous nitric oxide (NO) plays an important role in this process. In order to examine the role of NO in cardiomyocyte remodeling, male rats were acclimated to room temperature (22 ± 1 °C) or cold (4 ± 1 °C) and treated with 2.25% l-arginine·HCl or 0.01% l-NAME (N ω -nitro-l-arginine methyl ester)·HCl for 45 days. Untreated groups served as controls. Right heart ventricles were routinely prepared for light microscopic examination. Stereological estimations of volume densities of cardiomyocytes, surrounding blood vessels and connective tissue, as well as the morphometric measurements of cardiomyocyte diameters were performed. Tissue sections were also analyzed for structural alterations. We observed that both l-arginine and l-NAME supplementation induced cardiomyocyte hypertrophy, regardless of ambient temperature. However, cardiomyocyte hypertrophy was associated with fibrosis and extra collagen deposition only in the l-NAME treated group. Taken together, our results suggest that NO has a modulatory role in right heart ventricle remodeling by coordinating hypertrophy of cardiomyocytes and fibrous tissue preventing cardiac fibrosis.

Targeting the active site of the placental isozyme of alkaline phosphatase by phage-displayed scFv antibodies selected by a specific uncompetitive inhibitor

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Kala Mrinalini

2005-12-01

Full Text Available Abstract Background The isozymes of alkaline phosphatase, the tissue non-specific, intestinal and placental, have similar properties and a high degree of identity. The placental isozyme (PLAP is an oncofetal antigen expressed in several malignancies including choriocarcinoma, seminoma and ovarian carcinoma. We had earlier attempted to isolate PLAP-specific scFv from a synthetic human immunoglobulin library but were unable to do so, presumably because of the similarity between the isozymes. In this work, we have employed a PLAP-specific uncompetitive inhibitor, L-Phe-Gly-Gly, to select isozyme specific scFvs. An uncompetitive inhibitor binds to the enzyme in the presence of substrate and stabilizes the enzyme-substrate complex. Several uncompetitive inhibitors have varying degrees of isozyme specificity for human alkaline phosphatase isozymes. A specific uncompetitive inhibitor would be able to unmask conformational differences between the otherwise very similar molecules. Also, such inhibitors would be directed to regions at/close to the active site of the enzyme. In this work, the library was first incubated with PLAP and the bound clones then eluted by incubation with L-Phe-Gly-Gly along with the substrate, para-nitro phenyl phosphate (pNPP. The scFvs were then studied with regard to the biochemical modulation of their binding, isozyme specificity and effect on enzyme activity. Results Of 13 clones studied initially, the binding of 9 was inhibited by L-Phe-Gly-Gly (with pNPP and 2 clones were inhibited by pNPP alone. Two clones had absolute and 2 clones had partial specificity to PLAP. Two clones were cross-reactive with only one other isozyme. Three scFv clones, having an accessible His6-tag, were purified and studied for their modulation of enzyme activity. All the three scFvs inhibited PLAP activity with the kinetics of competitive inhibition. Cell ELISA could demonstrate binding of the specific scFvs to the cell surface expressed PLAP

Inhibitor development and mortality in non-severe hemophilia A.

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Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

2015-07-01

The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

Potential non-oncological applications of histone deacetylase inhibitors.

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Ververis, Katherine; Karagiannis, Tom C

2011-01-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

Color Naming Experiment in Mongolian Language

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Nandin-Erdene Osorjamaa

2015-11-01

Full Text Available There are numerous researches on color terms and names in many languages. In Mongolian language there are few doctoral theses on color naming. Cross cultural studies of color naming have demonstrated Semantic relevance in French and Mongolian color name Gerlee Sh. (2000; Comparisons of color naming across English and Mongolian Uranchimeg B. (2004; Semantic comparison between Russian and Mongolian idioms Enhdelger O. (1996; across symbolism Dulam S. (2007 and few others. Also a few articles on color naming by some Mongolian scholars are Tsevel, Ya. (1947, Baldan, L. (1979, Bazarragchaa, M. (1997 and others. Color naming studies are not sufficiently studied in Modern Mongolian. Our research is considered to be the first intended research on color naming in Modern Mongolian, because it is one part of Ph.D dissertation on color naming. There are two color naming categories in Mongolian, basic color terms and non- basic color terms. There are seven basic color terms in Mongolian. This paper aims to consider how Mongolian color names are derived from basic colors by using psycholinguistics associative experiment. It maintains the students and researchers to acquire the specific understanding of the differences and similarities of color naming in Mongolian and  English languages from the psycho-linguistic aspect.

Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy?

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Nolan, David

2005-01-01

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

Kinetics of modulatory role of Cyperus esculentus L. on the specific ...

African Journals Online (AJOL)

Background: The continuous search for new lead compounds as viable inhibitors of specific enzymes linked to carbohydrate metabolism has intensified. Cyperus esculentus L. is one of the therapeutically implicated botanicals against several degenerative diseases including diabetes mellitus. Materials and Methods: This ...

Variations in CCL3L gene cluster sequence and non-specific gene copy numbers

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Edberg Jeffrey C

2010-03-01

Full Text Available Abstract Background Copy number variations (CNVs of the gene CC chemokine ligand 3-like1 (CCL3L1 have been implicated in HIV-1 susceptibility, but the association has been inconsistent. CCL3L1 shares homology with a cluster of genes localized to chromosome 17q12, namely CCL3, CCL3L2, and, CCL3L3. These genes are involved in host defense and inflammatory processes. Several CNV assays have been developed for the CCL3L1 gene. Findings Through pairwise and multiple alignments of these genes, we have shown that the homology between these genes ranges from 50% to 99% in complete gene sequences and from 70-100% in the exonic regions, with CCL3L1 and CCL3L3 being identical. By use of MEGA 4 and BioEdit, we aligned sense primers, anti-sense primers, and probes used in several previously described assays against pre-multiple alignments of all four chemokine genes. Each set of probes and primers aligned and matched with overlapping sequences in at least two of the four genes, indicating that previously utilized RT-PCR based CNV assays are not specific for only CCL3L1. The four available assays measured median copies of 2 and 3-4 in European and African American, respectively. The concordance between the assays ranged from 0.44-0.83 suggesting individual discordant calls and inconsistencies with the assays from the expected gene coverage from the known sequence. Conclusions This indicates that some of the inconsistencies in the association studies could be due to assays that provide heterogenous results. Sequence information to determine CNV of the three genes separately would allow to test whether their association with the pathogenesis of a human disease or phenotype is affected by an individual gene or by a combination of these genes.

Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

International Nuclear Information System (INIS)

Phillips, D C; Xiao, Y; Lam, L T; Litvinovich, E; Roberts-Rapp, L; Souers, A J; Leverson, J D

2015-01-01

As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2 High ) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2 High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-X L -selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2 High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2 Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-X L inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2 Low ) that could benefit from BCL-X L (navitoclax)-driven combination therapy

Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

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Helton J Wiggers

Full Text Available A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i in the low micromolar range (3-60 µM acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM, yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE of 0.33 kcal mol(-1 atom(-1

Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay.

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Wiggers, Helton J; Rocha, Josmar R; Fernandes, William B; Sesti-Costa, Renata; Carneiro, Zumira A; Cheleski, Juliana; da Silva, Albérico B F; Juliano, Luiz; Cezari, Maria H S; Silva, João S; McKerrow, James H; Montanari, Carlos A

2013-01-01

A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound

Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats.

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Lojo, Nermin; Rasic, Zarko; Zenko Sever, Anita; Kolenc, Danijela; Vukusic, Darko; Drmic, Domagoj; Zoricic, Ivan; Sever, Marko; Seiwerth, Sven; Sikiric, Predrag

2016-01-01

Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and

Identification of Chalcones as Fasciola hepatica Cathepsin L Inhibitors Using a Comprehensive Experimental and Computational Approach.

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Florencia Ferraro

2016-07-01

Full Text Available Increased reports of human infections have led fasciolosis, a widespread disease of cattle and sheep caused by the liver flukes Fasciola hepatica and Fasciola gigantica, to be considered an emerging zoonotic disease. Chemotherapy is the main control measure available, and triclabendazole is the preferred drug since is effective against both juvenile and mature parasites. However, resistance to triclabendazole has been reported in several countries urging the search of new chemical entities and target molecules to control fluke infections.We searched a library of forty flavonoid derivatives for inhibitors of key stage specific Fasciola hepatica cysteine proteases (FhCL3 and FhCL1. Chalcones substituted with phenyl and naphtyl groups emerged as good cathepsin L inhibitors, interacting more frequently with two putative binding sites within the active site cleft of the enzymes. One of the compounds, C34, tightly bounds to juvenile specific FhCL3 with an IC50 of 5.6 μM. We demonstrated that C34 is a slow-reversible inhibitor that interacts with the Cys-His catalytic dyad and key S2 and S3 pocket residues, determinants of the substrate specificity of this family of cysteine proteases. Interestingly, C34 induces a reduction in NEJ ability to migrate through the gut wall and a loss of motility phenotype that leads to NEJ death within a week in vitro, while it is not cytotoxic to bovine cells.Up to date there are no reports of in vitro screening for non-peptidic inhibitors of Fasciola hepatica cathepsins, while in general these are considered as the best strategy for in vivo inhibition. We have identified chalcones as novel inhibitors of the two main Cathepsins secreted by juvenile and adult liver flukes. Interestingly, one compound (C34 is highly active towards the juvenile enzyme reducing larval ability to penetrate the gut wall and decreasing NEJ´s viability in vitro. These findings open new avenues for the development of novel agents to control

Significance of antioxidants in L-NAME-induced hypertension

Czech Academy of Sciences Publication Activity Database

Pecháňová, Olga; Kojšová, S.; Jendeková, L.; Paulis, L.; Janega, P.; Dovinová, I.; Dobešová, Zdenka; Šimko, F.; Babál, P.; Kuneš, Jaroslav; Zicha, Josef

2006-01-01

Roč. 24, č. S4 (2006), S341-S341 ISSN 0263-6352. [European Meeting on Hypertension /16./. 12.06.2006-15.06.2006, Madrid] Grant - others:VEGA(SK) 2/6148/26; VEGA(SK) 1/3429/06 Keywords : antioxidants * L-NAME * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

Characterization and pharmacological properties of a novel multifunctional Kunitz inhibitor from Erythrina velutina seeds.

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Richele J A Machado

Full Text Available Inhibitors of peptidases isolated from leguminous seeds have been studied for their pharmacological properties. The present study focused on purification, biochemical characterization and anti-inflammatory and anticoagulant evaluation of a novel Kunitz trypsin inhibitor from Erythrina velutina seeds (EvTI. Trypsin inhibitors were purified by ammonium sulfate (30-60%, fractionation followed by Trypsin-Sepharose affinity chromatography and reversed-phase high performance liquid chromatography. The purified inhibitor showed molecular mass of 19,210.48 Da. Furthermore, a second isoform with 19,228.16 Da was also observed. The inhibitor that showed highest trypsin specificity and enhanced recovery yield was named EvTI (P2 and was selected for further analysis. The EvTI peptide fragments, generated by trypsin and pepsin digestion, were further analyzed by MALDI-ToF-ToF mass spectrometry, allowing a partial primary structure elucidation. EvTI exhibited inhibitory activity against trypsin with IC50 of 2.2×10(-8 mol.L(-1 and constant inhibition (Ki of 1.0×10(-8 mol.L(-1, by a non-competitive mechanism. In addition to inhibit the activity of trypsin, EvTI also inhibited factor Xa and neutrophil elastase, but do not inhibit thrombin, chymotrypsin or peptidase 3. EvTI was investigated for its anti-inflammatory and anti-coagulant properties. Firstly, EvTI showed no cytotoxic effect on human peripheral blood cells. Nevertheless, the inhibitor was able to prolong the clotting time in a dose-dependent manner by using in vitro and in vivo models. Due to anti-inflammatory and anticoagulant EvTI properties, two sepsis models were here challenged. EvTI inhibited leukocyte migration and specifically acted by inhibiting TNF-α release and stimulating IFN-α and IL-12 synthesis. The data presented clearly contribute to a better understanding of the use of Kunitz inhibitors in sepsis as a bioactive agent capable of interfering in blood coagulation and inflammation.

PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules.

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Geng, Qiaohong; Jiao, Peifu; Jin, Peng; Su, Gaoxing; Dong, Jinlong; Yan, Bing

2018-02-12

The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of aliskiren, telmisartan and torsemide on cardiac dysfunction in l-nitro arginine methyl ester (l-NAME induced hypertension in rats

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Sawsan A. Sadek

2015-11-01

Full Text Available Comparative study of cardio protective effect of aliskiren, telmisartan, and torsemide was carried out on l-nitro arginine methyl ester (l-NAME induced hypertension in rats. The three drugs were given daily for 8 weeks simultaneously with l-NAME, with a control group for each drug and l-NAME. The degree of protection was assessed by measurement of systolic blood pressure and heart rate of animals every two weeks. At the end of the experimental period blood sampling was carried out for estimation of the level of NO2−/NO3−. After which animals were sacrificed for heart dissection to detect collagen types I and III gene expression. Histopathological study was done to evaluate the extension of collagen deposits. The study revealed that the three drugs decreased blood pressure significantly compared to l-NAME. There was no significant difference between aliskiren and telmisartan in all measurements, but there was significant decrease in measurements of both aliskiren and telmisartan treated groups compared to torsemide starting from 4th week. There were insignificant changes in pulse rate values between the three l-NAME treated groups through the experiment. The three drugs significantly increased NO compared to l-NAME. Collagen I and III gene expression was significantly decreased by the three drugs but the highest percentage of inhibition was with telmisartan compared to l-NAME. Comparing the percentage inhibition of cardiac fibrosis, there was insignificant difference between telmisartan and torsemide treated groups while both were superior to aliskiren. In conclusion, further experimental studies are required to elucidate the potential cardioprotective mechanisms of aliskiren, telmisartan and torsemide, and assess their efficacy in treatment of heart failure.

HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

DEFF Research Database (Denmark)

Vanangamudi, Murugesan; Poongavanam, Vasanthanathan; Namasivayam, Vigneshwaran

2017-01-01

BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising......: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine...

Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors

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Crouch, Brian T.; Duer, Joy; Wang, Roujia; Gallagher, Jennifer; Hall, Allison; Soo, Mary Scott; Hughes, Philip; Haystead, Timothy A. J.; Ramanujam, Nirmala

2018-03-01

Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in several key hallmarks of cancer, in breast cancer provides an exciting opportunity to identify residual disease during surgery. We developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens using a fluorescence microendoscope with a field of view of 750 μm and subcellular resolution of 4 μm. HS-27 consists of an FDA approved Hsp90 inhibitor tethered to fluorescein isothiocyanate (EX 488nm, EM 525nm). Here, we optimized ex vivo HS-27 administration in pre-clinical breast cancer models and validated our approach on 21 patients undergoing standard of care ultrasound guided core needle biopsy. HS-27 administration time was fixed at 1- minute to minimize imaging impact on clinical workflow. HS-27 and HS-217 (non-specific control) doses were modulated from 1 μM up to 100 μM to identify the dose maximizing the ratio of specific uptake (HS-27 fluorescence) to non-specific uptake (HS-217 fluorescence). The specificity ratio was maximized at 100 μM and was significantly greater than all other doses (pcancer makes this technology attractive for assessing tumor margins, as one agent can be used for all subtypes.

Analysis of binding properties and specificity through identification of the interface forming residues (IFR for serine proteases in silico docked to different inhibitors

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da Silveira Carlos H

2010-10-01

Full Text Available Abstract Background Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR. We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes. Results We propose a novel method for describing binding properties and delineating serine proteases specificity by compiling an exhaustive table of interface forming residues (IFR for serine proteases and their inhibitors. Currently, the Protein Data Bank (PDB does not contain all the data that our analysis would require. Therefore, an in silico approach was designed for building corresponding complexes The IFRs are obtained by "rigid body docking" among 70 structurally aligned, sequence wise non-redundant, serine protease structures with 3 inhibitors: bovine pancreatic trypsin inhibitor (BPTI, ecotine and ovomucoid third domain inhibitor. The table (matrix of all amino acid positions at the interface and their respective occupancy is created. We also developed a new computational protocol for predicting IFRs for those complexes which were not deciphered experimentally so far, achieving accuracy of at least 0.97. Conclusions The serine proteases interfaces prefer polar (including glycine residues (with some exceptions. Charged residues were found to be uniquely prevalent at the

Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases in silico docked to different inhibitors.

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Ribeiro, Cristina; Togawa, Roberto C; Neshich, Izabella A P; Mazoni, Ivan; Mancini, Adauto L; Minardi, Raquel C de Melo; da Silveira, Carlos H; Jardine, José G; Santoro, Marcelo M; Neshich, Goran

2010-10-20

Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes. We propose a novel method for describing binding properties and delineating serine proteases specificity by compiling an exhaustive table of interface forming residues (IFR) for serine proteases and their inhibitors. Currently, the Protein Data Bank (PDB) does not contain all the data that our analysis would require. Therefore, an in silico approach was designed for building corresponding complexes. The IFRs are obtained by "rigid body docking" among 70 structurally aligned, sequence wise non-redundant, serine protease structures with 3 inhibitors: bovine pancreatic trypsin inhibitor (BPTI), ecotine and ovomucoid third domain inhibitor. The table (matrix) of all amino acid positions at the interface and their respective occupancy is created. We also developed a new computational protocol for predicting IFRs for those complexes which were not deciphered experimentally so far, achieving accuracy of at least 0.97. The serine proteases interfaces prefer polar (including glycine) residues (with some exceptions). Charged residues were found to be uniquely prevalent at the interfaces between the "miscellaneous-virus" subfamily

ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

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Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

2013-09-01

NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

Protective effects of long-term administration of Ziziphus jujuba fruit extract on cardiovascular responses in L-NAME hypertensive rats.

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Mohebbati, Reza; Bavarsad, Kosar; Rahimi, Maryam; Rakhshandeh, Hasan; Khajavi Rad, Abolfazl; Shafei, Mohammad Naser

2018-01-01

Ziziphus jujuba stimulates the release of nitric oxide (NO). Because NO is involved in cardiovascular regulations, in this study the effects of hydroalcoholic extract of Z. jujuba on cardiovascular responses in acute NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats were evaluated. Rats were divided into 6 group (n=6): 1) saline, 2) L-NAME received (10mg/kg) intravenously, 3) sodium nitroprusside (SNP) (50µg/kg)+L-NAME group received SNP before L-NAME and 4-6) three groups of Z. jujuba (100, 200 and 400mg/kg) that treated for four weeks and on the 28 th day, L-NAME was injected. Femoral artery and vein were cannulated for recording cardiovascular responses and drug injection, respectively. Systolic blood pressure (SBP), Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously. Maximal changes (∆) of SBP, MAP and HR were calculated and compared to control and L-NAME groups. In L-NAME group, maximal ΔSBP (L-NAME: 44.15±4.0 mmHg vs control: 0.71±2.1 mmHg) and ΔMAP (L-NAME: 40.8±4.0 mmHg vs control: 0.57±1.6 mmHg) significantly increased (p0.05). All doses of Z. jujuba attenuated maximal ∆SBP and ∆MAP induced by L-NAME but only the lowest dose (100 mg/kg) had significant effects (ΔSBP: 20.36±5.6 mmHg vs L-NAME: 44.1±4.0 mmHg and ΔMAP: 20.8±4.5 mmHg vs L-NAME: 40.8±3.8 mmHg (pL-NAME group (p>0.05). Because long-term consumption of Z. jujuba extract, especially its lowest dose, attenuated cardiovascular responses induced by L-NAME, we suggest that Z. jujuba has potential beneficial effects in prevention of hypertension induced by NO deficiency.

Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project.

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Prior, Nieves; Remor, Eduardo; Gómez-Traseira, Carmen; López-Serrano, Concepción; Cabañas, Rosario; Contreras, Javier; Campos, Ángel; Cardona, Victoria; Cimbollek, Stefan; González-Quevedo, Teresa; Guilarte, Mar; de Rojas, Dolores Hernández Fernández; Marcos, Carmen; Rubio, María; Tejedor-Alonso, Miguel Ángel; Caballero, Teresa

2012-07-20

There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version.

The milk-derived peptides Val-Pro-Pro and Ile-Pro-Pro attenuate arterial dysfunction in L-NAME-treated rats.

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Nonaka, Atsuko; Nakamura, Teppei; Hirota, Tatsuhiko; Matsushita, Akiko; Asakura, Masanori; Ohki, Kohji; Kitakaze, Masafumi

2014-08-01

Both endothelial dysfunction and arterial stiffness are surrogate markers of atherosclerosis and thus cardiovascular (CV) events. The milk-derived peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) inhibit angiotensin-converting enzyme, dilate blood vessels ex vivo and stimulate nitric oxide (NO) production in cells. In this study, we investigated the effects of either VPP or IPP on arterial function and on target organ damage in vivo. Male Wistar rats were treated with N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 1 g l(-1)), L-NAME+VPP (0.3 g l(-1)) or L-NAME+IPP (0.3 g l(-1)) in their drinking water for 8 weeks. Plasma nitrite and nitrate (NOx) levels were significantly increased in normal Wistar rats after supplementation with either VPP or IPP but not in rats that were chronically treated with L-NAME. Acetylcholine-induced vasorelaxation in the thoracic aorta ring was impaired by L-NAME, whereas vasorelaxation was significantly greater in mice treated with L-NAME+VPP for 1 or 4 weeks or L-NAME+IPP for 4 weeks than in mice treated with L-NAME alone. Four weeks of treatment with either VPP or IPP attenuated the increase in pulse wave velocity (PWV) that was induced by L-NAME. Cardiac and renal damage were observed after 8 weeks of treatment with L-NAME, and either VPP or IPP attenuated this damage. These results show that VPP or IPP attenuates arterial dysfunction and suggest that milk-derived peptides might prevent CV damage.

Intake of Blueberry Fermented by Lactobacillus plantarum Affects the Gut Microbiota of L-NAME Treated Rats

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Jie Xu

2013-01-01

Full Text Available Prebiotics, probiotics, or synbiotics can be used as means to regulate the microbiota to exert preventative or beneficial effects to the host. However, not much is known about the effect of the gut microbiota on hypertension which is a major risk factor of cardiovascular disease and also a symptom of the metabolic syndrome. The NG-nitro-L-arginine methyl ester (L-NAME induced hypertensive rats were used in order to test the effect of a synbiotic dietary supplement of Lactobacillus plantarum HEAL19 either together with fermented blueberry or with three phenolic compounds synthesized during fermentation. The experimental diets did not lower the blood pressure after 4 weeks. However, the fermented blueberries together with live L. plantarum showed protective effect on liver cells indicated by suppressed increase of serum alanine aminotransferase (ALAT levels. The diversity of the caecal microbiota was neither affected by L-NAME nor the experimental diets. However, inhibition of the nitric oxide synthesis by L-NAME exerted a selection pressure that led to a shift in the bacterial composition. The mixture of fermented blueberries with the bacterial strain altered the caecal microbiota in different direction compared to L-NAME, while the three phenolic compounds together with the bacteria eliminated the selection pressure from the L-NAME.

In silico panning for a non-competitive peptide inhibitor

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Ikebukuro Kazunori

2007-01-01

Full Text Available Abstract Background Peptide ligands have tremendous therapeutic potential as efficacious drugs. Currently, more than 40 peptides are available in the market for a drug. However, since costly and time-consuming synthesis procedures represent a problem for high-throughput screening, novel procedures to reduce the time and labor involved in screening peptide ligands are required. We propose the novel approach of 'in silico panning' which consists of a two-stage screening, involving affinity selection by docking simulation and evolution of the peptide ligand using genetic algorithms (GAs. In silico panning was successfully applied to the selection of peptide inhibitor for water-soluble quinoprotein glucose dehydrogenase (PQQGDH. Results The evolution of peptide ligands for a target enzyme was achieved by combining a docking simulation with evolution of the peptide ligand using genetic algorithms (GAs, which mimic Darwinian evolution. Designation of the target area as next to the substrate-binding site of the enzyme in the docking simulation enabled the selection of a non-competitive inhibitor. In all, four rounds of selection were carried out on the computer; the distribution of the docking energy decreased gradually for each generation and improvements in the docking energy were observed over the four rounds of selection. One of the top three selected peptides with the lowest docking energy, 'SERG' showed an inhibitory effect with Ki value of 20 μM. PQQGDH activity, in terms of the Vmax value, was 3-fold lower than that of the wild-type enzyme in the presence of this peptide. The mechanism of the SERG blockage of the enzyme was identified as non-competitive inhibition. We confirmed the specific binding of the peptide, and its equilibrium dissociation constant (KD value was calculated as 60 μM by surface plasmon resonance (SPR analysis. Conclusion We demonstrate an effective methodology of in silico panning for the selection of a non

Involvement of NO/cGMP pathway in the antidepressant-like effect of gabapentin in mouse forced swimming test.

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Ostadhadi, Sattar; Kordjazy, Nastaran; Haj-Mirzaian, Arya; Ameli, Sanaz; Akhlaghipour, Golnoosh; Dehpour, AhmadReza

2016-04-01

Based on clinical studies regarding the beneficial effect of gabapentin in depression, we aimed to evaluate the antidepressant-like properties of gabapentin in mice and also the participation of nitric oxide (NO)/cyclic guanosine monophosphate pathway in this effect. The following drugs were used in this study: gabapentin; N(G)-nitro-L-arginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor; 7-nitroindazole, a specific neuronal NOS inhibitor; aminoguanidine, a specific inducible NOS inhibitor; L-arginine, a NO precursor; and sildenafil, a phosphodiestrase inhibitor. Finally, we studied the behavioral effects through the forced swimming test (FST) and the changes of the hippocampus NO level through nitrite assay. The immobility time was significantly reduced after gabapentin administration. Co-administration of non-effective doses of gabapentin and L-NAME or 7-nitroindazole (7-NI) resulted in antidepressant-like effect in FST, while aminoguanidine did not affect the immobility time of gabapentin-treated mice. Furthermore, the antidepressant-like property of gabapentin was prevented by L-arginine or sildenafil. Also, the hippocampal nitrite level was significantly lower in gabapentin-treated mice relative to saline-injected mice, and co-administration of 7-NI with sub-effective gabapentin caused a significant decrease in hippocampal nitrite levels. Our results indicate that the antidepressant-like effect of gabapentin in the mice FST model is mediated at least in part through nitric oxide/cyclic guanosine monophosphate (cGMP) pathway.

Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity.

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Gillner, Danuta; Armoush, Nicola; Holz, Richard C; Becker, Daniel P

2009-11-15

The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical bacterial enzyme for the construction of the bacterial cell wall. A screen biased toward compounds containing zinc-binding groups (ZBG's) including thiols, carboxylic acids, boronic acids, phosphonates and hydroxamates has delivered a number of micromolar inhibitors of DapE from Haemophilus influenzae, including the low micromolar inhibitor L-captopril (IC(50)=3.3 microM, K(i)=1.8 microM). In vitro antimicrobial activity was demonstrated for L-captopril against Escherichia coli.

Discovery of Specific Inhibitors for Intestinal E. coli  β-Glucuronidase through In Silico Virtual Screening

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Ta-Chun Cheng

2015-01-01

Full Text Available Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino-1-(3-pyridy-1-butanone (NNK and 1,2-dimethylhydrazine (DMH, of reactive oxygen species (ROS. However, intestinal E. coli   β-glucuronidase (eβG has been considered pivotal to colorectal carcinogenesis. Specific inhibition of eβG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific eβG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against eβG but not human βG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS are highly effective and selective to inhibit eβG activity. Compound 4041  (IC50=2.8 μM shows a higher inhibiting ability than compound 7145  (IC50=31.6 μM against eβG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413 at active site of eβG via hydrogen-bonding interactions. These novel NYBS-based eβG specific inhibitors may provide as novel candidate compounds, which specifically inhibit eβG to reduce eβG-based carcinogenesis and intestinal injury.

Effects of inhibitors of protein kinase C and NO-synthase on the radiation-induced cytogenetic adaptive response in Chinese hamster cells in culture

International Nuclear Information System (INIS)

Gil'yano, N.Ya.; Bondarev, G.N.; Bikineeva, E.G.; Krasotskaya, G.I.; Noskin, L.A.

2001-01-01

The effect of the serine-threonin kinase inhibitor - staurosporine and inhibitor of NO-synthase - L-NAME on the radiation-induced adaptive response were studied in fibroblasts of Chinese hamster in culture. It is shown that staurosporine and L-NAME inhibit cytogenetic adaptive response induced by β-particles in low doses. Inhibition is not connected with radiosensitizing effect of these agents. L-NAME decreases significantly the γ-rays-induced chromosome aberration yield also. Study confirms the role of protein kinase C in induction of the adaptive response and participation of NO-synthase in this process is noticed for the first time [ru

Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

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Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

2016-01-01

Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

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Shifaa M. Abdin

2018-01-01

Full Text Available Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1, and its ligand, programmed death-ligand 1 (PD-L1, via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors.

Science.gov (United States)

Abdin, Shifaa M; Zaher, Dana M; Arafa, El-Shaimaa A; Omar, Hany A

2018-01-25

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

Classification of Cytochrome P450 1A2 Inhibitors and Non-Inhibitors by Machine Learning Techniques

DEFF Research Database (Denmark)

Vasanthanathan, Poongavanam; Taboureau, Olivier; Oostenbrink, Chris

2009-01-01

of CYP1A2 inhibitors and non-inhibitors. Training and test sets consisted of about 400 and 7000 compounds, respectively. Various machine learning techniques, like binary QSAR, support vector machine (SVM), random forest, kappa nearest neighbors (kNN), and decision tree methods were used to develop...

Hydrogen sulfide ameliorated L-NAME-induced hypertensive heart disease by the Akt/eNOS/NO pathway.

Science.gov (United States)

Jin, Sheng; Teng, Xu; Xiao, Lin; Xue, Hongmei; Guo, Qi; Duan, Xiaocui; Chen, Yuhong; Wu, Yuming

2017-12-01

Reductions in hydrogen sulfide (H 2 S) production have been implicated in the pathogenesis of hypertension; however, no studies have examined the functional role of hydrogen sulfide in hypertensive heart disease. We hypothesized that the endogenous production of hydrogen sulfide would be reduced and exogenous hydrogen sulfide would ameliorate cardiac dysfunction in N ω -nitro- L-arginine methyl ester ( L-NAME)-induced hypertensive rats. Therefore, this study investigated the cardioprotective effects of hydrogen sulfide on L-NAME-induced hypertensive heart disease and explored potential mechanisms. The rats were randomly divided into five groups: Control, Control + sodium hydrosulfide (NaHS), L-NAME, L-NAME + NaHS, and L-NAME + NaHS + glibenclamide (Gli) groups. Systolic blood pressure was monitored each week. In Langendorff-isolated rat heart, cardiac function represented by ±LV dP/dt max and left ventricular developing pressure was recorded after five weeks of treatment. Hematoxylin and Eosin and Masson's trichrome staining and myocardium ultrastructure under transmission electron microscopy were used to evaluate cardiac remodeling. The plasma nitric oxide and hydrogen sulfide concentrations, as well as nitric oxide synthases and cystathionine-γ-lyase activity in left ventricle tissue were determined. The protein expression of p-Akt, Akt, p-eNOS, and eNOS in left ventricle tissue was analyzed using Western blot. After five weeks of L-NAME treatment, there was a time-dependent hypertension, cardiac remodeling, and dysfunction accompanied by a decrease in eNOS phosphorylation, nitric oxide synthase activity, and nitric oxide concentration. Meanwhile, cystathionine-γ-lyase activity and hydrogen sulfide concentration were also decreased. NaHS treatment significantly increased plasma hydrogen sulfide concentration and subsequently promoted the Akt/eNOS/NO pathway which inhibited the development of hypertension and attenuated cardiac remodeling and

Antihypertensive Effects of Roselle-Olive Combination in L-NAME-Induced Hypertensive Rats

Directory of Open Access Journals (Sweden)

Rehab F. Abdel-Rahman

2017-01-01

Full Text Available This study aimed to evaluate the antihypertensive efficacy of a new combination therapy of Hibiscus sabdariffa and Olea europaea extracts (2 : 1; Roselle-Olive, using N(G-nitro-L-arginine-methyl ester- (L-NAME- induced hypertensive model. Rats received L-NAME (50 mg/kg/day, orally for 4 weeks. Concurrent treatment with Roselle-Olive (500, 250, and 125 mg/kg/day for 4 weeks resulted in a dose-dependent decrease in both systolic and diastolic blood pressure, reversed the L-NAME-induced suppression in serum nitric oxide (NO, and improved liver and kidney markers, lipid profile, and oxidative status. Furthermore, Roselle-Olive significantly lowered the elevated angiotensin-converting enzyme activity (ACE and showed a marked genoprotective effect against oxidative DNA damage in hypertensive rats. Roselle-Olive ameliorated kidney and heart lesions and reduced aortic media thickness. Real-time PCR and immunohistochemistry showed an enhanced endothelial nitric oxide synthase (eNOS gene and protein expression in both heart and kidney of Roselle-Olive-treated rats. To conclude, our data revealed that Roselle-Olive is an effective combination in which H. sabdariffa and O. europaea synergistically act to control hypertension. These effects are likely to be mediated by antioxidant and genoprotective actions, ACE inhibition, and eNOS upregulation by Roselle-Olive constituents. These findings provide evidences that Roselle-Olive combination affords efficient antihypertensive effect with a broad end-organ protective influence.

Antihypertensive Effects of Roselle-Olive Combination in L-NAME-Induced Hypertensive Rats.

Science.gov (United States)

Abdel-Rahman, Rehab F; Hessin, Alyaa F; Abdelbaset, Marwan; Ogaly, Hanan A; Abd-Elsalam, Reham M; Hassan, Salah M

2017-01-01

This study aimed to evaluate the antihypertensive efficacy of a new combination therapy of Hibiscus sabdariffa and Olea europaea extracts (2 : 1; Roselle-Olive), using N(G)-nitro-L-arginine-methyl ester- (L-NAME-) induced hypertensive model. Rats received L-NAME (50 mg/kg/day, orally) for 4 weeks. Concurrent treatment with Roselle-Olive (500, 250, and 125 mg/kg/day for 4 weeks) resulted in a dose-dependent decrease in both systolic and diastolic blood pressure, reversed the L-NAME-induced suppression in serum nitric oxide (NO), and improved liver and kidney markers, lipid profile, and oxidative status. Furthermore, Roselle-Olive significantly lowered the elevated angiotensin-converting enzyme activity (ACE) and showed a marked genoprotective effect against oxidative DNA damage in hypertensive rats. Roselle-Olive ameliorated kidney and heart lesions and reduced aortic media thickness. Real-time PCR and immunohistochemistry showed an enhanced endothelial nitric oxide synthase (eNOS) gene and protein expression in both heart and kidney of Roselle-Olive-treated rats. To conclude, our data revealed that Roselle-Olive is an effective combination in which H. sabdariffa and O. europaea synergistically act to control hypertension. These effects are likely to be mediated by antioxidant and genoprotective actions, ACE inhibition, and eNOS upregulation by Roselle-Olive constituents. These findings provide evidences that Roselle-Olive combination affords efficient antihypertensive effect with a broad end-organ protective influence.

Gender differences in colour naming performance for gender specific body shape images.

Science.gov (United States)

Elliman, N A; Green, M W; Wan, W K

1998-03-01

Males are increasingly subjected to pressures to conform to aesthetic body stereotypes. There is, however, comparatively little published research on the aetiology of male body shape concerns. Two experiments are presented, which investigate the relationship between gender specific body shape concerns and colour-naming performance. Each study comprised a between subject design, in which each subject was tested on a single occasion. A pictorial version of a modified Stroop task was used in both studies. Subjects colour-named gender specific obese and thin body shape images and semantically homogeneous neutral images (birds) presented in a blocked format. The first experiment investigated female subjects (N = 68) and the second investigated males (N = 56). Subjects also completed a self-report measure of eating behaviour. Currently dieting female subjects exhibited significant colour-naming differences between obese and neutral images. A similar pattern of colour-naming performance was found to be related to external eating in the male subjects.

Different effect of l-NAME treatment on susceptibility to decompression sickness in male and female rats.

Science.gov (United States)

Mazur, Aleksandra; Buzzacott, Peter; Lambrechts, Kate; Wang, Qiong; Belhomme, Marc; Theron, Michael; Popov, Georgi; Distefano, Giovanni; Guerrero, Francois

2014-11-01

Vascular bubble formation results from supersaturation during inadequate decompression contributes to endothelial injuries, which form the basis for the development of decompression sickness (DCS). Risk factors for DCS include increased age, weight-fat mass, decreased maximal oxygen uptake, chronic diseases, dehydration, and nitric oxide (NO) bioavailability. Production of NO is often affected by diving and its expression-activity varies between the genders. Little is known about the influence of sex on the risk of DCS. To study this relationship we used an animal model of Nω-nitro-l-arginine methyl ester (l-NAME) to induce decreased NO production. Male and female rats with diverse ages and weights were divided into 2 groups: treated with l-NAME (in tap water; 0.05 mg·mL(-1) for 7 days) and a control group. To control the distribution of nitrogen among tissues, 2 different compression-decompression protocols were used. Results showed that l-NAME was significantly associated with increased DCS in female rats (p = 0.039) only. Weight was significant for both sexes (p = 0.01). The protocol with the highest estimated tissue pressures in the slower compartments was 2.6 times more likely to produce DCS than the protocol with the highest estimated tissue pressures in faster compartments. The outcome of this study had significantly different susceptibility to DCS after l-NAME treatment between the sexes, while l-NAME per se had no effect on the likelihood of DCS. The analysis also showed that for the appearance of DCS, the most significant factors were type of protocol and weight.

Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

DEFF Research Database (Denmark)

Fedorov, Oleg; Huber, Kilian; Eisenreich, Andreas

2011-01-01

There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19......, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix aC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19...... effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue...

Mechanism for the differentiation of EoL-1 cells into eosinophils by histone deacetylase inhibitors.

Science.gov (United States)

Kaneko, Motoko; Ishihara, Kenji; Takahashi, Aki; Hong, Jangja; Hirasawa, Noriyasu; Zee, Okpyo; Ohuchi, Kazuo

2007-01-01

EoL-1 cells have a FIP1L1-PDGFRA fusion gene which causes the transformation of eosinophilic precursor cells into leukemia cells. Recently, we suggested that the induction of differentiation of EoL-1 cells into eosinophils by the HDAC inhibitors apicidin and n-butyrate is due to the continuous inhibition of HDACs. However, neither apicidin nor n-butyrate inhibited the expression of FIP1L1-PDGFRA mRNA, although both these inhibitors suppressed cell proliferation. Therefore, in this study, we analyzed whether the levels of FIP1L1-PDGFRalpha protein and phosphorylated-Stat5 involved in the signaling for the proliferation of EoL-1 cells are attenuated by HDAC inhibitors. EoL-1 cells were incubated in the presence of apicidin, TSA or n-butyrate. FIP1L1-PDGFRalpha and phosphorylated-Stat5 were detected by Western blotting. Treatment of EoL-1 cells with apicidin at 100 nM or n-butyrate at 500 microM decreased the levels of FIP1L1-PDGFRalpha protein and phosphorylated-Stat5, while that with trichostatin A at 30 nM did not. The decrease in the level of FIP1L1-PDGFRalpha protein caused by apicidin and n-butyrate might be one of the mechanisms by which EoL-1 cells are induced to differentiate into eosinophils by these HDAC inhibitors.

Macrophage populations and cardiac sympathetic denervation during L-NAME-induced hypertension in rats

DEFF Research Database (Denmark)

Neves, S R S; Machado, C R S; Pinto, A M T

2006-01-01

The rat model of hypertension induced by prolonged treatment with Nomega-nitro-L-arginine methyl ester (L-NAME) has been extensively used. However, the effects on cardiac autonomic innervation are unknown. Here, the cardiac sympathetic innervation is analyzed in parallel with myocardial lesions a...

PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data.

Science.gov (United States)

Aguiar, Pedro N; De Mello, Ramon Andrade; Hall, Peter; Tadokoro, Hakaru; Lima Lopes, Gilberto de

2017-05-01

The treatment of non-small-cell lung cancer has changed after the development of the immune checkpoint inhibitors. Although the most studied biomarker is PD-L1 expression, its clinical significance is still debatable. In this article, we show the updated survival analysis of all published data. We searched in network and conference data sources for relevant clinical studies of immunotherapy for non-small-cell lung cancer that assessed the PD-L1 expression even as an exploratory analysis. The updated survival hazard ratios (HR) were included in the analysis. 14 studies with 2857 patients were included (2019 treated with immunotherapy). The response rate was as higher among PD-L1-positive patients (RR: 2.19, 95% CI: 1.63-2.94). PD-L1 expression was also related to better progression-free survival (HR: 0.69, 95% CI: 0.57-0.85) and better overall survival (HR: 0.77, 95% CI: 0.67-0.89). PD-L1 overexpression predicts activity as well as better survival for patients treated with immune checkpoint inhibitors.

Ethylglyoxal bis(guanylhydrazone) as an inhibitor of polyamine biosynthesis in L1210 leukemia cells.

Science.gov (United States)

Seppänen, P; Ruohola, H; Jänne, J

1984-04-16

Ethylglyoxal bis(guanylhydrazone), a close derivative of the known anti-cancer drug methylglyoxal bis(guanylhydrazone), is also a powerful inhibitor of S-adenosylmethionine decarboxylase (EC 4.1.1.50), the enzyme needed for the synthesis of spermidine and spermine. There were, however, marked differences between the ethyl and methyl derivatives of glyoxal bis(guanylhydrazone) when tested in cultured L1210 cells. The cellular accumulation of ethylglyoxal bis(guanylhydrazone) represented only a fraction (20-25%) of that of the methyl derivative. Moreover, polyamine depletion, which is known to strikingly stimulate the uptake of methylglyoxal bis(guanylhydrazone), decreased, if anything, the uptake of ethylglyoxal bis(guanylhydrazone) by L1210 cells. The compound produced spermidine and spermine depletion fully comparable to that achieved with methylglyoxal bis(guanylhydrazone) at micromolar concentrations. Ethylglyoxal bis(guanylhydrazone) was growth-inhibitory to L1210 cells and produced an additive antiproliferative action when used together with 2-difluoromethylornithine. Ethylglyoxal bis(guanylhydrazone) was distinctly less effective than methylglyoxal bis(guanylhydrazone) in releasing bound polyamines from isolated cell organelles in vitro. Ethylglyoxal bis(guanylhydrazone) was also devoid of the early and profound mitochondrial toxicity typical to methylglyoxal bis(guanylhydrazone). These findings may indicate that this compound is a more specific inhibitor of polyamine biosynthesis with less intracellular polyamine 'receptor-site' activity than methylglyoxal bis(guanylhydrazone).

Photocontrol of the mitotic kinesin Eg5 using a novel S-trityl-L-cysteine analogue as a photochromic inhibitor.

Science.gov (United States)

Ishikawa, Kumiko; Tohyama, Kanako; Mitsuhashi, Shinya; Maruta, Shinsaku

2014-04-01

Because the mitotic kinesin Eg5 is essential for the formation of bipolar spindles during eukaryotic cell division, it has been considered as a potential target for cancer treatment. A number of specific and potent inhibitors of Eg5 are known. S-trityl-L-cysteine is one of the inhibitors of Eg5 whose molecular mechanism of inhibition was well studied. The trityl group of S-trityl-L-cysteine was shown to be a key moiety required for potent inhibition. In this study, we synthesized a novel photochromic S-trityl-L-cysteine analogue, 4-(N-(2-(N-acetylcysteine-S-yl) acetyl) amino)-4'- (N-(2-(N-(triphenylmethyl)amino)acetyl)amino)azobenzene (ACTAB), composed of a trityl group, azobenzene and N-acetyl-L-cysteine, which exhibits cis-trans photoisomerization in order to photocontrol the function of Eg5. ACTAB exhibited cis-trans photoisomerization upon alternating irradiation at two different wavelengths in the visible range, 400 and 480 nm. ACTAB induced reversible changes in the inhibitory activity of ATPase and motor activities correlating with the cis-trans photoisomerization. Compared with cis-ACTAB, trans-ACTAB reduced ATPase activity and microtubule gliding velocity more significantly. These results suggest that ACTAB could be used as photochromic inhibitor of Eg5 to achieve photocontrol of living cells.

Flurbiprofen : A non-selective cyclooxygenase (COX) inhibitor for treatment of non-infectious, non-necrotising anterior scleritis

Science.gov (United States)

Agrawal, Rupesh; Lee, Cecilia; Gonzalez-Lopez, Julio J.; Khan, Sharmina; Rodrigues, Valeria; Pavesio, Carlos

2016-01-01

Objective To analyse the safety and efficacy of a non-selective cyclo-oxygenase (COX) inhibitor in the management of non-infectious, non-necrotising anterior scleritis. Methods Retrospective chart review of 126 patients with non-necrotising anterior scleritis treated with oral flurbiprofen (Froben®(Abbott Healthcare)) with ( group B, n=61) or without topical steroids (group A, n=65) was performed and time to remission was plotted. Results The observed incidence rate was 1.07 (95% CI: 0.57–1.99) per 1000 person-years with failure rate of 0.68 (95% CI: 0.22–2.12) per 1000 person-years in group A and 1.41 (95% CI: 0.67–2.96) per 1000 person-years in group B. The failure rate was 3.97(1.89–9.34) per 1000 person-years with hazard ratio of 10.01 ( 95% CI: 2.52–39.65; p<0.001) for patients with associated systemic disease. Conclusion To our best knowledge, this is the first and largest case series on the safety and efficacy of a non-selective COX inhibitor in the management of anterior scleritis. PMID:26308394

Association of hypovitaminosis Dwith persistent non-specific musculoskeletal pains

International Nuclear Information System (INIS)

Alam, H.M.A.; Kamran, M.; Rehman, S.U.; Khan, D.A.; Hussain, K.

2017-01-01

The study was conducted in Pakistani population to find association of vitamin D deficiency with persistent non-specific musculoskeletal pains by comparing with pain free controls. Study Design: Case control study. Material and Methods: Patients aged 12 years or more presenting to Medical OPD with persistent nonspecific musculoskeletal pains for more than 3 months were selected as cases, while healthy individuals served as controls Results: A total of 60 cases (patients with persistent non-specific pains) presenting to medical outpatients department at Military Hospital Rawalpindi and 60 controls were studied. Mean age of cases was 43.9 +- 14.0 years and amongst controls were 33.2 +- 17.8 years. Mean serum vitamin D level of 32.8 nmol/L was reported in cases whereas mean serum vitamin D level amongst controls was 26.7 +- 17.8 nmol/L. Hypovitaminosis D amongst cases and controls was 86.6% and 95% respectively. The proportion of vitamin D deficiency did not differ significantly as compared to controls. There was non-significant difference in proportion of deficiency amongst cases and controls. Conclusion: Overall there was no association between persistent non-specific musculoskeletal pains and vitamin D deficiency. (author)

The effect of L-Arginine on the brain tissue of stressed rats

Directory of Open Access Journals (Sweden)

Batoul Ebadi

2010-01-01

Full Text Available Introduction: This study was conducted to determine the possible beneficial results of L-arginine on prefrontal cortex of rats which impressed by immobilization stress to define the synchronous impression of stress and nitric oxide (NO on evolution of prefrontal cortex of rats after birth. Methods: Forty-eight one month, male Wistar rats were divided into two groups: stressed and non-stressed. L-Arginine (200 mg/kg as a NO synthase (NOS inducer and L-NAME (2O mg/kg were injected intraperitonealy (IP and 7- nitroindazde (25 mg/kg as non-specific was injected subcutaneously (S.C. for 4 weeks. The kind of stress was immobilization for 4 weeks, every other day. The brain was removed after this period and each brain divided into two parts in a coronal section manner. Anterior part used for histological studies with H&E staining and posterior part used for measurement of NO production using spectrophotometer at 540 nm wavelengh. Results: Statistical analysis of microscopic and light microscopic finding showed that thickness of prefrontal cortex and NO production were significantly decreased in stressed rats and especially in groups which received 7- nitroindazole and L-NAME and L-arginine could reverse these results. Discussion: According to this research, we could say that L-arginine decreases the cortical damages in stressed rats and 7-nitroindazole and L-NAME increase this damage in non-stressed group. Although in non stressed groups, L-arginine, L-NAME and 7- nitroindazole were all non-protective and damaging.

The effect of L-Arginine on the brain tissue of stressed rats

Directory of Open Access Journals (Sweden)

Batoul Ebadi

2010-01-01

Full Text Available   Abstract  Introduction: This study was conducted to determine the possible beneficial results of L-arginine on prefrontal cortex of rats which impressed by immobilization stress to define the synchronous impression of stress and nitric oxide (NO on evolution of prefrontal cortex of rats after birth. Methods: Forty-eight one month, male Wistar rats were divided into two groups: stressed and non-stressed. L-Arginine (200 mg/kg as a NO synthase (NOS inducer and L-NAME (2O mg/kg were injected intraperitonealy (IP and 7- nitroindazde (25 mg/kg as non-specific was injected subcutaneously (S.C. for 4 weeks. The kind of stress was immobilization for 4 weeks, every other day. The brain was removed after this period and each brain divided into two parts in a coronal section manner. Anterior part used for histological studies with H&E staining and posterior part used for measurement of NO production using spectrophotometer at 540 nm wavelengh. Results: Statistical analysis of microscopic and light microscopic finding showed that thickness of prefrontal cortex and NO production were significantly decreased in stressed rats and especially in groups which received 7- nitroindazole and L-NAME and L-arginine could reverse these results. Discussion: According to this research, we could say that L-arginine decreases the cortical damages in stressed rats and 7-nitroindazole and L-NAME increase this damage in non-stressed group. Although in non stressed groups, L-arginine, L-NAME and 7- nitroindazole were all non-protective and damaging.

Effect of phosphodiesterase inhibitors on human arteries in vitro

NARCIS (Netherlands)

Vroom, M. B.; Pfaffendorf, M.; van Wezel, H. B.; van Zwieten, P. A.

1996-01-01

In the present study, we investigated if the relaxant effects of phosphodiesterase (PDE) III inhibitors on human vessels could be inhibited by a nitric oxide synthase blocker, L-NAME, or by a blocker of ATP-sensitive potassium channels (KATP), glibenclamide. The experiments were performed using an

Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

Energy Technology Data Exchange (ETDEWEB)

Tabackman, Alexa A.; Frankson, Rochelle; Marsan, Eric S.; Perry, Kay; Cole, Kathryn E. (Ithaca); (Cornell); (Christopher Newport U)

2016-11-04

Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

Synthesis of suicide inhibitors of monoamine oxidase: carbon-11 labeled clorgyline, L-deprenyl and D-deprenyl

International Nuclear Information System (INIS)

MacGregor, R.R.; Fowler, J.S.; Wolf, A.P.; Halldin, C.; Langstroem, B.

1988-01-01

The suicide inhibitors of monoamine oxidase type A and B, clorgyline and L-deprenyl have been labeled with carbon-11 by [ 11 C]methylation of the norbases with [ 11 C]H 3 I. The less active enantiomer of deprenyl (D-deprenyl) was also labeled using this procedure. The synthesis time was 35 minutes, the radiochemical yield was 25-40% and the specific activity was 0.8-2.0 Ci/μmol (calculated to EOB). Procedures for synthesis of the precursor norbases as well as the synthesis of unlabeled clorgyline, L-deprenyl and D-deprenyl are given. (author)

The effects of L-arginine, D-arginine, L-name and methylene blue on channa striatus-induced peripheral antinociception in mice.

Science.gov (United States)

Zakaria, Zainul Amiruddin; Sulaiman, Mohd Rosian; Somchit, Muhammad Nazrul; Jais, Abdul Manan Mat; Ali, Daud Israf

2005-08-03

To determine the involvement of nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway in aqueous supernatant of haruan (Channa striatus) fillet (ASH) antinociception using the acetic acid-induced abdominal constriction test. The ASH was prepared by soaking fresh haruan fillet in chloroform:methanol (CM) (2/1 (v/v)) for 72 h followed by evaporation of the upper layer supernatant to remove any solvent residues. The supernatant was then subjected to a freeze-drying process (48 h) followed by doses preparation. Subcutaneous (SC) administration of ASH alone (0.170, 0.426 and 1.704 mg/kg) exhibited a dose-dependent antinociception. On the other hand, 20 mg/kg (SC) of L-arginine and MB exhibited a significant nociception and antinociception, while D-arginine and L-NAME did not produce any effect at all. Pre-treatment with L-arginine was found to significantly reverse the three respective doses of ASH antinociception; pre-treatment with D-arginine did not produce any significant change in the ASH activity; pre-treatment with L-NAME only significantly increased the 0.170 and 0.426 mg/kg ASH antinociception; and pre-treatment with MB significantly enhanced the respective doses of ASH antinociception, respectively. Furthermore, co-treatment with L-NAME significantly enhanced the L-arginine reversal effect on 0.426 mg/kg ASH antinociception. In addition, MB significantly reversed the L-arginine nociception on 0.426 mg/kg ASH. These finding suggest ASH antinociception involves the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. The presence of NO was found to reverse ASH antinociceptive activity while blocking of cGMP system enhanced it.

Assessment the effect of NO inhibition on hippocampal normetanephrine level in stress and non-stress conditions in adult male rats

Directory of Open Access Journals (Sweden)

Hana Molahoveizeh

2016-01-01

Full Text Available Background: Nitric oxide (NO has a role in the regulation of neurotransmitters release such as norepinephrine, in the hippocampus.Normetanephrine (NMN is a metabolite of norepinephrine created by action of catechol-O-methyl transferase (COMT on norepinephrine. Several studies have shown that various stresses increased release of norepinephrine and its metabolites. Therefore in the present study, the role of Nitric oxide in regulation of norepinephrine release and its metabolism was investigated by administration of L-NAME (NO synthase inhibitor in stressed and non-stressed rats. Materials and Methods: For this purpose, 50 adult rats were divided into 10 groups, of which 5 groups were exposed to restraint stress while another 5 groups were without stress. These two set of groups included intact, saline and L-NAME (20, 40, 80 mg/kg. Thirty minutes after intraperituneal injection of L-NAME, brains removed, the hippocampus dissected, weighed, homogenized and centrifuged then amount of NMN measured by ELISA kit. Results: The results showed that in non-stressed condition amount of NMN were significantly increased in group that received L-NAME (80 mg/kg in comparison with other groups but in stress condition, amount of NMN was significantly decreased in groups that received L-NAME (20,40,80 mg/kg, in comparison with control and saline groups. Comparison between stress and non-stressed groups showed that stress alone cause an increase in amount of NMN in control and saline groups. Conclusion: In conclusion, NO synthesis inhibition produced opposite responses with respect to NMN amount in the presence or absence of stress, and probably L-NAME preventing the effect of stress on increasing NMN levels mediated by nitrergic pathway.

40 CFR 721.6440 - Polyamine urea-for-malde-hyde condensate (specific name).

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Polyamine urea-for-malde-hyde condensate (specific name). 721.6440 Section 721.6440 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.6440 Polyamine urea-for-malde-hyde condensate...

[Prospect and Current Situation of Immune Checkpoint Inhibitors 
in First-line Treatment in Advanced Non-small Cell Lung Cancer Patients].

Science.gov (United States)

Wang, Haiyang; Yu, Xiaoqing; Fan, Yun

2017-06-20

With the breakthroughs achieved of programmed death-1 (PD-1)/PD-L1 inhibitors monotherapy as first-line and second-line treatment in advanced non-small cell lung cancer (NSCLC), the treatment strategy is gradually evolving and optimizing. Immune combination therapy expands the benefit population and improves the curative effect. A series of randomized phase III trials are ongoing. In this review, we discuss the prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced NSCLC patients.

‘Neptune’ between ‘Hesperus’ and ‘Vulcan’: On descriptive names and non-existence

OpenAIRE

Arrieta Urtizberea, Agustín

2005-01-01

[EN]This work will focus on some aspects of descriptive names. The New Theory of Reference, in line with Kripke, takes descriptive names to be proper names. I will argue in this paper that descriptive names and certain theory in reference to them, even when it disagrees with the New Theory of Reference, can shed light on our understanding of (some) non-existence statements. I define the concept of descriptive name for hypothesised object (DNHO). My thesis being that DNHOs are, ...

KINETICS OF MODULATORY ROLE OF Cyperus esculentus L. ON THE SPECIFIC ACTIVITY OF KEY CARBOHYDRATE METABOLIZING ENZYMES.

Science.gov (United States)

Sabiu, Saheed; Ajani, Emmanuel Oladipo; Sunmonu, Taofik Olatunde; Ashafa, Anofi Omotayo Tom

2017-01-01

The continuous search for new lead compounds as viable inhibitors of specific enzymes linked to carbohydrate metabolism has intensified. Cyperus esculentus L. is one of the therapeutically implicated botanicals against several degenerative diseases including diabetes mellitus. This study evaluated the antioxidant and mechanism(s) of inhibitory potential of aqueous extract of C. esculentus on α-amylase and α-glucosidase in vitro . The extract was investigated for its radical scavenging and hypoglycaemic potentials using standard experimental procedures. Lineweaver-Burke plot was used to predict the manner in which the enzymes were inhibited. The data obtained revealed that the extract moderately and potently inhibited the specific activities of α -amylase and α -glucosidase, respectively. The inhibition was concentration-related with respective IC 50 values of 5.19 and 0.78 mg/mL relative to that of the control (3.72 and 3.55 mg/mL). The extract also significantly scavenged free radicals and the effects elicited could be ascribed to its phytoconstituents. The respective competitive and non-competitive mode of action of the extract is due to its inhibitory potentials on the activities of α -amylase and α -glucosidase. Going forward, in addition to completely characterize the exact compound(s) responsible for the elicited activity in this study, pertinent attention will be given to the in vivo evaluation of the identified constituents.

Isozyme-specific enzyme inhibitors. 14. 5'(R)-C-[(L-homocystein-S-yl)methyl]adenosine 5'-(beta,gamma-imidotriphosphate), a potent inhibitor of rat methionine adenosyltransferases.

Science.gov (United States)

Kappler, F; Vrudhula, V M; Hampton, A

1987-09-01

The title compound is a covalent adduct of L-methionine (Met) and beta,gamma-imido-ATP. In its synthesis the N-Boc derivative of 5'(R)-C-(aminomethyl)-N6-benzoyl-5'-O-tosyl-2',3'-O- isopropylidenadenosine was converted by the successive actions of CF3CO2H and HNO2 into the corresponding 5'(R)-C-hydroxymethyl derivative. Treatment of this with disodium L-homocysteinate led to attack of sulfur at C6', apparently via a 5',6'-epoxide, and to total stereoselective inversion at C5' to furnish, after debenzoylation, 5'(R)-C-(L-homocystein-S-ylmethyl)-2',3'-O-isopropylidene ade nosine. The 5' configuration was established by conversion of this into the known 5'(S)-C-methyl-2',3'-O-isopropylidene adenosine with Raney nickel. The alpha-amino acid residue was protected as an N-Boc methyl ester, after which the 5'-hydroxyl was phosphorylated with benzyl phosphate and dicyclohexylcarbodiimide. The phosphoanhydride bond with inorganic imidodiphosphate was then created by established methods. Finally, blocking groups were removed under conditions that gave the desired adduct with no racemization of its L-methionine residue. It was a potent inhibitor [KM(ATP)/Ki = 1080; KM(Met)/Ki = 7.7] of the M-2 (normal tissue) form of rat methionine adenosyltransferase and of the M-T (hepatoma tissue) form [KM(ATP)/Ki = 670; KM(Met)/Ki = 22]. Inhibitions were competitive with respect to ATP or to L-methionine, indicating a dual substrate site mode of binding to the enzyme forms.

Seed-Specific Stable Expression of the ?-AI1 Inhibitor in Coffee Grains and the In Vivo Implications for the Development of the Coffee Berry Borer

OpenAIRE

Albuquerque, ?rika V. S.; Bezerra, Caroline A.; Romero, Juan V.; Valencia, Jorge W. A.; Valencia-Jim?nez, Arnubio; Pimenta, Lucas M.; Barbosa, Aulus E. A. D.; Silva, Maria C. M.; Meneguim, Ana M.; S?, Maria Eug?nia L.; Engler, Gilbert; de Almeida-Engler, Janice; Fernandez, Diana; Grossi-de-S?, Maria F.

2015-01-01

Genetic transformation of coffee (Coffea spp.), the second most traded commodity worldwide, is an alternative approach to introducing features that cannot be introgressed by traditional crossings. The transgenic stability, heritability and quantitative and spatial expression patterns of the seed-specific promoter phytohemagglutinin (PHA-L) from Phaseolus vulgaris were characterized in genetically modified C. arabica expressing the ?-amylase inhibitor-1 (?-AI1) gene. The ?-AI1 inhibitor shows ...

Indexing concepts and/or named entities Indicizzare concetti e/o named entities

Directory of Open Access Journals (Sweden)

Pino Buizza

2011-12-01

Full Text Available

A partire da un punto di vista semantico più che morfologico, l'articolo è focalizzato il problema del significato dei nomi propri, con contributi della filosofia del linguaggio e della linguistica semantica. Sono indagate le entità individuali: il loro isolamento all’interno della rete di soggetti e la relazione esemplificativa, il trattamento nelle classificazioni. Le profonde diversità rilevate fra concetti e entità denominate suggeriscono di dichiararle esplicitamente da un punto di vista teorico e di adottare dispositivi che diano risultati unitari ma chiaramente distinguibili nei sistemi di recupero dell’informazione.  
Questo contributo è stato presentato col titolo Indexing concepts and/or named entities all'11th ISKO Conference, Paradigms and conceptual systems in knowledge organization, Roma, 23-26 febbraio 2010, non pubblicato negli atti, e qui leggermente ampliato.

Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

Directory of Open Access Journals (Sweden)

Yuxin Zhang

2012-02-01

Full Text Available Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.

Sildenafil preserves diastolic relaxation after reduction by L-NAME and increases phosphodiesterase-5 in the intercalated discs of cardiac myocytes and arterioles

Directory of Open Access Journals (Sweden)

Silvia Elaine Ferreira-Melo

2011-01-01

Full Text Available OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME. METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part by the inhibition of phosphodiesterase-5.

The correct name in Oenothera for Gauradrummondii (Onagraceae).

Science.gov (United States)

Wagner, Warren L; Hoch, Peter C; Zarucchi, James L

2015-01-01

In 2007, Wagner and Hoch proposed the new name Oenotheraxenogaura W.L.Wagner & Hoch for the species then known as Gauradrummondii (Spach) Torrey & A. Gray (non Oenotheradrummondii Hooker, 1834). However, the authors overlooked the availability of Gaurahispida Bentham (1840) for this species. Accordingly, we herewith make the appropriate new combination for this species, Oenotherahispida (Bentham) W.L.Wagner, Hoch & Zarucchi, and place Oenotheraxenogaura in synonymy.

A review of issues of nomenclature and taxonomy of Hypericum perforatum L. and Kew's Medicinal Plant Names Services.

Science.gov (United States)

Dauncey, Elizabeth Anne; Irving, Jason Thomas Whitley; Allkin, Robert

2017-10-16

To review which names are used to refer to Hypericum perforatum L. in health regulation and medicinal plant references, and the potential for ambiguity or imprecision. Structured searches of Kew's Medicinal Plant Names Services Resource, supplemented with other online bibliographic resources, found that the scientific name Hypericum perforatum L. is used consistently in the literature, but variation between subspecies is rarely considered by researchers. Research is still published using only the common name 'St John's wort' despite it being imprecise; at least 80 other common names are also used for this plant in multiple languages. Ambiguous and alternative plant names can lead to ineffective regulation, misinterpretation of literature, substitution of raw material or the failure to locate all published research. Kew's Medicinal Plant Names Services (MPNS) maps all names used for each plant in medicinal plant references onto current taxonomy, thereby providing for disambiguation and comprehensive access to the regulations and references that cite that plant, regardless of the name used. MPNS also supplies the controlled vocabulary for plant names now required for compliance with a new standard (Identification of Medicinal Products, IDMP) adopted by medicines regulators worldwide. © 2017 Royal Pharmaceutical Society.

Novel gaseous ethylene binding inhibitor prevents ethylene effects in potted flowering plants

Energy Technology Data Exchange (ETDEWEB)

Serek, M.; Reid, M.S. (Univ. of California, Davis, CA (United States). Dept. of Environmental Horticulture); Sisler, E.C. (North Carolina State Univ., Raleigh, NC (United States). Dept. of Biochemistry)

1994-11-01

A 6-hour fumigation of flowering Begonia xelatior hybrida Fotsch. Najada' and Rosa', B. xtuberhybrida Voss. Non-Stop', Kalanchoe blossfeldiana Poelln. Tropicana', and Rosa hybrida L. Victory Parade' plants with 1-MCP, (formerly designated as SIS-X), a gaseous nonreversible ethylene binding inhibitor, strongly inhibited exogenous ethylene effects such as bud and flower drop, leaf abscission, and accelerated flower senescence. The inhibitory effects of 1-MCP increased linearly with concentration, and at 20 nl-liter[sup [minus]1] this compound gave equal protection to that afforded by spraying the plants with a 0.5 STS mM solution. Chemical names used: 1-methylcyclopropene (1-MCP), silver thiosulfate (STS).

A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing.

Science.gov (United States)

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.

Resistance training controls arterial blood pressure in rats with L-NAME- induced hypertension.

Science.gov (United States)

Araujo, Ayslan Jorge Santos de; Santos, Anne Carolline Veríssimo dos; Souza, Karine dos Santos; Aires, Marlúcia Bastos; Santana-Filho, Valter Joviniano; Fioretto, Emerson Ticona; Mota, Marcelo Mendonça; Santos, Márcio Roberto Viana

2013-04-01

Arterial hypertension is a multifactorial chronic condition caused by either congenital or acquired factors. To evaluate the effects of Resistance Training (RT) on arterial pressure, and on vascular reactivity and morphology, of L-NAME-treated hypertensive rats. Male Wistar rats (200 - 250 g) were allocated into Sedentary Normotensive (SN), Sedentary Hypertensive (SH) and Trained Hypertensive (TH) groups. Hypertension was induced by adding L-NAME (40 mg/Kg) to the drinking water for four weeks. Arterial pressure was evaluated before and after RT. RT was performed using 50% of 1RM, 3 sets of 10 repetitions, 3 times per week for four weeks. Vascular reactivity was measured in rat mesenteric artery rings by concentration-response curves to sodium nitroprusside (SNP); phenylephrine (PHE) was also used for histological and stereological analysis. Resistance training inhibited the increase in mean and diastolic arterial pressures. Significant reduction was observed in Rmax (maximal response) and pD2 (potency) of PHE between SH and TH groups. Arteries demonstrated normal intima, media and adventitia layers in all groups. Stereological analysis demonstrated no significant difference in luminal, tunica media, and total areas of arteries in the SH and TH groups when compared to the SN group. Wall-to-lumen ratio of SH arteries was significantly different compared to SN arteries (parteries. RT was able to prevent an increase in blood pressure under the conditions in this study. This appears to involve a vasoconstrictor regulation mechanism and maintenance of luminal diameter in L-NAME induced hypertensive rats.

The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective.

Science.gov (United States)

Guirgis, Helmy M

2018-02-20

The impact of programmed death receptor-ligand1 (PD-L1) on costs and value of the immune check point inhibitors (ICPI) has received minimal attention. 1- Design a sliding scale to grade survival in 2nd-line non-small-cell lung cancer (NSCLC). 2- Compare costs and value of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc). Previously reported median overall survival (OS) and prices posted by parent company were utilized. The OS gains over controls in days were graded (gr) from A+ to D. Docetaxel costs were calculated for 6-12 cycles and the ICPI for 1 year. Adverse events treatment costs (AEsTC) were reported separately. The cost/life-year gain (C/LYG) was computed as drug yearly-cost/OS gain over control in days × 360 days. The relative value of the ICPI were expressed as $100,000/C/LYG. Costs of Doc 6 cycles were $23,868, OS/gr 87/C, AEs gr ¾ > 20%, AEsTC $1978 and 6- 12 cycle C/LYG $98,764 -$197,528. Nivo, Atezo and Pembro gr ¾ were  10%. Atezolizumab OS/g were 87/B and C/LYG $551,407 improving in enriched PD-L1 to 162/A and $332,020 respectively. Pembrolizumab in PD-L1 > 1.0% demonstrated OS/g 57/C and C/LYG $659,059 improving in > 50% PD-L1 to 201/A and $186,897. PD-L1 enrichment increased RV of Nivo from 0.18 to 0.56, Atezo from 0.16 to 0.66 and Pembro from 0.15 to 0.53. Simplified methodology to grade OS and weigh value of anticancer drugs was proposed. In 2nd-line non-squamous NSCLC, value of Doc, Nivo, Atezo and Pembro regardless of PDL-1 expression were limited and modest. Enrichment of PD-L1 resulted in unprecedented OS, improved grades and enhanced value at seemingly justifiable costs.

L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta.

Science.gov (United States)

Wong, Emily S W; Man, Ricky Y K; Ng, Kwok F J; Leung, Susan W S; Vanhoutte, Paul M

2018-03-01

The α2-adrenergic sedative/anesthetic agent dexmedetomidine exerts biphasic effects on isolated arteries, causing endothelium-dependent relaxations at concentrations at or below 30 nM, followed by contractions at higher concentrations. L-arginine is a common substrate of endothelial nitric oxide synthase and arginases. This study was designed to investigate the role of L-arginine in modulating the overall vascular response to dexmedetomidine. Isometric tension was measured in isolated aortic rings of Sprague Dawley rats. Cumulative concentrations of dexmedetomidine (10 nM to 10 μM) were added to quiescent rings (with and without endothelium) after previous incubation with vehicle, N-nitro-L-arginine methyl ester hydrochloride (L-NAME; nitric oxide synthase inhibitor), prazosin (α1-adrenergic antagonist), rauwolscine (α2-adrenergic antagonist), L-arginine, (S)-(2-boronethyl)-L-cysteine hydrochloride (arginase inhibitor), N-hydroxy-L-arginine (arginase inhibitor), urea and/or ornithine. In some preparations, immunofluorescent staining, immunoblotting, or measurement of urea content were performed. Dexmedetomidine did not contract control rings with endothelium but evoked concentration-dependent increases in tension in such rings treated with L-NAME (Emax 50 ± 4%) or after endothelium-removal (Emax 74 ± 5%; N = 7 to 12). Exogenous L-arginine augmented the dexmedetomidine-induced contractions in the presence of L-NAME (Emax 75 ± 3%). This potentiation was abolished by (S)-(2-boronethyl)-L-cysteine hydrochloride (Emax 16 ± 4%) and N-hydroxy-L-arginine (Emax 18 ± 4%). Either urea or ornithine, the downstream arginase products, had a similar potentiating effect as L-arginine. Immunoassay measurements demonstrated an upregulation of arginase I by L-arginine treatment in the presence of L-NAME (N = 4). These results suggest that when vascular nitric oxide homeostasis is impaired, the potentiation of the vasoconstrictor effect of

Involvement of NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effects of topiramate in mice forced swimming test.

Science.gov (United States)

Ostadhadi, Sattar; Khan, Muhammad Imran; Norouzi-Javidan, Abbas; Chamanara, Mohsen; Jazaeri, Farahnaz; Zolfaghari, Samira; Dehpour, Ahmad-Reza

2016-04-01

Topiramate (TPM) is an agent primarily used in the treatment of epilepsy. Using mice model of forced swimming test (FST) the current study was basically aimed to investigate the influence of TPM on depression by inhibiting NMDA receptor and nitric oxide-cGMP production. When TPM was administered in a dose of 20 and 30 mg/kg by i.p. route it reduced the immobility time during FST. However this effect of TPM (30 mg/kg, i.p.) in the FST was abolished when the mice were pretreated either with NMDA (75 mg/kg, i.p.), or l-arginine (750 mg/kg, i.p. NO precursor), or sildenafil (5mg/kg, i.p. Phosphodiesterase 5 inhibitor). The immobility time in the FST was reduced after administration of L-NAME (10mg/kg, i.p, a non-specific NOS inhibitor), 7-nitoinidazol (30 mg/kg, i.p. a nNOS inhibitor) or MK-801 (0.05 mg/kg, i.p, a NMDA receptor antagonist) in combination with a subeffective dose of TPM (10mg/kg, i.p.) as compared with single use of either drug. Co-administrated of lower doses of MK-801 (0.01 mg/kg) or L-NAME (1mg/kg) failed to effect immobility time. However, simultaneous administration of these two agents in the same doses with subeffective dose of TPM (10mg/kg, i.p.), reduced the immobility time during FST. None of these drugs were found to have a profound effect on the locomotor activity per se during the open field test. Taken together, our data demonstrates that TPM exhibit antidepressant-like effect which is accomplished either due to inhibition of NMDA receptors or NO-cGMP production. Copyright © 2016 Elsevier Inc. All rights reserved.

L-Cysteine/D,L-homocysteine-regulated ileum motility via system L and B°(,+) transporter: Modification by inhibitors of hydrogen sulfide synthesis and dietary treatments.

Science.gov (United States)

Yamane, Satoshi; Nomura, Ryouya; Yanagihara, Madoka; Nakamura, Hiroyuki; Fujino, Hiromichi; Matsumoto, Kenjiro; Horie, Syunji; Murayama, Toshihiko

2015-10-05

Previous studies including ours demonstrated that L-cysteine treatments decreased motility in gastrointestinal tissues including the ileum via hydrogen sulfide (H2S), which is formed from sulfur-containing amino acids such as L-cysteine and L-homocysteine. However, the amino acid transport systems involved in L-cysteine/L-homocysteine-induced responses have not yet been elucidated in detail; therefore, we investigated these systems pharmacologically by measuring electrical stimulation (ES)-induced contractions with amino acids in mouse ileum preparations. The treatments with L-cysteine and D,L-homocysteine inhibited ES-induced contractions in ileum preparations from fasted mice, and these responses were decreased by the treatment with 2-aminobicyclo[2.2.1]heptane-2-carboxylate (BCH), an inhibitor of systems L and B°(,+). The results obtained using ileum preparations and a model cell line (PC12 cells) with various amino acids and BCH showed that not only L-cysteine, but also aminooxyacetic acid and D,L-propargylglycine, which act as H2S synthesis inhibitors, appeared to be taken up by these preparations/cells in L and B°(,+) system-dependent manners. The L-cysteine and D,L-homocysteine responses were delayed and abolished, respectively, in ileum preparations from fed mice. Our results suggested that the regulation of ileum motility by L-cysteine and D,L-homocysteine was dependent on BCH-sensitive systems, and varied depending on feeding in mice. Therefore, the effects of aminooxyacetic acid and D,L-propargylglycine on transport systems need to be considered in pharmacological analyses. Copyright © 2015 Elsevier B.V. All rights reserved.

Fatty acid synthase inhibitors isolated from Punica granatum L

International Nuclear Information System (INIS)

Jiang, He-Zhong; Ma, Qing-Yun; Liang, Wen-Juan; Huang, Sheng-Zhuo; Dai, Hao-Fu; Wang, Peng-Cheng; Zhao, You-Xing; Fan, Hui-Jin; Ma, Xiao-Feng

2012-01-01

The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC 50 value of 10.3 μmol L -1 . (author)

Fatty acid synthase inhibitors isolated from Punica granatum L

Energy Technology Data Exchange (ETDEWEB)

Jiang, He-Zhong [School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, (China); Ma, Qing-Yun; Liang, Wen-Juan; Huang, Sheng-Zhuo; Dai, Hao-Fu; Wang, Peng-Cheng; Zhao, You-Xing, E-mail: zhaoyx1011@163.com [Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou (China); Fan, Hui-Jin; Ma, Xiao-Feng, E-mail: maxiaofeng@gucas.ac.cn [College of Life Sciences, Graduate University of Chinese Academy of Sciences, Beijing (China)

2012-05-15

The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC{sub 50} value of 10.3 {mu}mol L{sup -1}. (author)

PD-L1-specific T cells

DEFF Research Database (Denmark)

Ahmad, Shamaila Munir; Borch, Troels Holz; Hansen, Morten

2016-01-01

-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy...... for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses...

Antidiabetic Indian Plants: A Good Source of Potent Amylase Inhibitors

Directory of Open Access Journals (Sweden)

Menakshi Bhat

2011-01-01

Full Text Available Diabetes is known as a multifactorial disease. The treatment of diabetes (Type II is complicated due to the inherent patho-physiological factors related to this disease. One of the complications of diabetes is post-prandial hyperglycemia (PPHG. Glucosidase inhibitors, particularly α-amylase inhibitors are a class of compounds that helps in managing PPHG. Six ethno-botanically known plants having antidiabetic property namely, Azadirachta indica Adr. Juss.; Murraya koenigii (L. Sprengel; Ocimum tenuflorum (L. (syn: Sanctum; Syzygium cumini (L. Skeels (syn: Eugenia jambolana; Linum usitatissimum (L. and Bougainvillea spectabilis were tested for their ability to inhibit glucosidase activity. The chloroform, methanol and aqueous extracts were prepared sequentially from either leaves or seeds of these plants. It was observed that the chloroform extract of O. tenuflorum; B. spectabilis; M. koenigii and S. cumini have significant α-amylase inhibitory property. Plants extracts were further tested against murine pancreatic, liver and small intestinal crude enzyme preparations for glucosidase inhibitory activity. The three extracts of O. tenuflorum and chloroform extract of M. koenigi showed good inhibition of murine pancreatic and intestinal glucosidases as compared with acarbose, a known glucosidase inhibitor.

Classification of Breast Cancer Resistant Protein (BCRP) Inhibitors and Non-Inhibitors Using Machine Learning Approaches.

Science.gov (United States)

Belekar, Vilas; Lingineni, Karthik; Garg, Prabha

2015-01-01

The breast cancer resistant protein (BCRP) is an important transporter and its inhibitors play an important role in cancer treatment by improving the oral bioavailability as well as blood brain barrier (BBB) permeability of anticancer drugs. In this work, a computational model was developed to predict the compounds as BCRP inhibitors or non-inhibitors. Various machine learning approaches like, support vector machine (SVM), k-nearest neighbor (k-NN) and artificial neural network (ANN) were used to develop the models. The Matthews correlation coefficients (MCC) of developed models using ANN, k-NN and SVM are 0.67, 0.71 and 0.77, and prediction accuracies are 85.2%, 88.3% and 90.8% respectively. The developed models were tested with a test set of 99 compounds and further validated with external set of 98 compounds. Distribution plot analysis and various machine learning models were also developed based on druglikeness descriptors. Applicability domain is used to check the prediction reliability of the new molecules.

Class side effects: decreased pressure in the lower oesophageal and the pyloric sphincters after the administration of dopamine antagonists, neuroleptics, anti-emetics, L-NAME, pentadecapeptide BPC 157 and L-arginine.

Science.gov (United States)

Belosic Halle, Zeljka; Vlainic, Josipa; Drmic, Domagoj; Strinic, Dean; Luetic, Kresimir; Sucic, Mario; Medvidovic-Grubisic, Maria; Pavelic Turudic, Tatjana; Petrovic, Igor; Seiwerth, Sven; Sikiric, Predrag

2017-05-17

The ulcerogenic potential of dopamine antagonists and L-NAME in rats provides unresolved issues of anti-emetic neuroleptic application in both patients and experimental studies. Therefore, in a 1-week study, we examined the pressures within the lower oesophageal and the pyloric sphincters in rats [assessed manometrically (cm H 2 O)] after dopamine neuroleptics/prokinetics, L-NAME, L-arginine and stable gastric pentadecapeptide BPC 157 were administered alone and/or in combination. Medication (/kg) was given once daily intraperitoneally throughout the 7 days, with the last dose at 24 h before pressure assessment. Given as individual agents to healthy rats, all dopamine antagonists (central [haloperidol (6.25 mg, 16 mg, 25 mg), fluphenazine (5 mg), levomepromazine (50 mg), chlorpromazine (10 mg), quetiapine (10 mg), olanzapine (5 mg), clozapine (100 mg), sulpiride (160 mg), metoclopramide (25 mg)) and peripheral(domperidone (10 mg)], L-NAME (5 mg) and L-arginine (100 mg) decreased the pressure within both sphincters. As a common effect, this decreased pressure was rescued, dose-dependently, by BPC 157 (10 µg, 10 ng) (also note that L-arginine and L-NAME given together antagonized each other's responses). With haloperidol, L-NAME worsened both the lower oesophageal and the pyloric sphincter pressure, while L-arginine ameliorated lower oesophageal sphincter but not pyloric sphincter pressure, and antagonized L-NAME effect. With domperidone, L-arginine originally had no effect, while L-NAME worsened pyloric sphincter pressure. This effect was opposed by L-arginine. All these effects were further reversed towards a stronger beneficial effect, close to normal pressure values, by the addition of BPC 157. In addition, NO level was determined in plasma, sphincters and brain tissue. Thiobarbituric acid reactive substances (TBARS) were also assessed. Haloperidol increased NO levels (in both sphincters, the plasma and brain), consistently producing increased

PEGylated DX-1000: Pharmacokinetics and Antineoplastic Activity of a Specific Plasmin Inhibitor

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Laetitia Devy

2007-11-01

Full Text Available Novel inhibitors of the urokinase-mediated plasminogen (plg activation system are potentially of great clinical benefit as anticancer treatments. Using phage display, we identified DX-1000 a tissue factor pathway inhibitor-derived Kunitz domain protein which is a specific high-affinity inhibitor of plasmin (pin (Ki = 99 pM. When tested in vitro, DX-1000 blocks plasminmediated pro-matrix metal loproteinase-9 (proMMP-9 activation on cells and dose-dependently inhibits tube formation, while not significantly affecting hemostasis and coagulation. However, this low-molecular weight protein inhibitor (~ 7 kDa exhibits rapid plasma clearance in mice and rabbits, limiting its potential clinical use in chronic diseases. After site-specific PEGylation, DX-1000 retains its activity and exhibits a decreased plasma clearance. This PEGylated derivative is effective in vitro, as well as potent in inhibiting tumor growth of green fluorescent protein (GFP-labeled MDA-MB-231 cells. 4PEG-DX-1000 treatment causes a significant reduction of urokinase-type plasminogen activator (uPA and plasminogen expressions, a reduction of tumor proliferation, and vascularization. 4PEG-DX-1000 treatment significantly decreases the level of active mitogenactivated protein kinase (MAPK in the primary tumors and reduces metastasis incidence. Together, our results demonstrate the potential value of plasmin inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.

Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.

Science.gov (United States)

Sabatino, Manuela; Rotili, Dante; Patsilinakos, Alexandros; Forgione, Mariantonietta; Tomaselli, Daniela; Alby, Fréderic; Arimondo, Paola B; Mai, Antonello; Ragno, Rino

2018-03-01

Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis. Although numerous DOT1L inhibitors have been several structural data published no pronounced computational efforts have been yet reported. In these studies a first tentative of multi-stage and LB/SB combined approach is reported in order to maximize the use of available data. Using co-crystallized ligand/DOT1L complexes, predictive 3-D QSAR and COMBINE models were built through a python implementation of previously reported methodologies. The models, validated by either modeled or experimental external test sets, proved to have good predictive abilities. The application of these models to an internal library led to the selection of two unreported compounds that were found able to inhibit DOT1L at micromolar level. To the best of our knowledge this is the first report of quantitative LB and SB DOT1L inhibitors models and their application to disclose new potential epigenetic modulators.

Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches

Science.gov (United States)

Sabatino, Manuela; Rotili, Dante; Patsilinakos, Alexandros; Forgione, Mariantonietta; Tomaselli, Daniela; Alby, Fréderic; Arimondo, Paola B.; Mai, Antonello; Ragno, Rino

2018-03-01

Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis. Although numerous DOT1L inhibitors have been several structural data published no pronounced computational efforts have been yet reported. In these studies a first tentative of multi-stage and LB/SB combined approach is reported in order to maximize the use of available data. Using co-crystallized ligand/DOT1L complexes, predictive 3-D QSAR and COMBINE models were built through a python implementation of previously reported methodologies. The models, validated by either modeled or experimental external test sets, proved to have good predictive abilities. The application of these models to an internal library led to the selection of two unreported compounds that were found able to inhibit DOT1L at micromolar level. To the best of our knowledge this is the first report of quantitative LB and SB DOT1L inhibitors models and their application to disclose new potential epigenetic modulators.

CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

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Alessandra Citro

Full Text Available CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control. The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

Invertase proteinaceous inhibitor of Cyphomandra betacea Sendt fruits.

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Ordóñez, R M; Isla, M I; Vattuone, M A; Sampietro, A R

2000-01-01

This work describes a new invertase proteinaceous inhibitor from Cyphomandra betacea Sendt. (tomate de arbol) fruits. The proteinaceous inhibitor was isolated and purified from a cell wall preparation. The pH stability, kinetics of the inhibition of the C. betacea invertase, inhibition of several higher plant invertases and lectin nature of the inhibitor were studied. The inhibitor structure involves a single polypeptide (Mr = 19000), as shown by gel filtration and SDS-PAGE determinations. N-terminal aminoacid sequence was determined. The properties and some structural features of the inhibitor are compared with the proteinaceous inhibitors from several plant species (Beta vulgaris L., Ipomoea batatas L. and Lycopersicon esculentum Mill.). All these inhibitors share lectinic properties, some common epitopes, some aminoacid sequences and a certain lack of specificity towards invertases of different species, genera and even plant family. In consequence, the inhibitors appear to belong to the same lectin family. It is now known that some lectins are part of the defence mechanism of higher plants against fungi and bacteria and this is a probable role of the proteinaceous inhibitors.

The Potency of White Rice (Oryza sativa), Black Rice (Oryza sativa L. indica), and Red Rice (Oryza nivara) as Antioxidant and Tyrosinase Inhibitor

Science.gov (United States)

Batubara, I.; Maharni, M.; Sadiah, S.

2017-04-01

Rice is known to have many beneficial biological activities and is often used as “bedak dingin”, a face powder. The content of vitamins, minerals, fiber, and several types of antioxidants, such as ferulic acid, phytic acid, tocopherol, and oryzanols [1-2] are predicted to be potential as a tyrosinase inhibitor. The purpose of this study is to determine the potency of extracts from there types of rice, namely white, red, and black rice as an antioxidant and tyrosinase inhibitor. The rice was extracted with three different solvents, n-hexane, ethyl acetate, and methanol. The results showed that the highest antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl method was found in the methanol extract of black rice (IC50 290 μg/mL). Meanwhile, ethyl acetate extract of white rice has the highest antioxidant activity withphosphomolybdic acid method (41 mmol α-tocopherol equivalents/g sample). Thus, methanol extract of black rice and ethyl acetate extract of white rice are potential as an antioxidant. For tyrosinase inhibitor, n-hexane extract of red rice (IC50 3156 μg/mL) was the most active extract. The active component for radical scavenging is polar compound and for antioxidant by phosphomolybdate method is less polar compounds in black rice methanol extract based on TLC bioautogram. In conclusion, the black rice is the most potent in antioxidant while red rice is for tyrosinase inhibition.

Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats

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Nyadjeu Paulin

2013-01-01

Full Text Available Abstract Background Previous study showed that the aqueous extract of the stem bark of Cinnamomum zeylanicum possesses antihypertensive and vasodilatory properties. The present work investigates the acute and chronic antihypertensive effects of the methanol extract of Cinnamomum zeylanicum stem bark (MECZ in L-NAME-induced hypertensive rats. Methods The acute antihypertensive effects of MECZ (5, 10 and 20 mg/kg administered intravenously were evaluated in rats in which acute arterial hypertension has been induced by intravenous administration of L-NAME (20 mg/kg. For chronic antihypertensive effects, animals were treated with L-NAME (40 mg/kg/day plus the vehicle or L-NAME (40 mg/kg/day in combination with captopril (20 mg/kg/day or MECZ (300 mg/kg/day and compared with control group receiving only distilled water. All drugs were administered per os and at the end of the experiment that lasted for four consecutive weeks, blood pressure was measured by invasive method and blood samples were collected for the determination of the lipid profile. The heart and aorta were collected, weighed and used for both histological analysis and determination of NO tissue content. Results Acute intravenous administration of C. zeylanicum extract (5, 10 and 20 mg/kg to L-NAME-induced hypertensive rats provoked a long-lasting decrease in blood pressure. Mean arterial blood pressure decreased by 12.5%, 26.6% and 30.6% at the doses of 5, 10 and 20 mg/kg, respectively. In chronic administration, MECZ and captopril significantly prevented the increase in blood pressure and organs’ weights, as well as tissue histological damages and were able to reverse the depletion in NO tissue’s concentration. The MECZ also significantly lower the plasma level of triglycerides (38.1%, total cholesterol (32.1% and LDL-cholesterol (75.3% while increasing that of HDL-cholesterol (58.4% with a significant low atherogenic index (1.4 versus 5.3 for L-NAME group. Conclusion MECZ

2-Fluoro-L-Fucose Is a Metabolically Incorporated Inhibitor of Plant Cell Wall Polysaccharide Fucosylation

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Wallace, Ian S.

2015-01-01

The monosaccharide L-fucose (L-Fuc) is a common component of plant cell wall polysaccharides and other plant glycans, including the hemicellulose xyloglucan, pectic rhamnogalacturonan-I (RG-I) and rhamnogalacturonan-II (RG-II), arabinogalactan proteins, and N-linked glycans. Mutations compromising the biosynthesis of many plant cell wall polysaccharides are lethal, and as a result, small molecule inhibitors of plant cell wall polysaccharide biosynthesis have been developed because these molecules can be applied at defined concentrations and developmental stages. In this study, we characterize novel small molecule inhibitors of plant fucosylation. 2-fluoro-L-fucose (2F-Fuc) analogs caused severe growth phenotypes when applied to Arabidopsis seedlings, including reduced root growth and altered root morphology. These phenotypic defects were dependent upon the L-Fuc salvage pathway enzyme L-Fucose Kinase/ GDP-L-Fucose Pyrophosphorylase (FKGP), suggesting that 2F-Fuc is metabolically converted to the sugar nucleotide GDP-2F-Fuc, which serves as the active inhibitory molecule. The L-Fuc content of cell wall matrix polysaccharides was reduced in plants treated with 2F-Fuc, suggesting that this molecule inhibits the incorporation of L-Fuc into these polysaccharides. Additionally, phenotypic defects induced by 2F-Fuc treatment could be partially relieved by the exogenous application of boric acid, suggesting that 2F-Fuc inhibits RG-II biosynthesis. Overall, the results presented here suggest that 2F-Fuc is a metabolically incorporated inhibitor of plant cellular fucosylation events, and potentially suggest that other 2-fluorinated monosaccharides could serve as useful chemical probes for the inhibition of cell wall polysaccharide biosynthesis. PMID:26414071

Design, Synthesis and Evaluation of Ribose-modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors

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Hu, Xiuqin; Wang, Disha; Tong, Yi; Tong, Linjiang; Wang, Xia; Zhu, Lili; Xie, Hua; Li, Shiliang; Yang, You; Xu, Yufang

2017-11-01

The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants.

Identification of STAT1 and STAT3 specific inhibitors using comparative virtual screening and docking validation.

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Malgorzata Szelag

Full Text Available Signal transducers and activators of transcription (STATs facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (hSTATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the 'STAT-comparative binding affinity value' and 'ligand binding pose variation' as selection criteria. In silico screening of a multi-million clean leads (CL compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our

Insights into the molecular mechanism of action of Celastraceae sesquiterpenes as specific, non-transported inhibitors of human P-glycoprotein.

Science.gov (United States)

Muñoz-Martínez, Francisco; Reyes, Carolina P; Pérez-Lomas, Antonio L; Jiménez, Ignacio A; Gamarro, Francisco; Castanys, Santiago

2006-01-01

Dihydro-beta-agarofuran sesquiterpenes from Celastraceae have been recently shown to bind to human P-glycoprotein (Pgp), functioning as specific, mixed-type inhibitors of its drug transport activity, as well as multidrug resistance (MDR) modulators in vitro. However, nothing is known about whether such compounds are themselves transported by Pgp, or whether they affect Pgp expression as well as its activity, or about the location of their binding site within the protein. We performed transport experiments with a newly synthesized fluorescent sesquiterpene derivative, which retains the anti-Pgp activity of its natural precursor. This probe was poorly transported by Pgp, MRP1, MRP2 and BCRP transporters, compared with classical MDR substrates. Moreover, Pgp did not confer cross-resistance to the most potent dihydro-beta-agarofurans, which did not affect Pgp expression levels in several MDR cell lines. Finally, we observed competitive and non-competitive interactions between one of such dihydro-beta-agarofurans (Mama12) and classical Pgp modulators such as cyclosporin A, verapamil, progesterone, vinblastine and GF120918. These findings suggest that multidrug ABC transporters do not confer resistance to dihydro-beta-agarofurans and could not affect their absorption and biodistribution in the body. Moreover, we mapped their binding site(s) within Pgp, which may prove useful for the rational design of improved modulators based on the structure of dihydro-beta-agarofurans.

Ellagic Acid Prevents L-NAME-Induced Hypertension via Restoration of eNOS and p47phox Expression in Rats

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Thewarid Berkban

2015-06-01

Full Text Available The effect of ellagic acid on oxidative stress and hypertension induced by Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME was investigated. Male Sprague-Dawley rats were administrated with L-NAME (40 mg/kg/day for five weeks. L-NAME induced high systolic blood pressure (SBP and increased heart rate (HR, hindlimb vascular resistance (HVR and oxidative stress. Concurrent treatment with ellagic acid (7.5 or 15 mg/kg prevented these alterations. Co-treatment with ellagic acid was associated with up-regulation of endothelial nitric oxide synthase (eNOS protein production and alleviation of oxidative stress as indicated by decreased superoxide production in the vascular tissue, reduced plasma malondialdehyde levels, reduced NADPH oxidase subunit p47phox expression and increased plasma nitrate/nitrite levels. Our results indicate that ellagic acid attenuates hypertension by reducing NADPH oxidase subunit p47phox expression, which prevents oxidative stress and restores NO bioavailability.

The correct name in Oenothera for Gaura drummondii (Onagraceae

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Warren L. Wagner

2015-05-01

Full Text Available In 2007, Wagner and Hoch proposed the new name Oenothera xenogaura W.L.Wagner & Hoch for the species then known as Gaura drummondii (Spach Torrey & A. Gray (non O. drummondii Hooker, 1834. However, the authors overlooked the availability of Gaura hispida Bentham (1840 for this species. Accordingly, we herewith make the appropriate new combination for this species, O. hispida (Bentham W.L.Wagner, Hoch & Zarucchi, and place O. xenogaura in synonymy.

The correct name in Oenothera for Gaura drummondii (Onagraceae)

OpenAIRE

Wagner,Warren; Hoch,Peter C.; Zarucchi,James L.

2015-01-01

Abstract In 2007, Wagner and Hoch proposed the new name Oenothera xenogaura W.L.Wagner & Hoch for the species then known as Gaura drummondii (Spach) Torrey & A. Gray (non Oenothera drummondii Hooker, 1834). However, the authors overlooked the availability of Gaura hispida Bentham (1840) for this species. Accordingly, we herewith make the appropriate new combination for this species, Oenothera hispida (Bentham) W.L.Wagner, Hoch & Zarucchi, and place Oenothera xenogaura in synonymy.

Acetylation site specificities of lysine deacetylase inhibitors in human cells

DEFF Research Database (Denmark)

Schölz, Christian; Weinert, Brian Tate; Wagner, Sebastian A

2015-01-01

Lysine deacetylases inhibitors (KDACIs) are used in basic research, and many are being investigated in clinical trials for treatment of cancer and other diseases. However, their specificities in cells are incompletely characterized. Here we used quantitative mass spectrometry (MS) to obtain acety......1-α, providing a possible mechanistic explanation of its adverse, pro-inflammatory effects. Our results offer a systems view of KDACI specificities, providing a framework for studying function of acetylation and deacetylases....

ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

Science.gov (United States)

2010-05-01

imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305(5682):399-401 3. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob... Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid...araldehyde (5) (10 mmol), glacial acetic acid (5 mL), and a catalytic amount (100 lL ) of benzyl amine was re- fluxed for 5–8 h. After completion of

2-Fluoro-L-Fucose Is a Metabolically Incorporated Inhibitor of Plant Cell Wall Polysaccharide Fucosylation.

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Jose A Villalobos

Full Text Available The monosaccharide L-fucose (L-Fuc is a common component of plant cell wall polysaccharides and other plant glycans, including the hemicellulose xyloglucan, pectic rhamnogalacturonan-I (RG-I and rhamnogalacturonan-II (RG-II, arabinogalactan proteins, and N-linked glycans. Mutations compromising the biosynthesis of many plant cell wall polysaccharides are lethal, and as a result, small molecule inhibitors of plant cell wall polysaccharide biosynthesis have been developed because these molecules can be applied at defined concentrations and developmental stages. In this study, we characterize novel small molecule inhibitors of plant fucosylation. 2-fluoro-L-fucose (2F-Fuc analogs caused severe growth phenotypes when applied to Arabidopsis seedlings, including reduced root growth and altered root morphology. These phenotypic defects were dependent upon the L-Fuc salvage pathway enzyme L-Fucose Kinase/ GDP-L-Fucose Pyrophosphorylase (FKGP, suggesting that 2F-Fuc is metabolically converted to the sugar nucleotide GDP-2F-Fuc, which serves as the active inhibitory molecule. The L-Fuc content of cell wall matrix polysaccharides was reduced in plants treated with 2F-Fuc, suggesting that this molecule inhibits the incorporation of L-Fuc into these polysaccharides. Additionally, phenotypic defects induced by 2F-Fuc treatment could be partially relieved by the exogenous application of boric acid, suggesting that 2F-Fuc inhibits RG-II biosynthesis. Overall, the results presented here suggest that 2F-Fuc is a metabolically incorporated inhibitor of plant cellular fucosylation events, and potentially suggest that other 2-fluorinated monosaccharides could serve as useful chemical probes for the inhibition of cell wall polysaccharide biosynthesis.

Propiconazole is a specific and accessible brassinosteroid (BR) biosynthesis inhibitor for Arabidopsis and maize.

Science.gov (United States)

Hartwig, Thomas; Corvalan, Claudia; Best, Norman B; Budka, Joshua S; Zhu, Jia-Ying; Choe, Sunghwa; Schulz, Burkhard

2012-01-01

Brassinosteroids (BRs) are steroidal hormones that play pivotal roles during plant development. In addition to the characterization of BR deficient mutants, specific BR biosynthesis inhibitors played an essential role in the elucidation of BR function in plants. However, high costs and limited availability of common BR biosynthetic inhibitors constrain their key advantage as a species-independent tool to investigate BR function. We studied propiconazole (Pcz) as an alternative to the BR inhibitor brassinazole (Brz). Arabidopsis seedlings treated with Pcz phenocopied BR biosynthetic mutants. The steady state mRNA levels of BR, but not gibberellic acid (GA), regulated genes increased proportional to the concentrations of Pcz. Moreover, root inhibition and Pcz-induced expression of BR biosynthetic genes were rescued by 24epi-brassinolide, but not by GA(3) co-applications. Maize seedlings treated with Pcz showed impaired mesocotyl, coleoptile, and true leaf elongation. Interestingly, the genetic background strongly impacted the tissue specific sensitivity towards Pcz. Based on these findings we conclude that Pcz is a potent and specific inhibitor of BR biosynthesis and an alternative to Brz. The reduced cost and increased availability of Pcz, compared to Brz, opens new possibilities to study BR function in larger crop species.

Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

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Alessandra Ammazzalorso

2016-10-01

Full Text Available Matrix metalloproteinases (MMPs are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.

The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria

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Agnieszka E. Laudy

2017-01-01

Full Text Available The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs, against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC value determination in the presence of 1 mM MgSO4. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100–800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT)

Energy Technology Data Exchange (ETDEWEB)

Curtin, Michael L.; Heyman, H. Robin; Clark, Richard F.; Sorensen, Bryan K.; Doherty, George A.; Hansen, T. Matthew; Frey, Robin R.; Sarris, Kathy A.; Aguirre, Ana L.; Shrestha, Anurupa; Tu, Noah; Woller, Kevin; Pliushchev, Marina A.; Sweis, Ramzi F.; Cheng, Min; Wilsbacher, Julie L.; Kovar, Peter J.; Guo, Jun; Cheng, Dong; Longenecker, Kenton L.; Raich, Diana; Korepanova, Alla V.; Soni, Nirupama B.; Algire, Mikkel A.; Richardson, Paul L.; Marin, Violeta L.; Badagnani, Ilaria; Vasudevan, Anil; Buchanan, F.Greg; Maag, David; Chiang, Gary G.; Tse, Chris; Michaelides, Michael R. (AbbVie)

2017-08-01

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

Wheat Subtilisin/Chymotrypsin Inhibitor (WSCI) as a scaffold for novel serine protease inhibitors with a given specificity.

Science.gov (United States)

Tedeschi, Francesca; Di Maro, Antimo; Facchiano, Angelo; Costantini, Susan; Chambery, Angela; Bruni, Natalia; Capuzzi, Valeria; Ficca, Anna Grazia; Poerio, Elia

2012-10-30

WSCI (Wheat Subtilisin/Chymotrypsin Inhibitor) is a small protein belonging to the Potato inhibitor I family exhibiting a high content of essential amino acid. In addition to bacterial subtilisins and mammalian chymotrypsins, WSCI inhibits chymotrypsin-like activities isolated from digestive traits of a number of insect larvae. In vivo, as suggested for many plant proteinase inhibitors, WSCI seems to play a role of natural defence against attacks of pests and pathogens. The functional region of WSCI, containing the inhibitor reactive site (Met48-Glu49), corresponds to an extended flexible loop (Val42-Asp53) whose architecture is somehow stabilized by a number of secondary interactions established with a small β-sheet located underneath. The aim of this study was to employ a WSCI molecule as a stable scaffold to obtain recombinant inhibitors with new acquired anti-proteinase activity or, alternatively, inactive WSCI variants. A gene sequence coding for the native WSCI, along with genes coding for muteins with different specficities, could be exploited to obtain transformed non-food use plants with improved insect resistance. On the other hand, the genetic transformation of cereal plants over-expressing inactive WSCI muteins could represent a possible strategy to improve the nutritional quality of cereal-based foods, without risk of interference with human or animal digestive enzymes. Here, we described the characterization of four muteins containing single/multiple amino acid substitutions at the WSCI reactive site and/or at its proximity. Modalities of interaction of these muteins with proteinases (subtilisin, trypsin and chymotrypsin) were investigated by time course hydrolysis and molecular simulations studies.

[Recent Advances and Prospect of Advanced Non-small Cell Lung Cancer Targeted 
Therapy: Focus on Small Molecular Tyrosine Kinase Inhibitors].

Science.gov (United States)

Zhang, Guowei; Wang, Huijuan; Ma, Zhiyong

2017-04-20

At present the treatment of advanced non-small cell lung cancer enters a targeted era and develops rapidly. New drugs appear constantly. Small molecular tyrosine kinase inhibitors have occupied the biggest piece of the territory, which commonly have a clear biomarker as predictor, and show remarkable effect in specific molecular classification of patients. The epidermal growth factor tyrosine kinase inhibitors such as gefitinib, erlotinib, icotinib and anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib have brought a milestone advance. In recent years new generations of tyrosine kinase inhibitors have achieved a great success in patients with acquired resistance to the above two kinds of drugs. At the same time new therapeutic targets are constantly emerging. So in this paper, we reviewed and summarized the important drugs and clinical trails on this topic, and made a prospect of the future development.

Recent Advances and Prospect of Advanced Non-small Cell Lung Cancer Targeted 
Therapy: Focus on Small Molecular Tyrosine Kinase Inhibitors

Directory of Open Access Journals (Sweden)

Guowei ZHANG

2017-04-01

Full Text Available At present the treatment of advanced non-small cell lung cancer enters a targeted era and develops rapidly. New drugs appear constantly. Small molecular tyrosine kinase inhibitors have occupied the biggest piece of the territory, which commonly have a clear biomarker as predictor, and show remarkable effect in specific molecular classification of patients. The epidermal growth factor tyrosine kinase inhibitors such as gefitinib, erlotinib, icotinib and anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib have brought a milestone advance. In recent years new generations of tyrosine kinase inhibitors have achieved a great success in patients with acquired resistance to the above two kinds of drugs. At the same time new therapeutic targets are constantly emerging. So in this paper, we reviewed and summarized the important drugs and clinical trails on this topic, and made a prospect of the future development.

A selective phosphodiesterase 10A inhibitor reduces l-dopa-induced dyskinesias in parkinsonian monkeys.

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Beck, Goichi; Maehara, Shunsuke; Chang, Phat Ly; Papa, Stella M

2018-03-06

Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia. The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials. Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined. MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or

All-trans-retinoic acid enhances apoptosis induction by tyrosine kinase inhibitors in the eosinophilic leukemia-derived EoL-1 cell line.

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Robert, Carine; Apàti, Agota; Chomienne, Christine; Papp, Béla

2008-02-01

Imatinib and retinoids induce apoptosis in FIP1L1/PDGFRalpha-positive EoL-1 leukemia cells. Although imatinib induces complete remission in most FIP1L1/PDGFRalpha-positive patients, response to imatinib is sometimes suboptimal. In order to enhance the potency of the molecularly targeted therapy of eosinophilic leukemia, we investigated the effect of retinoids combined with tyrosine kinase inhibitors on EoL-1 cells. We demonstrate that retinoids combined with tyrosine kinase inhibitors lead to enhanced apoptosis induction in EoL-1 cells. Our results suggest that tyrosine kinase inhibitors combined with retinoids may constitute a valuable therapeutic approach for sensitive neoplasias that may display enhanced anti-leukemic potency when compared to single drug treatments.

Changes in endogenous growth inhibitors in onion bulbs (Allium cepa L. cv. Sochaczewska during storage

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Elżbieta Kielak

2013-12-01

Full Text Available Changes in inhibitor activity in the onion bulbs (Allium cepa L. cv. Sochaczewska during storage were investigated. Onions were dried under an umbrella roof until October 15th or November 15th and thereafter stored in a cold-room at 0-1°C until May 15th. The activity of inhibitors fluctuated markedly during the storage period. At least two peaks and two decreases of inhibitor activity were observed. The weather conditions seemed to strongly influence the level and the date of appearance of inhibitors in onions. Higher inhibitor activity is usually connected with better storage and less sprouting of onions during storage. Prolonged drying under an umbrella roof enhanced onion quality after storage only in these cases when it actually improved the drying of onions.

Non-target-site resistance to ALS-inhibiting herbicides in a Sagittaria trifolia L. population.

Science.gov (United States)

Zhao, Bochui; Fu, Danni; Yu, Yang; Huang, Chengtian; Yan, Kecheng; Li, Pingsheng; Shafi, Jamil; Zhu, He; Wei, Songhong; Ji, Mingshan

2017-08-01

Sagittaria trifolia L. is one of the most competitive weeds in rice fields in northeastern China. The continuous use of acetolactate synthase (ALS)-inhibitors has led to the evolution of herbicide resistant S. trifolia. A subpopulation BC1, which was derived from the L1 population, was analyzed using DNA sequencing and ALS enzyme activity assays and levels of resistance to five ALS-inhibiting herbicides was determined. DNA sequencing and ALS enzyme assays revealed no amino acid substitutions and no significant differences in enzyme sensitivity between susceptible and resistant populations. Whole-plant dose-response experiments showed that the BC1 population exhibited different levels of resistance (resistance ratios ranging from 2.14 to 51.53) to five ALS herbicides, and the addition of malathion (P450 inhibitor) to bensulfuron-methyl, penoxsulam and bispyribac-sodium strongly reduced the dry weight accumulation of the BC1 population compared with the effects of the three herbicides alone. The results of the present study demonstrated that the BC1 population has evolved non-target-site resistance to ALS-inhibiting herbicides. Copyright © 2017 Elsevier Inc. All rights reserved.

Alkaloids extract of Retama monosperma (L.) Boiss. seeds used as novel eco-friendly inhibitor for carbon steel corrosion in 1 M HCl solution: Electrochemical and surface studies

Energy Technology Data Exchange (ETDEWEB)

El Hamdani, Naoual; Fdil, Rabiaa [Laboratoire de Chimie Bioorganique, Faculté des Sciences, Université Chouaib Doukkali, B.P. 20, M-24000 El Jadida (Morocco); Tourabi, Mustapha [Laboratoire de Catalyse et de Corrosion des Matériaux (LCCM), Faculté des Sciences, Université Chouaib Doukkali, B.P. 20, M-24000 El Jadida (Morocco); Jama, Charafeddine [UMET-PSI, CNRS UMR 8207, ENSCL, Université Lille 1, CS 90108, F-59652 Villeneuve d’Ascq Cedex (France); Bentiss, Fouad, E-mail: fbentiss@enscl.fr [Laboratoire de Catalyse et de Corrosion des Matériaux (LCCM), Faculté des Sciences, Université Chouaib Doukkali, B.P. 20, M-24000 El Jadida (Morocco); UMET-PSI, CNRS UMR 8207, ENSCL, Université Lille 1, CS 90108, F-59652 Villeneuve d’Ascq Cedex (France)

2015-12-01

Graphical abstract: - Highlights: • AERS is good eco-friendly corrosion inhibitor for carbon steel in 1 M HCl. • AERS acts as mixed-type inhibitor in 1 M HCl medium. • AERS adsorption is well described by Langmuir isotherm. • Surface analyses were used to explain the AERS mechanism of carbon steel corrosion inhibition. - Abstract: Current research efforts now focus on the development of non-toxic, inexpensive and environmentally friendly corrosion inhibitors as alternatives to different organic and non-organic compounds. In this field, alkaloids extract of Retama monosperma (L.) Boiss. seeds (AERS) was tested for the first time as corrosion inhibitor for carbon steel in 1 M HCl medium using electrochemical and surface characterization techniques. The obtained results showed that this plant extract's acts as an efficient corrosion inhibitor for carbon steel in 1 M HCl and an inhibition efficiency of 94.4% was reached with 400 mg/L of AERS at 30 °C. Ac impedance experimental data revealed a frequency distribution of the capacitance, simulated as constant phase element. Impedance results demonstrated that the addition of the AERS in the corrosive solution decreases the charge capacitance and simultaneously increases the function of the charge/discharge of the interface, facilitating the formation of an adsorbed layer over the steel surface. Polarization curves indicated that AERS is a mixed inhibitor. Adsorption of such alkaloid extract on the steel surface obeyed to the Langmuir adsorption isotherm. X-ray photoelectron spectroscopy (XPS) showed that the inhibition of steel corrosion in normal hydrochloric solution by AERS is mainly controlled by a physisorption process and the inhibitive layer is composed of an iron oxide/hydroxide mixture where AERS molecules are incorporated.

Non-tricyclic and Non-selective Serotonin Reuptake Inhibitor Antidepressants and Recurrent Falls in Frail Older Women.

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Naples, Jennifer G; Kotlarczyk, Mary P; Perera, Subashan; Greenspan, Susan L; Hanlon, Joseph T

2016-12-01

To determine the risk of recurrent falls associated with antidepressants other than tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs) among frail older women. This is a secondary analysis of the Zoledronic acid in frail Elders to STrengthen bone, or ZEST, trial data treated as a longitudinal cohort in 181 frail, osteoporotic women aged ≥65 years in long-term care. The primary exposure was individual non-TCA/non-SSRI antidepressants (i.e., serotonin norepinephrine reuptake inhibitors, mirtazapine, trazodone, and bupropion) at baseline and 6 months. The main outcome was recurrent (at least two) falls within 6 months after antidepressant exposure. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were derived using a generalized estimating equations model. At least 15% of women experienced recurrent falls between 0-6 and 6-12 months. At baseline and 6 months, 18.2% and 6.9% had a non-TCA/non-SSRI antidepressant, respectively. Adjusting for demographics, health status, and other drugs that increase risk of falls, non-TCA/non-SSRI antidepressant exposure significantly increased the risk of recurrent falls (AOR: 2.14; 95% CI: 1.01-4.54). Fall risk further increased after removing bupropion from the non-TCA/non-SSRI antidepressant group in sensitivity analyses (AOR: 2.73; 95% CI: 1.24-6.01). Other antidepressant classes may not be safer than TCAs/SSRIs with respect to recurrent falls in frail older women. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Non-specific immunization against babesiosis

International Nuclear Information System (INIS)

Cox, F.E.G.

1980-01-01

The rodent babesias, Babesia rodhaini and the less virulent B. microti, are useful models with which to study immunity to and immunization against babesiosis. In contrast with the difficulty in inducing specific immunity to these parasites it is comparatively easy to induce non-specific immunity by prior exposure to related and unrelated intra-erythrocytic protozoa, micro-organisms such as Mycobacterium bovis (BCG) and Corynebacterium parvum, microbial extracts and muramyl dipeptide. This non-specific immunity is long lasting and extremely effective. It is characterized by the facts that (a) it occurs early in the infection at the height of the first peak of parasitaemia, and (b) it involves the intra-erythrocytic death of the parasites. After the primary parasitaemia has resolved, some parasites continue to persist at a low level and when introduced into clean mice produce only low-level 'attenuated' infections in these. Non-specific immunity is not equally effective in all strains of mice. It is suggested that immunity to babesiosis, and infections caused by other intra-erythrocytic protozoa, involves two mechanisms, the first non-specific and the second specific. The actual balance between these two mechanisms varies from parasite to parasite and from host to host. An effective vaccine would have to be based on an understanding of the roles of non-specific immunity in the actual disease under consideration, and would ideally combine an adjuvant that would also stimulate non-specific immunity and an attenuated strain of parasite that would induce a specific response. (author)

Description of the L76V resistance protease mutation in HIV-1 B and "non-B" subtypes.

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Charlotte Charpentier

Full Text Available OBJECTIVE: To describe the prevalence of the L76V protease inhibitors resistance-associated mutation (PI-RAM in relation with patients' characteristics and protease genotypic background in HIV-1 B- and "non-B"-infected patients. METHODS: Frequency of the L76V mutation between 1998 and 2010 was surveyed in the laboratory database of 3 clinical centers. Major PI-RAMs were identified according to the IAS-USA list. Fisher's and Wilcoxon tests were used to compare variables. RESULTS: Among the overall 29,643 sequences analyzed, the prevalence of L76V was 1.50%, while was 5.42% in PI-resistant viruses. Since 2008 the prevalence of L76V was higher in "non-B"-infected than in B-infected patients each year. Median time since diagnosis of HIV-1 infection and median time under antiretroviral-based regimen were both shorter in "non-B"- than in B-infected patients (8 vs 11 years, P<0.0001; and 7 vs 8 years, P = 0.004. In addition, "non-B"-infected patients had been pre-exposed to a lower number of PI (2 vs 3, P = 0.016. The L76V was also associated with a lower number of major PI-RAMs in "non-B" vs B samples (3 vs 4, P = 0.0001, and thus it was more frequent found as single major PI-RAM in "non-B" vs B subtype (10% vs 2%, P = 0.014. CONCLUSIONS: We showed an impact of viral subtype on the selection of the L76V major PI-RAM with a higher prevalence in "non-B" subtypes observed since 2008. In addition, in "non-B"-infected patients this mutation appeared more rapidly and was associated with less PI-RAM.

Description of the L76V resistance protease mutation in HIV-1 B and "non-B" subtypes.

Science.gov (United States)

Charpentier, Charlotte; Lambert-Niclot, Sidonie; Alteri, Claudia; Storto, Alexandre; Flandre, Philippe; Svicher, Valentina; Perno, Carlo-Federico; Brun-Vézinet, Françoise; Calvez, Vincent; Marcelin, Anne-Geneviève; Ceccherini-Silberstein, Francesca; Descamps, Diane

2013-01-01

To describe the prevalence of the L76V protease inhibitors resistance-associated mutation (PI-RAM) in relation with patients' characteristics and protease genotypic background in HIV-1 B- and "non-B"-infected patients. Frequency of the L76V mutation between 1998 and 2010 was surveyed in the laboratory database of 3 clinical centers. Major PI-RAMs were identified according to the IAS-USA list. Fisher's and Wilcoxon tests were used to compare variables. Among the overall 29,643 sequences analyzed, the prevalence of L76V was 1.50%, while was 5.42% in PI-resistant viruses. Since 2008 the prevalence of L76V was higher in "non-B"-infected than in B-infected patients each year. Median time since diagnosis of HIV-1 infection and median time under antiretroviral-based regimen were both shorter in "non-B"- than in B-infected patients (8 vs 11 years, P<0.0001; and 7 vs 8 years, P = 0.004). In addition, "non-B"-infected patients had been pre-exposed to a lower number of PI (2 vs 3, P = 0.016). The L76V was also associated with a lower number of major PI-RAMs in "non-B" vs B samples (3 vs 4, P = 0.0001), and thus it was more frequent found as single major PI-RAM in "non-B" vs B subtype (10% vs 2%, P = 0.014). We showed an impact of viral subtype on the selection of the L76V major PI-RAM with a higher prevalence in "non-B" subtypes observed since 2008. In addition, in "non-B"-infected patients this mutation appeared more rapidly and was associated with less PI-RAM.

Kinetic comparison of tissue non-specific and placental human alkaline phosphatases expressed in baculovirus infected cells: application to screening for Down's syndrome.

Science.gov (United States)

Denier, Colette C; Brisson-Lougarre, Andrée A; Biasini, Ghislaine G; Grozdea, Jean J; Fournier, Didier D

2002-01-01

In humans, there are four alkaline phosphatases, and each form exhibits a characteristic pattern of tissue distribution. The availability of an easy method to reveal their activity has resulted in large amount of data reporting correlations between variations in activity and illnesses. For example, alkaline phosphatase from neutrophils of mothers pregnant with a trisomy 21 fetus (Down's syndrome) displays significant differences both in its biochemical and immunological properties, and in its affinity for some specific inhibitors. To analyse these differences, the biochemical characteristics of two isozymes (non specific and placental alkaline phosphatases) were expressed in baculovirus infected cells. Comparative analysis of the two proteins allowed us to estimate the kinetic constants of denaturation and sensitivity to two inhibitors (L-p-bromotetramisole and thiophosphate), allowing better discrimination between the two enzymes. These parameters were then used to estimate the ratio of the two isoenzymes in neutrophils of pregnant mothers with or without a trisomy 21 fetus. It appeared that the placental isozyme represented 13% of the total activity of neutrophils of non pregnant women. This proportion did not significantly increase with normal pregnancy. By contrast, in pregnancies with trisomy 21 fetus, the proportion reached 60-80% of activity. Over-expression of the placental isozyme compared with the tissue-nonspecific form in neutrophils of mother with a trisomy 21 fetus may explain why the characteristics of the alkaline phosphatase in these cells is different from normal. Application of this knowledge could improve the potential of using alkaline phosphatase measurements to screen for Down's syndrome.

Kinetic comparison of tissue non-specific and placental human alkaline phosphatases expressed in baculovirus infected cells: application to screening for Down's syndrome

Science.gov (United States)

Denier, Colette C; Brisson-Lougarre, Andrée A; Biasini, Ghislaine G; Grozdea, Jean J; Fournier, Didier D

2002-01-01

Background In humans, there are four alkaline phosphatases, and each form exibits a characteristic pattern of tissue distribution. The availability of an easy method to reveal their activity has resulted in large amount of data reporting correlations between variations in activity and illnesses. For example, alkaline phosphatase from neutrophils of mothers pregnent with a trisomy 21 fetus (Down's syndrome) displays significant differences both in its biochemical and immunological properties, and in its affinity for some specific inhibitors. Results To analyse these differences, the biochemical characteristics of two isozymes (non specific and placental alkaline phosphatases) were expressed in baculovirus infected cells. Comparative analysis of the two proteins allowed us to estimate the kinetic constants of denaturation and sensitivity to two inhibitors (L-p-bromotetramisole and thiophosphate), allowing better discrimination between the two enzymes. These parameters were then used to estimate the ratio of the two isoenzymes in neutrophils of pregnant mothers with or without a trisomy 21 fetus. It appeared that the placental isozyme represented 13% of the total activity of neutrophils of non pregnant women. This proportion did not significantly increase with normal pregnancy. By contrast, in pregnancies with trisomy 21 fetus, the proportion reached 60–80% of activity. Conclusion Over-expression of the placental isozyme compared with the tissue-nonspecific form in neutrophils of mother with a trisomy 21 fetus may explain why the characteristics of the alkaline phosphatase in these cells is different from normal. Application of this knowledge could improve the potential of using alkaline phosphatase measurements to screen for Down's syndrome. PMID:11818032

Kinetic comparison of tissue non-specific and placental human alkaline phosphatases expressed in baculovirus infected cells: application to screening for Down's syndrome

Directory of Open Access Journals (Sweden)

Grozdea Jean J

2002-01-01

Full Text Available Abstract Background In humans, there are four alkaline phosphatases, and each form exibits a characteristic pattern of tissue distribution. The availability of an easy method to reveal their activity has resulted in large amount of data reporting correlations between variations in activity and illnesses. For example, alkaline phosphatase from neutrophils of mothers pregnent with a trisomy 21 fetus (Down's syndrome displays significant differences both in its biochemical and immunological properties, and in its affinity for some specific inhibitors. Results To analyse these differences, the biochemical characteristics of two isozymes (non specific and placental alkaline phosphatases were expressed in baculovirus infected cells. Comparative analysis of the two proteins allowed us to estimate the kinetic constants of denaturation and sensitivity to two inhibitors (L-p-bromotetramisole and thiophosphate, allowing better discrimination between the two enzymes. These parameters were then used to estimate the ratio of the two isoenzymes in neutrophils of pregnant mothers with or without a trisomy 21 fetus. It appeared that the placental isozyme represented 13% of the total activity of neutrophils of non pregnant women. This proportion did not significantly increase with normal pregnancy. By contrast, in pregnancies with trisomy 21 fetus, the proportion reached 60–80% of activity. Conclusion Over-expression of the placental isozyme compared with the tissue-nonspecific form in neutrophils of mother with a trisomy 21 fetus may explain why the characteristics of the alkaline phosphatase in these cells is different from normal. Application of this knowledge could improve the potential of using alkaline phosphatase measurements to screen for Down's syndrome.

Side Effects of Nitrification Inhibitors on Non Target Microbial Processes in Soils

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Johannes Carl Gottlieb Ottow

2011-01-01

Full Text Available Agricultural chemicals have been used extensively in modern agriculture and toxicological studies suggest a great potential for inducing undesirable effects on non target organisms. A model experiment was conducted in order to determine side effects of three nitrification inhibitors (NIs, 3,4dimethylpyrazolephosphate = DMPP, 4-Chlor-methylpyrazole phosphate = ClMPP and dicyandiamide = DCD on non target microbial processes in soils. Side effects and dose response curve of three NIs were quantified under laboratory conditions using silty clay, loam and a sandy soils. Dehydrogenase, dimethylsulfoxide reductase as well as nitrogenase activity (NA and potential denitrification capacity were measured as common and specific non target microbial processes. The influence of 5-1000 times the base concentration, dose response curves were examined, and no observable effect level = NOEL, as well as effective dose ED10 and ED50 (10% and 50% inhibition were calculated. The NOEL for microbial non target processes were about 30–70 times higher than base concentration in all investigated soils. The potential denitrification capacity revealed to be the most sensitive parameter. ClMPP exhibited the strongest influence on the non target microbial processes in the three soils. The NOEL, ED10 and ED50 values were higher in clay than in loamy or sandy soil. The NIs was the most effective in sandy soils.

Vasoactive systems in L-NAME hypertension: the role of inducible nitric oxide synthase

Czech Academy of Sciences Publication Activity Database

Pecháňová, Olga; Dobešová, Zdenka; Čejka, Jakub; Kuneš, Jaroslav; Zicha, Josef

2004-01-01

Roč. 22, č. 1 (2004), s. 167-173 ISSN 0263-6352 R&D Projects: GA ČR GA305/03/0769; GA MŠk LN00A069 Grant - others:VEGA(SK) 2/3185/23; SAV(SK) APVT51-017902 Institutional research plan: CEZ:AV0Z5011922 Keywords : nitric oxide synthase * L-NAME hypertension * aminoguanidine Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.871, year: 2004

Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials.

Science.gov (United States)

Khunger, Monica; Rakshit, Sagar; Pasupuleti, Vinay; Hernandez, Adrian V; Mazzone, Peter; Stevenson, James; Pennell, Nathan A; Velcheti, Vamsidhar

2017-08-01

Programmed death 1 (PD-1) programmed death-ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune-mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD-1 and PD-L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian-Laird random effects models. We compared incidences between PD-1 and PD-L1 inhibitors and between treatment naive and previously treated patients. Nineteen trials (12 with PD-1 inhibitors [n = 3,232] and 7 with PD-L1 inhibitors [n = 1,806]) were identified. PD-1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD-L1 inhibitors (3.6%; 95% CI, 2.4%-4.9% vs 1.3%; 95% CI, 0.8%-1.9%, respectively; P = .001). PD-1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%-1.7% vs 0.4%; 95% CI, 0%-0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%-6.3% vs 2.8%; 95% CI, 1.7%- 4%; P = .03). There was a higher incidence of pneumonitis with use of PD-1 inhibitors compared with PD-L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

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Hongbiao Huang

Full Text Available Combinations of proteasome inhibitors and histone deacetylases (HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like activity assay. Here we report that (i the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii the combination also synergistically inhibits tumor growth in vivo; (iii two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.

Science.gov (United States)

Tang, Chunlei; Zhu, Xiaoyun; Huang, Dandan; Zan, Xin; Yang, Baowei; Li, Ying; Du, Xiaoyong; Qian, Hai; Huang, Wenlong

2012-06-01

Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

A screen for kinase inhibitors identifies antimicrobial imidazopyridine aminofurazans as specific inhibitors of the Listeria monocytogenes PASTA kinase PrkA.

Science.gov (United States)

Schaenzer, Adam J; Wlodarchak, Nathan; Drewry, David H; Zuercher, William J; Rose, Warren E; Striker, Rob; Sauer, John-Demian

2017-10-13

Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial P enicillin-binding-protein A nd S erine/ T hreonine kinase- A ssociated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to β-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to β-lactam therapy. Despite this interest, only limited progress has been made in identifying functional inhibitors of the PASTA kinases that have both activity against the intact microbe and high kinase specificity. Here, we report the results of a small-molecule screen that identified GSK690693, an imidazopyridine aminofurazan-type kinase inhibitor that increases the sensitivity of the intracellular pathogen Listeria monocytogenes to various β-lactams by inhibiting the PASTA kinase PrkA. GSK690693 potently inhibited PrkA kinase activity biochemically and exhibited significant selectivity for PrkA relative to the Staphylococcus aureus PASTA kinase Stk1. Furthermore, other imidazopyridine aminofurazans could effectively inhibit PrkA and potentiate β-lactam antibiotic activity to varying degrees. The presence of the 2-methyl-3-butyn-2-ol (alkynol) moiety was important for both biochemical and antimicrobial activity. Finally, mutagenesis studies demonstrated residues in the back pocket of the active site are important for GSK690693 selectivity. These data suggest that targeted screens can successfully identify PASTA kinase inhibitors with both biochemical and antimicrobial specificity. Moreover, the imidazopyridine aminofurazans represent a family of PASTA kinase inhibitors that have the potential to be optimized for selective PASTA kinase inhibition.

l-Citrulline ameliorates cerebral blood flow during cortical spreading depression in rats: Involvement of nitric oxide- and prostanoids-mediated pathway

Directory of Open Access Journals (Sweden)

Yuki Kurauchi

2017-03-01

Full Text Available l-Citrulline is a potent precursor of l-arginine, and exerts beneficial effect on cardiovascular system via nitric oxide (NO production. Migraine is one of the most popular neurovascular disorder, and imbalance of cerebral blood flow (CBF observed in cortical spreading depression (CSD contributes to the mechanism of migraine aura. Here, we investigated the effect of l-citrulline on cardiovascular changes to KCl-induced CSD. in rats. Intravenous injection of l-citrulline prevented the decrease in CBF, monitored by laser Doppler flowmetry, without affecting mean arterial pressure and heart rate during CSD. Moreover, l-citrulline attenuated propagation velocity of CSD induced by KCl. The effect of l-citrulline on CBF change was prevented by l-NAME, an inhibitor of NO synthase, but not by indomethacin, an inhibitor of cyclooxygenase. On the other hand, attenuation effect of l-citrulline on CSD propagation velocity was prevented not only by l-NAME but also by indomethacin. In addition, propagation velocity of CSD was attenuated by intravenous injection of NOR3, a NO donor, which was diminished by ODQ, an inhibitor of soluble guanylyl cyclase. These results suggest that NO/cyclic GMP- and prostanoids-mediated pathway differently contribute to the effect of l-citrulline on the maintenance of CBF.

Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity.

LENUS (Irish Health Repository)

Seymour, C B

2003-11-17

l-Deprenyl (R-(-)-deprenyl, selegiline) is an inhibitor of monoamine oxidase-B (MAO-B) that is known to protect nerve cells from a variety of chemical and physical insults. As apoptosis is a common mechanism of radiation-induced cell death, the effect of l-deprenyl on the survival of cultured cells and tissue explants was studied following exposure to gamma radiation. The results obtained were compared with the effects of the less-selective MAO-B inhibitor pargyline and the MAO-A inhibitor clorgyline. l-Deprenyl at a concentration of 10(-9) M protected the nontumorigenic cell line (HaCaT) and normal human urothelial explants from the effects of cobalt-60 gamma radiation, but did not protect tumorigenic human cell lines HaCaT-ras, HPV-transfected human keratinocytes (HPV-G cells), or PC3. Human bladder carcinoma explants were not protected. Clorgyline showed a smaller protective effect of normal cells, whereas pargyline had no effect. Radiation-induced delayed effects (genomic instability measured as delayed cell death) were prevented in normal cells by l-deprenyl but, interestingly, deprenyl appeared to increase the amount of delayed death in the tumorigenic cell lines. Studies using l-deprenyl prior to the exposure of nonmalignant cells to cisplatin showed that cell death due to this agent was also reduced. Treatment of cultures of nontumorigenic cells with l-deprenyl or clorgyline significantly increased the levels of the protein Bcl-2 following irradiation, but there was no such effect on the already-elevated levels of this protein in the tumour samples. Since the Bcl-2 has been shown to be an inhibitor of apoptosis or programmed cell death, this would imply that the protective effects of l-deprenyl and clorgyline involve activation of antiapoptotic pathways within the normal cell. This hypothesis is supported by data showing reduced levels of apoptosis in HaCAT cells and in normal bladder explant cultures following treatment with l-deprenyl.

Covalent cross-linking of insulin-like growth factor-1 to a specific inhibitor from human serum

International Nuclear Information System (INIS)

Ooi, G.T.; Herington, A.C.

1986-01-01

Previous studies have shown that a specific inhibitor of insulin-like growth factor (IGF) action in vitro can be isolated from normal human serum and subsequently partially purified on an IGF-affinity column. The ability of the inhibitor to bind the IGFs has now been confirmed directly using covalent cross-linking techniques. When 125 I-IGF-1 was cross-linked to inhibitor using disuccinimidyl suberate, five specifically labelled bands were seen on SDS-PAGE and autoradiography. Two bands (MW 21.5 K and 25.5 K) were intensely labelled, while the remaining three (MW 37 K, 34 K and 18 K) appeared as minor bands only. Inhibitor bioactivity, following further analysis by hydrophobic interaction chromatography or Con A-Sepharose affinity chromatography, was always associated with the presence of the 21.5 K and/or 25.5 K bands

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

Science.gov (United States)

Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

2015-01-01

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.

Non-specific immunization against parasites

International Nuclear Information System (INIS)

Cox, F.E.G.

1981-01-01

Non-specific resistance to tumours can be induced by pretreating animals with micro-organisms, microbial extracts or various synthetic substances. Mycobacterium bovis, Corynebacterium parvum and a number of other micro-organisms also protect mice against rodent piroplasms and there is evidence that they are also protective against other parasites including Schistosoma mansoni. The actual mechanisms of non-specific immunity are still unclear but it is influenced by both the genetic make-up of the host and the nature of the parasite. Non-specific immunization may be a possible alternative to specific immunization and may avoid many of the potential immunopathological changes induced during parasite infections. Irradiated vaccines (Dictyocaulus viviparus, schistomiasis) are mentioned marginally only

Task-specific ionic liquid as a new green inhibitor of mild steel corrosion

Energy Technology Data Exchange (ETDEWEB)

Kowsari, E., E-mail: kowsarie@aut.ac.ir [Department of Chemistry, Amirkabir University of Technology, No. 424, Hafez Avenue, 1591634311 Tehran (Iran, Islamic Republic of); Payami, M. [Department of Chemistry, Amirkabir University of Technology, No. 424, Hafez Avenue, 1591634311 Tehran (Iran, Islamic Republic of); Amini, R.; Ramezanzadeh, B. [Department of Surface Coating and Corrosion, Institute for Color Science and Technology (ICST), PO 16765-654 Tehran (Iran, Islamic Republic of); Javanbakht, M. [Department of Chemistry, Amirkabir University of Technology, No. 424, Hafez Avenue, 1591634311 Tehran (Iran, Islamic Republic of)

2014-01-15

The corrosion inhibition effects of an imidazolium-based task specific ionic liquid (TSIL) were investigated on a low carbon steel in 1 M HCl solution. Samples were exposed to 1 M HCl solution without and with different concentrations of TSIL. Weight loss measurements, potentiodynamic polarization test, electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM), atomic force microscope (AFM) and contact angle measurements were utilized to investigate the inhibition effects of TSIL. The results obtained from the polarization studies revealed that both the anodic and cathodic branches slopes affected in the presence of TSIL. It was shown that TSIL behaved as a mixed type inhibitor with a dominant effect on the anodic reaction rate depression. It was shown that the increase in polarization resistance and the decrease in corrosion current density were more pronounced using 100 mg/L of TSIL after 2 h immersion time. It was also shown that the adsorption of TSIL followed a Langmuir adsorption isotherm.

Brand name and generic proton pump inhibitor prescriptions in the United States: insights from the national ambulatory medical care survey (2006-2010).

Science.gov (United States)

Gawron, Andrew J; Feinglass, Joseph; Pandolfino, John E; Tan, Bruce K; Bove, Michiel J; Shintani-Smith, Stephanie

2015-01-01

Introduction. Proton pump inhibitors (PPI) are one of the most commonly prescribed medication classes with similar efficacy between brand name and generic PPI formulations. Aims. We determined demographic, clinical, and practice characteristics associated with brand name PPI prescriptions at ambulatory care visits in the United States. Methods. Observational cross sectional analysis using the National Ambulatory Medical Care Survey (NAMCS) of all adult (≥18 yrs of age) ambulatory care visits from 2006 to 2010. PPI prescriptions were identified by using the drug entry code as brand name only or generic available formulations. Descriptive statistics were reported in terms of unweighted patient visits and proportions of encounters with brand name PPI prescriptions. Global chi-square tests were used to compare visits with brand name PPI prescriptions versus generic PPI prescriptions for each measure. Poisson regression was used to determine the incidence rate ratio (IRR) for generic versus brand PPI prescribing. Results. A PPI was prescribed at 269.7 million adult ambulatory visits, based on 9,677 unweighted visits, of which 53% were brand name only prescriptions. In 2006, 76.0% of all PPI prescriptions had a brand name only formulation compared to 31.6% of PPI prescriptions in 2010. Visits by patients aged 25-44 years had the greatest proportion of brand name PPI formulations (57.9%). Academic medical centers and physician-owned practices had the greatest proportion of visits with brand name PPI prescriptions (58.9% and 55.6% of visits with a PPI prescription, resp.). There were no significant differences in terms of median income, patient insurance type, or metropolitan status when comparing the proportion of visits with brand name versus generic PPI prescriptions. Poisson regression results showed that practice ownership type was most strongly associated with the likelihood of receiving a brand name PPI over the entire study period. Compared to HMO visits

Potential role for epidermal growth factor receptor inhibitors in combined-modality therapy for non-small-cell lung cancer

International Nuclear Information System (INIS)

Kim, Dong Wook; Choy, Hak

2004-01-01

There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology/oncology. The epidermal growth factor receptor (EGFR) has been a molecular target of significant interest and investigation, and preclinical and clinical studies support a role for targeted therapy in a variety of cancers, including non-small-cell lung cancer (NSCLC) via compounds that specifically inhibit EGFR. ZD1839, IMC-C225, and OSI-774 are the most clinically developed of these compounds. Interestingly, preclinical studies have demonstrated that EGFR inhibitors may have radiation-sensitizing properties, as well as increased cytotoxic activity in combination with chemotherapeutic agents, suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of Stage III NSCLC. Therefore, clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of EGFR inhibitors to the standard combined-modality regimen (chemotherapy/radiation therapy ± surgery) for Stage III NSCLC. This article reviews preclinical and clinical data supporting the role for EGFR inhibitors alone or in combination with chemotherapy/radiation therapy for locally advanced NSCLC. Also, it will provide an overview of ongoing and proposed clinical studies investigating the potential role for EGFR inhibitors in Stage III NSCLC

Engineering the substrate and inhibitor specificities of human coagulation Factor VIIa

DEFF Research Database (Denmark)

Larsen, Katrine S; Østergaard, Henrik; Bjelke, Jais R

2007-01-01

The remarkably high specificity of the coagulation proteases towards macromolecular substrates is provided by numerous interactions involving the catalytic groove and remote exosites. For FVIIa [activated FVII (Factor VII)], the principal initiator of coagulation via the extrinsic pathway, several...... for FVIIa by marked changes in primary substrate specificity and decreased rates of antithrombin III inhibition. Interestingly, these changes do not necessarily coincide with an altered ability to activate Factor X, demonstrating that inhibitor and macromolecular substrate selectivity may be engineered...

Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression

Directory of Open Access Journals (Sweden)

Putcharawipa Maneesai

2016-02-01

Full Text Available This study examined the effect of Carthamus tinctorius (CT extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO bioavailability, oxidative stress and renin-angiotensin system (RAS in Nω-Nitro-l-arginine methyl ester (l-NAME-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day: captopril (5 mg/kg/day or CT extract (300 mg/kg/day plus captopril (5 mg/kg/day for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS.

[Kinetic study on inhibition effects of dansyl-L-phenylalanine and L-phenylalanine on calf intestinal alkaline phosphatase].

Science.gov (United States)

Li, Li-Na; Wu, Yu-Qing; Buchet, René

2009-10-01

To evaluate the inhibition effect of dansyl-L-phenylalanine on calf intestinal alkaline phosphatase (CIAP), UV-Vis spectrophotometric method was employed. It was found that dansyl-L-phenylalanine can selectively inhibit CIAP. The kinetic inhibition processes of dansyl-L-phenylalanine and L-phenylalanine were comparatively studied. The authors' finding elucidates that at the optimized alkaline pH of alkaline phosphatase (pH 10.4) and 37 degrees C, dansyl-L-phenylalanine can inhibit alkaline phosphatase activity of CIAP efficiently and specifically, similar as L-phenylalanine. Both inhibition types were uncompetitive inhibition resulting from the double reciprocal curve fitting of upsilon versus substrate concentrations, and the inhibition constants Ki of both inhibitors were determined to be 2.3 and 1.1 mmol L(-1) respectively, both of which were at millimolar level. The investigation of the inhibition effect of dansyl modified L-phenylalanine on calf intestinal alkaline phosphatase not only helped get insight into the detailed inhibition mechanism of L-phenylalanine on tissue specific alkaline phosphatase, such as in the case of intestinal alkaline phosphatase, but also provided the possibility to employ fluorescence spectroscopy by labeling the specific inhibitors of alkaline phosphatase with chromophoric groups.

Effects of l-tryptophan on the growth, intestinal enzyme activities and non-specific immune response of sea cucumber (Apostichopus japonicus Selenka) exposed to crowding stress.

Science.gov (United States)

Zhang, Endong; Dong, Shuanglin; Wang, Fang; Tian, Xiangli; Gao, Qinfeng

2018-04-01

In order to reveal the effects of l-tryptophan (Trp) on the physiology and immune response of sea cucumber (Apostichopus japonicus Selenka) exposed to crowding stress, four density groups of sea cucumbers (i.e. 4, 8, 16 and 32 individuals per 40 L water, represented as L, ML, MH and H) were fed with diets containing 0, 1, 3 and 5% l-tryptophan respectively for 75 days. The results showed that the specific growth rates (SGR) of the sea cucumber fed with diet with 3% Trp (L, 2.1; ML, 1.76; MH, 1.2; H, 0.7) were significantly higher than those fed with basal diet without Trp supplementation (P sea cucumber fed diets with Trp (3%) had significantly higher phagocytic activities (0.28 OD540/10 6  cells, H) in coelomic fluid and respiratory burst activities (0.105 OD630/10 6  cells, MH) (P < .05). The results suggested that Trp cannot improve superoxide dismutase (SOD) activity at L, ML and MH densities. The alkaline phosphatase activity (AKP) significantly decreased at H stress density. Under the experimental conditions, the present results confirmed that a diet supplemented with 3% Trp was able to enhance intestinal enzyme activities, non-specific immune response and higher growth performance of A. japonicus. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pre-equilibrium competitive library screening for tuning inhibitor association rate and specificity toward serine proteases.

Science.gov (United States)

Cohen, Itay; Naftaly, Si; Ben-Zeev, Efrat; Hockla, Alexandra; Radisky, Evette S; Papo, Niv

2018-04-16

High structural and sequence similarity within protein families can pose significant challenges to the development of selective inhibitors, especially toward proteolytic enzymes. Such enzymes usually belong to large families of closely similar proteases and may also hydrolyze, with different rates, protein- or peptide-based inhibitors. To address this challenge, we employed a combinatorial yeast surface display library approach complemented with a novel pre-equilibrium, competitive screening strategy for facile assessment of the effects of multiple mutations on inhibitor association rates and binding specificity. As a proof of principle for this combined approach, we utilized this strategy to alter inhibitor/protease association rates and to tailor the selectivity of the amyloid β-protein precursor Kunitz protease inhibitor domain (APPI) for inhibition of the oncogenic protease mesotrypsin, in the presence of three competing serine proteases, anionic trypsin, cationic trypsin and kallikrein-6. We generated a variant, designated APPI P13W/M17G/I18F/F34V , with up to 30-fold greater specificity relative to the parental APPI M17G/I18F/F34V protein, and 6500- to 230 000-fold improved specificity relative to the wild-type APPI protein in the presence of the other proteases tested. A series of molecular docking simulations suggested a mechanism of interaction that supported the biochemical results. These simulations predicted that the selectivity and specificity are affected by the interaction of the mutated APPI residues with nonconserved enzyme residues located in or near the binding site. Our strategy will facilitate a better understanding of the binding landscape of multispecific proteins and will pave the way for design of new drugs and diagnostic tools targeting proteases and other proteins. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-Based Virtual Screening

Directory of Open Access Journals (Sweden)

Qianqian Wang

2018-03-01

Full Text Available Protein arginine methyltransferase 5 (PRMT5 is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors. In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied. MTT results showed that compound T1551 decreased cell viability of A549 and H460 non-small cell lung cancer cell lines. By inhibiting the methyltransferase activity of PRMT5, T1551 reduced the global level of H4R3 symmetric dimethylation (H4R3me2s. T1551 also downregulated the expression of oncogene FGFR3 and eIF4E, and disturbed the activation of related PI3K/AKT/mTOR and ERK signaling in A549 cell. Finally, we investigated the conformational spaces and identified collective motions important for description of T1551/PRMT5 complex by using molecular dynamics simulation and normal mode analysis methods. This study provides a novel non-SAM-competitive hit compound for developing small molecules targeting PRMT5 in non-small cell lung cancer.

Impact of angiotensin and endothelin converting enzymes and related bradykinin on renal functions in L-NAME hypertensive rats

Science.gov (United States)

Omar, Ali Zainal; Maulood, Ismail M.

2017-09-01

The renin-angiotensin system (RAS), one of the most important hormonal systems, controls the kidney functions by regulating fluid volume, and electrolyte balance. The current study included the effects of kinin-kallikrein system (KKS) and its interaction with both angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE) on some of kidney function test parameters. In the present experiment, rats were divided into six groups, the first group was infused with normal saline, the second group was L-NG-Nitroarginine methyl ester (L-NAME) treated rats, third group was bradykinin (BK), forth group was captopril (ACEi), fifth group was phosphoramidon (ECEi), sixth group was a combination of BK with phosphoramidon. L-NAME was intravenously infused for one hour to develop systematic hypertension in male rats. After one hour of infusion, the results showed that L-NAME significantly increased serum creatinine. While, it decreased glomerular filtration rate (GFR), and K+ excretion rate. Moreover, BK increased packed cell volume PCV%, serum creatinine and K+ ion concentration. While, it reduced GFR, serum Ca+2 ion concentration, K+ and Na+ excretion rates. On the other hand, captopril infusion showed its effect by reduction in GFR, serum Ca+2 ion and electrolyte excretion rates. Phosphoramidon an ECEi dramatically reduced serum Ca+2 ion, but it increased pH, GFR and Ca+2 excretion rate. The results suggested that BK and Captopril each alone severely reduces GFR value. Interestingly, inhibition of ET-1 production via phosphoramidon could markedly elevate GFR values.

Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability.

Science.gov (United States)

Zwicker, Jeffery D; Diaz, Nicolas A; Guerra, Alfredo J; Kirchhoff, Paul D; Wen, Bo; Sun, Duxin; Carruthers, Vern B; Larsen, Scott D

2018-06-01

The neurotropic protozoan Toxoplasma gondii is the second leading cause of death due to foodborne illness in the US, and has been designated as one of five neglected parasitic infections by the Center for Disease Control and Prevention. Currently, no treatment options exist for the chronic dormant-phase Toxoplasma infection in the central nervous system (CNS). T. gondii cathepsin L (TgCPL) has recently been implicated as a novel viable target for the treatment of chronic toxoplasmosis. In this study, we report the first body of SAR work aimed at developing potent inhibitors of TgCPL with selectivity vs the human cathepsin L. Starting from a known inhibitor of human cathepsin L, and guided by structure-based design, we were able to modulate the selectivity for Toxoplasma vs human CPL by nearly 50-fold while modifying physiochemical properties to be more favorable for metabolic stability and CNS penetrance. The overall potency of our inhibitors towards TgCPL was improved from 2 μM to as low as 110 nM and we successfully demonstrated that an optimized analog 18b is capable of crossing the BBB (0.5 brain/plasma). This work is an important first step toward development of a CNS-penetrant probe to validate TgCPL as a feasible target for the treatment of chronic toxoplasmosis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Attitudes of physicians and pharmacists towards International Non-proprietary Name prescribing in Belgium.

Science.gov (United States)

Van Bever, Elien; Elseviers, Monique; Plovie, Marijke; Vandeputte, Lieselot; Van Bortel, Luc; Vander Stichele, Robert

2015-03-01

International Non-proprietary Name (INN) prescribing is the use of the name of the active ingredient(s) instead of the brand name for prescribing. In Belgium, INN prescribing began in 2005 and a major policy change occurred in 2012. The aim was to explore the opinions of Dutch-speaking general practitioners (GPs) and pharmacists. An electronic questionnaire with 39 five-point Likert scale statements and one open question was administered in 2013. Multivariate analysis was performed with multiple linear regression on a sum score for benefit statements and for drawback statements. Answers to the open question were qualitatively analysed. We received 745 valid responses with a representable sample for both subgroups. Participants perceived the motives to introduce INN prescribing as purely economic (to reduce pharmaceutical expenditures for the government and the patient). Participants accepted the concept of INN prescribing, but 88% stressed the importance of guaranteed treatment continuity, especially in older, chronic patients, to prevent patient confusion, medication non-adherence and erroneous drug use. In conclusion, the current way in which INN prescribing is applied in Belgium leads to many concerns among primary health professionals about patient confusion and medication adherence. Slightly adapting the current concept of INN prescribing to these concerns can turn INN prescribing into one of the major policies in Belgium to reduce pharmaceutical expenditures and to stimulate rational drug prescribing. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

DOT1L inhibitor improves early development of porcine somatic cell nuclear transfer embryos

DEFF Research Database (Denmark)

Tao, Jia; Zhang, Yu; Zuo, Xiaoyuan

2017-01-01

Incomplete epigenetic reprogramming of the genome of donor cells causes poor early and full-term developmental efficiency of somatic cell nuclear transfer (SCNT) embryos. Previous research indicate that inhibition of the histone H3 K79 methyltransferase DOT1L, using a selective pharmacological...... inhibitor EPZ004777 (EPZ), significantly improved reprogramming efficiency during the generation of mouse induced pluripotent stem cells. However, the roles of DOT1L in porcine nuclear transfer-mediated cellular reprogramming are not yet known. Here we showed that DOT1L inhibition via 0.5 nM EPZ treatment...

5α-Reductase inhibitor is less effective in men with small prostate volume and low serum prostatic specific antigen level.

Science.gov (United States)

Lin, Victor C; Liao, Chun-Hou; Wang, Chung-Cheng; Kuo, Hann-Chorng

2015-09-01

Large total prostate volumes (TPVs) or high serum prostate-specific antigen (PSA) levels indicate high-risk clinical progression of benign prostatic hyperplasia. This prospective study investigated the treatment outcome of combined 5α-reductase inhibitor and α-blocker in patients with and without large TPVs or high PSA levels. Men aged ≥ 45 years with International Prostate Symptom scores (IPSS) ≥ 8, TPV ≥ 20 mL, and maximum flow rate ≤ 15 mL/s received a combination therapy (dutasteride plus doxaben) for 2 years. Patients with baseline PSA ≥ 4 ng/mL underwent prostatic biopsy for excluding malignancy. The changes in the parameters from baseline to 24 months after combination therapy were compared in those with and without TPV ≥ 40 mL or PSA levels ≥ 1.5 ng/mL. A total of 285 patients (mean age 72 ± 9 years) completed the study. Combination therapy resulted in significant continuous improvement in IPSS, quality of life index, maximum flow rate, and postvoid residual (all p < 0.0001) regardless of baseline TPV or PSA levels. However, only patients with baseline TPV ≥ 40 mL had significant improvements in IPSS-storage subscore, voided volume, reduction in TPV, transitional zone index, and PSA levels. In addition, patients with baseline TPV < 40 mL and PSA < 1.5 ng/mL had neither a reduction in TPV nor a decrease in serum PSA level. A high TPV indicates more outlet resistance, whereas elevated serum PSA level reflects glandular proliferation. Thus, patients with TPV<40 mL and low PSA levels has less benefit from 5α-reductase inhibitor therapy. The therapeutic effect of combined treatment may arise mainly from the α-blocker in these patients. Copyright © 2013. Published by Elsevier B.V.

Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide.

Science.gov (United States)

Mousavi, Seyyedeh Elaheh; Saberi, Pegah; Ghasemkhani, Naeemeh; Fakhraei, Nahid; Mokhtari, Rezvan; Dehpour, Ahmad Reza

2018-01-01

Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, possesses antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory properties. The aim of the present study was to investigate the effect of licofelone on lipopolysaccharide (LPS)-induced depression in a mouse model and also a possible role for nitric oxide (NO). To elucidate the role of NO on this effect of licofelone (5 and 20 mg/kg, i.p.), L-NAME, a non-specific NO synthase (NOS) inhibitor; aminoguanidine (AG), a specific inducible NOS (iNOS) inhibitor; 7-nitroindazole (7-NI) a preferential neuronal NOS inhibitor (nNOS) and; L-arginine (L-Arg), as a NO donor, were used. The animal's behaviors were evaluated employing forced swimming test (FST), tail suspension test (TST) and open field test (OFT). LPS (0.83 mg/kg, i.p.) induced depressive-like behavior increasing immobility time in FST and TST. Conversely, licofelone (20 mg/kg i.p.) reversed the depressive effect of LPS and lowered the immobility time in FST and TST. On the other hand, pretreatment with L-Arg also reversed the antidepressant-like effect of licofelone (20 mg/kg) in FST and TST. On the other hand, L-NAME (10 and 30 mg/kg), AG (50 and 100 mg/kg) and 7-NI (60 mg/kg) could potentiate licofelone (5 mg/kg) and lowered the immobility duration. NO down-regulation possibly through iNOS and nNOS inhibition may involve in the antidepressant property of licofelone. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Mechanism for the decrease in the FIP1L1-PDGFRalpha protein level in EoL-1 cells by histone deacetylase inhibitors.

Science.gov (United States)

Ishihara, Kenji; Kaneko, Motoko; Kitamura, Hajime; Takahashi, Aki; Hong, Jang Ja; Seyama, Toshio; Iida, Koji; Wada, Hiroshi; Hirasawa, Noriyasu; Ohuchi, Kazuo

2008-01-01

Acetylation and deacetylation of proteins occur in cells in response to various stimuli, and are reversibly catalyzed by histone acetyltransferase and histone deacetylase (HDAC), respectively. EoL-1 cells have an FIP1L1-PDGFRA fusion gene that causes transformation of eosinophilic precursor cells into leukemia cells. The HDAC inhibitors apicidin and n-butyrate suppress the proliferation of EoL-1 cells and induce differentiation into eosinophils by a decrease in the protein level of FIP1L1-PDGFRalpha without affecting the mRNA level for FIP1L1-PDGFRA. In this study, we analyzed the mechanism by which the protein level of FIP1L1-PDGFRalpha is decreased by apicidin and n-butyrate. EoL-1 cells were incubated in the presence of the HDAC inhibitors apicidin, trichostatin A or n-butyrate. The protein levels of FIP1L1-PDGFRalpha and phosphorylated eIF-2alpha were determined by Western blotting. Actinomycin D and cycloheximide were used to block RNA synthesis and protein synthesis, respectively, in the chasing experiment of the amount of FIP1L1-PDGFRalpha protein. When apicidin- and n-butyrate-treated EoL-1 cells were incubated in the presence of actinomycin D, the decrease in the protein level of FIP1L1-PDGFRalpha was significantly enhanced when compared with controls. In contrast, the protein levels were not changed by cycloheximide among these groups. Apicidin and n-butyrate induced the continuous phosphorylation of eIF-2alpha for up to 8 days. The decrease in the level of FIP1L1-PDGFRalpha protein by continuous inhibition of HDAC may be due to the decrease in the translation rate of FIP1L1-PDGFRA. Copyright 2008 S. Karger AG, Basel.

[Specific inhibitors of cyclooxygenase-2 (COX-2): current knowledge and perspectives].

Science.gov (United States)

Rioda, W T; Nervetti, A

2001-01-01

The Authors summarize the current knowledge on a new class of nonsteroidal anti-inflammatory drugs (NSAIDs), the coxib (celecoxib and rofecoxib), in the treatment of rheumatic diseases. Celecoxib and rofecoxib are selective cyclooxygenase-2 (COX-2) inhibitors which possess the same anti-inflammatory and analgesic activities, but a better gastric tolerability compared to the non-selective COX-1 and COX-2 inhibitors. The Authors also report other possible therapeutic effects of these NSADIs as evidenced by the more recent data of the literature. Celecoxib seems to reduce the incidence of new polyps in patients with familial adenomatous polyposis. It has been suggested the use of celecoxib as a protective drug against the development of colorectal cancer. Other (neoplastic) or pre-neoplastic conditions, such as bladder dysplasia, Barret esophagus, attinic keratosis and Alzheimer's disease seem to have benefit from this class of drugs.

Identification of tyrosinase specific inhibitors from Xanthium strumarium fruit extract using ultrafiltration-high performance liquid chromatography.

Science.gov (United States)

Wang, Zhiqiang; Hwang, Seung Hwan; Huang, Bo; Lim, Soon Sung

2015-10-01

In this study, a strategy based on ultrafiltration-high performance liquid chromatography coupled with diode array detection (UF-HPLC-DAD) was proposed for screening tyrosinase specific inhibitors in Xanthii fructus. The false negatives were distinguished by optimizing the UF-HPLC-DAD parameters to reduce the background noise; the false positives were distinguished by introducing a blocked tyrosinase in the control group for comparison. To obtain the best blocker, the competitive experiments were performed using various known ligands. Using this strategy, three competitive inhibitors (protocatechuic acid; 3,5-di-O-caffeoylquinic acid; and 1,5-di-O-caffeoylquinic acid) and one mixed-type inhibitor (chlorogenic acid) were identified. These results were verified using tyrosinase inhibition assay, kinetic analysis, and structural simulation of the complex. Our experimental results suggest that the proposed strategy could be useful for high-throughput identification of tyrosinase specific inhibitors in natural products. Copyright © 2015 Elsevier B.V. All rights reserved.

Side Effects of Nitrification Inhibitors on Non Target Microbial Processes in Soils

OpenAIRE

Johannes Carl Gottlieb Ottow; Gero Benckiser; Ferisman Tindaon

2011-01-01

Agricultural chemicals have been used extensively in modern agriculture and toxicological studies suggest a great potential for inducing undesirable effects on non target organisms. A model experiment was conducted in order to determine side effects of three nitrification inhibitors (NIs, 3,4dimethylpyrazolephosphate = DMPP, 4-Chlormethylpyrazole phosphate = ClMPP and dicyandiamide = DCD) on non target microbial processes in soils. Side effects and dose response curve of three NIs were quanti...

Complete inactivation of HIV-1 using photo-labeled non-nucleoside reverse transcriptase inhibitors.

Science.gov (United States)

Rios, Adan; Quesada, Jorge; Anderson, Dallas; Goldstein, Allan; Fossum, Theresa; Colby-Germinario, Susan; Wainberg, Mark A

2011-01-01

We demonstrate that a photo-labeled derivative of the non-nucleoside reverse transcriptase inhibitor (NNRTI) dapivirine termed DAPY, when used together with exposure to ultraviolet light, was able to completely and irreversibly inactivate both HIV-1 RT activity as well as infectiousness in each of a T cell line and peripheral blood mononuclear cells. Control experiments using various concentrations of DAPY revealed that a combination of exposure to ultraviolet light together with use of the specific, high affinity photo-labeled compound was necessary for complete inactivation to occur. This method of HIV RT inactivation may have applicability toward preservation of an intact viral structure and warrants further investigation in regard to the potential of this approach to elicit a durable, broad protective immune response. Copyright © 2010 Elsevier B.V. All rights reserved.

Treinamento resistido controla a pressão arterial de ratos hipertensos induzidos por l-NAME

Directory of Open Access Journals (Sweden)

Ayslan Jorge Santos de Araujo

2013-04-01

Full Text Available FUNDAMENTO: A hipertensão arterial é uma síndrome multifatorial, crônica, causada tanto por fatores congênitos ou adquiridos. OBJETIVO: Avaliar os efeitos do treinamento físico resistido (TR sobre pressão arterial, reatividade e morfologia vascular de ratos hipertensos induzidos por L-NAME. MÉTODOS: Ratos Wistar machos (200-250 g foram divididos em 3 grupos: normotenso sedentário (NS, hipertenso sedentário (HS e hipertenso treinado (HT. A hipertensão foi induzida pela administração de L-NAME (40 mg/kg na água de beber por 4 semanas. A pressão arterial foi avaliada antes e após o TR. O TR foi realizado utilizando 50% de 1RM, em 3 séries de 10 repetições, 3 vezes por semana, durante quatro semanas. A reatividade vascular foi mensurada em artéria mesentérica superior por curvas concentração resposta ao nitroprussiato de sódio (NPS e fenilefrina (FEN. Além disso, foram realizadas análises histológicas e estereológicas. RESULTADOS: O TR inibiu o aumento das pressões arteriais média e diastólica. Foi observada uma redução significativa na resposta máxima e na potência da FEN entre os grupos HS e HT. A análise histológica evidenciou aspecto normal para as túnicas íntima, média e adventícia em todos os grupos. Não houve diferença significativa nas áreas do lúmen, da túnica média e total das artérias dos grupos HS e HT em relação ao NS. A razão parede/lúmen arterial do grupo HS apresentou diferença significativa em relação ao NS (p < 0,05, mas esta não foi diferente do HT. CONCLUSÕES: O TR foi capaz de prevenir a elevação da pressão arterial sob as condições deste estudo. Este controle parece envolver a regulação de mecanismo vasoconstritor e a manutenção do diâmetro luminal de ratos hipertensos induzidos por L-NAME.

Spectral L2/L1 norm: A new perspective for spectral kurtosis for characterizing non-stationary signals

Science.gov (United States)

Wang, Dong

2018-05-01

Thanks to the great efforts made by Antoni (2006), spectral kurtosis has been recognized as a milestone for characterizing non-stationary signals, especially bearing fault signals. The main idea of spectral kurtosis is to use the fourth standardized moment, namely kurtosis, as a function of spectral frequency so as to indicate how repetitive transients caused by a bearing defect vary with frequency. Moreover, spectral kurtosis is defined based on an analytic bearing fault signal constructed from either a complex filter or Hilbert transform. On the other hand, another attractive work was reported by Borghesani et al. (2014) to mathematically reveal the relationship between the kurtosis of an analytical bearing fault signal and the square of the squared envelope spectrum of the analytical bearing fault signal for explaining spectral correlation for quantification of bearing fault signals. More interestingly, it was discovered that the sum of peaks at cyclic frequencies in the square of the squared envelope spectrum corresponds to the raw 4th order moment. Inspired by the aforementioned works, in this paper, we mathematically show that: (1) spectral kurtosis can be decomposed into squared envelope and squared L2/L1 norm so that spectral kurtosis can be explained as spectral squared L2/L1 norm; (2) spectral L2/L1 norm is formally defined for characterizing bearing fault signals and its two geometrical explanations are made; (3) spectral L2/L1 norm is proportional to the square root of the sum of peaks at cyclic frequencies in the square of the squared envelope spectrum; (4) some extensions of spectral L2/L1 norm for characterizing bearing fault signals are pointed out.

Comparative studies of the endonucleases from two related Xenopus laevis retrotransposons, Tx1L and Tx2L: target site specificity and evolutionary implications.

Science.gov (United States)

Christensen, S; Pont-Kingdon, G; Carroll, D

2000-01-01

In the genome of the South African frog, Xenopus laevis, there are two complex families of transposable elements, Tx1 and Tx2, that have identical overall structures, but distinct sequences. In each family there are approximately 1500 copies of an apparent DNA-based element (Tx1D and Tx2D). Roughly 10% of these elements in each family are interrupted by a non-LTR retrotransposon (Tx1L and Tx2L). Each retrotransposon is flanked by a 23-bp target duplication of a specific D element sequence. In earlier work, we showed that the endonuclease domain (Tx1L EN) located in the second open reading frame (ORF2) of Tx1L encodes a protein that makes a single-strand cut precisely at the expected site within its target sequence, supporting the idea that Tx1L is a site-specific retrotransposon. In this study, we express the endonuclease domain of Tx2L (Tx2L EN) and compare the target preferences of the two enzymes. Each endonuclease shows some preference for its cognate target, on the order of 5-fold over the non-cognate target. The observed discrimination is not sufficient, however, to explain the observation that no cross-occupancy is observed - that is, L elements of one family have never been found within D elements of the other family. Possible sources of additional specificity are discussed. We also compare two hypotheses regarding the genome duplication event that led to the contemporary pseudotetraploid character of Xenopus laevis in light of the Tx1L and Tx2L data.

Effect of specific enzyme inhibitors on replication, total genome DNA repair and on gene-specific DNA repair after UV irradiation in CHO cells

Energy Technology Data Exchange (ETDEWEB)

Jones, J.C.; Stevsner, Tinna; Bohr, Vilhelm A. (National Cancer Institute, NIH, Bethesda, MD (USA). Division of Cancer Treatment, Laboratory of Molecular Pharmacology); Mattern, M.R. (Smith Kline Beecham Pharmaceuticals, King of Prussia, PA (USA). Department of Biomolecular Discovery)

1991-09-01

The effects were studied of some specific enzyme inhibitors on DNA repair and replication after UV damage in Chinese hamster ovary cells. The DNA repair was studied at the level of the average, overall genome and also in the active dihydrofolate reductase gene. Replication was measured in the overall genome. The inhibitors were tested of DNA poly-merase {alpha} and {delta} (aphidicolin), of poly(ADPr) polymerase (3-aminobenzamide), of ribonucleotide reductase (hydroxyurea), of topo-isomerase I (camptothecin), and of topoisomerase II (merbarone, VP-16). In addition, the effects were tested of the potential topoisomerase I activator, {beta}-lapachone. All of these compounds inhibited genome replication and all topoisomerase inhibitors affected the overall genome repair; {beta}-lapachone stimulated it. None of these compounds had any effect on the gene-specific repair. (author). 36 refs.; 3 figs.; 2 tabs.

Hyposmotic stimulation-induced nitric oxide production in outer hair cells of the guinea pig cochlea.

Science.gov (United States)

Takeda-Nakazawa, Hiroko; Harada, Narinobu; Shen, Jing; Kubo, Nobuo; Zenner, Hans-Peter; Yamashita, Toshio

2007-08-01

Nitric oxide (NO) production during hyposmotic stimulation in outer hair cells (OHCs) of the guinea pig cochlea was investigated using the NO sensitive dye DAF-2. Simultaneous measurement of the cell length and NO production showed rapid hyposmotic-induced cell swelling to precede NO production in OHCs. Hyposmotic stimulation failed to induce NO production in the Ca2+-free solution. L-NG-nitroarginine methyl ester (L-NAME), a non-specific NO synthase inhibitor and gadolinium, a stretch-activated channel blocker inhibited the hyposmotic stimulation-induced NO production whereas suramin, a P2 receptor antagonist did not. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor inhibited the hyposmotic stimulation-induced increase in the intracellular Ca2+ concentrations ([Ca2+]i) while L-NAME enhanced it. 1H-[1,2,4]oxadiazole[4,3a]quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase (PKG) mimicked effects of L-NAME on the Ca2+ response. Transient receptor potential vanilloid 4 (TRPV4), an osmo- and mechanosensitive channel was expressed in the OHCs by means of immunohistochemistry. 4alpha-phorbol 12,13-didecanoate, a TRPV4 synthetic activator, induced NO production in OHCs. These results suggest that hyposmotic stimulation can induce NO production by the [Ca2+]i increase, which is presumably mediated by the activation of TRPV4 in OHCs. NO conversely inhibits the Ca2+ response via the NO-cGMP-PKG pathway by a feedback mechanism.

Crystal Structure of the Homo sapiens Kynureninase-3-Hydroxyhippuric Acid Inhibitor Complex: Insights into the Molecular Basis Of Kynureninase Substrate Specificity

Energy Technology Data Exchange (ETDEWEB)

Lima,Santiago; Kumar,Sunil; Gawandi,Vijay; Momany,Cory; Phillips,Robert S.; (Georgia)

2009-02-23

Homo sapiens kynureninase is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the hydrolytic cleavage of 3-hydroxykynurenine to yield 3-hydroxyanthranilate and L-alanine as part of the tryptophan catabolic pathway leading to the de novo biosynthesis of NAD{sup +}. This pathway results in quinolinate, an excitotoxin that is an NMDA receptor agonist. High levels of quinolinate have been correlated with the etiology of neurodegenerative disorders such as AIDS-related dementia and Alzheimer's disease. We have synthesized a novel kynureninase inhibitor, 3-hydroxyhippurate, cocrystallized it with human kynureninase, and solved the atomic structure. On the basis of an analysis of the complex, we designed a series of His-102, Ser-332, and Asn-333 mutants. The H102W/N333T and H102W/S332G/N333T mutants showed complete reversal of substrate specificity between 3-hydroxykynurenine and L-kynurenine, thus defining the primary residues contributing to substrate specificity in kynureninases.

The discovery of novel tartrate-based TNF-[alpha] converting enzyme (TACE) inhibitors

Energy Technology Data Exchange (ETDEWEB)

Rosner, Kristin E.; Guo, Zhuyan; Orth, Peter; Shipps, Jr., Gerald W.; Belanger, David B.; Chan, Tin Yau; Curran, Patrick J.; Dai, Chaoyang; Deng, Yongqi; Girijavallabhan, Vinay M.; Hong, Liwu; Lavey, Brian J.; Lee, Joe F.; Li, Dansu; Liu, Zhidan; Popovici-Muller, Janeta; Ting, Pauline C.; Vaccaro, Henry; Wang, Li; Wang, Tong; Yu, W.; Zhou, G.; Niu, X.; Sun, J.; Kozlowski, J.A.; Lundell, D.J.; Madison, V.; McKittrick, B.; Piwinski, J.J.; Shih, N.Y.; Siddiqui, M. Arshad; Strickland, Corey O. (SPRI)

2010-09-17

A novel series of TNF-{alpha} convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.

What's in a Name

Science.gov (United States)

Bush, Sarah B.; Albanese, Judith; Karp, Karen S.

2016-01-01

Historically, some baby names have been more popular during a specific time span, whereas other names are considered timeless. The Internet article, "How to Tell Someone's Age When All You Know Is Her Name" (Silver and McCann 2014), describes the phenomenon of the rise and fall of name popularity, which served as a catalyst for the…

Inhibitor specificity of recombinant and endogenous caspase-9.

Science.gov (United States)

Ryan, Ciara A; Stennicke, Henning R; Nava, Victor E; Burch, Jennifer B; Hardwick, J Marie; Salvesen, Guy S

2002-01-01

Apoptosis triggered through the intrinsic pathway by radiation and anti-neoplastic drugs is initiated by the activation of caspase-9. To elucidate control mechanisms in this pathway we used a range of synthetic and natural reagents. The inhibitory potency of acetyl-Asp-Glu-Val-Asp-aldehyde ('Ac-DEVD-CHO'), benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone ('Z-VAD-FMK') and the endogenous caspase inhibitor X-chromosome-linked inhibitor of apoptosis protein ('XIAP') against recombinant caspase-9 were predictive of the efficacy of these compounds in a cell-free system. However, the viral proteins CrmA and p35, although potent inhibitors of recombinant caspase-9, had almost no ability to block caspase-9 in this system. These findings were also mirrored in cell expression studies. We hypothesize that the viral inhibitors CrmA and p35 are excluded from reacting productively with the natural form of active caspase-9 in vivo, making the potency of inhibitors highly context-dependent. This is supported by survival data from a mouse model of apoptosis driven by Sindbis virus expressing either p35 or a catalytic mutant of caspase-9. These results consolidate previous findings that CrmA is a potent inhibitor of caspase-9 in vitro, yet fails to block caspase-9-mediated cell death. PMID:12067274

Toward precision medicine with next-generation EGFR inhibitors in non-small-cell lung cancer

Directory of Open Access Journals (Sweden)

Yap TA

2014-09-01

Full Text Available Timothy A Yap,1,2 Sanjay Popat1,3 1Lung Cancer Unit, Department of Medicine, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom; 2The Institute of Cancer Research, London, United Kingdom; 3National Heart and Lung Institute, London, United Kingdom Abstract: The use of genomics to discover novel targets and biomarkers has placed the field of oncology at the forefront of precision medicine. First-generation epidermal growth factor receptor (EGFR inhibitors have transformed the therapeutic landscape of EGFR mutant non-small-cell lung carcinoma through the genetic stratification of tumors from patients with this disease. Somatic EGFR mutations in lung adenocarcinoma are now well established as predictive biomarkers of response and resistance to small-molecule EGFR inhibitors. Despite early patient benefit, primary resistance and subsequent tumor progression to first-generation EGFR inhibitors are seen in 10%–30% of patients with EGFR mutant non-small-cell lung carcinoma. Acquired drug resistance is also inevitable, with patients developing disease progression after only 10–13 months of antitumor therapy. This review details strategies pursued in circumventing T790M-mediated drug resistance to EGFR inhibitors, which is the most common mechanism of acquired resistance, and focuses on the clinical development of second-generation EGFR inhibitors, exemplified by afatinib (BIBW2992. We discuss the rationale, mechanism of action, clinical efficacy, and toxicity profile of afatinib, including the LUX-Lung studies. We also discuss the emergence of third-generation irreversible mutant-selective inhibitors of EGFR and envision the future management of EGFR mutant lung adenocarcinoma. Keywords: afatinib, EGFR, erlotinib, gefitinib, LUX-Lung, NSCLC 

Beneficial effects of Acer okamotoanum sap on L-NAME-induced hypertension-like symptoms in a rat model.

Science.gov (United States)

Yang, Hyun; Hwang, Inho; Koo, Tae-Hyoung; Ahn, Hyo-Jin; Kim, Sun; Park, Mi-Jin; Choi, Won-Sil; Kang, Ha-Young; Choi, In-Gyu; Choi, Kyung-Chul; Jeung, Eui-Bae

2012-02-01

The sap of Acer okamotoanum has been termed 'bone-benefit-water' in Korea owing to its mineral and sugar content. In particular, the calcium (Ca) and potassium (K) concentrations of the sap of Acer okamotoanum are 40- and 20-times higher, respectively, than commercial spring water. In the present study, we examined whether Acer okamotoanum sap improves or prevents hypertension-like symptoms in a rat model. Male Sprague-Dawley rats (8-weeks-old) were provided commercial spring water supplemented with 25, 50 or 100% Acer okamotoanum sap, 3% potassium ions (K+) or captopril, and treated daily for 2 weeks with NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/day) by subcutaneous injection, in order to induce hypertensive symptoms. Rats were euthanized 6 h following the final injection. To assess the effect of the sap on hypertension-like symptoms, we examined the mean blood pressure (BP), protein levels and localization of endothelial nitric oxide synthase (eNOS) in the descending aorta of the rats. BP levels were significantly lower in hypertensive rats received 25, 50 and 100% sap compared with rats who were administered only commercial spring water. Protein levels of eNOS were repressed in L-NAME-only-treated rats, but were elevated in the descending aorta of rats administered captopril, K+ water and Acer okamotoanum sap (25, 50 and 100%) up to the level of the sham group provided commercial spring water, and then injected with dimethyl sulfoxide for the same period of time. Localized eNOS protein was abundantly expressed in the perivascular descending aorta adipose tissue of the rats. Taken together, these results demonstrated that the sap of Acer okamotoanum ameliorated high BP induced by L-NAME treatment in a rat model.

Structure and Inhibitor Specificity of L,D-Transpeptidase (LdtMt2) from Mycobacterium tuberculosis and Antibiotic Resistance: Calcium Binding Promotes Dimer Formation.

Science.gov (United States)

Gokulan, Kuppan; Khare, Sangeeta; Cerniglia, Carl E; Foley, Steven L; Varughese, Kottayil I

2018-03-09

The final step of peptidoglycan (PG) synthesis in all bacteria is the formation of cross-linkage between PG-stems. The cross-linking between amino acids in different PG chains gives the peptidoglycan cell wall a 3-dimensional structure and adds strength and rigidity to it. There are two distinct types of cross-linkages in bacterial cell walls. D,D-transpeptidase (D,D-TPs) generate the classical 4➔3 cross-linkages and the L,D-transpeptidase (L,D-TPs) generate the 3➔3 non-classical peptide cross-linkages. The present study is aimed at understanding the nature of drug resistance associated with L,D-TP and gaining insights for designing novel antibiotics against multi-drug resistant bacteria. Penicillin and cephalosporin classes of β-lactams cannot inhibit L,D-TP function; however, carbapenems inactivate its function. We analyzed the structure of L,D-TP of Mycobacterium tuberculosis in the apo form and in complex with meropenem and imipenem. The periplasmic region of L,D-TP folds into three domains. The catalytic residues are situated in the C-terminal domain. The acylation reaction occurs between carbapenem antibiotics and the catalytic Cys-354 forming a covalent complex. This adduct formation mimics the acylation of L,D-TP with the donor PG-stem. A novel aspect of this study is that in the crystal structures of the apo and the carbapenem complexes, the N-terminal domain has a muropeptide unit non-covalently bound to it. Another interesting observation is that the calcium complex crystallized as a dimer through head and tail interactions between the monomers.

Potential Cardiovascular and Renal Protective Effects of Vitamin D and Coenzyme Q10 in l-NAME-Induced Hypertensive Rats.

Science.gov (United States)

Shamardl, Hanan A; El-Ashmony, Sahar M; Kamel, Hala F; Fatani, Sameer H

2017-08-01

Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l-NAME hypertensive rats. Hypertension was induced in rats by l-NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l-NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured. Compared to the l-NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-α and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent. The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Core outcome measurement instruments for clinical trials in non-specific low back pain

NARCIS (Netherlands)

Chiarotto, Alessandro; Boers, Maarten; Deyo, Richard A; Buchbinder, Rachelle; Corbin, Terry P; Costa, Leonardo O P; Foster, Nadine E; Grotle, Margreth; Koes, Bart W; Kovacs, Francisco M; Christine Lin, Chung-Wei; Maher, Chris G; Pearson, Adam M; Peul, Wilco C; Schoene, Mark L; Turk, Dennis C; van Tulder, Maurits W; Terwee, Caroline B; Ostelo, Raymond W

2017-01-01

To standardize outcome reporting in clinical trials of patients with non-specific low back pain (LBP), an international multidisciplinary panel recommended physical functioning, pain intensity, and health-related quality of life (HRQoL) as core outcome domains. Given the lack of consensus on

High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

Energy Technology Data Exchange (ETDEWEB)

Chen, Zhi-wei; Vignaud, Caroline; Jaafar, Adil; Lévy, Bernard; Guéritte, Françoise; Guénard, Daniel; Lederer, Florence; Mathews, F. Scott (CNRS-UMR); (WU-MED)

2012-05-24

Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent L-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b{sub 2} (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC{sub 50} in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 {angstrom} resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two other inhibitors with human GOX and spinach GOX. These compounds differ from CCPST in having the sulfur replaced with a nitrogen in the five-membered ring as well as different hydrophobic substituents. The possible reason for the {approx}100-fold difference in affinity between these two series of inhibitors is discussed. The present results indicate that specificity is an issue in the quest for therapeutic inhibitors of either LCHAO or GOX, but they may give leads for this quest.

BAY 41-2272 Treatment Improves Acetylcholine-Induced Aortic Relaxation in L-NAME Hypertensive Rats.

Science.gov (United States)

Prawez, Shahid; Ahanger, Azad Ahmad; Singh, Thakur Uttam; Mishra, Santosh Kumar; Sarkar, Souvendra Nath; Kumar, Dinesh

2016-12-01

Hypertension, an emerging problem of recent era, and many pathophysiological factors are participating to produce the disease. Nitric oxide (NO) is an important constituent to ameliorate hypertensive condition. Inhibition of endogenous NO synthase by L-N G -Nitroarginine methyl ester (L-NAME) was responsible for generating hypertension in rats. BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine), a soluble guanylyl cyclase activator, restricts rise of blood pressure and shows cardioprotective activity. The aim of the present study was to analyze effect of short-term BAY 41-2272 treatment on blood pressure and vascular function. Male Wistar rats were randomly divided into three groups such as control (group-A), hypertensive (group-B), and BAY 41-2272-treated hypertensive (group-C) rats. Normal saline was administered intramuscularly to control rats for last 3 days (days 40, 41, and 42) of total 42 days treatment, whereas rats of group-B and group-C were treated with L-NAME hydrochloride in drinking water at 50 mg/kg body weight daily for 42 days. Also, normal saline and BAY 41-2272 were administered for last 3 days at two different dosages at 1 and 3 mg/kg body weight/day intramuscularly to group-B and group-C rats, respectively. Administration of BAY 41-2272 for 3 days was not sufficient enough to decrease mean arterial pressure of hypertensive rats significantly. BAY at both the treatment dosages significantly ameliorate acetylcholine-induced maximal aortic relaxation compared with BAY-untreated hypertensive rats. Findings of the present study indicate that even shorter period of BAY 41-2272 treatment (3 days) improves vascular relaxation.

Antihypertensive mechanisms of chronic captopril (CPT) or N-Acetylcysteine (NAC) treatment in L-NAME hypertensive rats

Czech Academy of Sciences Publication Activity Database

Dobešová, Zdenka; Zicha, Josef; Pecháňová, Olga; Kuneš, Jaroslav

2005-01-01

Roč. 46, č. 4 (2005), s. 912-913 ISSN 0194-911X. [Annual Meeting of the European Council for Cardiovascular Research (ECCR) /10./. 14.10.2005-16.10.2005, La Colle sur Loup] R&D Projects: GA MZd(CZ) NR7786 Keywords : antihypertensive mechanism * captopril * N-Acetylcysteine * L-NAME hypertension Subject RIV: ED - Physiology

Enhancement of cadmium bioremediation by endophytic bacterium Bacillus sp. L14 using industrially used metabolic inhibitors (DCC or DNP)

International Nuclear Information System (INIS)

Luo Shenglian; Xiao Xiao; Xi Qiang; Wan Yong; Chen Liang; Zeng Guangming; Liu Chengbin; Guo Hanjun; Chen Jueliang

2011-01-01

Bioremediations of cadmium by endophytic bacterium (EB) L14 (Bacillus sp.) in the presence of industrially used metabolic inhibitors (DCC or DNP) were investigated. In the presence of DCC or DNP, the biomass population of EB L14 was greatly inhibited. However, the cadmium removal of EB L14 increased from 73.6% (in the absence of DCC or DNP) to 93.7% and 80.8%, respectively. The analysis of total and intracellular cadmium concentrations during 24 h of incubation indicated that this enhanced cadmium removal was the inhibition effect of DCC or DNP on the cations export resistance system of EB L14. This unique property strongly indicated the superiority of this endophyte for practical application in cadmium bioremediation in the presence of industrially used metabolic inhibitors.

On the History of the Name Ruslan

Directory of Open Access Journals (Sweden)

Roza Yu. Namitokova

2016-12-01

Full Text Available The authors postulate that there exists a common stock of Russian personal names resulting from a partial blending of national anthroponymicons. The main part of the paper focuses on the history of the personal name Ruslan which has etymological ties with the widespread Turkic name Arslan having the pre-onomastic meaning ‘lion’. The authors study the variation of the name in Russian folklore and in the 15th–17th centuries documents and historical sources. They also pay particular attention to the role of Pushkin’s poem Ruslan and Ludmila in the formation of the associative background of the studied name and to various onomastic derivatives, the latter include patronyms, surnames and the female name Ruslana. The author conclude that the name Ruslan became especially popular in Soviet and post-Soviet periods when it acquired a specific “semantic aura”, namely, in Caucasus where Ruslan became a kind of mark of Russian identity and, thus, contributed to the unification of the anthroponymic space. This conclusion was verified in the course of a survey done among 40 respondents representing different peoples of Caucasus. For most respondents the name has positive connotations and is associated with the Turkic name Arslan and the name of Pushkin’s character. However, some respondents consider it as a “non-Muslim”, Russian name and point out that it is often perceived as such outside Russia. The history of the name Ruslan and the ways of its transonymisation can be an interesting object for further research, especially due to the emergence of new communication technologies and onomastic discourses.

Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen

Science.gov (United States)

LeBeau, Aaron M.; Singh, Pratap; Isaacs, John T.; Denmeade, Samuel R.

2012-01-01

SUMMARY Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a Ki for PSA of 65 nM. The inhibitor had a 60-fold higher Ki for chymotrypsin. A validated model of PSA’s catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme. PMID:18635003

Metal corrosion inhibitors and ecology

International Nuclear Information System (INIS)

Krasts, H.; Svarce, J.; Berge, B.

1999-01-01

The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

Tumor specific cytotoxicity of arctigenin isolated from herbal plant Arctium lappa L.

Science.gov (United States)

Susanti, Siti; Iwasaki, Hironori; Itokazu, Yukiyoshi; Nago, Mariko; Taira, Naoyuki; Saitoh, Seikoh; Oku, Hirosuke

2012-10-01

The effectiveness of cancer chemotherapy is often limited by the toxicity to other tissues in the body. Therefore, the identification of non-toxic chemotherapeutics from herbal medicines remains to be an attractive goal to advance cancer treatments. This study evaluated the cytotoxicity profiles of 364 herbal plant extracts, using various cancer and normal cell lines. The screening found occurrence of A549 (human lung adenocarcinoma) specific cytotoxicity in nine species of herbal plants, especially in the extract of Arctium lappa L. Moreover, purification of the selective cytotoxicity in the extract of Arctium lappa L. resulted in the identification of arctigenin as tumor specific agent that showed cytotoxicity to lung cancer (A549), liver cancer (HepG2) and stomach cancer (KATO III) cells, while no cytotoxicity to several normal cell lines. Arctigenin specifically inhibited the proliferation of cancer cells, which might consequently lead to the induction of apoptosis. In conclusion, this study found that arctigenin was one of cancer specific phytochemicals, and in part responsible for the tumor selective cytotoxicity of the herbal medicine.

L1 and L2 Picture Naming in Mandarin-English Bilinguals: A Test of Bilingual Dual Coding Theory

Science.gov (United States)

Jared, Debra; Poh, Rebecca Pei Yun; Paivio, Allan

2013-01-01

This study examined the nature of bilinguals' conceptual representations and the links from these representations to words in L1 and L2. Specifically, we tested an assumption of the Bilingual Dual Coding Theory that conceptual representations include image representations, and that learning two languages in separate contexts can result in…

Myxoviruses do not induce non-specific alterations in membrane permeability early on in infection

International Nuclear Information System (INIS)

Foster, K.A.; Micklem, K.J.; Bogomolova, N.N.; Boriskin, Y.S.; Pasternak, C.A.

1983-01-01

The permeability characteristics of cells infected with myxoviruses have been studied by measuring the concentrative uptake of nutrients, the concentration of intracellular K + , and the maintenance of the Na + gradient across the plasma membrane. Cells either show no change at all (Sendai virus-infected BHK cells and measles virus-infected Vero cells) or they show a decreased ability to concentrate nutrients, while intracellular K + and the Na + gradient remain unchanged (Sendai and influenza virus-infected L-1210 cells, measles virus-infected lymphocytes and mumps virus-infected L-41 cells). In no case, therefore, was a change observed that resembles the non-specific increase in membrane permeability induced by haemolytic paramyxoviruses (35, 42) or the non-specific membrane leakiness postulated to take place in infected cells (8, 9). A preliminary account of some of these findings has been presented (39)

Pengaruh Penambahan Inhibitor Alami terhadap Laju Korosi pada Material Pipa dalam Larutan Air Laut Buatan

Directory of Open Access Journals (Sweden)

Ardi Prasetia Yanuar

2017-01-01

Full Text Available Korosi merupakan penurunan mutu logam akibat adanya reaksi elektrokimia dengan lingkungannya. Banyak faktor yang dapat menyebabkan korosi suatu material, salah satu diantaranya yakni pengaruh konsentrasi media korosi. Ada banyak metode untuk menghambat proses terjadinya korosi. Salah satu diantara banyak metode yaitu penggunaan inhibitor. Inhibitor organik salah satu jenis inhibitor yang bersifat non-toksik, murah, sudah tersedia di alam, mudah diperbaharui dan tidak merusak lingkungan. Inhibitor organik tersebut diperoleh dengan mengekstrak beberapa bahan yang ada di alam. Dalam penetilitian ini inhibitor yang digunakan antara lain daun jambu biji, daun teh, kedelai dan kopi. Inhibitor tersebut digunakan pada material pipa baja dalam media air laut buatan yang memiliki kadar salinitas 35 ‰. Metode perhitungan laju korosi baja menggunakan metode weight loss dan electroplating. Laju korosi paling kecil yakni sebesar 3.10 mpy untuk API 5L dan 1.94 mpy untuk ASTM A53 dengan inhibitor daun teh. Inhibitor yang kurang maksimal dalam menghambat laju korosi yaitu inhibitor kopi yakni 6.12 mpy untuk API 5L dan 2.66 mpy untuk ASTM A53. Nilai laju korosi spesimen API 5L dan ASTM A53 yang tidak menggunakan inhibitor masing-masing 50.26 mpy dan 3.83 mpy. Inhibitor teh memiliki nilai effisiensi mencapai 93.83%. Sedangkan daun jambu biji memiliki nilai effisiensi mencapai 93.45%. Nilai effisiensi inhibitor kedelai mencapai 91.72% dan inhibitor kopi memiliki nilai effisiensi paling rendah hanya mencapai 87.83%.

Inhibitors of serotonin reuptake and specific imipramine binding in human blood plasma

International Nuclear Information System (INIS)

Brusov, O.S.; Fomenko, A.M.; Katasonov, A.B.; Lidemann, R.R.

1985-01-01

This paper describes a method of extraction of endogenous inhibitors of specific IMI binding and of 5-HT reuptake, from human blood plasma and the heterogeneity of these compounds is demonstrated. Specific binding was determined as the difference between binding of 3 H-IMI in the absence and in the presence of 50 microM IMI. Under these conditions, specific binding amounted to 70-80% of total binding of 3 H-IMI. It is shown that extract obtained from human blood contains a material which inhibits dose-dependently both 5-HT reuptake and specific binding of 3 H-IMI. Gel-chromatography of extracts of human blood plasma on Biogel P-2 is also shown

Quality of life in non-melanoma skin cancer--the skin cancer quality of life (SCQoL) questionnaire

DEFF Research Database (Denmark)

Vinding, Gabrielle Randskov; Christensen, Karl Bang; Esmann, Solveig

2013-01-01

BACKGROUND: Disease-specific quality of life (QoL) questionnaires are increasingly used to provide patient-reported out-come measures in both malignant and non-malignant disease. OBJECTIVE: To create, validate and test the psychometrics of the Skin Cancer Quality of Life (SCQoL), which was designed...... to measure health-related QoL in patients with non-melanoma skin cancer affecting any area and undergoing any therapy. METHODS AND MATERIALS: The SCQoL was developed in a stepwise approach. Three pilot studies (testing content and face validity) and psychometric testing (scale structure, reliability, domains...

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

Science.gov (United States)

Vandeveer, Amanda J; Fallon, Jonathan K; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W

2016-05-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR. ©2016 American Association for Cancer Research.

Seed-specific stable expression of the alpha-AI1 inhibitor in coffee grains and the in vivo implications for the development of the coffee berry borer

OpenAIRE

Albuquerque, E. V. S.; Bezerra, C. A.; Romero, J. V.; Valencia, J. W. A.; Valencia-Jimenez, A.; Pimenta, L. M.; Barbosa, Aead; Silva, M. C. M.; Meneguim, A. M.; Sa, M. E. L.; Engler, G.; de Almeida-Engler, J.; Fernandez, Diana; Grossi-de-Sa, M. F.

2015-01-01

Genetic transformation of coffee (Coffea spp.), the second most traded commodity worldwide, is an alternative approach to introducing features that cannot be introgressed by traditional crossings. The transgenic stability, heritability and quantitative and spatial expression patterns of the seed-specific promoter phytohemagglutinin (PHA-L) from Phaseolus vulgaris were characterized in genetically modified C. arabica expressing the alpha-amylase inhibitor-1 (alpha-AI1) gene. The alpha-AI1 inhi...

On the effect of minocycline on the depressive-like behavior of mice repeatedly exposed to malathion: interaction between nitric oxide and cholinergic system.

Science.gov (United States)

Saeedi Saravi, Seyed Soheil; Amirkhanloo, Roya; Arefidoust, Alireza; Yaftian, Rahele; Saeedi Saravi, Seyed Sobhan; Shokrzadeh, Mohammad; Dehpour, Ahmad Reza

2016-06-01

This study was performed to investigate the antidepressant-like effect of minocycline in mice exposed to organophosphate pesticide malathion and possible involvement of nitric oxide/cGMP pathway in this paradigm. Mice were administered specific doses of malathion once daily for 7 consecutive days. After induction of depression, different doses of minocycline were daily injected alone or combined with non-specific NOS inhibitor, L-NAME, specific inducible NOS inhibitor, AG, NO precursor, L-arginine, and PDE5I, sildenafil. After locomotion assessment in open-field test, immobility times were recorded in the FST and TST. Moreover, hippocampal nitrite concentrations and acetylcholinesterase activity were measured. The results showed that repeated exposure to malathion induces depressive-like behavior at dose of 250 mg/kg. Minocycline (160 mg/kg) significantly reduced immobility times in FST and TST (P minocycline (80 mg/kg) with either L-NAME (3 mg/kg) or AG (25 mg/kg) significantly exerted a robust antidepressant-like effect in FST and TST (P minocycline at the same dose which has antidepressant-like effect, significantly reduced hippocampal nitrite concentration. The investigation indicates the essential role for NO/cGMP pathway in malathion-induced depressive-like behavior and antidepressant-like effect of minocycline. Moreover, the interaction between nitrergic and cholinergic systems are suggested to be involved in malathion-induced depression.

A potential human hepatocellular carcinoma inhibitor from Bauhinia purpurea L. seeds: from purification to mechanism exploration.

Science.gov (United States)

Fang, Evandro Fei; Bah, Clara Shui Fern; Wong, Jack Ho; Pan, Wen Liang; Chan, Yau Sang; Ye, Xiu Juan; Ng, Tzi Bun

2012-02-01

A 20-kDa Kunitz-type trypsin-chymotrypsin inhibitor, Bauhinia purpurea trypsin inhibitor (BPLTI), has been isolated from the seeds of B. purpurea L. by using liquid chromatography procedures that involved ion exchange chromatography on Sp-Sepharose and Mono S and gel filtration on Superdex 75. BPLTI demonstrated protease inhibitory activities of 7226 BAEE units/mg and 65 BTEE units/mg toward trypsin and α-chymotrypsin, respectively. BPLTI was relatively thermal (0-60°C) and pH (3-10) stable and its activity could be decreased by dithiothreitol treatment. BPLTI exhibited a wide spectrum of anti-proliferative and pro-apoptotic activities especially on human hepatocellular carcinoma Hep G2 cells. However, it was devoid of a significant antiproliferative effect on immortal human hepatic WRL 68 cells. We show here that BPLTI stimulates apoptosis in Hep G2 cells, including (1) evoking DNA damage including the production of chromatin condensation and apoptotic bodies; (2) induction of cell apoptosis/necrosis; (3) mitochondrial membrane depolarization; and (4) increasing the production of cytokines. Taken together, our findings show for the first time that purified protease inhibitor from B. purpurea L. seeds is a promising candidate for the treatment of human hepatocellular carcinoma.

Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein

International Nuclear Information System (INIS)

Zencir, Sevil; Ovee, Mohiuddin; Dobson, Melanie J.; Banerjee, Monimoy; Topcu, Zeki; Mohanty, Smita

2011-01-01

Highlights: → Brain-specific angiogenesis inhibitor 2 (BAI2) is a new partner protein for GIP. → BAI2 interaction with GIP was revealed by yeast two-hybrid assay. → Binding of BAI2 to GIP was characterized by NMR, CD and fluorescence. → BAI2 and GIP binding was mediated through the C-terminus of BAI2. -- Abstract: The vast majority of physiological processes in living cells are mediated by protein-protein interactions often specified by particular protein sequence motifs. PDZ domains, composed of 80-100 amino acid residues, are an important class of interaction motif. Among the PDZ-containing proteins, glutaminase interacting protein (GIP), also known as Tax Interacting Protein TIP-1, is unique in being composed almost exclusively of a single PDZ domain. GIP has important roles in cellular signaling, protein scaffolding and modulation of tumor growth and interacts with a number of physiological partner proteins, including Glutaminase L, β-Catenin, FAS, HTLV-1 Tax, HPV16 E6, Rhotekin and Kir 2.3. To identify the network of proteins that interact with GIP, a human fetal brain cDNA library was screened using a yeast two-hybrid assay with GIP as bait. We identified brain-specific angiogenesis inhibitor 2 (BAI2), a member of the adhesion-G protein-coupled receptors (GPCRs), as a new partner of GIP. BAI2 is expressed primarily in neurons, further expanding GIP cellular functions. The interaction between GIP and the carboxy-terminus of BAI2 was characterized using fluorescence, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy assays. These biophysical analyses support the interaction identified in the yeast two-hybrid assay. This is the first study reporting BAI2 as an interaction partner of GIP.

Nitrite and nitroso compounds can serve as specific catalase inhibitors.

Science.gov (United States)

Titov, Vladimir Yu; Osipov, Anatoly N

2017-03-01

We present evidence that nitrite and nitrosothiols, nitrosoamines and non-heme dinitrosyl iron complexes can reversibly inhibit catalase with equal effectiveness. Catalase activity was evaluated by the permanganatometric and calorimetric assays. This inhibition is not the result of chemical transformations of these compounds to a single inhibitor, as well as it is not the result of NO release from these substances (as NO traps have no effect on the extent of inhibition). It was found that chloride and bromide in concentration above 80 mM and thiocyanate in concentration above 20 μM enhance catalase inhibition by nitrite and the nitroso compounds more than 100 times. The inhibition degree in this case is comparable with that induced by azide. We propose that the direct catalase inhibitor is a positively charged NO-group. This group acquires a positive charge in the active center of enzyme by interaction of nitrite or nitroso compounds with some enzyme groups. Halides and thiocyanate protect the NO + group from hydration and thus increase its inhibition effect. It is probable that a comparatively low chloride concentration in many cells is the main factor to protect catalase from inhibition by nitrite and nitroso compounds.

Constructing and enforcing "authentic" identity online: Facebook, real names, and non-normative identities

OpenAIRE

Haimson, Oliver L.; Hoffmann, Anna Lauren

2016-01-01

Despite the participatory and democratic promises of Web 2.0, many marginalized individuals with fluid or non-normative identities continue to struggle to represent themselves online. Facebook users, in particular, are told to use “authentic identities,” an idea reinforced throughout the site’s documentation, “real name” and other policies, and in public statements by company representatives. Facebook’s conception of authenticity and real names, however, has created problems for certain users...

Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia.

Science.gov (United States)

Tamura, Satoru; Kaneko, Masafumi; Shiomi, Atsushi; Yang, Guang-Ming; Yamaura, Toshiaki; Murakami, Nobutoshi

2010-03-15

Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1. Copyright 2010 Elsevier Ltd. All rights reserved.

Een nieuwe naam voor Arenaria serpyllifolia L. var. macrocarpa Lloyd

NARCIS (Netherlands)

Gutermann, W.; Mennema, J.

1983-01-01

The name Arenaria serpyllifoiia L. var. macrocarpa Lloyd is illegitimate, because of the existence of the earlier non-synonymous A. serpyllifolia0 macrocarpa Godron. As on the level of variety no other name is available, we call the taxon A renaria serpylli/olia L. var. Iloydn (Jord.) Gutermann et

Generic versus brand-name drugs used in cardiovascular diseases.

Science.gov (United States)

Manzoli, Lamberto; Flacco, Maria Elena; Boccia, Stefania; D'Andrea, Elvira; Panic, Nikola; Marzuillo, Carolina; Siliquini, Roberta; Ricciardi, Walter; Villari, Paolo; Ioannidis, John P A

2016-04-01

This meta-analysis aimed to compare the efficacy and adverse events, either serious or mild/moderate, of all generic versus brand-name cardiovascular medicines. We searched randomized trials in MEDLINE, Scopus, EMBASE, Cochrane Controlled Clinical Trial Register, and ClinicalTrials.gov (last update December 1, 2014). Attempts were made to contact the investigators of all potentially eligible trials. Two investigators independently extracted and analyzed soft (including systolic blood pressure, LDL cholesterol, and others) and hard efficacy outcomes (including major cardiovascular adverse events and death), minor/moderate and serious adverse events. We included 74 randomized trials; 53 reported ≥1 efficacy outcome (overall sample 3051), 32 measured mild/moderate adverse events (n = 2407), and 51 evaluated serious adverse events (n = 2892). We included trials assessing ACE inhibitors (n = 12), anticoagulants (n = 5), antiplatelet agents (n = 17), beta-blockers (n = 11), calcium channel blockers (n = 7); diuretics (n = 13); statins (n = 6); and others (n = 3). For both soft and hard efficacy outcomes, 100 % of the trials showed non-significant differences between generic and brand-name drugs. The aggregate effect size was 0.01 (95 % CI -0.05; 0.08) for soft outcomes; -0.06 (-0.71; 0.59) for hard outcomes. All but two trials showed non-significant differences in mild/moderate adverse events, and aggregate effect size was 0.07 (-0.06; 0.20). Comparable results were observed for each drug class and in each stratified meta-analysis. Overall, 8 serious possibly drug-related adverse events were reported: 5/2074 subjects on generics; 3/2076 subjects on brand-name drugs (OR 1.69; 95 % CI 0.40-7.20). This meta-analysis strengthens the evidence for clinical equivalence between brand-name and generic cardiovascular drugs. Physicians could be reassured about prescribing generic cardiovascular drugs, and health care organization about endorsing their wider

Fluency Effects on Brand Name Recognition and Preference

DEFF Research Database (Denmark)

Erz, Antonia; Christensen, Bo

2014-01-01

Existing research has not provided a clear understanding of processing fluency effects on memory. In a laboratory experiment with novel non-words, we found a recognition advantage of fluent non-words over moderately fluent and disfluent non-words. This advantage diminished when non-words were...... presented as novel brand names in different product contexts. We further tested a preference reversal in favor of disfluency and found that disfluent brand names (non-words) were equally disliked across different products contexts. A preference reversal could be observed when fluent names were preferred...

Abbreviations for device names: a proposed methodology with specific examples.

Science.gov (United States)

Alam, Murad; Dover, Jeffrey S; Alam, Murad; Goldman, Mitchel P; Kaminer, Michael S; Orringer, Jeffrey; Waldorf, Heidi; Alam, Murad; Avram, Mathew; Cohen, Joel L; Draelos, Zoe Diana; Dover, Jeffrey S; Hruza, George; Kilmer, Suzanne; Lawrence, Naomi; Lupo, Mary; Metelitsa, Andrei; Nestor, Mark; Ross, E Victor

2013-04-01

Many devices used in dermatology lack generic names. If investigators use commercial device names, they risk the appearance of bias. Alternatively, reliance on ad-hoc names and abbreviations may confuse readers who do not recognize these. To develop a system for assigning abbreviations to denote devices commonly used in dermatology. Secondarily, to use this system to create abbreviations for FDA-approved neurotoxins and prepackaged injectable soft-tissue augmentation materials. The American Society for Dermatologic Surgery convened a Lexicon Task Force in March 2012. One charge of this Task Force was to develop criteria for assigning abbreviations to medical devices. A modified consensus process was used. Abbreviations to denote devices were to be: based on a standardized approach; transparent to the casual reader; markedly brief; and in all cases, different than the commercial names. Three-letter all caps abbreviations, some with subscripts, were assigned to denote each of the approved neurotoxins and fillers. A common system of abbreviations for medical devices in dermatology may avoid the appearance of bias while ensuring effective communication. The proposed system may be expanded to name other devices, and the ensuing abbreviations may be suitable for journal articles, continuing medical education lectures, or other academic or clinical purposes. © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.

Isozyme-specific fluorescent inhibitor of glutathione s-transferase omega 1.

Science.gov (United States)

Son, Junghyun; Lee, Jae-Jung; Lee, Jun-Seok; Schüller, Andreas; Chang, Young-Tae

2010-05-21

Recently, the glutathione S-transferase omega 1 (GSTO1) is suspected to be involved in certain cancers and neurodegenerative diseases. However, profound investigation on the pathological roles of GSTO1 has been hampered by the lack of specific methods to determine or modulate its activity in biological systems containing other isoforms with similar catalytic function. Here, we report a fluorescent compound that is able to inhibit and monitor the activity of GSTO1. We screened 43 fluorescent chemicals and found a compound (6) that binds specifically to the active site of GSTO1. We observed that compound 6 inhibits GSTO1 by covalent modification but spares other isoforms in HEK293 cells and demonstrated that compound 6 could report the activity of GSTO1 in NIH/3T3 or HEK293 cells by measuring the fluorescence intensity of the labeled amount of GSTO1 in SDS-PAGE. Compound 6 is a useful tool to study GSTO1, applicable as a specific inhibitor and an activity reporter.

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation

DEFF Research Database (Denmark)

Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch

2015-01-01

) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced...... to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4...

Regression of L-NAME - induced hypertension: the role of NO-pathway and endothelium-derived constricting factor

Czech Academy of Sciences Publication Activity Database

Paulis, Ĺudovít; Zicha, Josef; Kuneš, Jaroslav; Hojná, Silvie; Kojšová, S.; Pecháňová, O.; Šimko, F.

2006-01-01

Roč. 24, č. S4 (2006), S7-S7 ISSN 0263-6352. [European Meeting on Hypertension /16./. 12.06.2006-15.06.2006, Madrid] R&D Projects: GA MZd(CZ) NR7786; GA ČR(CZ) GA305/03/0769 Grant - others:VEGA(SK) 1/3429/0; APVT(SK) 51-02704 Keywords : L-NAME * hypertension * nitric oxide Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

Isolation and characterization of a specific endogenous Na+, K+-ATPase inhibitor from bovine adrenal

International Nuclear Information System (INIS)

Tamura, M.; Lam, T.T.; Inagami, T.

1988-01-01

In order to identify a specific endogenous Na + ,K + -ATPase inhibitor which could possibly be related to salt-dependent hypertension, the authors looked for substances in the methanol extract of bovine whole adrenal which show all of the following properties: (i) inhibitory activity for Na + ,K + -ATPase; (ii) competitive displacing activity against [ 3 H]ouabain binding to the enzyme; (iii) inhibitory activity for 86 Rb uptake into intact human erythrocytes; and (iv) cross-reactivity with sheep anti-digoxin-specific antibody. After stepwise fractionation of the methanol extract of bovine adrenal glands by chromatography on a C 18 open column, a 0-15% acetonitrile fraction was fractionated by high-performance liquid chromatography on a Zorbax octadecylsilane column. One of the most active fractions in 0-15% acetonitrile was found to exhibit all of the four types of the activities. It was soluble in water and was distinct from various substances which have been known to inhibit Na + ,K + -ATPase. These results strongly suggest that this water-soluble nonpeptidic Na + ,K + -ATPase inhibitor may be a specific endogenous regulator for the ATPase

North-American norms for name disagreement: pictorial stimuli naming discrepancies.

Directory of Open Access Journals (Sweden)

Mary O'Sullivan

Full Text Available Pictorial stimuli are commonly used by scientists to explore central processes; including memory, attention, and language. Pictures that have been collected and put into sets for these purposes often contain visual ambiguities that lead to name disagreement amongst subjects. In the present work, we propose new norms which reflect these sources of name disagreement, and we apply this method to two sets of pictures: the Snodgrass and Vanderwart (S&V set and the Bank of Standardized Stimuli (BOSS. Naming responses of the presented pictures were classified within response categories based on whether they were correct, incorrect, or equivocal. To characterize the naming strategy where an alternative name was being used, responses were further divided into different sub-categories that reflected various sources of name disagreement. Naming strategies were also compared across the two sets of stimuli. Results showed that the pictures of the S&V set and the BOSS were more likely to elicit alternative specific and equivocal names, respectively. It was also found that the use of incorrect names was not significantly different across stimulus sets but that errors were more likely caused by visual ambiguity in the S&V set and by a misuse of names in the BOSS. Norms for name disagreement presented in this paper are useful for subsequent research for their categorization and elucidation of name disagreement that occurs when choosing visual stimuli from one or both stimulus sets. The sources of disagreement should be examined carefully as they help to provide an explanation of errors and inconsistencies of many concepts during picture naming tasks.

Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

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Nicolas Sluis-Cremer

2013-11-01

Full Text Available HIV-1 reverse transcriptase (RT plays a central role in HIV infection. Current United States Federal Drug Administration (USFDA-approved antiretroviral therapies can include one of five approved non-nucleoside RT inhibitors (NNRTIs, which are potent inhibitors of RT activity. Despite their crucial clinical role in treating and preventing HIV-1 infection, their mechanism of action remains elusive. In this review, we introduce RT and highlight major advances from experimental and computational biophysical experiments toward an understanding of RT function and the inhibitory mechanism(s of NNRTIs.

Histological evaluation of the rat dental pulp after indirect capping with sildenafil or L-NAME incorporated into a bioadhesive thermoresponsive system

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Rogério Rodrigues Cupertino

2016-06-01

Full Text Available We evaluated the histological dental pulp state in vivo after indirect pulp capping using sildenafil or LG-nitro-L-arginine (L-NAME, incorporated into a new bioadhesive thermoresponsive system (BTS. Male Wistar rats were subjected to an upper and lower first molar class I cavity preparation followed by indirect pulp capping with sildenafil or L-NAME. Calcium hydroxide (CaOH2 was used as a control. The teeth and surrounding bone were properly dissected and processed for Nissl’s staining. Pulp state was evaluated considering the morphological aspects of the inflammatory response, type of inflammatory infiltrate, organization of the odontoblast layer, blood vessel condition, and presence of abscesses or necrosis. The results were expressed as average of observations. The most intense inflammatory response was observed 3 days after the cavity preparation. No identified changes were detected in the dental pulp response of the molars treated with L-NAME compared with those treated with CaOH2. A dual effect was observed in the teeth treated with sildenafil. While low sildenafil concentration (0.015% w w-1 promoted effects comparable to CaOH2, at a higher concentration (0.15% w w-1, sildenafil caused a severe inflammatory response and pulp necrosis. This pioneering suggest that NO pathway activity may be a determinant in the process of dental pulp healing.

Seed-Specific Stable Expression of the α-AI1 Inhibitor in Coffee Grains and the In Vivo Implications for the Development of the Coffee Berry Borer.

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Albuquerque, Érika V S; Bezerra, Caroline A; Romero, Juan V; Valencia, Jorge W A; Valencia-Jiménez, Arnubio; Pimenta, Lucas M; Barbosa, Aulus E A D; Silva, Maria C M; Meneguim, Ana M; Sá, Maria Eugênia L; Engler, Gilbert; de Almeida-Engler, Janice; Fernandez, Diana; Grossi-de-Sá, Maria F

Genetic transformation of coffee ( Coffea spp.), the second most traded commodity worldwide, is an alternative approach to introducing features that cannot be introgressed by traditional crossings. The transgenic stability, heritability and quantitative and spatial expression patterns of the seed-specific promoter phytohemagglutinin (PHA-L) from Phaseolus vulgaris were characterized in genetically modified C. arabica expressing the α-amylase inhibitor-1 ( α-AI1 ) gene. The α-AI1 inhibitor shows considerable activity toward digestive enzymes of the coffee berry borer (CBB) Hypothenemus hampei . This insect pest expends its life cycle almost entirely in coffee berries. Transgene containment in the fruit is important to meeting food and environmental safety requirements for releasing genetically modified (GM) crops. PCR analysis of T2 coffee plants showed a Mendelian single-copy segregation pattern. Ectopic transgene expression was only detected in coffee grains, as demonstrated by reverse transcription-PCR analysis of different plant tissues. An intense immunocytochemical signal associated with α-AI1 protein expression was localized to endospermic cells. In addition, a delay in the larval development of CBB was observed after challenging transgenic coffee seeds with the insect. These results indicate that the PHA-L promoter might be a useful tool in coffee for the seed-specific expression of genes related to coffee bean productivity, quality and pest protection. The biotechnological applicability of the α-AI1 gene for controlling CBB is also discussed. This work is the first report showing a seed-specific transgene expression in coffee plants.

Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

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Otari, K V; Upasani, C D

2015-08-01

The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

A mixed-method study on the generic and ostomy-specific quality of life of cancer and non-cancer ostomy patients.

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Jansen, Femke; van Uden-Kraan, Cornelia F; Braakman, J Annemieke; van Keizerswaard, Paulina M; Witte, Birgit I; Verdonck-de Leeuw, Irma M

2015-06-01

The aim of this study is to compare the generic and ostomy-specific quality of life (QoL) between cancer and non-cancer ostomy patients using a mixed-method design. All patients with an ostomy participating in the Stomapanel of the Dutch Ostomy Association were asked to complete a generic (RAND-36) and ostomy-specific (Stoma-QoL) QoL questionnaire. In addition, open-ended questions on symptoms, restrictions or adaptations influencing daily life were included. The generic and ostomy-specific QoL between cancer and non-cancer ostomy patients were compared using linear regression analyses. Qualitative responses were analysed using content analysis. In total, 668 patients were included: 379 cancer patients (80 % colorectal, 17 % bladder and 3 % other) and 289 non-cancer patients (38 % colitis ulcerosa, 22 % Crohn's disease and 40 % other) with a colostomy (55 %), ileostomy (31 %) and/or urostomy (16 %). Adjusted for gender, age, type of ostomy and time elapsed since ostomy surgery, cancer ostomy patients scored higher (better) on Stoma-QoL (β = 2.1) and all RAND-36 domains (9.1 ostomy patients. Of the 33 themes coded for in the content analysis, fatigue or sleeplessness, leakages, pain, bladder or bowel complaints, physical functioning or activity, travelling or being away from home, other daily activities (including work), clothing and diet were among the 10 most frequently reported themes, although ranking differed between both patient groups. Besides, cancer ostomy patients frequently reported on the impact on (engaging in a) relationship or sexual intimacy and non-cancer ostomy patients frequently reported to be relieved of symptoms and restrictions in daily life. Cancer patients reported better generic and ostomy-specific QoL than non-cancer ostomy patients. In both cancer and non-cancer ostomy patients, fatigue or sleeplessness, leakages, pain, bladder or bowel complaints, physical functioning or activity, travelling or being away from home, other daily

Immune checkpoint inhibitors: the new frontier in non–small cell lung cancer treatment

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El-Osta HE

2016-08-01

Full Text Available Hazem El-Osta, Kamran Shahid, Glenn M Mills, Prakash Peddi Department of Medicine, Division of Hematology-Oncology, Louisiana State University Health Sciences Center, Shreveport, LA, USA Abstract: Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. Keywords: checkpoint inhibitors, immunotherapy, nivolumab, non-small-cell lung cancer, pembrolizumab, programmed death-1, programmed death ligand-1

Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2).

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Edwards, Noel; Anderson, Catriona M H; Gatfield, Kelly M; Jevons, Mark P; Ganapathy, Vadivel; Thwaites, David T

2011-01-01

The H(+)-coupled amino acid transporter PAT2 (SLC36A2) transports the amino acids proline, glycine, alanine and hydroxyproline. A physiological role played by PAT2 in amino acid reabsorption in the renal proximal tubule is demonstrated by mutations in SLC36A2 that lead to an iminoglycinuric phenotype (imino acid and glycine uria) in humans. A number of proline, GABA and tryptophan derivatives were examined to determine if they function either as transported substrates or non-transported inhibitors of PAT2. The compounds were investigated following heterologous expression of rat PAT2 in Xenopus laevis oocytes. PAT2 function was characterised by: radiotracer uptake and competition (cis-inhibition) studies; radiotracer efflux and trans-stimulation; and measurement of substrate-induced positive inward current by two-electrode voltage-clamp. In general, the proline derivatives appeared to be transported substrates and the relative ability to induce current flow was closely related to the inhibitory effects on PAT2-mediated l-[(3)H]proline uptake. In contrast, certain heterocyclic GABA derivatives (e.g. l-pipecolic acid) were translocated only slowly. Finally, the tryptophan derivatives inhibited PAT2 function but did not undergo transport. l-Proline uptake was inhibited by 5-hydroxy-l-tryptophan (IC(50) 1.6±0.4mM), α-methyl-d,l-tryptophan (3.5±1.5mM), l-tryptophan, 1-methyl-l-tryptophan and indole-3-propionic acid. Although neither 5-hydroxy-l-tryptophan nor α-methyl-d,l-tryptophan were able to elicit inward current in PAT2-expressing oocytes both reduced the current evoked by l-proline. 5-Hydroxy-l-tryptophan and α-methyl-d,l-tryptophan were unable to trans-stimulate l-proline efflux from PAT2-expressing oocytes, confirming that the two compounds act as non-transported blockers of PAT2. These two tryptophan derivatives should prove valuable experimental tools in future investigations of the physiological roles of PAT2. Copyright © 2010 Elsevier B.V. All rights

Generic versus brand-name North American topical glaucoma drops.

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Mammo, Zaid N; Flanagan, John G; James, David F; Trope, Graham E

2012-02-01

To determine whether brand-name glaucoma drops differ from generic equivalents in bottle design, viscosity, surface tension, and volume in North America. Experimental study. We studied 5 bottles each of 11 kinds of glaucoma drops. Density-based calculations of drop volume were assessed using 0.1 mg analytic balance. Viscosity was measured using rotational rheometery. Bottle tip diameter was measured using 0.05 mm Vernier calipers. Surface tension was measured using a Fisher Scientific (Ottawa, ON) tensiometer. For the American brand-name Timoptic XE, the average drop volume was 38 ± 3.1 μL versus 24 ± 1.5 μL of Timolol GFS (p brand-name Timoptic XE, the average drop volume was 42 ± 4.0 μL versus 25 ± 2 μL of timolol maleate EX (p brand-name Timoptic drop volume was 28 ± 1.4 μL versus 35 ± 1.9 μL Apo-Timop (p brand-name Timoptic delivered significantly smaller drop volumes than generic Apo-Timop. Careful consideration should be given to drop viscosity and bottle design when generic ophthalmic products are evaluated for interchangeability and market entry. Copyright © 2012 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Chronic and acute effects of different antihypertensive drugs on femoral artery relaxations of L-NAME hypertensive rats

Czech Academy of Sciences Publication Activity Database

Sládková, M.; Kojšová, S.; Jendeková, L.; Pecháňová, Olga

2007-01-01

Roč. 56, Suppl.2 (2007), S85-S91 ISSN 0862-8408 Grant - others:VEGA(SK) 2/6148/26; VEGA(SK) 1/3429/06; -(SK) APVV-0586-06 Institutional research plan: CEZ:AV0Z50110509 Keywords : L-NAME induced hypertension * indapamide * hydrochlorothiazide * captopril Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.505, year: 2007

Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis

OpenAIRE

Koppikar, Priya; Abdel-Wahab, Omar; Hedvat, Cyrus; Marubayashi, Sachie; Patel, Jay; Goel, Aviva; Kucine, Nicole; Gardner, Jeffrey R.; Combs, Andrew P.; Vaddi, Kris; Haley, Patrick J.; Burn, Timothy C.; Rupar, Mark; Bromberg, Jacqueline F.; Heaney, Mark L.

2010-01-01

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we descri...

L-Citrulline Protects Skeletal Muscle Cells from Cachectic Stimuli through an iNOS-Dependent Mechanism.

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Daniel J Ham

Full Text Available Dietary L-citrulline is thought to modulate muscle protein turnover by increasing L-arginine availability. To date, the direct effects of increased L-citrulline concentrations in muscle have been completely neglected. Therefore, we determined the role of L-citrulline in regulating cell size during catabolic conditions by depriving mature C2C12 myotubes of growth factors (serum free; SF or growth factors and nutrients (HEPES buffered saline; HBS. Cells were treated with L-citrulline or equimolar concentrations of L-arginine (positive control or L-alanine (negative control and changes in cell size and protein turnover were assessed. In myotubes incubated in HBS or SF media, L-citrulline improved rates of protein synthesis (HBS: +63%, SF: +37% and myotube diameter (HBS: +18%, SF: +29%. L-citrulline treatment substantially increased iNOS mRNA expression (SF: 350%, HBS: 750%. The general NOS inhibitor L-NAME and the iNOS specific inhibitor aminoguanidine prevented these effects in both models. Depriving myotubes in SF media of L-arginine or L-leucine, exacerbated wasting which was not attenuated by L-citrulline. The increased iNOS mRNA expression was temporally associated with increases in mRNA of the endogenous antioxidants SOD1, SOD3 and catalase. Furthermore, L-citrulline prevented inflammation (LPS and oxidative stress (H2O2 induced muscle cell wasting. In conclusion, we demonstrate a novel direct protective effect of L-citrulline on skeletal muscle cell size independent of L-arginine that is mediated through induction of the inducible NOS (iNOS isoform. This discovery of a nutritional modulator of iNOS mRNA expression in skeletal muscle cells could have substantial implications for the treatment of muscle wasting conditions.

Pharmacophore Selection and Redesign of Non-nucleotide Inhibitors of Anthrax Edema Factor

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Maria Estrella Jimenez

2012-11-01

Full Text Available Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF, an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin’s basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.

Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor.

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Schein, Catherine H; Chen, Deliang; Ma, Lili; Kanalas, John J; Gao, Jian; Jimenez, Maria Estrella; Sower, Laurie E; Walter, Mary A; Gilbertson, Scott R; Peterson, Johnny W

2012-11-08

Antibiotic treatment may fail to protect individuals, if not started early enough, after infection with Bacillus anthracis, due to the continuing activity of toxins that the bacterium produces. Stable and easily stored inhibitors of the edema factor toxin (EF), an adenylyl cyclase, could save lives in the event of an outbreak, due to natural causes or a bioweapon attack. The toxin's basic activity is to convert ATP to cAMP, and it is thus in principle a simple phosphatase, which means that many mammalian enzymes, including intracellular adenylcyclases, may have a similar activity. While nucleotide based inhibitors, similar to its natural substrate, ATP, were identified early, these compounds had low activity and specificity for EF. We used a combined structural and computational approach to choose small organic molecules in large, web-based compound libraries that would, based on docking scores, bind to residues within the substrate binding pocket of EF. A family of fluorenone-based inhibitors was identified that inhibited the release of cAMP from cells treated with EF. The lead inhibitor was also shown to inhibit the diarrhea caused by enterotoxigenic E. coli (ETEC) in a murine model, perhaps by serving as a quorum sensor. These inhibitors are now being tested for their ability to inhibit Anthrax infection in animal models and may have use against other pathogens that produce toxins similar to EF, such as Bordetella pertussis or Vibrio cholera.

Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase

NARCIS (Netherlands)

Overkleeft, H. S.; Renkema, G. H.; Neele, J.; Vianello, P.; Hung, I. O.; Strijland, A.; van der Burg, A. M.; Koomen, G. J.; Pandit, U. K.; Aerts, J. M.

1998-01-01

The existence of a non-lysosomal glucosylceramidase in human cells has been documented (van Weely, S., Brandsma, M., Strijland, A., Tager, J. M., and Aerts, J. M. F. G. (1993) Biochim. Biophys. Acta 1181, 55-62). Hypothetically, the activity of this enzyme, which is localized near the cell surface,

Non toxic biodegradable cationic gemini surfactants as novel corrosion inhibitor for mild steel in hydrochloric acid medium and synergistic effect of sodium salicylate: Experimental and theoretical approach

Energy Technology Data Exchange (ETDEWEB)

Mobin, Mohammad, E-mail: drmmobin@hotmail.com; Aslam, Ruby; Aslam, Jeenat

2017-04-15

Two biodegradable, non toxic cationic gemini surfactants having ester linkage in the spacer namely, C{sub m}H{sub 2m+1}(CH{sub 3}){sub 2}N{sup +}(CH{sub 2}COOCH{sub 2}){sub 2}N{sup +}(CH{sub 3}){sub 2}C{sub m}H{sub 2m+1}.2Cl{sup -} (m-E2-m, m = 12, 14), were synthesized and characterized using elemental analysis, FT-IR and {sup 1}H-NMR. The corrosion inhibition performance of synthesized compounds separately and in combination with sodium salicylate (SS), along with the nature and stability of inhibitive film, for mild steel (MS) in 1 M HCl solution at 30–60 °C was evaluated using weight loss, potentiodynamic polarization, EIS, UV–visible spectroscopy, FTIR, SEM/EDAX, TGA and quantum chemical calculations. Results of the studies confirm m-E2-m as effective corrosion inhibitor for MS in HCl; the inhibition effect being synergistically strengthened in presence of SS. The synthesized compounds act as mixed type inhibitor and adsorb on MS surface in accordance with Langmuir adsorption isotherm. Experimentally measured inhibition efficiencies are correlated with the molecular parameters obtained using PM6 semi-empirical method. Empirical results are in good agreement with the theoretical predictions. - Graphical abstract: (a) Optimized geometry of studied inhibitors by PM6 method with (b) HOMO and (c) LUMO orbital occupation. - Highlights: • Environment friendly gemini surfactants were studied as corrosion inhibitor for MS. • Studied compounds act as good inhibitor for MS corrosion in 1 M HCl at 30–60 °C. • η of inhibitors is synergistically increased in presence of sodium salicylate. • The synthesized cationic gemini surfactants act as mixed-type inhibitor. • Experimentally obtained results are in good agreement with theoretical results.

Effect of ionizing radiation on reducing the several inhibitors in codling moth Cydia pomonella (L.) medium

International Nuclear Information System (INIS)

Mohamad, F. A.

2008-01-01

The medium for Codling moth, Cydia pomonella (L) was sterilized using ionizing radiation (0, 5, 15 and 25 KGy) or heat (cooking for 40 minutes.). inhibitors were also added either on the top of the diet or by mixing it with the diet. The results showed that all Codling moth larvae in the ionizing radiation sterilized diet died before reaching the 4th larval instar. Results of using both radiation and cooking for sterilizing the diet gave variable results; those treated with 15 KGy gave significantly more moths with higher weight and more fecundity. The results also showed that increasing the amount of microbial inhibitors in diet negatively affected the number of produced moth and their biological characteristics. Consequently irradiation could be a mean for reducing the amount of chemical inhibitors added to the diet. (author)

Biochemical characterization of CTX-M-15 from Enterobacter cloacae and designing a novel non-β-lactam-β-lactamase inhibitor.

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Mohammad Faheem

Full Text Available The worldwide dissemination of CTX-M type β-lactamases is a threat to human health. Previously, we have reported the spread of bla(CTX-M-15 gene in different clinical strains of Enterobacteriaceae from the hospital settings of Aligarh in north India. In view of the varying resistance pattern against cephalosporins and other β-lactam antibiotics, we intended to understand the correlation between MICs and catalytic activity of CTX-M-15. In this study, steady-state kinetic parameters and MICs were determined on E. coli DH5α transformed with bla(CTX-M-15 gene that was cloned from Enterobacter cloacae (EC-15 strain of clinical background. The effect of conventional β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam on CTX-M-15 was also studied. We have found that tazobactam is the best among these inhibitors against CTX-M-15. The inhibition characteristic of tazobactam is defined by its very low IC(50 value (6 nM, high affinity (K(i = 0.017 µM and better acylation efficiency (k(+2/K' = 0.44 µM(-1s(-1. It forms an acyl-enzyme covalent complex, which is quite stable (k(+3 = 0.0057 s(-1. Since increasing resistance has been reported against conventional β-lactam antibiotic-inhibitor combinations, we aspire to design a non-β-lactam core containing β-lactamase inhibitor. For this, we screened ZINC database and performed molecular docking to identify a potential non-β-lactam based inhibitor (ZINC03787097. The MICs of cephalosporin antibiotics in combination with this inhibitor gave promising results. Steady-state kinetics and molecular docking studies showed that ZINC03787097 is a reversible inhibitor which binds non-covalently to the active site of the enzyme through hydrogen bonds and hydrophobic interactions. Though, it's IC(50 (180 nM is much higher than tazobactam, it has good affinity for CTX-M-15 (K(i = 0.388 µM. This study concludes that ZINC03787097 compound can be used as seed molecule to design more

Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.

Science.gov (United States)

Migliore, Marco; Pontis, Silvia; Fuentes de Arriba, Angel Luis; Realini, Natalia; Torrente, Esther; Armirotti, Andrea; Romeo, Elisa; Di Martino, Simona; Russo, Debora; Pizzirani, Daniela; Summa, Maria; Lanfranco, Massimiliano; Ottonello, Giuliana; Busquet, Perrine; Jung, Kwang-Mook; Garcia-Guzman, Miguel; Heim, Roger; Scarpelli, Rita; Piomelli, Daniele

2016-09-05

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of inhibition of serine palmitoyltransferase (SPT and sphingosine kinase 1 (SphK1 on palmitate induced insulin resistance in L6 myotubes.

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Agnieszka Mikłosz

Full Text Available BACKGROUND: The objective of this study was to examine the effects of short (2 h and prolonged (18 h inhibition of serine palmitoyltransferase (SPT and sphingosine kinase 1 (SphK1 on palmitate (PA induced insulin resistance in L6 myotubes. METHODS: L6 myotubes were treated simultaneously with either PA and myriocin (SPT inhibitor or PA and Ski II (SphK1inhibitor for different time periods (2 h and 18 h. Insulin stimulated glucose uptake was measured using radioactive isotope. Expression of insulin signaling proteins was determined using Western blot analyses. Intracellular sphingolipids content [sphinganine (SFA, ceramide (CER, sphingosine (SFO, sphingosine-1-phosphate (S1P] were estimated by HPLC. RESULTS: Our results revealed that both short and prolonged time of inhibition of SPT by myriocin was sufficient to prevent ceramide accumulation and simultaneously reverse palmitate induced inhibition of insulin-stimulated glucose transport. In contrast, prolonged inhibition of SphK1 intensified the effect of PA on insulin-stimulated glucose uptake and attenuated further the activity of insulin signaling proteins (pGSK3β/GSK3β ratio in L6 myotubes. These effects were related to the accumulation of sphingosine in palmitate treated myotubes. CONCLUSION: Myriocin is more effective in restoration of palmitate induced insulin resistance in L6 myocytes, despite of the time of SPT inhibition, comparing to SKII (a specific SphK1 inhibitor. Observed changes in insulin signaling proteins were related to the content of specific sphingolipids, namely to the reduction of ceramide. Interestingly, inactivation of SphK1 augmented the effect of PA induced insulin resistance in L6 myotubes, which was associated with further inhibition of insulin stimulated PKB and GSK3β phosphorylation, glucose uptake and the accumulation of sphingosine.

Phosphorescent inner filter effect-based sensing of xanthine oxidase and its inhibitors with Mn-doped ZnS quantum dots.

Science.gov (United States)

Tang, Dandan; Zhang, Jinyi; Zhou, Rongxin; Xie, Ya-Ni; Hou, Xiandeng; Xu, Kailai; Wu, Peng

2018-05-10

Overexpression and crystallization of uric acid have been recognized as the course of hyperuricemia and gout, which is produced via xanthine oxidase (XOD)-catalyzed oxidation of xanthine. Therefore, the medicinal therapy of hyperuricemia and gout is majorly based on the inhibition of the XOD enzymatic pathway. The spectroscopic nature of xanthine and uric acid, namely both absorption (near the ultraviolet region) and emission (non-fluorescent) characteristics, hinders optical assay development for XOD analysis. Therefore, the state-of-the-art analysis of XOD and the screening of XOD inhibitors are majorly based on chromatography. Here, we found the near ultraviolet absorption of uric acid overlapped well with the absorption of a large bandgap semiconductor quantum dots, ZnS. On the other hand, the intrinsic weak fluorescence of ZnS QDs can be substantially improved via transition metal ion doping. Therefore, herein, we developed an inner filter effect-based assay for XOD analysis and inhibitor screening with Mn-doped ZnS QDs. The phosphorescence of Mn-doped ZnS QDs could be quenched by uric acid generated from xanthine catabolism by XOD, leading to the phosphorescence turn-off detection of XOD with a limit of detection (3σ) of 0.02 U L-1. Furthermore, the existence of XOD inhibitors could inhibit the XOD enzymatic reaction, resulting in weakened phosphorescence quenching. Therefore, the proposed assay could also be explored for the facile screening analysis of XOD inhibitors, which is important for the potential medicinal therapy of hyperuricemia and gout.

Tyrosinase inhibitors from Calceolaria integrifolia s.l.: Calceolaria talcana aerial parts.

Science.gov (United States)

Muñoz, Evelyn; Avila, Jose G; Alarcón, Julio; Kubo, Isao; Werner, Enrique; Céspedes, Carlos L

2013-05-08

As a defense mechanism of the aerial parts of Calceolaria talcana (Calceolariaceae; formerly Scrophulariaceae) against herbivore offenses and insect pest attack, diterpenoids, triterpenoids, phenylethanoids, flavonoids, and iridoids are rapidly accumulated along the aerial parts, resulting in a unique natural biopesticide complex from this plant. In addition to verbascoside a series of known compounds were screened for their inhibitory activity against mushroom tyrosinase and protease enzymes. Ethyl acetate and n-hexane extracts, together with cyclopropyl-7,15-ent-pimaradiene (1), abietatriene (2), ursolic acid (3), α-lupeol (4), β-sitosterol (5), 2-hydroxy-3-(1,1-dimethylallyl)-1,4-naphthoquinone (6), α-dunnione (7), verbascoside (8), martynoside (9), and some known model compounds proved to be inhibitors of oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) catalyzed by tyrosinase (EC 1.14.18.1) with an IC50 between 10.0 and 200 ppm or μM, respectively, suggesting that phenolic moieties in the molecules assayed are important for the activity.

Non-steroidal anti-inflammatory drugs, Cyclooxygenase-2 inhibitors and paracetamol use in Queensland and in the whole of Australia

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Tett Susan E

2008-09-01

Full Text Available Abstract Background Cross national drug utilization studies can provide information about different influences on physician prescribing. This is important for medicines with issues around safety and quality of use, like non selective non-steroidal anti-inflammatory drugs (ns-NSAIDs and cyclo-oxygenase-2 (COX-2 inhibitors. To enable comparison of prescription medicine use across different jurisdictions with a range of population sizes, data first need to be compared within Australia to understand whether use in a smaller sub-population may be considered as representative of the total use within Australia. The aim of this study was to compare the utilization of non selective NSAID, COX-2 inhibitors and paracetamol between Queensland and Australia. Method Dispensing data were obtained for concession beneficiaries for Australia for ns-NSAIDs, COX-2 inhibitors and paracetamol subsidized by the PBS over the period 1997–2003. The same data were purchased for Queensland. Data were converted to Defined Daily Dose (DDD/1000 beneficiaries/day (World Health Organization anatomical therapeutic chemical classification, 2005. Results Total NSAID and paracetamol consumption were similar in Australia and Queensland. Ns-NSAID use decreased sharply with the introduction of COX-2 inhibitors (from approximately 80 to 40 DDD/1000 beneficiaries/day. Paracetamol was constant (approximately 45 DDD/1000 beneficiaries/day. COX-2 inhibitors consumption was initially higher in Queensland than in the whole of Australia. Conclusion Despite initial divergence in celecoxib use between Queensland and Australia, the use of ns-NSAIDs, COX-2 inhibitors and paracetamol overall, in concession beneficiaries, was comparable in Australia and Queensland.

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable?

Science.gov (United States)

Carlini, P; Frassoldati, A; De Marco, S; Casali, A; Ruggeri, E M; Nardi, M; Papaldo, P; Fabi, A; Paoloni, F; Cognetti, F

2001-11-01

There are few clinical data on the sequential use of aromatase inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR + PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC) patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR). who had already received non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) or anastrozole (ANZ). Twenty postmenopausal women with MBC were analysed in this retrospective two-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire population treated with FOR showed an overall CB of 55% (11 of 20) with a median duration of 15 months and median time to progression (TTP) of 6 months. Formestane 250 mg once bi-weekly seems to be an attractive alternative third-line hormonal therapy for the treatment of patients with MBC, previously treated with nSAI.

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity

Science.gov (United States)

Lee, Jae-Geun; Kang, Dong Gu; Yu, Jung Re; Kim, Youngree; Kim, Jinsoek; Koh, Gwanpyo

2011-01-01

Background Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents. Methods Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects. Results ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; PADA activity was correlated with fasting plasma glucose (r=0.258, P9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; PADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; PADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect. PMID:21738897

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity.

Science.gov (United States)

Lee, Jae-Geun; Kang, Dong Gu; Yu, Jung Re; Kim, Youngree; Kim, Jinsoek; Koh, Gwanpyo; Lee, Daeho

2011-04-01

Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents. Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects. ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; PADA activity was correlated with fasting plasma glucose (r=0.258, P9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; PADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; PADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect.

Tissue-Specific Methylation of Long Interspersed Nucleotide Element-1 of Homo Sapiens (L1Hs) During Human Embryogenesis and Roles in Neural Tube Defects.

Science.gov (United States)

Wang, L; Chang, S; Guan, J; Shangguan, S; Lu, X; Wang, Z; Wu, L; Zou, J; Zhao, H; Bao, Y; Qiu, Z; Niu, B; Zhang, T

2015-01-01

Epigenetic regulation of long interspersed nucleotide element-1 (LINE-1) retrotransposition events plays crucial roles during early development. Previously we showed that LINE-1 hypomethylation in neuronal tissues is associated with pathogenesis of neural tube defect (NTD). Herein, we further evaluated LINE-1 Homo sapiens (L1Hs) methylation in tissues derived from three germ layers of stillborn NTD fetuses, to define patterns of tissue specific methylation and site-specific hypomethylation at CpG sites within an L1Hs promoter region. Stable, tissue-specific L1Hs methylation patterns throughout three germ layer lineages of the fetus, placenta, and maternal peripheral blood were observed. Samples from maternal peripheral blood exhibited the highest level of L1Hs methylation (64.95%) and that from placenta showed the lowest (26.82%). Between samples from NTDs and controls, decrease in L1Hs methylation was only significant in NTD-affected brain tissue at 7.35%, especially in females (8.98%). L1Hs hypomethylation in NTDs was also associated with a significant increase in expression level of an L1Hs-encoded transcript in females (r = -0.846, p = 0.004). This could be due to genomic DNA instability and alternation in chromatins accessibility resulted from abnormal L1Hs hypomethylation, as showed in this study with HCT-15 cells treated with methylation inhibitor 5-Aza.

Effects of L-arginine and Nω-nitro-L-arginine methylester on learning and memory and α7 nAChR expression in the prefrontal cortex and hippocampus of rats

Institute of Scientific and Technical Information of China (English)

Xiao-Ming Wei; Wei Yang; Li-Xia Liu; Wen-Xiu Qi

2013-01-01

Nitric oxide (NO) is a novel type of neurotransmitter that is closely associated with synaptic plasticity,learning and memory.In the present study,we assessed the effects of L-arginine and Nω-nitro-L-arginine methylester (L-NAME,a nitric oxide synthase inhibitor) on learning and memory.Rats were assigned to three groups receiving intracerebroventricular injections of L-Arg (the NO precursor),L-NAME,or 0.9％ NaCI (control),once daily for seven consecutive days.Twelve hours after the last injection,they underwent an electric shock-paired Y maze test.Twenty-four hours later,the rats' memory of the safe illuminated arm was tested.After that,the levels of NO and α7 nicotinic acetylcholine receptor (α7 nAChR) in the prefrontal cortex and hippocampus were assessed using an NO assay kit,and immunohistochemistry and Western blots,respectively.We found that,compared to controls,L-Arg-treated rats received fewer foot shocks and made fewer errors to reach the learning criterion,and made fewer errors during the memory-testing session.In contrast,L-NAME-treated rats received more foot shocks and made more errors than controls to reach the learning criterion,and made more errors during the memory-testing session.In parallel,NO content in the prefrontal cortex and hippocampus was higher in L-Arg-treated rats and lower in L-NAME rats,compared to controls.Similarly,α7 nAChR immunoreactivity and protein expression in the prefrontal cortex and hippocampus were higher in L-Arg-treated rats and lower in L-NAME rats,compared to controls.These results suggest that the modulation of NO content in the brain correlates with α7 nAChR distribution and expression in the prefrontal cortex and hippocampus,as well as with learning and memory performance in the Y-maze.

Toxicity to cotton boll weevil Anthonomus grandis of a trypsin inhibitor from chickpea seeds.

Science.gov (United States)

de P G Gomes, Angélica; Dias, Simoni C; Bloch, Carlos; Melo, Francislete R; Furtado, José R; Monnerat, Rose G; Grossi-de-Sá, Maria F; Franco, Octávio L

2005-02-01

Cotton (Gossypium hirsutum L.) is an important agricultural commodity, which is attacked by several pests such as the cotton boll weevil Anthonomus grandis. Adult A. grandis feed on fruits and leaf petioles, reducing drastically the crop production. The predominance of boll weevil digestive serine proteinases has motivated inhibitor screenings in order to discover new ones with the capability to reduce the digestion process. The present study describes a novel proteinase inhibitor from chickpea seeds (Cicer arietinum L.) and its effects against A. grandis. This inhibitor, named CaTI, was purified by using affinity Red-Sepharose Cl-6B chromatography, followed by reversed-phase HPLC (Vydac C18-TP). SDS-PAGE and MALDI-TOF analyses, showed a unique monomeric protein with a mass of 12,877 Da. Purified CaTI showed significant inhibitory activity against larval cotton boll weevil serine proteinases (78%) and against bovine pancreatic trypsin (73%), when analyzed by fluorimetric assays. Although the molecular mass of CaTI corresponded to alpha-amylase/trypsin bifunctional inhibitors masses, no inhibitory activity against insect and mammalian alpha-amylases was observed. In order to observe CaTI in vivo effects, an inhibitor rich fraction was added to an artificial diet at different concentrations. At 1.5% (w/w), CaTI caused severe development delay, several deformities and a mortality rate of approximately 45%. These results suggested that CaTI could be useful in the production of transgenic cotton plants with enhanced resistance toward cotton boll weevil.

Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors

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Annegret Ulke-Lemée

2010-05-01

Full Text Available Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine; therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but its dysfunction is associated with morbidity and mortality. Rho-associated protein kinase (ROCK is central to calcium-independent, actomyosin-mediated contractile force generation in the vasculature, thereby playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence supports an important role for ROCK in the increased vasoconstriction and remodeling observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications might also benefit from ROCK inhibition. Apart from the importance of ROCK in smooth muscle contraction, a variety of other protein kinases are known to play similar roles in regulating contractile force. The zipper-interacting protein kinase (ZIPK and integrin-linked kinase (ILK are two well-described regulators of contraction. The relative contribution of each kinase to contraction depends on the muscle bed as well as hormonal and neuronal stimulation. Unfortunately, specific inhibitors for ZIPK and ILK are still in the development phase, but the success of fasudil suggests that inhibitors for these other kinases may also have valuable clinical applications. Notably, the directed inhibition of ZIPK with a pseudosubstrate molecule shows unexpected effects on the contractility of gastrointestinal smooth muscle.

Undergoing Diagnostic Evaluation for Possible Cancer Affects the Health-Related Quality of Life in Patients Presenting with Non-Specific Symptoms

DEFF Research Database (Denmark)

Larsen, Ellen Frøsig Moseholm; Rydahl Hansen, Susan; Lindhardt, Bjarne Ørskov

2016-01-01

Aim Undergoing diagnostic evaluation for possible cancer can affect health-related quality of life (HRQoL). The aims of this study were to examine the HRQoL in patients undergoing a diagnostic evaluation for possible cancer due to non-specific symptoms and further to investigate the impact of socio...... diagnosis had the greatest effect on HRQoL around the time of diagnosis. Conclusions Patients with non-specific symptoms reported an affected HRQoL while undergoing a diagnostic evaluation for possible cancer. Morbidity, being unemployed and receiving a cancer diagnosis had the greatest effect on HRQo...... in the study; 680 (81%) also completed follow-up. Twenty-two percent of the patients received a cancer diagnosis at the end of follow-up. Patients presented initially with a high burden of symptoms, less role and emotional functioning and a lower global health/QoL. Most domains improved after diagnosis...

Effects of tumor necrosis factor alpha antagonist, platelet activating factor antagonist, and nitric oxide synthase inhibitor on experimental otitis media with effusion.

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Kim, Dong-Hyun; Park, Yong-Soo; Jeon, Eun-Ju; Yeo, Sang-Won; Chang, Ki-Hong; Lee, Seung Kyun

2006-08-01

We studied the inflammatory responses in otitis media with effusion induced by lipopolysaccharide (LPS) in rats, and compared the preventive effects of tumor necrosis factor (TNF) soluble receptor type I (sTNFRI, a TNF-alpha antagonist), platelet activating factor antagonist, and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). We used 2 control groups of Sprague Dawley rats (untreated and saline-treated) and 4 experimental groups, which all received an intratympanic injection of LPS, followed in 3 groups by experimental treatment of the same ear. The LPS group had no additional treatment. The L-NAME group received intraperitoneal injection of L-NAME and was reinjected after 12 hours. The A-85783 group was first given an intraperitoneal injection of A-85783. The sTNFRI group was first given an intratympanic injection of sTNFRI. Twenty-four hours after the initial intratympanic injection of LPS, temporal bones from each group were examined histopathologically and the vascular permeability of the middle ear mucosa was measured by Evans blue vital dye staining. The L-NAME, A-85783, and sTNFRI groups showed significantly reduced capillary permeability, subepithelial edema, and infiltration of inflammatory cells in comparison with the LPS group. There were no differences in capillary permeability, subepithelial edema, or infiltration of inflammatory cells between the A-85783 and sTNFRI groups. The L-NAME group showed no difference in vascular permeability or subepithelial edema in comparison with the A-85783 and sTNFRI groups, but showed more infiltration of inflammatory cells. We conclude that sTNFRI, A-85783, and L-NAME can be proposed as alternative future treatments for otitis media with effusion. However, L-NAME may be the least effective of these agents.

Crystal structures of Leishmania mexicana arginase complexed with α,α-disubstituted boronic amino-acid inhibitors

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Hai, Yang; Christianson, David W.

2016-03-16

Leishmaniaarginase is a potential drug target for the treatment of leishmaniasis because this binuclear manganese metalloenzyme initiatesde novopolyamine biosynthesis by catalyzing the hydrolysis of L-arginine to generate L-ornithine and urea. The product L-ornithine subsequently undergoes decarboxylation to yield putrescine, which in turn is utilized for spermidine biosynthesis. Polyamines such as spermidine are essential for the growth and survival of the parasite, so inhibition of enzymes in the polyamine-biosynthetic pathway comprises an effective strategy for treating parasitic infections. To this end, two X-ray crystal structures ofL. mexicanaarginase complexed with α,α-disubstituted boronic amino-acid inhibitors based on the molecular scaffold of 2-(S)-amino-6-boronohexanoic acid are now reported. Structural comparisons with human and parasitic arginase complexes reveal interesting differences in the binding modes of the additional α-substituents,i.e.the D side chains, of these inhibitors. Subtle differences in the three-dimensional contours of the outer active-site rims among arginases from different species lead to different conformations of the D side chains and thus different inhibitor-affinity trends. The structures suggest that it is possible to maintain affinity while fine-tuning intermolecular interactions of the D side chain of α,α-disubstituted boronic amino-acid inhibitors in the search for isozyme-specific and species-specific arginase inhibitors.

Optimal Classes of Chemotherapeutic Agents Sensitized by Specific Small-Molecule Inhibitors of Akt In Vitro and In Vivo

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Yan Shi

2005-11-01

Full Text Available Akt is a serine/threonine kinase that transduces survival signals from survival/growth factors. Deregulation and signal imbalance in cancer cells make them prone to apoptosis. Upregulation or activation of Akt to aid the survival of cancer cells is a common theme in human malignancies. We have developed small-molecule Akt inhibitors that are potent and specific. These Akt inhibitors can inhibit Akt activity and block phosphorylation by Akt on multiple downstream targets in cells. Synergy in apoptosis induction was observed when Akt inhibitors were combined with doxorubicin or camptothecin. Akt inhibitor-induced enhancement of topoisomerase inhibitor cytotoxicity was also evident in long-term cell survival assay. Synergy with paclitaxel in apoptosis induction was evident in cells pretreated with paclitaxel, and enhancement of tumor delay by paclitaxel was demonstrated through cotreatment with Akt inhibitor Compound A (A-443654. Combination with other classes of chemotherapeutic agents did not yield any enhancement of cytotoxicity. These findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment.

Etiologies et pronostic des comas non-traumatiques de l'enfant a l ...

African Journals Online (AJOL)

Objectif. Déterminer la fréquence, le profil clinique, l'étiologie et l'évolution du coma non traumatique de l'enfant de un mois à 16 ans. Méthode. Tous les cas consécutifs de coma identifiés dans les services de pédiatrie du CHU de Lomé ont fait l'objet d'une étude prospective à partir d'une fiche d'enquête préétablie.

A novel method for screening the glutathione transferase inhibitors

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Węgrzyn Grzegorz

2009-03-01

Full Text Available Abstract Background Glutathione transferases (GSTs belong to the family of Phase II detoxification enzymes. GSTs catalyze the conjugation of glutathione to different endogenous and exogenous electrophilic compounds. Over-expression of GSTs was demonstrated in a number of different human cancer cells. It has been found that the resistance to many anticancer chemotherapeutics is directly correlated with the over-expression of GSTs. Therefore, it appears to be important to find new GST inhibitors to prevent the resistance of cells to anticancer drugs. In order to search for glutathione transferase (GST inhibitors, a novel method was designed. Results Our results showed that two fragments of GST, named F1 peptide (GYWKIKGLV and F2 peptide (KWRNKKFELGLEFPNL, can significantly inhibit the GST activity. When these two fragments were compared with several known potent GST inhibitors, the order of inhibition efficiency (measured in reactions with 2,4-dinitrochlorobenzene (CDNB and glutathione as substrates was determined as follows: tannic acid > cibacron blue > F2 peptide > hematin > F1 peptide > ethacrynic acid. Moreover, the F1 peptide appeared to be a noncompetitive inhibitor of the GST-catalyzed reaction, while the F2 peptide was determined as a competitive inhibitor of this reaction. Conclusion It appears that the F2 peptide can be used as a new potent specific GST inhibitor. It is proposed that the novel method, described in this report, might be useful for screening the inhibitors of not only GST but also other enzymes.

Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.

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Christian Prebensen

Full Text Available Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

Efficacy and tolerability of naproxen/esomeprazole magnesium tablets compared with non-specific NSAIDs and COX-2 inhibitors: a systematic review and network analyses

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Datto C

2013-02-01

Full Text Available Catherine Datto,1 Richard Hellmund,1 Mohd Kashif Siddiqui21AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA; 2HERON PVT India, Chandigarh, UT, IndiaAbstract: Non-steroidal anti-inflammatory drugs (NSAIDs, such as non-selective NSAIDs (nsNSAIDs or selective cyclooxygenase-2 (COX-2 inhibitors, are commonly prescribed for arthritic pain relief in patients with osteoarthritis (OA, rheumatoid arthritis (RA, or ankylosing spondylitis (AS. Treatment guidelines for chronic NSAID therapy include the consideration for gastroprotection for those at risk of gastric ulcers (GUs associated with the chronic NSAID therapy. The United States Food and Drug Administration has approved naproxen/esomeprazole magnesium tablets for the relief of signs and symptoms of OA, RA, and AS, and to decrease the risk of developing GUs in patients at risk of developing NSAID-associated GUs. The European Medical Association has approved this therapy for the symptomatic treatment of OA, RA, and AS in patients who are at risk of developing NSAID-associated GUs and/or duodenal ulcers, for whom treatment with lower doses of naproxen or other NSAIDs is not considered sufficient. Naproxen/esomeprazole magnesium tablets have been compared with naproxen and celecoxib for these indications in head-to-head trials. This systematic literature review and network meta-analyses of data from randomized controlled trials was performed to compare naproxen/esomeprazole magnesium tablets with a number of additional relevant comparators. For this study, an original review examined MEDLINE®, Embase®, and the Cochrane Controlled Trials Register from database start to April 14, 2009. Using the same methodology, a review update was conducted to December 21, 2009. The systematic review and network analyses showed naproxen/esomeprazole magnesium tablets have an improved upper gastrointestinal tolerability profile (dyspepsia and gastric or gastroduodenal ulcers over several active comparators (naproxen

Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α

International Nuclear Information System (INIS)

Maeda, Naoki; Kokai, Yasuo; Ohtani, Seiji; Sahara, Hiroeki; Kuriyama, Isoko; Kamisuki, Shinji; Takahashi, Shunya; Sakaguchi, Kengo; Sugawara, Fumio; Yoshida, Hiromi; Sato, Noriyuki; Mizushina, Yoshiyuki

2007-01-01

In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol α from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol α with IC 50 value of 0.5 μM, and did not influence the activities of other replicative pols such as pols δ and ε, but also showed no effect on pol α activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD 50 values of 38.0-44.4 μM. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol α-specific inhibitor, but also as a candidate drug for anti-cancer treatment

In silico simulations of STAT1 and STAT3 inhibitors predict SH2 domain cross-binding specificity.

Science.gov (United States)

Szelag, Malgorzata; Sikorski, Krzysztof; Czerwoniec, Anna; Szatkowska, Katarzyna; Wesoly, Joanna; Bluyssen, Hans A R

2013-11-15

Signal transducers and activators of transcription (STATs) comprise a family of transcription factors that are structurally related and which participate in signaling pathways activated by cytokines, growth factors and pathogens. Activation of STAT proteins is mediated by the highly conserved Src homology 2 (SH2) domain, which interacts with phosphotyrosine motifs for specific contacts between STATs and receptors and for STAT dimerization. By generating new models for human (h)STAT1, hSTAT2 and hSTAT3 we applied comparative in silico docking to determine SH2-binding specificity of the STAT3 inhibitor stattic, and of fludarabine (STAT1 inhibitor). Thus, we provide evidence that by primarily targeting the highly conserved phosphotyrosine (pY+0) SH2 binding pocket stattic is not a specific hSTAT3 inhibitor, but is equally effective towards hSTAT1 and hSTAT2. This was confirmed in Human Micro-vascular Endothelial Cells (HMECs) in vitro, in which stattic inhibited interferon-α-induced phosphorylation of all three STATs. Likewise, fludarabine inhibits both hSTAT1 and hSTAT3 phosphorylation, but not hSTAT2, by competing with the highly conserved pY+0 and pY-X binding sites, which are less well-preserved in hSTAT2. Moreover we observed that in HMECs in vitro fludarabine inhibits cytokine and lipopolysaccharide-induced phosphorylation of hSTAT1 and hSTAT3 but does not affect hSTAT2. Finally, multiple sequence alignment of STAT-SH2 domain sequences confirmed high conservation between hSTAT1 and hSTAT3, but not hSTAT2, with respect to stattic and fludarabine binding sites. Together our data offer a molecular basis that explains STAT cross-binding specificity of stattic and fludarabine, thereby questioning the present selection strategies of SH2 domain-based competitive small inhibitors. © 2013 Elsevier B.V. All rights reserved.

A new and specific non-NMDA receptor antagonist, FG 9065, blocks L-AP4-evoked depolarization in rat cerebral cortex.

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Sheardown, M J

1988-04-13

L(+)-AP4 (2-amino-4-phosphonobutyrate) depolarized slices of rat cerebral cortex, when applied following a 2 min priming application of quisqualate. This response diminishes with time and is not seen after NMDA application. A new selective non-N-methyl-D-aspartate (NMDA) antagonist, 6-cyano-7-nitro-2,3-dihydroxyquinoxaline (FG 9065), inhibits the L(+)-AP4 depolarization. It is argued that the response is mediated indirectly by postsynaptic quisqualate receptors.

99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen

International Nuclear Information System (INIS)

Xu, Xiaoping; Zhang, Jianping; Hu, Silong; He, Simin; Bao, Xiao; Ma, Guang; Luo, Jianmin; Cheng, Jingyi; Zhang, Yingjian

2017-01-01

Introduction: Prostate-specific membrane antigen (PSMA) is a well-established target in the development of radiopharmaceuticals for the diagnosis and therapy of prostate cancer (PCa). In this study, we evaluated a novel 99m Tc-labeled small molecular inhibitor of PSMA. Methods: This new small-molecular inhibitor of PSMA, 6-hydrazinonicotinate-Aminocaproic acid-Lysine-Urea-Glutamate (HYNIC-ALUG) was radiolabeled by 99m Tc and was evaluated both in vitro and in vivo using PCa models (PC-3 and LNCaP). Radiation dosimetry was assessed in mice. Results: 99m Tc-HYNIC-ALUG showed excellent stability in different media. A cell assay preliminarily displayed its specificity for PSMA. The inhibitor showed good pharmacokinetics making it suitable for in vivo imaging. PC-3-derived tumors showed no obvious radioactive uptake; however, the LNCaP-derived tumors showed very high radioactive uptake which was significantly decreased by the selective PSMA inhibitor 2-PMPA. Biodistribution in LNCaP xenografts showed an optimum tumor-to-blood ratio of 24.23 ± 3.54 at 2 h. Tumor uptake was also decreased in the inhibition experiment with 2-PMPA (19.45 ± 2.14%ID/g versus 1.42 ± 0.15%ID/g at 2 h). The effective dose of the 99m Tc-HYNIC-ALUG was 8.4E-04 mSv/MBq. Conclusions: A new 99m Tc-labeled PSMA inhibitor with specific accumulation in PSMA-positive tumors and low background in other organs was synthesized. The radiopharmaceutical also showed very low radiation dosimetry. This agent may significantly improve the diagnosis, staging, and subsequent monitoring of therapeutic effects in PCa patients.

Specific and non-specific match effects in negative priming.

Science.gov (United States)

Labossière, Danielle I; Leboe-McGowan, Jason P

2018-01-01

The negative priming effect occurs when withholding a response to a stimulus impairs generation of subsequent responding to a same or a related stimulus. Our goal was to use the negative priming procedure to obtain insights about the memory representations generated by ignoring vs. attending/responding to a prime stimulus. Across three experiments we observed that ignoring a prime stimulus tends to generate higher identity-independent, non-specific repetition effects, owing to an overlap in the coarse perceptual form of a prime distractor and a probe target. By contrast, attended repetition effects generate predominantly identity-specific sources of facilitation. We use these findings to advocate for using laboratory phenomena to illustrate general principles that can be of practical use to non-specialists. In the case of the negative priming procedure, we propose that the procedure provides a useful means for investigating attention/memory interactions, even if the specific cause (or causes) of negative priming effects remain unresolved. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor

OpenAIRE

Fang, Pengfei; Han, Hongyan; Wang, Jing; Chen, Kaige; Chen, Xin; Guo, Min

2015-01-01

Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits P. falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report 3 crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all 3 structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of...

Differentiation of eosinophilic leukemia EoL-1 cells into eosinophils induced by histone deacetylase inhibitors.

Science.gov (United States)

Ishihara, Kenji; Takahashi, Aki; Kaneko, Motoko; Sugeno, Hiroki; Hirasawa, Noriyasu; Hong, JangJa; Zee, OkPyo; Ohuchi, Kazuo

2007-03-06

EoL-1 cells differentiate into eosinophils in the presence of n-butyrate, but the mechanism has remained to be elucidated. Because n-butyrate can inhibit histone deacetylases, we hypothesized that the inhibition of histone deacetylases induces the differentiation of EoL-1 cells into eosinophils. In this study, using n-butyrate and two other histone deacetylase inhibitors, apicidin and trichostatin A, we have analyzed the relationship between the inhibition of histone deacetylases and the differentiation into eosinophils in EoL-1 cells. It was demonstrated that apicidin and n-butyrate induced a continuous acetylation of histones H4 and H3, inhibited the proliferation of EoL-1 cells without attenuating the level of FIP1L1-PDGFRA mRNA, and induced the expression of markers for mature eosinophils such as integrin beta7, CCR1, and CCR3 on EoL-1 cells, while trichostatin A evoked a transient acetylation of histones and induced no differentiation into eosinophils. These findings suggest that the continuous inhibition of histone deacetylases in EoL-1 cells induces the differentiation into mature eosinophils.

RAPID NAMING IN CHILDREN WITH SPECIFIC LANGUAGE IMPAIRMENT AND IN CHILDREN WITH TYPICAL LANGUAGE DEVELOPMENT

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Neda MILOSHEVIĆ

2017-03-01

Full Text Available Aimed at the detailed insight into the phonological ability of Serbian-speaking children of preschool age, with and without language impairment, the ability of rapid naming was examined. Method: Operationalization of the set goal was carried out by using the Test for evaluating reading and writing pre-skills. In describing and analyzing the obtained data, methods of descriptive and inferential statistics were used. The sample included 120 subjects of both gender, 40 children diagnosed with specific language impairment (SLI, age from 5,11 to 7 years, and 80 children with typical language development (TLD, age between 5,11 and 7 years, with no statistically significant differences in relation to age and gender of the participants. Results: Summing up the overall results and achievements of children with SLI and children with TLD, we concluded that there are statistically significant differences in the rapid naming between children with specific language impairment and children with typical language development. Conclusions: As it is a global trend to work on preventing disorders and obstructions, and phonological skills in this age are a timely indicator of the development of reading and writing skills, the examined children with SLI are at risk for the occurrence of obstructions and disorders in the area of reading and writing abilities.

Involvement of nitric oxide in granisetron improving effect on scopolamine-induced memory impairment in mice.

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Javadi-Paydar, Mehrak; Zakeri, Marjan; Norouzi, Abbas; Rastegar, Hossein; Mirazi, Naser; Dehpour, Ahmad Reza

2012-01-06

Granisetron, a serotonin 5-HT(3) receptor antagonist, widely used as an antiemetic drug following chemotherapy, has been found to improve learning and memory. In this study, effects of granisetron on spatial recognition memory and fear memory and the involvement of nitric oxide (NO) have been determined in a Y-maze and passive avoidance test. Granisetron (3, 10mg/kg, intraperitoneally) was administered to scopolamine-induced memory-impaired mice prior to acquisition, consolidation and retrieval phases, either in the presence or in the absence of a non-specific NO synthase inhibitor, l-NAME (3, 10mg/kg, intraperitoneally); a specific inducible NO synthase (iNOS) inhibitor, aminoguanidine (100mg/kg); and a NO precursor, l-arginine (750 mg/kg). It is demonstrated that granisetron improved memory acquisition in a dose-dependent manner, but it was ineffective on consolidation and retrieval phases of memory. The beneficial effect of granisetron (10mg/kg) on memory acquisition was significantly reversed by l-NAME (10mg/kg) and aminoguanidine (100mg/kg); however, l-arginine (750 mg/kg) did not potentiate the effect of sub-effective dose of granisetron (3mg/kg) in memory acquisition phase. It is concluded that nitric oxide is probably involved in improvement of memory acquisition by granisetron in both spatial recognition memory and fear memory. This article is part of a Special Issue entitled The Cognitive Neuroscience. Copyright © 2011 Elsevier B.V. All rights reserved.

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

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van Velzen, A S; Eckhardt, C L; Peters, M; Leebeek, F W G; Escuriola-Ettingshausen, C; Hermans, C; Keenan, R; Astermark, J; Male, C; Peerlinck, K; le Cessie, S; van der Bom, J G; Fijnvandraat, K

2017-07-01

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians

A Common Mechanism in Verb and Noun Naming Deficits in Alzheimer's Patients

Science.gov (United States)

Almor, Amit; Aronoff, Justin M.; MacDonald, Maryellen C.; Gonnerman, Laura M.; Kempler, Daniel; Hintiryan, Houri; Hayes, UnJa L.; Arunachalam, Sudha; Andersen, Elaine S.

2009-01-01

We tested the ability of Alzheimer's patients and elderly controls to name living and non-living nouns, and manner and instrument verbs. Patients' error patterns and relative performance with different categories showed evidence of graceful degradation for both nouns and verbs, with particular domain-specific impairments for living nouns and…

Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.

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Giroud, Maude; Dietzel, Uwe; Anselm, Lilli; Banner, David; Kuglstatter, Andreas; Benz, Jörg; Blanc, Jean-Baptiste; Gaufreteau, Delphine; Liu, Haixia; Lin, Xianfeng; Stich, August; Kuhn, Bernd; Schuler, Franz; Kaiser, Marcel; Brun, Reto; Schirmeister, Tanja; Kisker, Caroline; Diederich, François; Haap, Wolfgang

2018-04-26

Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( K i < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC 50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.

Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii.

Science.gov (United States)

Phillips, Robert S; Anderson, Andrew D; Gentry, Harvey G; Güner, Osman F; Bowen, J Phillip

2017-04-15

Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of k cat and k cat /K m comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with K I values lower than the K m for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a K I value of 1.5μM. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The K I for this compound was found to be 34μM, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO. Copyright © 2017 Elsevier Ltd. All rights reserved.

Radioiodinated 4-iodo-L-meta-tyrosine, a system L selective artificial amino acid: molecular design and transport characterization in Chinese hamster ovary cells (CHO-K1 cells)

Energy Technology Data Exchange (ETDEWEB)

Shikano, Naoto, E-mail: sikano@ipu.ac.j [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kotani, Takashi; Nakajima, Syuichi; Ogura, Masato; Nakazawa, Shinya [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Sagara, Jun-ichi [Center for Humanities and Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kobayashi, Masato [Division of Health Science, Graduate School of Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 9200-942 (Japan); Baba, Takeshi; Yamaguchi, Naoto [Center for Medical Science, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kubota, Nobuo [Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394 (Japan); Kawai, Keiichi [Division of Health Science, Graduate School of Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 9200-942 (Japan)

2010-11-15

Introduction: High expression of the system L amino acid transporter has been observed in clinically important tissues including tumors and the blood-brain barrier. We examined amino acid transport system L selectivity of {sup 14}C(U)-L-tyrosine ({sup 14}C-Tyr), {sup 125}I-4-iodo-L-meta-tyrosine (4-{sup 125}I-mTyr), {sup 125}I-6-iodo-L-meta-tyrosine (6-{sup 125}I-mTyr), {sup 125}I-3-iodo-{alpha}-methyl-L-tyrosine ({sup 125}I-IMT) and {sup 125}I-3-iodo-L-tyrosine (3-{sup 125}I-Tyr) using Chinese hamster ovary cells (CHO-K1). Methods: Cells in the exponential growth phase were incubated with 18.5 kBq of labeled amino acid in 2 mL of phosphate-buffered saline-based uptake solution and an uptake solution with/without Na{sup +} at 37{sup o}C or 4{sup o}C. We examined the effects of the following compounds (1.0 mM) on transport: 2-(methylamino)isobutyric acid (a specific inhibitor of system A, in Na{sup +}-containing uptake solution); 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (a specific inhibitor of system L, in Na{sup +}-free uptake solution); sodium azide and 2,4-dinitrophenol (NaN{sub 3} and DNP, inhibitors of the generation of adenosine triphosphate); p-aminohippurate and tetraethylammonium (PAH and TEA, inhibitors of organic anion and cation transporters); and L- and D-isomers of natural amino acids. Results: {sup 14}C-Tyr exhibited affinity for systems L, A and ASC. 4-{sup 125}I-mTyr and 3-{sup 125}I-Tyr exhibited high specificity for system L, whereas 6-{sup 125}I-mTyr and {sup 125}I-IMT exhibited affinity for both systems L and ASC. Uptake of 4-{sup 125}I-mTyr was markedly reduced by incubation at 4 {sup o}C, and was not significantly inhibited by NaN{sub 3}, DNP, PAH or TEA. The inhibition profiles of the L- and D-isomers of natural amino acids indicated that system L mediates the transport of 4-{sup 125}I-mTyr. Conclusions: 4-{sup 125}I-mTyr exhibited the greatest system L specificity (93.46{+-}0.13%) of all of the tested amino acids.

Crystal structures of Mycobacterium tuberculosis GlgE and complexes with non-covalent inhibitors

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Lindenberger, Jared J.; Veleti, Sri Kumar; Wilson, Brittney N.; Sucheck, Steven J.; Ronning, Donald R. (Toledo)

2015-08-06

GlgE is a bacterial maltosyltransferase that catalyzes the elongation of a cytosolic, branched α-glucan. In Mycobacterium tuberculosis (M. tb), inactivation of GlgE (Mtb GlgE) results in the rapid death of the organism due to a toxic accumulation of the maltosyl donor, maltose-1-phosphate (M1P), suggesting that GlgE is an intriguing target for inhibitor design. In this study, the crystal structures of the Mtb GlgE in a binary complex with maltose and a ternary complex with maltose and a maltosyl-acceptor molecule, maltohexaose, were solved to 3.3 Å and 4.0 Å, respectively. The maltohexaose structure reveals a dominant site for α-glucan binding. To obtain more detailed interactions between first generation, non-covalent inhibitors and GlgE, a variant Streptomyces coelicolor GlgEI (Sco GlgEI-V279S) was made to better emulate the Mtb GlgE M1P binding site. The structure of Sco GlgEI-V279S complexed with α-maltose-C-phosphonate (MCP), a non-hydrolyzable substrate analogue, was solved to 1.9 Å resolution, and the structure of Sco GlgEI-V279S complexed with 2,5-dideoxy-3-O-α-D-glucopyranosyl-2,5-imino-D-mannitol (DDGIM), an oxocarbenium mimic, was solved to 2.5 Å resolution. These structures detail important interactions that contribute to the inhibitory activity of these compounds, and provide information on future designs that may be exploited to improve upon these first generation GlgE inhibitors.

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis

Directory of Open Access Journals (Sweden)

Peng-Fei Wang

2017-10-01

Full Text Available Background: Treatment of cancers with programmed cell death protein 1 (PD-1 pathway inhibitors can lead to immune-related adverse events (irAEs, which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs.Methods: The MEDLINE, EMBASE, and Cochrane databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1 treatment; irAEs; and cancer. R© package Meta was used to pool incidence.Results: Forty-six studies representing 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents were included in the meta-analysis. The anti-PD-1/PD-L1 agents included nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and BMS-936559. The tumor types were melanomas, Hodgkin lymphomas, urothelial carcinomas, breast cancers, non-small cell lung cancers, renal cell carcinomas (RCC, colorectal cancers, and others. We described irAEs according to organ systems, namely, the skin (pruritus, rash, maculopapular rash, vitiligo, and dermatitis, endocrine system (hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency, digestive system (colitis, diarrhea, pancreatitis, and increased AST/ALT/bilirubin, respiratory system (pneumonitis, lung infiltration, and interstitial lung disease, and urinary system (increased creatinine, nephritis, and renal failure. In patients treated with the PD-1 signaling inhibitors, the overall incidence of irAEs was 26.82% (95% CI, 21.73–32.61; I2, 92.80 in any grade and 6.10% (95% CI, 4.85–7.64; I2, 52.00 in severe grade, respectively. The development of irAEs was unrelated to the dose of anti-PD-1/PD-L1 agents. The incidence of particular irAEs varied when different cancers were treated with different drugs. The incidence of death due to irAEs was around 0.17%.Conclusion: The occurrence of irAEs was organ-specific and related to drug and tumor types.

Orally administered L-arginine and glycine are highly effective against acid reflux esophagitis in rats

Science.gov (United States)

Nagahama, Kenji; Nishio, Hikaru; Yamato, Masanori; Takeuchi, Koji

2012-01-01

Summary Background Reflux esophagitis is caused mainly by excessive exposure of the mucosa to gastric contents. In the present study, we examined the effect of several amino acids on acid reflux esophagitis in rats. Material/Methods After 18 h of fasting, acid reflux esophagitis was induced by ligating both the pylorus and the transitional region between the forestomach and the corpus under ether anesthesia, and the animals were killed 4 h later. The severity of esophagitis was reduced by the oral administration of omeprazole, a proton pump inhibitor, or pepstatin, a specific pepsin inhibitor. Results The development of esophageal lesions was dose-dependently prevented by L-arginine and glycine, given intragastrically (i.g.) after the ligation, with complete inhibition obtained at 250 mg/kg and 750 mg/kg, respectively, and these effects were not influenced by the prior s.c. administration of indomethacin or L-NAME. By contrast, both L-alanine and L-glutamine given i.g. after the ligation aggravated these lesions in a dose-dependent manner. These amino acids had no effect on acid secretion but increased the pH of the gastric contents to 1.8~2.3 due to their buffering action. Conclusions The results confirmed an essential role for acid and pepsin in the pathogenesis of acid reflux esophagitis in the rat model and further suggested that various amino acids affect the severity of esophagitis in different ways, due to yet unidentified mechanisms; L-alanine and L-glutamine exert a deleterious effect on the esophagitis, while L-arginine and glycine are highly protective, independent of endogenous prostaglandins and nitric oxide. PMID:22207112

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

Energy Technology Data Exchange (ETDEWEB)

Lasko, Loren M.; Jakob, Clarissa G.; Edalji, Rohinton P.; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L.; Hansen, T. Matt; Risi, Roberto M.; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T.; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G.; Martin, Ruth L.; Torrent, Maricel; Chiang, Gary G.; Karukurichi, Kannan; Langston, J. William; Weinert, Brian T.; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H.; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A.; Rosenberg, Saul H.; Michaelides, Michael R.; Lai, Albert; Bromberg, Kenneth D. (AbbVie); (UCopenhagen); (Petra Pharma); (UPENN); (JHU); (Van Drie); (Faraday)

2017-09-27

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

Rational discovery of dengue type 2 non-competitive inhibitors.

Science.gov (United States)

Heh, Choon H; Othman, Rozana; Buckle, Michael J C; Sharifuddin, Yusrizam; Yusof, Rohana; Rahman, Noorsaadah A

2013-07-01

Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target, and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13 341 small compounds, with the backbone structures of chalcone, flavanone, and flavone, available in the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared with the standard ligand. Inhibition assay of the selected top-ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared with the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents. © 2013 John Wiley & Sons A/S.

Comparison of Alzheimer's disease with vascular dementia and non-dementia using specific voxel-based Z score maps

International Nuclear Information System (INIS)

Ishii, Shirou; Shishido, Fumio; Miyajima, Masayuki; Sakuma, Koutarou; Shigihara, Takeshi; Tameta, Tadanobu; Miyazaki, Makoto; Kuroda, Hiroshi

2009-01-01

We investigated the ability to discriminate between Alzheimer's disease (AD) and vascular dementia (VaD), and between AD and non-dementia using the program ''easy Z score imaging system'' (eZIS) developed by Matsuda et al., for the diagnosis of very early AD. Of 201 patients, we investigated 12 patients with AD, 10 with VaD, and 9 with non-dementia, who underwent brain perfusion single-photon emission computed tomography by technetium-99m ethyl cysteinate dimer ( 99m Tc-ECD) between February 2005 and September 2006. The sensitivity and specificity of the indicators of specific volume of interest (VOI) analysis, namely, severity, extent, and ratio were evaluated for the distinction of AD from VaD and non-dementia. There was a significant difference in all the criteria for severity, extent, and ratio between AD and non-dementia cases and in the ratio between AD and VaD. Between AD and non-dementia, the sensitivity and specificity of severity were 100% and 45%, respectively, using the cutoff value of 1.19. When using the cutoff value of 14.2 for extent, the sensitivity and specificity were both 100%. Using the cutoff value of 2.22 for ratio, the sensitivity of 42% and specificity of 100% were demonstrated. When comparing AD with VaD, using the cutoff value of 2.22 for ratio, the sensitivity and specificity were 42% and 100%, respectively. Using the cutoff value of 1.5 for ratio, the sensitivity and specificity between AD and VaD were 92% and 80%, respectively, thereby showing the best results. The specific VOI analysis program of AD using specific voxel-based Z score maps is not influenced by interobserver differences among radiologists and is useful to discriminate AD from VaD and non-dementia. However, the setting of the cutoff value at each institution and comparison with original and eZIS images are suggested to distinguish better AD from VaD. (author)

16 CFR 303.41 - Use of fiber trademarks and generic names in advertising.

Science.gov (United States)

2010-01-01

... use of a fiber trademark shall require a full disclosure of the fiber content information required by... or generic name is used in non-required information in advertising, such fiber trademark or generic... advertising. 303.41 Section 303.41 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC...

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors.

Science.gov (United States)

Li, Yingjun; Yu, Yang; Jin, Kun; Gao, Lixin; Luo, Tongchuan; Sheng, Li; Shao, Xin; Li, Jia

2014-09-01

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC50=1.18-8.01 μg/mL) and PTP1B (IC50=0.85-8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC50 values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na3VO4 (IC50=0.93 μg/mL) and oleanolic acid (IC50=0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Role of Non-specific and Specific Immune Systems in Poultry against Newcastle Disease

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Dyah Ayu Hewajuli

2015-09-01

Full Text Available Newcastle disease (ND is caused by avian paramyxovirus-1 which belong to Avulavirus genus and Paramyxoviridae family. The birds have abnormalities in humoral (bursa fabricius and cellular (thymus and spleen lymphoid organs. Lesions decrease the immune system. Immune system consists of non-specific and specific immune systems. The main components of non-specific immunity are physical and chemical barrier (feather and skin or mucosa, phagocytic cells (macrophages and natural killer, protein complement and the mediator of inflammation and cytokines. Interferons (IFNs belong to a group of cytokines that play a major role in the nonspecific or innate (natural immunity. The virulent ND virus encodes protein of V gene can be suppressed IFN type I. This leads to non-specific immune system fail to respond to the virulent strains resulting in severe pathogenicity. The defense mechanism of the host is replaced by specific immunity (adaptive immunity when natural immunity fails to overcome the infection. The specific immune system consists of humoral mediated immunity (HMI and cell-mediated immunity (CMI. The cells of immune system that react specifically with the antigen are B lymphocytes producing the antibodies, T lymphocytes that regulate the synthesis of antibodies and T cells as effector or the direct cytotoxic cells. Both non-specific and specific immunities are complementary against the invasion of ND virus in the birds. The objective of this article is to discuss the role of non specific and specific immune system in ND.

Unusual specific heat of almost dry L-cysteine and L-cystine amino acids.

Science.gov (United States)

Ishikawa, M S; Lima, T A; Ferreira, F F; Martinho, H S

2015-03-01

A detailed quantitative analysis of the specific heat in the 0.5- to 200-K temperature range for almost dry L-cysteine and its dimer, L-cystine, amino acids is presented. We report the occurrence of a sharp first-order transition at ∼76 K for L-cysteine associated with the thiol group ordering which was successfully modeled with the two-dimensional Ising model. We demonstrated that quantum rotors, two-level systems (TLS), Einstein oscillators, and acoustic phonons (the Debye model) are essential ingredients to correctly describe the overall experimental data. Our analysis pointed out the absence of the TLS contribution to the low temperature specific heat of L-cysteine. This result was similar to that found in other noncrystalline amorphous materials, e.g., amorphous silicon, low density amorphous water, and ultrastable glasses. L-cystine presented an unusual nonlinear acoustic dispersion relation ω(q)=vq0.95 and a Maxwell-Boltzmann-type distribution of tunneling barriers. The presence of Einstein oscillators with ΘE∼70 K was common in both systems and adequately modeled the boson peak contributions.

The control of neutrophil chemotaxis by inhibitors of cathepsin G and chymotrypsin.

Science.gov (United States)

Lomas, D A; Stone, S R; Llewellyn-Jones, C; Keogan, M T; Wang, Z M; Rubin, H; Carrell, R W; Stockley, R A

1995-10-06

Neutrophil chemotaxis plays an important role in the inflammatory response and when excessive or persistent may augment tissue damage. The effects of inhibitors indicated the involvement of one or more serine proteinases in human neutrophil migration and shape change in response to a chemoattractant. Monospecific antibodies, chloromethylketone inhibitors, and reactive-site mutants of alpha 1-antitrypsin and alpha 1-antichymotrypsin were used to probe the specificity of the proteinases involved in chemotaxis. Antibodies specific for cathepsin G inhibited chemotaxis. Moreover, rapid inhibitors of cathepsin G and alpha-chymotrypsin suppressed neutrophil chemotaxis to the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and zymosan-activated serum in multiple blind well assays and to fMLP in migration assays under agarose. The concentrations of antichymotrypsin mutants that reduced chemotaxis by 50% would inactivate free cathepsin G with a half-life of 1.5-3 s, whereas the concentrations of chloromethylketones required to produce a similar inhibition of chemotaxis would inactivate cathepsin G with a half-life of 345 s. These data suggest different modes of action for these two classes of inhibitors. Indeed the chloromethylketone inhibitors of cathepsin G (Z-Gly-Leu-Phe-CMK) and to a lesser extent of chymotrypsin (Cbz-Gly-Gly-Phe-CMK) mediated their effect by preventing a shape change in the purified neutrophils exposed to fMLP. Antichymotrypsin did not affect shape change in response to fMLP even at concentrations that were able to reduce neutrophil chemotaxis by 50%. These results support the involvement of cell surface proteinases in the control of cell migration and show that antichymotrypsin and chloromethylketones have differing modes of action. This opens the possibility for the rational design of anti-inflammatory agents targeted at neutrophil membrane enzymes.

Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

Science.gov (United States)

Kim, Se-Ho; Tangallapally, Rajendra; Kim, In Chul; Trovato, Richard; Parker, Daniel; Patton, J Scott; Reeves, Leslie; Bradford, Chad; Wettstein, Daniel; Baichwal, Vijay; Papac, Damon; Bajji, Ashok; Carlson, Robert; Yager, Kraig M

2015-11-15

Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Triterpenes as uncompetitive inhibitors of α-glucosidase from flowers of Punica granatum L.

Science.gov (United States)

Salah El Dine, Riham; Ma, Qiong; Kandil, Zeinab A; El-Halawany, Ali M

2014-01-01

The α-glucosidase and maltase inhibitory effects of Punica granatum L. flowers (PGF) were investigated. The methanol extract (PGFMe), n-hexane extract (PGFH), chloroform extract (PGFC) and the remaining water fraction (PGFW) were assayed for their α-glucosidase and maltase inhibitory effects. PGFW showed potent α-glucosidase inhibition with IC₅₀ of 0.8 μg/mL followed by PGFMe (IC₅₀ of 4.0 μg/mL) then PGFC (IC₅₀ of 5.21 μg/mL) in comparison to acarbose (0.9 μM). Due to its selectivity towards α-glucosidase, PGFC was subjected to bioactivity-guided isolation of its main active constituents. Five known compounds (1-5) were identified as β-sitosterol (1), oleanolic acid (2), ursolic acid (3), p-coumaric acid (4) and apigenin (5). Ursolic and oleanolic acids showed potent α-glucosidase inhibition (IC₅₀ of 39.0 and 35.0 μM, respectively), while they did not show significant maltase inhibition. Kinetic study using the double Lineweaver-Burk plot revealed that ursolic acid uncompetitively inhibited α-glucosidase in comparison with acarbose as a competitive inhibitor.

Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity.

Science.gov (United States)

Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio

2017-10-27

Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

Brand Suicide? Memory and Liking of Negative Brand Names.

Science.gov (United States)

Guest, Duncan; Estes, Zachary; Gibbert, Michael; Mazursky, David

2016-01-01

Negative brand names are surprisingly common in the marketplace (e.g., Poison perfume; Hell pizza, and Monster energy drink), yet their effects on consumer behavior are currently unknown. Three studies investigated the effects of negative brand name valence on brand name memory and liking of a branded product. Study 1 demonstrates that relative to non-negative brand names, negative brand names and their associated logos are better recognised. Studies 2 and 3 demonstrate that negative valence of a brand name tends to have a detrimental influence on product evaluation with evaluations worsening as negative valence increases. However, evaluation is also dependent on brand name arousal, with high arousal brand names resulting in more positive evaluations, such that moderately negative brand names are equally as attractive as some non-negative brand names. Study 3 shows evidence for affective habituation, whereby the effects of negative valence reduce with repeated exposures to some classes of negative brand name.

Brand Suicide? Memory and Liking of Negative Brand Names

Science.gov (United States)

Guest, Duncan; Estes, Zachary; Gibbert, Michael; Mazursky, David

2016-01-01

Negative brand names are surprisingly common in the marketplace (e.g., Poison perfume; Hell pizza, and Monster energy drink), yet their effects on consumer behavior are currently unknown. Three studies investigated the effects of negative brand name valence on brand name memory and liking of a branded product. Study 1 demonstrates that relative to non-negative brand names, negative brand names and their associated logos are better recognised. Studies 2 and 3 demonstrate that negative valence of a brand name tends to have a detrimental influence on product evaluation with evaluations worsening as negative valence increases. However, evaluation is also dependent on brand name arousal, with high arousal brand names resulting in more positive evaluations, such that moderately negative brand names are equally as attractive as some non-negative brand names. Study 3 shows evidence for affective habituation, whereby the effects of negative valence reduce with repeated exposures to some classes of negative brand name. PMID:27023872

AsmL Specification of a Ptolemy II Scheduler

DEFF Research Database (Denmark)

Lázaro Cuadrado, Daniel; Koch, Peter; Ravn, Anders Peter

2003-01-01

Ptolemy II is a tool that combines different computational models for simulation and design of embedded systems. AsmL is a software specification language based on the Abstract State Machine formalism. This paper reports on development of an AsmL model of the Synchronous Dataflow domain scheduler...

Naming Abilities in Low-Proficiency Second Language Learners

Science.gov (United States)

Borodkin, Katy; Faust, Miriam

2014-01-01

Difficulties in second language (L2) learning are often associated with recognizable learning difficulties in native language (L1), such as in dyslexia. However, some individuals have low L2 proficiency but intact L1 reading skills. These L2 learners experience frequent tip-of-the-tongue states while naming in L1, which indicates that they have a…

Stimulation of Oxytocin Receptor during Early Reperfusion Period Protects the Heart against Ischemia/Reperfusion Injury: the Role of Mitochondrial ATPSensitive Potassium Channel, Nitric Oxide, and Prostaglandins

Directory of Open Access Journals (Sweden)

Alireza Imani

2015-10-01

Full Text Available Postconditioning is a simple and safe strategy for cardioprotection and infarct size limitation. Ourprevious study showed that oxytocin (OT exerts postconditioning effect on ischemic/reperfused isolated ratheart. The aim of this study was to investigate the involvement of OT receptor, mitochondrial ATP-sensitivepotassium channel (mKATP, nitric oxide (NO and cyclooxygenase (COX pathways in OTpostconditioning. Isolated rat hearts were divided into10 groups and underwent 30 min of regional ischemiafollowed by 120 min of reperfusion (n =6. In I/R (ischemia/reperfusion group, ischemia and reperfusionwere induced without any treatment. In OT group, oxytocin was perfused 5 min prior to beginning ofreperfusion for 25 min. In groups 3-6, atosiban (oxytocin receptor blocker, L-NAME (N-Nitro-L-ArginineMethyl Ester, non-specific nitric oxide synthase inhibitor, 5-HD (5-hydroxydecanoate, mKATP inhibitorand indomethacin (cyclooxygenase inhibitor were infused prior to oxytocin administration. In others, thementioned inhibitors were perfused prior to ischemia without oxytocin infusion. Infarct size, ventricularhemodynamic, coronary effluent, malondialdehyde (MDA and lactate dehydrogenase (LDH were measuredat the end of reperfusion. OT perfusion significantly reduced infarct size, MDA and LDH in comparison withIR group. Atosiban, 5HD, L-NAME and indomethacin abolished the postconditioning effect of OT. Perfusionof the inhibitors alone prior to ischemia had no effect on infarct size, hemodynamic parameters, coronaryeffluent and biochemical markers as compared with I/R group. In conclusion, this study indicates thatpostconditioning effects of OT are mediated by activation of mKATP and production of NO andProstaglandins (PGs.

Theeffectivenessofginger compress on non-specific low back pain ...

African Journals Online (AJOL)

Theeffectivenessofginger compress on non-specific low back pain. ... for a total of ten sessions and control group (n=7) did not received any treatment. ... in pain relief and reduces functional disability in patients with non-specific low back pain.

Inhibition of the dapE-Encoded N-Succinyl-L,L-diaminopimelic Acid Desuccinylase from Neisseria meningitidis by L-Captopril

OpenAIRE

Starus, Anna; Nocek, Boguslaw; Bennett, Brian; Larrabee, James A.; Shaw, Daniel L.; Sae-Lee, Wisath; Russo, Marie T.; Gillner, Danuta M.; Makowska-Grzyska, Magdalena; Joachimiak, Andrzej; Holz, Richard C.

2015-01-01

Binding of the competitive inhibitor L-captopril to the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis (NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods. L-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE) with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a dose-responsive antibiotic activity toward Esch...

Fluorescent ligand fishing combination with in-situ imaging and characterizing to screen Hsp 90 inhibitors from Curcuma longa L. based on InP/ZnS quantum dots embedded mesoporous nanoparticles.

Science.gov (United States)

Hu, Yue; Fu, Anchen; Miao, Zhaoyi; Zhang, Xiaojing; Wang, Tianlin; Kang, An; Shan, Jinjun; Zhu, Dong; Li, Wei

2018-02-01

Although ligand fishing has been shown to be an efficient technique for the identification of bioactive components from complex mixtures such as natural products, it cannot be applied to biomedical image processing. Herein, a specific fluorescent ligand fishing combined with in situ imaging approach is presented for the identification of heat shock protein 90 (Hsp 90) inhibitors from complex matrixes, Curcuma longa L., using N-terminus immobilized Hsp 90α functionalized InP/ZnS quantum dots embedded mesoporous nanoparticles (i.e. Hsp 90α (NT)-FQDNs) as extraction sorbents and fluorescent tracer. The fished ligands were identified by liquid chromatography time-of-flight/mass spectrometry (LC-TOF/MS) and gas chromatography-mass spectrometry (GC-MS). Moreover, in situ imaging by confocal laser scanning microscopy (CLSM) was applied for evaluating the effect of fished-ligands on bioactivity-induced apoptosis morphologically in HeLa cells. MTT assay verified the bioactivity of the ligands and molecular docking results further provided convincing information to verify the feasible binding mode between ligands and protein. Twelve ligands as potential Hsp 90 inhibitors were ultimately fished and identified from Curcuma longa L. crude extracts. The proposed approach based on Hsp 90α functionalized nanocomposites is superior in the combination of highly specific screening efficiency and concurrent visual in situ imaging, which could have great promise for the development of other plant-derived Hsp 90 inhibitors, and providing a rapid and reliable platform for discovering biologically active molecules in natural products. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of SCAR marker specific to non-toxic Jatropha curcas L. and designing a novel multiplexing PCR along with nrDNA ITS primers to circumvent the false negative detection

KAUST Repository

Mastan, Shaik G.

2011-05-10

Jatropha curcas L., a multipurpose shrub, has acquired significant economic importance for its seed oil which can be converted to biodiesel an emerging alternative to petro-diesel. In addition to the commercial value, it is also having medicinal and even high nutritional value to use as animal fodder which is limited due to the toxicity. Development of molecular marker will enable to differentiate non-toxic from toxic variety of J. curcas in a mixed population and also for quality control since the toxic components of J. curcas has deleterious effect on animals. In the present study, the efforts were made to generate the specific SCAR marker for toxic and/or non-toxic J. curcas from RAPD markers. Among the markers specific for toxic and non-toxic varieties, four were selected, purified, cloned, sequenced, and designed primers out of which one set of primers NT-JC/SCAR I/OPQ15-F and R could able to discriminate the non-toxic with toxic Jatropha by giving expected 430 bp size amplification in non-toxic variety. Furthermore, novel multiplex PCR was designed using the nrDNA ITS primers to overcome the false negatives. Present work also demonstrates utility of the conserved regions of nrDNA coding genes in ruling out the artifacts in PCR-like false negatives frequently occur in SCAR due to various reasons. The specific SCAR markers generated in the present investigation will help to distinguish non-toxic from toxic varieties of J. curcas or vice versa, and isolated marker along with designed multiplex protocol has applications in quality control for selective cultivation of non-toxic variety and will also assist in breeding and molecular mapping studies. © 2011 Springer Science+Business Media, LLC.

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

DEFF Research Database (Denmark)

Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P

2017-01-01

-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft...... to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have...... also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent...

Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats.

Science.gov (United States)

Honda, Masashi; Yoshimura, Naoki; Hikita, Katsuya; Hinata, Nobuyuki; Muraoka, Kuniyasu; Saito, Motoaki; Chancellor, Michael B; Takenaka, Atsushi

2013-09-01

Glutamate is a major excitatory transmitter in the central nervous system, controlling lower urinary tract function. Five types of glutamate transporters such as GLAST (EAAT1), GLT-1 (EAAT2), EAAC-1 (EAAT3), EAAT4, and EAAT5 have been cloned so far. In the current study we tested whether L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), a non-selective inhibitor of glutamate transporters that increases endogenous glutamate concentration, can affect the micturition reflex in urethane anesthetized rats. Continuous cystometrograms (CMG, 0.04 ml/min infusion rate) were performed in two groups of urethane-anesthetized rats. A group of 18 rats was used for intrathecal administration of 1-10 µg of L-trans-PDC via an intrathecal catheter. In the second group of 18 rats, 1-10 µg of L-trans-PDC were administered intracerebroventricularly via a catheter inserted into the lateral ventricle. Micturition parameters were recorded and compared before and after drug administration. Intrathecal administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. Intracerebroventricular administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) also increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. The current results show that, in urethane-anesthetized rats, suppression of glutamate transporters by L-trans-PDC has an inhibitory effect on the micturition reflex at supraspinal and spinal sites, possibly via activation of glutamate-mediated inhibitory pathways. Copyright © 2012 Wiley Periodicals, Inc.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies

DEFF Research Database (Denmark)

Wemakor, Anthony; Casson, Karen; Garne, Ester

2015-01-01

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association be...

A Phase 1 Trial of an Immune Checkpoint Inhibitor plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer

Science.gov (United States)

2017-10-01

with Inoperable Stage I Non-Small Cell Lung Cancer PRINCIPAL INVESTIGATOR: Karen Kelly, MD CONTRACTING ORGANIZATION: University of California...Inhibitor plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer 5b. GRANT NUMBER W81XWH-15-2-0063...immune checkpoint inhibitor MPDL3280A (atezolizumab) in early stage inoperable non-small cell lung cancer . The trial is comprised of a traditional 3 + 3

Can You Say My Name?

DEFF Research Database (Denmark)

Erz, Antonia; Christensen, Bo T.

affect their judgments of people and objects. We extend this research by investigating the effect of phonological fluency on recognition and recall of novel non-word brand names in three laboratory experiments. The results provide us with a more fine-grained idea of fluency effects on memory of non...

Feeling-of-knowing for proper names.

Science.gov (United States)

Izaute, Marie; Chambres, Patrick; Larochelle, Serge

2002-12-01

The main objective of the presented study was to study feeling-of-knowing (FOK) in proper name retrieval. Many studies show that FOK can predict performance on a subsequent criterion test. Although feeling-of-knowing studies involve questions about proper names, none make this distinction between proper names and common names. Nevertheless, the specific character of proper names as a unique label referring to a person should allow participants to target precisely the desired verbal label. Our idea here was that the unique character of proper name information should result in more accurate FOK evaluations. In the experiment, participants evaluated feeling-of-knowing for proper and common name descriptions. The study demonstrates that FOK judgments are more accurate for proper names than for common names. The implications of the findings for proper names are briefly discussed in terms of feeling-of-knowing hypotheses.

What's in a Name? Sound Symbolism and Gender in First Names.

Directory of Open Access Journals (Sweden)

David M Sidhu

Full Text Available Although the arbitrariness of language has been considered one of its defining features, studies have demonstrated that certain phonemes tend to be associated with certain kinds of meaning. A well-known example is the Bouba/Kiki effect, in which nonwords like bouba are associated with round shapes while nonwords like kiki are associated with sharp shapes. These sound symbolic associations have thus far been limited to nonwords. Here we tested whether or not the Bouba/Kiki effect extends to existing lexical stimuli; in particular, real first names. We found that the roundness/sharpness of the phonemes in first names impacted whether the names were associated with round or sharp shapes in the form of character silhouettes (Experiments 1a and 1b. We also observed an association between femaleness and round shapes, and maleness and sharp shapes. We next investigated whether this association would extend to the features of language and found the proportion of round-sounding phonemes was related to name gender (Analysis of Category Norms. Finally, we investigated whether sound symbolic associations for first names would be observed for other abstract properties; in particular, personality traits (Experiment 2. We found that adjectives previously judged to be either descriptive of a figuratively 'round' or a 'sharp' personality were associated with names containing either round- or sharp-sounding phonemes, respectively. These results demonstrate that sound symbolic associations extend to existing lexical stimuli, providing a new example of non-arbitrary mappings between form and meaning.

Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

Science.gov (United States)

Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

2013-01-01

While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

Visual object naming in patients with small lesions centered at the left temporopolar region.

Science.gov (United States)

Campo, Pablo; Poch, Claudia; Toledano, Rafael; Igoa, José Manuel; Belinchón, Mercedes; García-Morales, Irene; Gil-Nagel, Antonio

2016-01-01

Naming is considered a left hemisphere function that operates according to a posterior-anterior specificity gradient, with more fine-grained information processed in most anterior regions of the temporal lobe (ATL), including the temporal pole (TP). Word finding difficulties are typically assessed using visual confrontation naming tasks, and have been associated with selective damage to ATL resulting from different aetiologies. Nonetheless, the role of the ATL and, more specifically, of the TP in the naming network is not completely established. Most of the accumulated evidence is based on studies on patients with extensive lesions, often bilateral. Furthermore, there is a considerable variability in the anatomical definition of ATL. To better understand the specific involvement of the left TP in visual object naming, we assessed a group of patients with an epileptogenic lesion centered at the TP, and compared their performance with that of a strictly matched control group. We also administered a battery of verbal and non-verbal semantic tasks that was used as a semantic memory baseline. Patients showed an impaired naming ability, manifesting in a certain degree of anomia and semantically related naming errors, which was influenced by concept familiarity. This pattern took place in a context of mild semantic dysfunction that was evident in different types and modalities of semantic tasks. Therefore, current findings demonstrate that a restricted lesion to the left TP can cause a significant deficit in object naming. Of importance, the observed semantic impairment was far from the devastating degradation observed in semantic dementia and other bilateral conditions.

L-Chicoric acid inhibits human immunodeficiency virus type 1 integration in vivo and is a noncompetitive but reversible inhibitor of HIV-1 integrase in vitro

International Nuclear Information System (INIS)

Reinke, Ryan A.; Lee, Deborah J.; McDougall, Brenda R.; King, Peter J.; Victoria, Joseph; Mao Yingqun; Lei Xiangyang; Reinecke, Manfred G.; Robinson, W. Edward

2004-01-01

The human immunodeficiency virus (HIV) integrase (IN) must covalently join the viral cDNA into a host chromosome for productive HIV infection. L-Chicoric acid (L-CA) enters cells poorly but is a potent inhibitor of IN in vitro. Using quantitative real-time polymerase chain reaction (PCR), L-CA inhibits integration at concentrations from 500 nM to 10 μM but also inhibits entry at concentrations above 1 μM. Using recombinant HIV IN, steady-state kinetic analyses with L-CA were consistent with a noncompetitive or irreversible mechanism of inhibition. IN, in the presence or absence of L-CA, was successively washed. Inhibition of IN diminished, demonstrating that L-CA was reversibly bound to the protein. These data demonstrate that L-CA is a noncompetitive but reversible inhibitor of IN in vitro and of HIV integration in vivo. Thus, L-CA likely interacts with amino acids other than those which bind substrate

Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives.

Science.gov (United States)

Tomasello, Chiara; Baldessari, Cinzia; Napolitano, Martina; Orsi, Giulia; Grizzi, Giulia; Bertolini, Federica; Barbieri, Fausto; Cascinu, Stefano

2018-03-01

In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months. Many genetic aberrations have been described as possible mechanisms of EGFR TKIs acquired resistance and can be clustered in four main sub-groups: 1. Development of secondary EGFR mutations; 2. Activation of parallel signaling pathways; 3. Histological transformation; 4. Activation of downstream signaling pathways. In this review we will describe the molecular alterations underlying each of these EGFR TKIs resistance mechanisms, focusing on the currently available and future therapeutic strategies to overcome these phenomena. Copyright © 2018 Elsevier B.V. All rights reserved.

Celecoxib versus a non-selective NSAID plus proton-pump inhibitor: what are the considerations?.

Science.gov (United States)

Chen, Judy T; Pucino, Frank; Resman-Targoff, Beth H

2006-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.

Development of novel arginase inhibitors for therapy of endothelial dysfunction

Directory of Open Access Journals (Sweden)

Jochen eSteppan

2013-09-01

Full Text Available Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO bioavailability, impaired NO signaling and an increase in the amount of reactive oxygen species (ROS. In the endothelium NO is produced by eNOS (endothelial nitric oxide synthase, for which L-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes L-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy-guanidinium or N-hydroxy-nor-L-arginine, and boronic acid derivatives, such as, 2(S-amino-6-boronohexanoic acid, and S-(2-boronoethyl-L-cysteine (BEC, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of α-α-disubstituted amino acid based arginase inhibitors (such as (R-2-amino-6-borono-2-(2-(piperidin-1-ylethylhexanoic acid, that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-β-D-glucopyranoside (PG. All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes.

Evaluation of some non-toxic thiadiazole derivatives as bronze corrosion inhibitors in aqueous solution

International Nuclear Information System (INIS)

Varvara, Simona; Muresan, Liana Maria; Rahmouni, Kamal; Takenouti, Hisasi

2008-01-01

The inhibiting effect of four innoxious thiadiazole derivatives (2-mercapto-5-amino-1,3,4-thiadiazole (MAT), 2-mercapto-5-acetylamino-1,3,4-thiadiazole (MAcAT), 2-mercapto-5-methyl-1,3,4-thiadiazole (MMeT) and 2-mercapto-5-phenylamino-1,3,4-thiadiazole (MPhAT)) on bronze corrosion in an aerated solution of 0.2 g L -1 Na 2 SO 4 + 0.2 g L -1 NaHCO 3 at pH 5 was studied by potentiodynamic voltammetry and electrochemical impedance spectroscopy. The corrosion parameters determined from the polarisation curves indicate that the addition of the investigated thiadiazole derivatives decreases both cathodic and anodic current densities, due to an inhibition of the corrosion process, through the adsorption of thiadiazoles on the bronze surface. The inhibiting effect of the investigated organic compounds appears to be more pronounced on the anodic process than on the cathodic one and, except for the case MPhAT, it is enhanced by the increases of the inhibitors' concentration. The adsorption of the thiadiazole derivatives on bronze was confirmed by the presence of the nitrogen atoms in the EDX spectra of the bronze exposed to inhibitor-containing solutions. The magnitude of polarisation resistance values and, consequently, the inhibition efficiencies are influenced by the molecular structure of thiadiazole derivatives. The strongest inhibition was noticed in the presence of compounds with phenyl amino- or amino-functionalities in their molecules. The maximum protection efficiencies were obtained by addition of: 5 mM MAT (95.9%), 1 mM MAcAT (95.7%), 5 mM MMeT (92.6%) and 0.1 mM MPhAT (97%). EIS measurements also revealed that the inhibitor effectiveness of the optimal concentrations of thiadiazole is time-dependent

Evaluation of some non-toxic thiadiazole derivatives as bronze corrosion inhibitors in aqueous solution

Energy Technology Data Exchange (ETDEWEB)

Varvara, Simona [Department of Topography, ' 1 Decembrie 1918' University, 11-13 Nicolae Iorga Street, 510009 Alba Iulia (Romania); Muresan, Liana Maria [Department of Physical Chemistry, ' Babes-Bolyai' University, 11 Arany-Janos Street, 400028 Cluj-Napoca (Romania)], E-mail: limur@chem.ubbcluj.ro; Rahmouni, Kamal; Takenouti, Hisasi [UPMC LISE - UPR 15 of the CNRS, ' Pierre and Marie Curie' University, Paris (France)

2008-09-15

The inhibiting effect of four innoxious thiadiazole derivatives (2-mercapto-5-amino-1,3,4-thiadiazole (MAT), 2-mercapto-5-acetylamino-1,3,4-thiadiazole (MAcAT), 2-mercapto-5-methyl-1,3,4-thiadiazole (MMeT) and 2-mercapto-5-phenylamino-1,3,4-thiadiazole (MPhAT)) on bronze corrosion in an aerated solution of 0.2 g L{sup -1} Na{sub 2}SO{sub 4} + 0.2 g L{sup -1} NaHCO{sub 3} at pH 5 was studied by potentiodynamic voltammetry and electrochemical impedance spectroscopy. The corrosion parameters determined from the polarisation curves indicate that the addition of the investigated thiadiazole derivatives decreases both cathodic and anodic current densities, due to an inhibition of the corrosion process, through the adsorption of thiadiazoles on the bronze surface. The inhibiting effect of the investigated organic compounds appears to be more pronounced on the anodic process than on the cathodic one and, except for the case MPhAT, it is enhanced by the increases of the inhibitors' concentration. The adsorption of the thiadiazole derivatives on bronze was confirmed by the presence of the nitrogen atoms in the EDX spectra of the bronze exposed to inhibitor-containing solutions. The magnitude of polarisation resistance values and, consequently, the inhibition efficiencies are influenced by the molecular structure of thiadiazole derivatives. The strongest inhibition was noticed in the presence of compounds with phenyl amino- or amino-functionalities in their molecules. The maximum protection efficiencies were obtained by addition of: 5 mM MAT (95.9%), 1 mM MAcAT (95.7%), 5 mM MMeT (92.6%) and 0.1 mM MPhAT (97%). EIS measurements also revealed that the inhibitor effectiveness of the optimal concentrations of thiadiazole is time-dependent.

[Design of an educational tool for Primary Care patients with chronic non-specific low back pain].

Science.gov (United States)

Díaz-Cerrillo, Juan Luis; Rondón-Ramos, Antonio

2015-02-01

Current scientific evidence on the management of chronic non-specific low back pain highlights the benefits of physical exercise. This goal is frequently undermined due to lack of education of the subjects on the multifactorial, benign, and non-specific nature of low back pain, which can lead to a chronic disease with genuine psychosocial risk factors. Its influence may not only interfere with individual decision to adopt more adaptive coping behaviors, but also with the endogenous mechanisms of pain neuromodulation. Thus, the educational strategies and control of these factors have become important objectives to be incorporated into the management of the disorder and research guidelines. This paper presents the theoretical models and the scientific basis on which it has based the design of an educational tool for patients with chronic non-specific low back pain treated in Primary Care physiotherapy. Structure, content and objectives are also presented. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Induction of CXC chemokines in human mesenchymal stem cells by stimulation with secreted frizzled-related proteins through non-canonical Wnt signaling.

Science.gov (United States)

Bischoff, David S; Zhu, Jian-Hua; Makhijani, Nalini S; Yamaguchi, Dean T

2015-12-26

To investigate the effect of secreted frizzled-related proteins (sFRPs) on CXC chemokine expression in human mesenchymal stem cells (hMSCs). CXC chemokines such as CXCL5 and CXCL8 are induced in hMSCs during differentiation with osteogenic differentiation medium (OGM) and may be involved in angiogenic stimulation during bone repair. hMSCs were treated with conditioned medium (CM) from L-cells expressing non-canonical Wnt5a protein, or with control CM from wild type L-cells, or directly with sFRPs for up to 10 d in culture. mRNA expression levels of both CXCL5 and CXCL8 were quantitated by real-time reverse transcriptase-polymerase chain reaction and secreted protein levels of these proteins determined by ELISA. Dose- (0-500 ng/mL) and time-response curves were generated for treatment with sFRP1. Signal transduction pathways were explored by western blot analysis with pan- or phosphorylation-specific antibodies, through use of specific pathway inhibitors, and through use of siRNAs targeting specific frizzled receptors (Fzd)-2 and 5 or the receptor tyrosine kinase-like orphan receptor-2 (RoR2) prior to treatment with sFRPs. CM from L-cells expressing Wnt5a, a non-canonical Wnt, stimulated an increase in CXCL5 mRNA expression and protein secretion in comparison to control L-cell CM. sFRP1, which should inhibit both canonical and non-canonical Wnt signaling, surprisingly enhanced the expression of CXCL5 at 7 and 10 d. Dickkopf1, an inhibitor of canonical Wnt signaling prevented the sFRP-stimulated induction of CXCL5 and actually inhibited basal levels of CXCL5 expression at 7 but not at 10 d post treatment. In addition, all four sFRPs isoforms induced CXCL8 expression in a dose- and time-dependent manner with maximum expression at 7 d with treatment at 150 ng/mL. The largest increases in CXCL5 expression were seen from stimulation with sFRP1 or sFRP2. Analysis of mitogen-activated protein kinase signaling pathways in the presence of OGM showed sFRP1-induced

Inhibition of the dapE-Encoded N-Succinyl-L,L-diaminopimelic Acid Desuccinylase from Neisseria meningitidis by L-Captopril.

Science.gov (United States)

Starus, Anna; Nocek, Boguslaw; Bennett, Brian; Larrabee, James A; Shaw, Daniel L; Sae-Lee, Wisath; Russo, Marie T; Gillner, Danuta M; Makowska-Grzyska, Magdalena; Joachimiak, Andrzej; Holz, Richard C

2015-08-11

Binding of the competitive inhibitor L-captopril to the dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis (NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods. L-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE) with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a dose-responsive antibiotic activity toward Escherichia coli. L-Captopril is also a competitive inhibitor of NmDapE with a Ki of 2.8 μM. To examine the nature of the interaction of L-captopril with the dinuclear active site of DapE, we have obtained electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) data for the enzymatically hyperactive Co(II)-substituted forms of both HiDapE and NmDapE. EPR and MCD data indicate that the two Co(II) ions in DapE are antiferromagnetically coupled, yielding an S = 0 ground state, and suggest a thiolate bridge between the two metal ions. Verification of a thiolate-bridged dinuclear complex was obtained by determining the three-dimensional X-ray crystal structure of NmDapE in complex with L-captopril at 1.8 Å resolution. Combination of these data provides new insights into binding of L-captopril to the active site of DapE enzymes as well as important inhibitor-active site residue interaction's. Such information is critical for the design of new, potent inhibitors of DapE enzymes.

Corrosion resistance of API 5L grade B steel with taro leaf (Colocasia esculenta) addition as corrosion inhibitor in HCl 0.1 M

Science.gov (United States)

Lestari, Yulinda; Priyotomo, Gadang

2018-05-01

Taro leaf (Colocasia esculenta) has the potential to be used as a corrosion inhibitor because it has a substance called polyphenol that binds to the hydroxyl group and essential amino acids. Taro leaf extract is taken by maceration method. In this study, the specimen was steel API 5L grade B that would measured the corosivity in 0.1 M HCl solution + taro leaf extract with a specific concentration (in ppm). Tests conducted by FTIR method taro leaves, potentiodynamic polarization (Tafel) and Electrochemical Impedance Spectroscopy (EIS). Based on the results revealed that there is a phenolic group in taro leaves, which has polyphenol content 0.053 % (mg/100 mg). The optimum composition of taro leaf extract is 4000 ppm which generate corrosion rate value of 30.22 mpy and efficiency inhibitor performance of 72.7 %. In this study, the Kads value of taro leaf extract ranged from 0.885 to greater than Kads value of ginger extract in hydrochloric acid solution. The high Kads values indicate a more efficient process of adsorption and better value of inhibition efficiency.

Absolute pitch: effects of timbre on note-naming ability.

Science.gov (United States)

Vanzella, Patrícia; Schellenberg, E Glenn

2010-11-11

Absolute pitch (AP) is the ability to identify or produce isolated musical tones. It is evident primarily among individuals who started music lessons in early childhood. Because AP requires memory for specific pitches as well as learned associations with verbal labels (i.e., note names), it represents a unique opportunity to study interactions in memory between linguistic and nonlinguistic information. One untested hypothesis is that the pitch of voices may be difficult for AP possessors to identify. A musician's first instrument may also affect performance and extend the sensitive period for acquiring accurate AP. A large sample of AP possessors was recruited on-line. Participants were required to identity test tones presented in four different timbres: piano, pure tone, natural (sung) voice, and synthesized voice. Note-naming accuracy was better for non-vocal (piano and pure tones) than for vocal (natural and synthesized voices) test tones. This difference could not be attributed solely to vibrato (pitch variation), which was more pronounced in the natural voice than in the synthesized voice. Although starting music lessons by age 7 was associated with enhanced note-naming accuracy, equivalent abilities were evident among listeners who started music lessons on piano at a later age. Because the human voice is inextricably linked to language and meaning, it may be processed automatically by voice-specific mechanisms that interfere with note naming among AP possessors. Lessons on piano or other fixed-pitch instruments appear to enhance AP abilities and to extend the sensitive period for exposure to music in order to develop accurate AP.

Absolute pitch: effects of timbre on note-naming ability.

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Patrícia Vanzella

2010-11-01

Full Text Available Absolute pitch (AP is the ability to identify or produce isolated musical tones. It is evident primarily among individuals who started music lessons in early childhood. Because AP requires memory for specific pitches as well as learned associations with verbal labels (i.e., note names, it represents a unique opportunity to study interactions in memory between linguistic and nonlinguistic information. One untested hypothesis is that the pitch of voices may be difficult for AP possessors to identify. A musician's first instrument may also affect performance and extend the sensitive period for acquiring accurate AP.A large sample of AP possessors was recruited on-line. Participants were required to identity test tones presented in four different timbres: piano, pure tone, natural (sung voice, and synthesized voice. Note-naming accuracy was better for non-vocal (piano and pure tones than for vocal (natural and synthesized voices test tones. This difference could not be attributed solely to vibrato (pitch variation, which was more pronounced in the natural voice than in the synthesized voice. Although starting music lessons by age 7 was associated with enhanced note-naming accuracy, equivalent abilities were evident among listeners who started music lessons on piano at a later age.Because the human voice is inextricably linked to language and meaning, it may be processed automatically by voice-specific mechanisms that interfere with note naming among AP possessors. Lessons on piano or other fixed-pitch instruments appear to enhance AP abilities and to extend the sensitive period for exposure to music in order to develop accurate AP.

The structure of FIV reverse transcriptase and its implications for non-nucleoside inhibitor resistance.

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Meytal Galilee

2018-01-01

Full Text Available Reverse transcriptase (RT is the target for the majority of anti-HIV-1 drugs. As with all anti-AIDS treatments, continued success of RT inhibitors is persistently disrupted by the occurrence of resistance mutations. To explore latent resistance mechanisms potentially accessible to therapeutically challenged HIV-1 viruses, we examined RT from the related feline immunodeficiency virus (FIV. FIV closely parallels HIV-1 in its replication and pathogenicity, however, is resistant to all non-nucleoside inhibitors (NNRTI. The intrinsic resistance of FIV RT is particularly interesting since FIV harbors the Y181 and Y188 sensitivity residues absent in both HIV-2 and SIV. Unlike RT from HIV-2 or SIV, previous efforts have failed to make FIV RT susceptible to NNRTIs concluding that the structure or flexibility of the feline enzyme must be profoundly different. We report the first crystal structure of FIV RT and, being the first structure of an RT from a non-primate lentivirus, enrich the structural and species repertoires available for RT. The structure demonstrates that while the NNRTI binding pocket is conserved, minor subtleties at the entryway can render the FIV RT pocket more restricted and unfavorable for effective NNRTI binding. Measuring NNRTI binding affinity to FIV RT shows that the "closed" pocket configuration inhibits NNRTI binding. Mutating the loop residues rimming the entryway of FIV RT pocket allows for NNRTI binding, however, it does not confer sensitivity to these inhibitors. This reveals a further layer of resistance caused by inherent FIV RT variances that could have enhanced the dissociation of bound inhibitors, or, perhaps, modulated protein plasticity to overcome inhibitory effects of bound NNRTIs. The more "closed" conformation of FIV RT pocket can provide a template for the development of innovative drugs that could unlock the constrained pocket, and the resilient mutant version of the enzyme can offer a fresh model for the study

Formation and characterization of non-growth states in Clostridium thermocellum: spores and L-forms

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Mearls Elizabeth B

2012-08-01

Full Text Available Abstract Background Clostridium thermocellum is an anaerobic thermophilic bacterium that exhibits high levels of cellulose solublization and produces ethanol as an end product of its metabolism. Using cellulosic biomass as a feedstock for fuel production is an attractive prospect, however, growth arrest can negatively impact ethanol production by fermentative microorganisms such as C. thermocellum. Understanding conditions that lead to non-growth states in C. thermocellum can positively influence process design and culturing conditions in order to optimize ethanol production in an industrial setting. Results We report here that Clostridium thermocellum ATCC 27405 enters non-growth states in response to specific growth conditions. Non-growth states include the formation of spores and a L-form-like state in which the cells cease to grow or produce the normal end products of metabolism. Unlike other sporulating organisms, we did not observe sporulation of C. thermocellum in low carbon or nitrogen environments. However, sporulation did occur in response to transfers between soluble and insoluble substrates, resulting in approximately 7% mature spores. Exposure to oxygen caused a similar sporulation response. Starvation conditions during continuous culture did not result in spore formation, but caused the majority of cells to transition to a L-form state. Both spores and L-forms were determined to be viable. Spores exhibited enhanced survival in response to high temperature and prolonged storage compared to L-forms and vegetative cells. However, L-forms exhibited faster recovery compared to both spores and stationary phase cells when cultured in rich media. Conclusions Both spores and L-forms cease to produce ethanol, but provide other advantages for C. thermocellum including enhanced survival for spores and faster recovery for L-forms. Understanding the conditions that give rise to these two different non-growth states, and the implications that

Small-molecule inhibitors of sodium iodide sym-porter function

International Nuclear Information System (INIS)

Lecat-Guillet, N.; Merer, G.; Lopez, R.; Rousseau, B.; Ambroise, Y.; Pourcher, T.

2008-01-01

The Na + /l - sym-porter (NIS) mediates iodide uptake into thyroid follicular cells. Although NIS has been cloned and thoroughly studied at the molecular level, the biochemical processes involved in post-translational regulation of NIS are still unknown. The purpose of this study was to identify and characterize inhibitors of NIS function. These small organic molecules represent a starting point in the identification of pharmacological tools for the characterization of NIS trafficking and activation mechanisms. screening of a collection of 17020 drug-like compounds revealed new chemical inhibitors with potencies down to 40 nM. Fluorescence measurement of membrane potential indicates that these inhibitors do not act by disrupting the sodium gradient. They allow immediate and total iodide discharge from preloaded cells in accord with a specific modification of NIS activity, probably through distinct mechanisms. (authors)

Small-molecule inhibitors of sodium iodide sym-porter function

Energy Technology Data Exchange (ETDEWEB)

Lecat-Guillet, N.; Merer, G.; Lopez, R.; Rousseau, B.; Ambroise, Y. [CEA, DSV, Dept Bioorgan Chem et Isotop Labelling, Inst Biol et Biotechnol iBiTecS, F-91191 Gif Sur Yvette (France); Pourcher, T. [Univ Nice Sophia Antipolis, Dept Biochem et Nucl Toxicol, F-06107 Nice (France)

2008-07-01

The Na{sup +}/l{sup -} sym-porter (NIS) mediates iodide uptake into thyroid follicular cells. Although NIS has been cloned and thoroughly studied at the molecular level, the biochemical processes involved in post-translational regulation of NIS are still unknown. The purpose of this study was to identify and characterize inhibitors of NIS function. These small organic molecules represent a starting point in the identification of pharmacological tools for the characterization of NIS trafficking and activation mechanisms. screening of a collection of 17020 drug-like compounds revealed new chemical inhibitors with potencies down to 40 nM. Fluorescence measurement of membrane potential indicates that these inhibitors do not act by disrupting the sodium gradient. They allow immediate and total iodide discharge from preloaded cells in accord with a specific modification of NIS activity, probably through distinct mechanisms. (authors)

An in silico high-throughput screen identifies potential selective inhibitors for the non-receptor tyrosine kinase Pyk2

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Meirson T

2017-05-01

Full Text Available Tomer Meirson, Abraham O Samson, Hava Gil-Henn Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel Abstract: The non-receptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2 is a critical mediator of signaling from cell surface growth factor and adhesion receptors to cell migration, proliferation, and survival. Emerging evidence indicates that signaling by Pyk2 regulates hematopoietic cell response, bone density, neuronal degeneration, angiogenesis, and cancer. These physiological and pathological roles of Pyk2 warrant it as a valuable therapeutic target for invasive cancers, osteoporosis, Alzheimer’s disease, and inflammatory cellular response. Despite its potential as a therapeutic target, no potent and selective inhibitor of Pyk2 is available at present. As a first step toward discovering specific potential inhibitors of Pyk2, we used an in silico high-throughput screening approach. A virtual library of six million lead-like compounds was docked against four different high-resolution Pyk2 kinase domain crystal structures and further selected for predicted potency and ligand efficiency. Ligand selectivity for Pyk2 over focal adhesion kinase (FAK was evaluated by comparative docking of ligands and measurement of binding free energy so as to obtain 40 potential candidates. Finally, the structural flexibility of a subset of the docking complexes was evaluated by molecular dynamics simulation, followed by intermolecular interaction analysis. These compounds may be considered as promising leads for further development of highly selective Pyk2 inhibitors. Keywords: virtual screen, efficiency metrics, MM-GBSA, molecular dynamics

Design and synthesis of N₁-aryl-benzimidazoles 2-substituted as novel HIV-1 non-nucleoside reverse transcriptase inhibitors.

Science.gov (United States)

Monforte, Anna-Maria; Ferro, Stefania; De Luca, Laura; Lo Surdo, Giuseppa; Morreale, Francesca; Pannecouque, Christophe; Balzarini, Jan; Chimirri, Alba

2014-02-15

A series of novel N1-aryl-2-arylthioacetamido-benzimidazoles were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Some of them proved to be effective in inhibiting HIV-1 replication at submicromolar and nanomolar concentration acting as HIV-1 non-nucleoside RT inhibitors (NNRTIs), with low cytotoxicity. The preliminary structure-activity relationship (SAR) of these new derivatives was discussed and rationalized by docking studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Isolation and characterization of a specific endogenous Na/sup +/, K/sup +/-ATPase inhibitor from bovine adrenal

Energy Technology Data Exchange (ETDEWEB)

Tamura, M.; Lam, T.T.; Inagami, T.

1988-06-14

In order to identify a specific endogenous Na/sup +/,K/sup +/-ATPase inhibitor which could possibly be related to salt-dependent hypertension, the authors looked for substances in the methanol extract of bovine whole adrenal which show all of the following properties: (i) inhibitory activity for Na/sup +/,K/sup +/-ATPase; (ii) competitive displacing activity against (/sup 3/H)ouabain binding to the enzyme; (iii) inhibitory activity for /sup 86/Rb uptake into intact human erythrocytes; and (iv) cross-reactivity with sheep anti-digoxin-specific antibody. After stepwise fractionation of the methanol extract of bovine adrenal glands by chromatography on a C/sub 18/ open column, a 0-15% acetonitrile fraction was fractionated by high-performance liquid chromatography on a Zorbax octadecylsilane column. One of the most active fractions in 0-15% acetonitrile was found to exhibit all of the four types of the activities. It was soluble in water and was distinct from various substances which have been known to inhibit Na/sup +/,K/sup +/-ATPase. These results strongly suggest that this water-soluble nonpeptidic Na/sup +/,K/sup +/-ATPase inhibitor may be a specific endogenous regulator for the ATPase.

On 'lost' indigenous etymological origins with the specific case of the name Ameiva.

Science.gov (United States)

Angeli, Nicole Frances

2018-01-01

Modern biology builds upon the historic exploration of the natural world. Recognizing the origin of a species' name is one path to honor the historic exploration and description of the natural world and the indigenous peoples that lived closely with organisms prior to their description. While digitization of historic papers catalogued in databases such as the Biodiversity Heritage Library (BHL) allows for searching of the first use and origin of names, the rapid pace of taxonomic publishing can occlude a thorough search for etymologies. The etymological origin of the genus name Ameiva is one such case; while unattributed in multiple recent works, it is of Tupí language origin. The first description was in the Historiae Rerum Naturalium Brasiliae by George Marcgrave (1648). Ameiva was the name used by Marcgrave's Amerindian hosts in 17 th century Dutch Brazil, where local people spoke the now extinct language Tupí. The Tupí origin was not lost, however, until as recently as the 2000s. Herein, the pre- and post-Linnaean use of the name Ameiva is traced and when the name is attributed to the Tupí language and to Marcgrave through time it is noted. The opportunity to discover and/or recover etymological origins, especially names from extinct and indigenous languages, provides insight into the early Western sciences. Careful study of etymology by naturalists is consistent with the idea that science is an evolving process with many predecessors to appreciate.

Detection of cut-off point for rapid automized naming test in good readers and dyslexics

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Zahra Soleymani

2014-01-01

Full Text Available Background and Aim: Rapid automized naming test is an appropriate tool to diagnose learning disability even before teaching reading. This study aimed to detect the cut-off point of this test for good readers and dyslexics.Methods: The test has 4 parts including: objects, colors, numbers and letters. 5 items are repeated on cards randomly for 10 times. Children were asked to name items rapidly. We studied 18 dyslexic students and 18 age-matched good readers between 7 and 8 years of age at second and third grades of elementary school; they were recruited by non-randomize sampling into 2 groups: children with developmental dyslexia from learning disabilities centers with mean age of 100 months, and normal children with mean age of 107 months from general schools in Tehran. Good readers selected from the same class of dyslexics.Results: The area under the receiver operating characteristic curve was 0.849 for letter naming, 0.892 for color naming, 0.971 for number naming, 0.887 for picture naming, and 0.965 totally. The overall sensitivity and specificity was 1 and was 0.79, respectively. The highest sensitivity and specificity were related to number naming (1 and 0.90, respectively.Conclusion: Findings showed that the rapid automized naming test could diagnose good readers from dyslexics appropriately.

Effects of Prolyl Hydroxylase Inhibitor L-mimosine on Dental Pulp in the Presence of Advanced Glycation End Products.

Science.gov (United States)

Müller, Heinz-Dieter; Cvikl, Barbara; Janjić, Klara; Nürnberger, Sylvia; Moritz, Andreas; Gruber, Reinhard; Agis, Hermann

2015-11-01

Proangiogenic prolyl hydroxylase (PHD) inhibitors represent a novel approach to stimulate tissue regeneration. Diabetes mellitus involves the accumulation of advanced glycation end products (AGEs). Here we evaluated the impact of AGEs on the response of human pulp tissue to the PHD inhibitor L-mimosine (L-MIM) in monolayer cultures of dental pulp-derived cells (DPCs) and tooth slice organ cultures. In monolayer cultures, DPCs were incubated with L-MIM and AGEs. Viability was assessed based on formazan formation, live-dead staining, annexin V/propidium iodide, and trypan blue exclusion assay. Vascular endothelial growth factor (VEGF), interleukin (IL)-6, and IL-8 production was evaluated by quantitative polymerase chain reaction and immunoassays. Furthermore, expression levels of odontoblast markers were assessed, and alizarin red staining was performed. Tooth slice organ cultures were performed, and VEGF, IL-6, and IL8 levels in their supernatants were measured by immunoassays. Pulp tissue vitality and morphology were assessed by MTT assay and histology. In monolayer cultures of DPCs, L-MIM at nontoxic concentrations increased the production of VEGF and IL-8 in the presence of AGEs. Stimulation with L-MIM decreased alkaline phosphatase levels and matrix mineralization also in the presence of AGEs, whereas no significant changes in dentin matrix protein 1 and dentin sialophosphoprotein expression were observed. In tooth slice organ cultures, L-MIM increased VEGF but not IL-6 and IL-8 production in the presence of AGEs. The pulp tissue was vital, and no signs of apoptosis or necrosis were observed. Overall, in the presence of AGEs, L-MIM increases the proangiogenic capacity, but decreases alkaline phosphatase expression and matrix mineralization. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Enhancement of vascular targeting by inhibitors of nitric oxide synthase

International Nuclear Information System (INIS)

Davis, Peter D.; Tozer, Gillian M.; Naylor, Matthew A.; Thomson, Peter; Lewis, Gemma; Hill, Sally A.

2002-01-01

Purpose: This study investigates the enhancement of the vascular targeting activity of the tubulin-binding agent combretastatin A4 phosphate (CA4P) by various inhibitors of nitric oxide synthases. Methods and Materials: The syngeneic tumors CaNT and SaS growing in CBA mice were used for this study. Reduction in perfused vascular volume was measured by injection of Hoechst 33342 24 h after drug administration. Necrosis (hematoxylin and eosin stain) was assessed also at 24 h after treatment. Combretastatin A4 phosphate was synthesized by a modification of the published procedure and the nitric oxide synthase inhibitors L-NNA, L-NMMA, L-NIO, L-NIL, S-MTC, S-EIT, AMP, AMT, and L-TC, obtained from commercial sources. Results: A statistically significant augmentation of the reduction in perfused vascular volume by CA4P in the CaNT tumor was observed with L-NNA, AMP, and AMT. An increase in CA4P-induced necrosis in the same tumor achieved significance with L-NNA, L-NMMA, L-NIL, and AMT. CA4P induced little necrosis in the SaS tumor, but combination with the inhibitors L-NNA, L-NMMA, L-NIO, S-EIT, and L-TC was effective. Conclusions: Augmentation of CA4P activity by nitric oxide synthase inhibitors of different structural classes supports a nitric oxide-related mechanism for this effect. L-NNA was the most effective inhibitor studied

Optimised production of L-glutaminase: A tumour inhibitor from ...

African Journals Online (AJOL)

Jane

2011-10-17

Oct 17, 2011 ... on the production of L-glutaminase was studied and accordingly, optimum conditions were ... tumour cells has been specifically compared with that in ... will be produced more easily by solid state fermentation ... Erlenmeyer conical flasks and moistened with 10 ml of salt solution ..... in a packed bed reactor.

The effects of watermelon (Citrullus lanatus) extracts and L-citrulline on rat uterine contractility.

Science.gov (United States)

Munglue, Phukphon; Eumkep, Graingsak; Wray, Susan; Kupittayanant, Sajeera

2013-04-01

In uterine smooth muscle, the effects of watermelon and its citrulline content are unknown. The aims of this study were therefore, to determine the effects of watermelon extract and citrulline on the myometrium and to investigate their mechanisms of action. The effects of extracts of watermelon flesh and rind and L-citrulline (64 μmol/L) were evaluated on 3 types of contractile activity; spontaneous, those elicited by potassium chloride (KCl) depolarization, or oxytocin (10 nmol/L) application in isolated rat uterus. Inhibitors of nitric oxide (NO) and its mechanisms of action, N ω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 μmol/L), LY83583 (1 μmol/L), and tetraethylamonium chloride (5 mmol/L), as well as Ca signaling pathways, were determined. Both flesh and rind extracts significantly decreased the force produced by all 3 mechanisms, in a dose-dependent manner. The extracts could also significantly decrease the force under conditions of sustained high Ca levels (depolarization and agonist) and when the force was produced only by sarcoplasmic reticulum (SR) Ca release. L-citrulline produced the same effects on force as watermelon extracts. With submaximal doses of extract, the additive effects of L-citrulline were found. The inhibitory effects of extracts and L-citrulline were reversed upon the addition of NO inhibitors, and pretreatment of tissues with these inhibitors prevented the actions of both extracts and L-citrulline. Thus, these data show that watermelon and citrulline are potent tocolytics, decreasing the force produced by calcium entry and SR release and arising by different pathways, including oxytocin stimulation. Their major mechanism is to stimulate the NO-cyclic guanosine monophosphate (cGMP) relaxant pathway.

E3L and F1L Gene Functions Modulate the Protective Capacity of Modified Vaccinia Virus Ankara Immunization in Murine Model of Human Smallpox

Directory of Open Access Journals (Sweden)

Asisa Volz

2018-01-01

Full Text Available The highly attenuated Modified Vaccinia virus Ankara (MVA lacks most of the known vaccinia virus (VACV virulence and immune evasion genes. Today MVA can serve as a safety-tested next-generation smallpox vaccine. Yet, we still need to learn about regulatory gene functions preserved in the MVA genome, such as the apoptosis inhibitor genes F1L and E3L. Here, we tested MVA vaccine preparations on the basis of the deletion mutant viruses MVA-ΔF1L and MVA-ΔE3L for efficacy against ectromelia virus (ECTV challenge infections in mice. In non-permissive human tissue culture the MVA deletion mutant viruses produced reduced levels of the VACV envelope antigen B5. Upon mousepox challenge at three weeks after vaccination, MVA-ΔF1L and MVA-ΔE3L exhibited reduced protective capacity in comparison to wildtype MVA. Surprisingly, however, all vaccines proved equally protective against a lethal ECTV infection at two days after vaccination. Accordingly, the deletion mutant MVA vaccines induced high levels of virus-specific CD8+ T cells previously shown to be essential for rapidly protective MVA vaccination. These results suggest that inactivation of the anti-apoptotic genes F1L or E3L modulates the protective capacity of MVA vaccination most likely through the induction of distinct orthopoxvirus specific immunity in the absence of these viral regulatory proteins.

Effects and Mechanisms of Checkpoint Inhibitors (CTLA-4, PD-1 and PD-L1 Inhibitors as New Immunotherapeutic Agents for Bladder Cancer

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Serdar Çelik

2018-04-01

Full Text Available Since intravesical Bacillus Calmette-Guerin (BCG began to be used for bladder cancer, our understanding of the importance of immune mechanisms in bladder cancer has steadily grown. With developments in immunotherapy in recent years, the use of new immunotherapeutic agents for bladder cancer, especially chemotherapy-resistant invasive and metastatic cancers, has opened the way for research in this area. Of these new therapeutic agents, this article reviews studies published on PubMed or listed on the ClinicalTrials.gov website as of December 2017 regarding the effects and mechanisms of action of checkpoint inhibitors [cytotoxic t-lymphocyte associated protein-4, programmed cell death 1 receptor (PD-1 and PD-1 ligand inhibitors] on bladder cancer. Because checkpoint inhibitors were first used for chemotherapy-resistant bladder cancer after identification of positive expression in tumor cells and especially in tumor-infiltrating mononuclear cells, significant objective response rates and survival advantages have been reported. Research continues regarding the use of these agents as first- and second-line treatment for metastatic disease in combination with chemotherapy; their efficacy in neoadjuvant, adjuvant, and bladder-preserving approaches to muscle-invasive bladder cancer (MIBC disease, and their use in non-muscle-invasize bladder cancer (NMIBC, especially BCG-refractory disease. Depending on the results of these ongoing studies, immunotherapy may direct the treatment of bladder cancer in the future.

Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease▿ †

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Young, Thomas P.; Parkin, Neil T.; Stawiski, Eric; Pilot-Matias, Tami; Trinh, Roger; Kempf, Dale J.; Norton, Michael

2010-01-01

Patterns of HIV-1 protease inhibitor (PI) resistance-associated mutations (RAMs) and effects on PI susceptibility associated with the L76V mutation were studied in a large database. Of 20,501 sequences with ≥1 PI RAM, 3.2% contained L76V; L76V was alone in 0.04%. Common partner mutations included M46I, I54V, V82A, I84V, and L90M. L76V was associated with a 2- to 6-fold decrease in susceptibility to lopinavir, darunavir, amprenavir, and indinavir and a 7- to 8-fold increase in susceptibility to atazanavir and saquinavir. PMID:20805393

Structural optimization of N1-aryl-benzimidazoles for the discovery of new non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1 strains.

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Monforte, Anna Maria; De Luca, Laura; Buemi, Maria Rosa; Agharbaoui, Fatima E; Pannecouque, Christophe; Ferro, Stefania

2018-02-01

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N 1 -aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse transcriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N 1 -aryl-2-arylthioacetamido-benzimidazoles and N 1 -aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

Science.gov (United States)

Zhu, Wei; Chen, Hui; Wang, Yulan; Wang, Jiang; Peng, Xia; Chen, Xianjie; Gao, Yinglei; Li, Chunpu; He, Yulong; Ai, Jing; Geng, Meiyu; Zheng, Mingyue; Liu, Hong

2017-07-27

A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure-activity relationship (SAR) of its analogues was then explored to afford novel FGFR inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound 3m not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L858R, DDR2, and ALK. Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.

Flavonoid glycosides isolated from unique legume plant extracts as novel inhibitors of xanthine oxidase.

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Chrysoula Spanou

Full Text Available Legumes and the polyphenolic compounds present in them have gained a lot of interest due to their beneficial health implications. Dietary polyphenolic compounds, especially flavonoids, exert antioxidant properties and are potent inhibitors of xanthine oxidase (XO activity. XO is the main contributor of free radicals during exercise but it is also involved in pathogenesis of several diseases such as vascular disorders, cancer and gout. In order to discover new natural, dietary XO inhibitors, some polyphenolic fractions and pure compounds isolated from two legume plant extracts were tested for their effects on XO activity. The fractions isolated from both Vicia faba and Lotus edulis plant extracts were potent inhibitors of XO with IC(50 values range from 40-135 µg/mL and 55-260 µg/mL, respectively. All the pure polyphenolic compounds inhibited XO and their K(i values ranged from 13-767 µM. Ten of the compounds followed the non competitive inhibitory model whereas one of them was a competitive inhibitor. These findings indicate that flavonoid isolates from legume plant extracts are novel, natural XO inhibitors. Their mode of action is under investigation in order to examine their potential in drug design for diseases related to overwhelming XO action.

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

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Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

Carly L. Crouch & Jonathan Stökl (eds.: In the Name of God. The Bible in the Colonial Discourse of Empire

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Judith Becker

2015-11-01

Full Text Available This contribution offers a review of Carly L. Crouch & Jonathan Stökl (eds.: In the Name of God. The Bible in the Colonial Discourse of Empire, Biblical Interpretation Series 126. Leiden: Brill, 2014. viii and 192 pages, € 98, ISBN 978-900-425-8334.

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

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Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-01-01

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

Face shape and face identity processing in behavioral variant fronto-temporal dementia: A specific deficit for familiarity and name recognition of famous faces.

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De Winter, François-Laurent; Timmers, Dorien; de Gelder, Beatrice; Van Orshoven, Marc; Vieren, Marleen; Bouckaert, Miriam; Cypers, Gert; Caekebeke, Jo; Van de Vliet, Laura; Goffin, Karolien; Van Laere, Koen; Sunaert, Stefan; Vandenberghe, Rik; Vandenbulcke, Mathieu; Van den Stock, Jan

2016-01-01

Deficits in face processing have been described in the behavioral variant of fronto-temporal dementia (bvFTD), primarily regarding the recognition of facial expressions. Less is known about face shape and face identity processing. Here we used a hierarchical strategy targeting face shape and face identity recognition in bvFTD and matched healthy controls. Participants performed 3 psychophysical experiments targeting face shape detection (Experiment 1), unfamiliar face identity matching (Experiment 2), familiarity categorization and famous face-name matching (Experiment 3). The results revealed group differences only in Experiment 3, with a deficit in the bvFTD group for both familiarity categorization and famous face-name matching. Voxel-based morphometry regression analyses in the bvFTD group revealed an association between grey matter volume of the left ventral anterior temporal lobe and familiarity recognition, while face-name matching correlated with grey matter volume of the bilateral ventral anterior temporal lobes. Subsequently, we quantified familiarity-specific and name-specific recognition deficits as the sum of the celebrities of which respectively only the name or only the familiarity was accurately recognized. Both indices were associated with grey matter volume of the bilateral anterior temporal cortices. These findings extent previous results by documenting the involvement of the left anterior temporal lobe (ATL) in familiarity detection and the right ATL in name recognition deficits in fronto-temporal lobar degeneration.

Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors.

Science.gov (United States)

Jayakumar, Jayanthi; Anishetty, Sharmila

2014-05-01

Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative genomic and plasmid analysis of beer-spoiling and non-beer-spoiling Lactobacillus brevis isolates.

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Bergsveinson, Jordyn; Ziola, Barry

2017-12-01

Beer-spoilage-related lactic acid bacteria (BSR LAB) belong to multiple genera and species; however, beer-spoilage capacity is isolate-specific and partially acquired via horizontal gene transfer within the brewing environment. Thus, the extent to which genus-, species-, or environment- (i.e., brewery-) level genetic variability influences beer-spoilage phenotype is unknown. Publicly available Lactobacillus brevis genomes were analyzed via BlAst Diagnostic Gene findEr (BADGE) for BSR genes and assessed for pangenomic relationships. Also analyzed were functional coding capacities of plasmids of LAB inhabiting extreme niche environments. Considerable genetic variation was observed in L. brevis isolated from clinical samples, whereas 16 candidate genes distinguish BSR and non-BSR L. brevis genomes. These genes are related to nutrient scavenging of gluconate or pentoses, mannose, and metabolism of pectin. BSR L. brevis isolates also have higher average nucleotide identity and stronger pangenome association with one another, though isolation source (i.e., specific brewery) also appears to influence the plasmid coding capacity of BSR LAB. Finally, it is shown that niche-specific adaptation and phenotype are plasmid-encoded for both BSR and non-BSR LAB. The ultimate combination of plasmid-encoded genes dictates the ability of L. brevis to survive in the most extreme beer environment, namely, gassed (i.e., pressurized) beer.

Structure-based methods to predict mutational resistance to diarylpyrimidine non-nucleoside reverse transcriptase inhibitors.

Science.gov (United States)

Azeem, Syeda Maryam; Muwonge, Alecia N; Thakkar, Nehaben; Lam, Kristina W; Frey, Kathleen M

2018-01-01

Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is a leading cause of HIV treatment failure. Often included in antiviral therapy, NNRTIs are chemically diverse compounds that bind an allosteric pocket of enzyme target reverse transcriptase (RT). Several new NNRTIs incorporate flexibility in order to compensate for lost interactions with amino acid conferring mutations in RT. Unfortunately, even successful inhibitors such as diarylpyrimidine (DAPY) inhibitor rilpivirine are affected by mutations in RT that confer resistance. In order to aid drug design efforts, it would be efficient and cost effective to pre-evaluate NNRTI compounds in development using a structure-based computational approach. As proof of concept, we applied a residue scan and molecular dynamics strategy using RT crystal structures to predict mutations that confer resistance to DAPYs rilpivirine, etravirine, and investigational microbicide dapivirine. Our predictive values, changes in affinity and stability, are correlative with fold-resistance data for several RT mutants. Consistent with previous studies, mutation K101P is predicted to confer high-level resistance to DAPYs. These findings were further validated using structural analysis, molecular dynamics, and an enzymatic reverse transcription assay. Our results confirm that changes in affinity and stability for mutant complexes are predictive parameters of resistance as validated by experimental and clinical data. In future work, we believe that this computational approach may be useful to predict resistance mutations for inhibitors in development. Published by Elsevier Inc.

Effect of a synesthete's photisms on name recall.

Science.gov (United States)

Mills, Carol Bergfeld; Innis, Joanne; Westendorf, Taryn; Owsianiecki, Lauren; McDonald, Angela

2006-02-01

A multilingual, colored-letter synesthete professor (MLS), 9 nonsynesthete multilingual professors and 4 nonsynesthete art professors learned 30 names of individuals (first and last name pairs) in three trials. They recalled the names after each trial and six months later, as well as performed cued recall trials initially and after six months. As hypothesized, MLS recalled significantly more names than control groups on all free recall tests (except after the first trial) and on cued recall tests. In addition, MLS gave qualitatively different reasons for remembering names than any individual control participant. MLS gave mostly color reasons for remembering the names, whereas nonsynesthetes gave reasons based on familiarity or language or art knowledge. Results on standardized memory tests showed that MLS had average performance on non-language visual memory tests (the Benton Visual Retention Test-Revised--BURT-R, and the Rey-Osterrieth Complex Figure Test--CFT), but had superior memory performance on a verbal test consisting of lists of nouns (Rey Auditory-Verbal Learning Test--RAVLT). MLS's synesthesia seems to aid memory for visually or auditorily presented language stimuli (names and nouns), but not for non-language visual stimuli (simple and complex figures).

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

Science.gov (United States)

Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

2018-03-28

Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of phosphodiesterase inhibitors on atrial dynamics induced by C-type natriuretic peptide in isolated beating rabbit atria

International Nuclear Information System (INIS)

Ding Dazhi; Cui Xun; Jin Xiunan; Lan Ying; Liu Liping; Hong Lan

2010-01-01

Objective: To investigate the effects of phosphodiesterase inhibitors (PDEI) on atrial dynamics induced by C-type natriuretic peptide (CNP) and the contents of cyclic nucleotide (cAMP, cGMP) in isolated beating rabbit atria. Methods: After the rabbits had been anesthetized, the hearts were removed rapidly. The left auricles were isolated and fixed on the atrial perfusion system. The atrial stroke volume and the pulse pressure were observed by CNP with or without PDEIs pretreatment. The contents of cAMP and cGMP were measured by radioimmunoassay. Results: (1)Compared with control cycle group, CNP (30.0 nmol · L -1 ) obviously decreased the atrial stroke volume and pulse pressure (P 0.05). (2)Compared with control cycle group, IBMX(1000.0 nmol · L -1 ), a non-selective inhibitor of PDE, significantly increased the atrial stroke volume, pulse pressure, cAMP and cGMP contents (P -1 ) plus CNP (30.0 nmol · L -1 )group and IBMX group (P>0.05). (3)Compared with control cycle group, EHNA(30.0 nmol · L -1 ), an inhibitor of PDE2, obviously decreased the atrial stroke volume and pulse pressure (P 0.05). EHNA(30.0 nmol · L -1 ) plus CNP (30.0 nmol · L -1 ) showed similar roles with EHNA only. (4)Compared with control cycle group, milrinone (1.0 nmol · L -1 ), an inhibitor of PDE3, significantly increased the content of cAMP (P 0.05). CNP (30.0 nmol · L -1 ) obviously decreased the atrial stroke volume and pulse pressure (P 0.05). Conclusion: CNP can inhibit atrial dynamics by increasing the content of cGMP, the different inhibitors of PDEs play different roles in the CNP-induced inhibition of atrial dynamics in isolated beating rabbit atria. (authors)

Geissoschizine methyl ether, a corynanthean-type indole alkaloid from Uncaria rhynchophylla as a potential acetylcholinesterase inhibitor.

Science.gov (United States)

Yang, Zhong-Duo; Duan, Dong-Zhu; Du, Juan; Yang, Ming-Jun; Li, Shuo; Yao, Xiao-Jun

2012-01-01

Geissoschizine methyl ether (1), a newly discovered strong acetylcholinesterase (AChE) inhibitor, along with six weakly active alkaloids, vallesiachotamine (2), hisuteine (3), hirsutine (4), isorhynchophylline (5), cisocorynoxeine (6) and corynoxeine (7) have been isolated from Uncaria rhynchophylla. Geissoschizine methyl ether (1) inhibited 50% of AChE activity at concentrations of 3.7 ± 0.3 µg mL(-1) while the IC(50) value of physostigmine as a standard was 0.013 ± 0.002 µg mL(-1). The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.

Natural compounds as corrosion inhibitors for highly cycled systems

Energy Technology Data Exchange (ETDEWEB)

Quraishi, M.A.; Farooqi, I.H.; Saini, P.A. [Corrosion Research Lab., Aligarh (India)

1999-11-01

Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

Susceptibility of recombinant porcine endogenous retrovirus reverse transcriptase to nucleoside and non-nucleoside inhibitors.

Science.gov (United States)

Wilhelm, M; Fishman, J A; Pontikis, R; Aubertin, A M; Wilhelm, F X

2002-12-01

Transplantation of organs, tissues or cells from pigs to humans could be a potential solution to the shortage of human organs for transplantation. Porcine endogenous retroviruses (PERVs) remain a major safety concern for porcine xenotransplantation. Thus, finding drugs that could be used as virological prophylaxis (or therapy) against PERV replication would be desirable. One of the most effective ways to block retroviral multiplication is to inhibit the enzyme reverse transcriptase (RT) which catalyzes the reverse transcription of viral RNA to proviral double-stranded DNA. We report here the cloning and expression of PERV RT and its susceptibility to several inhibitors. Our data demonstrate PERV susceptibility in vitro to the triphosphorylated nucleoside analog of zidovudine (AZT) and to ddGTP and to a lesser extent to ddTTP but almost no susceptibility to the non-nucleoside RT inhibitors tested.

[Immune checkpoint inhibitors (antibodies to PD1 and PD-L1), a new therapeutic weapon against non-small cell bronchial carcinoma].

Science.gov (United States)

Berghmans, T; Grigoriu, B; Sculier, J P; Meert, A P

2018-02-01

Classical therapeutic strategy for advanced and metastatic non-small cell lung cancer, without activable oncogenic driver mutation, has been based mainly on cytotoxic chemotherapy with modest benefits in terms of increased survival. A better understanding of the mechanisms involved in the regulation of the immune system led to the development of antibodies directed against immune checkpoints such as PD-L1. The first encouraging clinical data from phase I studies assessing anti-PD1 and anti-PD-L1 antibodies have been confirmed in randomised phase III trials. These new drugs now constitute a standard second-line treatment for metastatic tumours and in the future, at least for pembrolizumab, in the first line. Their adjuvant role after locoregional treatment with curative intent is currently under investigation. Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.

A porphodimethene chemical inhibitor of uroporphyrinogen decarboxylase.

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Kenneth W Yip

Full Text Available Uroporphyrinogen decarboxylase (UROD catalyzes the conversion of uroporphyrinogen to coproporphyrinogen during heme biosynthesis. This enzyme was recently identified as a potential anticancer target; its inhibition leads to an increase in reactive oxygen species, likely mediated by the Fenton reaction, thereby decreasing cancer cell viability and working in cooperation with radiation and/or cisplatin. Because there is no known chemical UROD inhibitor suitable for use in translational studies, we aimed to design, synthesize, and characterize such a compound. Initial in silico-based design and docking analyses identified a potential porphyrin analogue that was subsequently synthesized. This species, a porphodimethene (named PI-16, was found to inhibit UROD in an enzymatic assay (IC50 = 9.9 µM, but did not affect porphobilinogen deaminase (at 62.5 µM, thereby exhibiting specificity. In cellular assays, PI-16 reduced the viability of FaDu and ME-180 cancer cells with half maximal effective concentrations of 22.7 µM and 26.9 µM, respectively, and only minimally affected normal oral epithelial (NOE cells. PI-16 also combined effectively with radiation and cisplatin, with potent synergy being observed in the case of cisplatin in FaDu cells (Chou-Talalay combination index <1. This work presents the first known synthetic UROD inhibitor, and sets the foundation for the design, synthesis, and characterization of higher affinity and more effective UROD inhibitors.

Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin

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Jacquemont Céline

2012-04-01

Full Text Available Abstract Background Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. Results Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407. Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor, CA-074-Me (cathepsin B inhibitor and 17-AAG (HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF, but not in FA-deficient isogenic cells (2008. In addition, geldanamycin (HSP90 inhibitor and two CHK1 inhibitors (UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA

Does selective serotonin reuptake inhibitor (SSRI) fluoxetine affects mussel Mytilus galloprovincialis?

International Nuclear Information System (INIS)

Gonzalez-Rey, Maria; Bebianno, Maria João

2013-01-01

Fluoxetine (FLX) the active pharmaceutical ingredient (API) in Prozac ® is a widely prescribed psychoactive drug which ubiquitous occurrence in the aquatic environment is associated to a poor removal rate in waste-water treatment plant (WWTP) systems. This API acts as a selective serotonin reuptake inhibitor (SSRI) frequently reported to cause disrupting effects in non-target species. The objective of this study includes a multibiomarker response evaluation on mussel Mytilus galloprovincialis during two weeks exposure to 75 ng L −1 FLX assessing antioxidant enzymes activities – superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST); lipid peroxidation (LPO), acetylcholinesterase (AChE) neurotoxic response and endocrine disruption through alkali-labile phosphates (ALP) indirect measurement of vitellogenin-like proteins. Results show transient tissue-specific enzymatic responses and damage affecting mostly mussel gills. However, the clear ALP levels inhibition throughout time in both sex-differentiated gonads gives evidence to FLX reinforced action as an endocrine disruptor rather than an oxidative or neurotoxic inducer. - Highlights: ► Short-time exposure of Mytilus galloprovincialis to antidepressant fluoxetine. ► Tissue-specific transient antioxidant enzymes activities alteration. ► Lipid peroxidation (LPO) induction in exposed-tissues. ► Acetylcholinesterase (AChE) activity upregulation in exposed gills. ► ALP levels downregulation in exposed sex-differentiated mussels. - Exposure to 75 ng L −1 antidepressant fluoxetine (FLX) induces tissue-specific multibiomarker responses alteration in mussel Mytilus galloprovincialis.

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors.

Science.gov (United States)

Thomas, Ajit G; Rojas, Camilo; Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B; Auld, Douglas S; Ferraris, Dana V; Tsukamoto, Takashi; Slusher, Barbara S

2013-08-23

Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC(1280))) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline

OpenAIRE

Abassi, Zaid A; Binah, Ofer; Youdim, Moussa B H

2004-01-01

Selegiline is used for treating Parkinson's disease. Despite its efficacy, the clinical use of selegiline in combination with L-dihydroxphenylalanine in Parkinsonian patients is hampered by cardiovascular complications, such as hypotension. This study was designed to compare in rats the cardiovascular effects of selegiline and rasagiline, their metabolites L-methamphetamine and aminoindan (TVP-136), respectively, and the second rasagiline metabolite non-monoamine oxidase (MAO) inhibitor TVP-1...

Discovery and study of novel protein tyrosine phosphatase 1B inhibitors

Science.gov (United States)

Zhang, Qian; Chen, Xi; Feng, Changgen

2017-10-01

Protein tyrosine phosphatase 1B (PTP1B) is considered to be a target for therapy of type II diabetes and obesity. So it is of great significance to take advantage of a computer aided drug design protocol involving the structured-based virtual screening with docking simulations for fast searching small molecule PTP1B inhibitors. Based on optimized complex structure of PTP1B bound with specific inhibitor of IX1, structured-based virtual screening against a library of natural products containing 35308 molecules, which was constructed based on Traditional Chinese Medicine database@ Taiwan (TCM database@ Taiwan), was conducted to determine the occurrence of PTP1B inhibitors using the Lubbock module and CDOCKER module from Discovery Studio 3.1 software package. The results were further filtered by predictive ADME simulation and predictive toxic simulation. As a result, 2 good drug-like molecules, namely para-benzoquinone compound 1 and Clavepictine analogue 2 were identified ultimately with the dock score of original inhibitor (IX1) and the receptor as a threshold. Binding model analyses revealed that these two candidate compounds have good interactions with PTP1B. The PTP1B inhibitory activity of compound 2 hasn't been reported before. The optimized compound 2 has higher scores and deserves further study.

Immune-based Therapies for Non-small Cell Lung Cancer.

Science.gov (United States)

Rafei, Hind; El-Bahesh, Ehab; Finianos, Antoine; Nassereddine, Samah; Tabbara, Imad

2017-02-01

Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Comparison of Effect of Brassinosteroid and Gibberellin Biosynthesis Inhibitors on Growth of Rice Seedlings

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Tadashi Matusmoto

2016-01-01

Full Text Available Brassinosteroid (BR and gibberellin (GA are two predominant plant hormones that regulate plant cell elongation. Mutants disrupt the biosynthesis of these hormones and display different degrees of dwarf phenotypes in rice. Although the role of each plant hormone in promoting the longitudinal growth of plants has been extensively studied using genetic methods, their relationship is still poorly understood. In this study, we used two specific inhibitors targeting BR and GA biosynthesis to investigate the roles of BR and GA in growth of rice seedlings. Yucaizol, a specific inhibitor of BR biosynthesis, and Trinexapac-ethyl, a commercially available inhibitor of GA biosynthesis, were used. The effect of Yucaizol on rice seedlings indicated that Yucaizol significantly retarded stem elongation. The IC50 value was found to be approximately 0.8 μmol/L. Yucaizol also induced small leaf angle phenocopy in rice seedlings, similarly to BR-deficient rice, while Trinexapac-ethyl did not. When Yucaizol combined with Trinexapac-ethyl was applied to the rice plants, the mixture of these two inhibitors retarded stem elongation of rice at lower doses. Our results suggest that the use of a BR biosynthesis inhibitor combined with a GA biosynthesis inhibitor may be useful in the development of new technologies for controlling rice plant height.

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation.

Science.gov (United States)

Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-06-05

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu(406) is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Isolation of natural inhibitors of papain obtained from Carica papaya latex

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Rubens Monti

2004-09-01

Full Text Available Studies were carried out to natural papain inhibitor from papaya latex. Fresh latex from green fruits of Carica papaya was collected and immediately transported in ice bath to the lab, from which three fractions with inhibitor effect of esterase papain activity were isolated by latex dialysis, Sephadex G-25 gel filtration and ionic exchange chromatography in SP-Sephadex C-25. The isolated fractions, identified as inhibitors I and II, showed a negative reaction with ninhydrin; however, the fraction identified as P-III showed positive reaction with ninhydrin. Kinetics data showed non-competitive inhibition (inhibitor I and uncompetitive (inhibitors II and P-III.Este trabalho apresenta novos dados sobre inibidores naturais de papaína. O látex fresco de frutos verdes de Carica papaya foi coletado pela manhã em plantações da região de Araraquara, SP, Brasil e imediatamente transportado ao laboratório em banho de gelo. Três frações com efeito inibitório da atividade esterásica da papaína foram isoladas a partir do látex fresco, através de diálise, filtração em Sephadex G-25 e cromatografia em SP-Sephadex C-25. As frações isoladas identificadas como inibidores I e II, mostraram reação negativa à ninidrina; entretanto, a fração identificada como P-III mostrou reação positiva. Dados cinéticos revelaram inibição não-competitiva (inibidor I e incompetitiva (inibidores II e P-III.

Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis.

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Koppikar, Priya; Abdel-Wahab, Omar; Hedvat, Cyrus; Marubayashi, Sachie; Patel, Jay; Goel, Aviva; Kucine, Nicole; Gardner, Jeffrey R; Combs, Andrew P; Vaddi, Kris; Haley, Patrick J; Burn, Timothy C; Rupar, Mark; Bromberg, Jacqueline F; Heaney, Mark L; de Stanchina, Elisa; Fridman, Jordan S; Levine, Ross L

2010-04-08

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.

ACE and SGLT2 inhibitors: the future for non-diabetic and diabetic proteinuric renal disease.

Science.gov (United States)

Perico, Norberto; Ruggenenti, Piero; Remuzzi, Giuseppe

2017-04-01

Most chronic nephropathies progress relentlessly to end-stage kidney disease. Research in animals and humans has helped our understanding of the mechanisms of chronic kidney disease progression. Current therapeutic strategies to prevent or revert renal disease progression focus on reduction of urinary protein excretion and blood pressure control. Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors and/or angiotensin II type 1 receptor blockers is the most effective treatment to achieve these purposes in non-diabetic and diabetic proteinuric renal diseases. For those individuals in which nephroprotection by RAS blockade is only partial, sodium-glucose linked cotransporter-2 (SGLT2) inhibitors could be a promising new class of drugs to provide further renoprotective benefit when added on to RAS blockers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Slowing in reading and picture naming: the effects of aging and developmental dyslexia.

Science.gov (United States)

De Luca, Maria; Marinelli, Chiara Valeria; Spinelli, Donatella; Zoccolotti, Pierluigi

2017-10-01

We examined the slowing in vocal reaction times shown by dyslexic (compared to control) children with that of older (compared to younger) adults using an approach focusing on the detection of global, non-task-specific components. To address this aim, data were analyzed with reference to the difference engine (DEM) and rate and amount (RAM) models. In Experiment 1, typically developing children, children with dyslexia (both attending sixth grade), younger adults and older adults read words and non-words and named pictures. In Experiment 2, word and picture conditions were presented to dyslexic and control children attending eighth grade. In both experiments, dyslexic children were delayed in reading conditions, while they were unimpaired in naming pictures (a finding which indicates spared access to the phonological lexicon). The reading difficulty was well accounted for by a single multiplicative factor while only the residual effect of length (but not frequency and lexicality) was present after controlling for over-additivity using a linear mixed effects model with random slopes on critical variables. Older adults were slower than younger adults across reading and naming conditions. This deficit was well described by a single multiplicative factor. Thus, while slowing of information processing is limited to orthographic stimuli in dyslexic children, it cuts across verbal tasks in older adults. Overall, speed differences in groups such as dyslexic children and older adults can be effectively described with reference to deficits in domains encompassing a variety of experimental conditions rather than deficits in single specific task/conditions. The DEM and RAM prove effective in teasing out global vs. specific components of performance.

Efeito do lipopolissacarídio bacteriano sobre o esvaziamento gástrico de ratos: avaliação do pré-tratamento com Nw-nitro-L-arginine methyl ester (L-NAME The effect of bacterial lipopolysaccharide on the gastric emptying of rats: a pretreatment evaluation using Nw-nitro-L-arginine methyl ester (L-NAME

Directory of Open Access Journals (Sweden)

Edgard Ferro Collares

2006-09-01

Full Text Available RACIONAL: Há evidências de que o óxido nítrico participa do mecanismo de retardo do esvaziamento gástrico determinado pelo lipopolissacarídio bacteriano. OBJETIVO: Avaliar o efeito do pré-tratamento com Nw-nitro-L-arginine methyl ester, um inibidor competitivo das óxido nítrico-sintetases, sobre o fenômeno. MATERIAL E MÉTODOS: Utilizaram-se ratos, Wistar, machos, SPF ("specific-pathogen free", adultos, adaptados às condições do laboratório, que após 24 horas de jejum alimentar foram pré-tratados endovenosamente com veículo (salina ou Nw-nitro-L-arginine methyl ester nas doses de 0,5, 1, 2,5 e 5 mg/kg. No tratamento, administrou-se endovenosamente veículo (salina ou lipopolissacarídio (50 µg/kg. O intervalo entre o pré-tratamento e o tratamento foi de 10 minutos, e entre este e a avaliação do esvaziamento gástrico foi de 60 minutos. O esvaziamento gástrico foi avaliado indiretamente através da determinação da retenção gástrica da solução salina marcada com fenol vermelho 10 minutos após administração por via orogástrica. RESULTADOS: Entre os animais pré-tratados com veículo, o tratamento com lipopolissacarídio determinou elevação significativa da retenção gástrica (média = 57% em relação aos tratados com veículo (38,1%. O pré-tratamento com as diferentes doses de Nw-nitro-L-arginine methyl ester não modificou a retenção gástrica nos animais controles do tratamento. O pré-tratamento com Nw-nitro-L-arginine methyl ester com a dose de 1 mg/kg determinou redução discreta, mas significativa, na retenção gástrica (52% nos animais tratados com lipopolissacarídio, em relação ao observado naqueles com pré-tratamento e tratamento com veículo (35,9%. Nos animais pré-tratados com 2,5 e 5 mg/kg de Nw-nitro-L-arginine methyl ester e tratados com lipopolissacarídio, houve aumento significante da retenção gástrica (74,7% e 80,5%, respectivamente em relação aos seus controles pr

Ultra advanced projects. ; Naming hyper-hightech projects. (Cho) no tsuku project. ; Naming no shikumi

Energy Technology Data Exchange (ETDEWEB)

Goto, Y. (Ministry of International Trade and Industry, Tokyo (Japan))

1992-10-05

Significance of using 'super' for naming a project of technological development is discussed. Functions of naming are classified into (1) recognition, (2) display and (3) sales-promotion, whereby mechanism of naming of merchandise that is developed through the technique of 3 is considered. Further, the mechanism of naming is discussed in relation to marketing. It is pointed out that naming of merchandise is determined on the basis of (1) concept of planned goods and (2) marketing-mixes composed of goods, price, sales-roots and sales-promotion. The same mechanism works also in a project for technological development. Technical trends are caught and projects are targetted by taking supposed regimes into account, thereby the most suitable mix is formed. The mix in the technological development is assumed to be composed of purpose, specification, regime and sales-promotion. Two examples of the governmental projects by Ministry of International Trade and Industry, 'the big regime for research and development on industrial technologies' and 'the regime for development of the fundamental technologies in the next generation' are introduced and the significance of their naming is described. 2 tabs.

Two-dimensional NMR studies of squash family inhibitors. Sequence-specific proton assignments and secondary structure of reactive-site hydrolyzed Cucurbita maxima trypsin inhibitor III

Energy Technology Data Exchange (ETDEWEB)

Krisnamoorthi, R.; Yuxi Gong; Chanlan Sun Lin (Kansas State Univ., Manhattan (United States)); VanderVelde, D. (Univ. of Kansas, Lawrence (United States))

1992-01-28

The solution structure of reactive-site hydrolyzed Cucurbita maxima trypsin inhibitor III (CMTI-III*) was investigated by two-dimensional proton nuclear magnetic resonance (2D NMR) spectroscopy. CMTI-III*, prepared by reacting CMTI-III with trypsin which cleaved the Arg5-Ile6 peptide bond, had the two fragments held together by a disulfide linkage. Sequence-specific {sup 1}H NMR resonance assignments were made for all the 29 amino acid residues of the protein. The secondary structure of CMTI-III*, as deduced from NOESY cross peaks and identification of slowly exchanging hydrogens, contains two turns, a 3{sub 10}-helix, and a triple-stranded {beta}-sheet. Sequential proton assignments were also made for the virgin inhibitor, CMTI-III, at pH 4.71, 30C. Comparison of backbone hydrogen chemical shifts of CMTI-III and CMTI-III* revealed significant changes for residues located far away from the reactive-site region as well as for those located near it, indicating tertiary structural changes that are transmitted through most of the 29 residues of the inhibitor protein. These chemical shift changes were relatively small compared to changes that occurred upon hydrolysis of the reactive-site peptide bond between Arg 5 and Ile6 in CMTI-III.

Enzyme immunoassay for measurement of murine plasminogen activator inhibitor-1, employing a specific antibody produced by the DNA vaccine method.

Science.gov (United States)

Yamada, Takayuki; Takagi, Akira; Takeshita, Kyosuke; Yamamoto, Koji; Ito, Masafumi; Matsushita, Tadashi; Murate, Takashi; Saito, Hidehiko; Kojima, Tetsuhito

2003-01-01

We developed a sensitive immunoassay to determine the concentration of mouse plasminogen activator inhibitor-1. The assay was a non-competitive sandwich enzyme-linked immunosorbent assay (ELISA) based on the production of a specific polyclonal antibody against mouse plasminogen activator inhibitor type-1 (PAI-1) used both as a trapping and detecting antibody. This antibody was raised in a rabbit by direct introduction of the expression vector plasmid DNA encoding mouse PAI-1, instead of conventional immunization with the purified protein. The standard curve was constructed with a recombinant glutathione S-transferase (GST)-mouse PAI-1 fusion protein (GST-mPAI-1) and dose-response of the assay was linear for GST-mPAI-1 between 6.25 and 100 pM. In order to assess the consistency of the assay, we measured PAI-1 antigen in normal mouse pooled plasma several times. We found that the intra-assay and inter-assay coefficients of variation (CV) were 4.8% and 9.2%, respectively, indicating that the ELISA would be sufficiently repeatable and reproducible. In this assay, lipopolysaccharide (LPS)-injected mice showed substantially higher levels (22-fold) of plasma PAI-1 antigen than did control mice (12.5+/-2.4 vs. 0.58+/-0.16 nM), similar to results reported elsewhere. Taken together, the DNA vaccine method is extremely useful for preparing specific antibodies against mouse PAI-1, which can be utilized to establish the ELISA and analyze the profile of PAI-1 distributions in mice under various conditions. This approach might also be useful for immunological investigation of other coagulation factors and related proteins.

Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor.

Science.gov (United States)

Fang, Pengfei; Han, Hongyan; Wang, Jing; Chen, Kaige; Chen, Xin; Guo, Min

2015-06-18

Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits Plasmodium falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report three crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all three structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydropyran moiety of cladosporin are critical for the specificity of cladosporin against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure-driven drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Plasmin substrate binding site cooperativity guides the design of potent peptide aldehyde inhibitors.

Science.gov (United States)

Swedberg, Joakim E; Harris, Jonathan M

2011-10-04

Perioperative bleeding is a cause of major blood loss and is associated with increased rates of postoperative morbidity and mortality. To combat this, antifibrinolytic inhibitors of the serine protease plasmin are commonly used to reduce bleeding during surgery. The most effective and previously widely used of these is the broad range serine protease inhibitor aprotinin. However, adverse clinical outcomes have led to use of alternative serine lysine analogues to inhibit plasmin. These compounds suffer from low selectivity and binding affinity. Consequently, a concerted effort to discover potent and selective plasmin inhibitors has developed. This study used a noncombinatorial peptide library to define plasmin's extended substrate specificity and guide the design of potent transition state analogue inhibitors. The various substrate binding sites of plasmin were found to exhibit a higher degree of cooperativity than had previously been appreciated. Peptide sequences capitalizing on these features produced high-affinity inhibitors of plasmin. The most potent of these, Lys-Met(sulfone)-Tyr-Arg-H [KM(O(2))YR-H], inhibited plasmin with a K(i) of 3.1 nM while maintaining 25-fold selectivity over plasma kallikrein. Furthermore, 125 nM (0.16 μg/mL) KM(O(2))YR-H attenuated fibrinolysis in vitro with an efficacy similar to that of 15 nM (0.20 μg/mL) aprotinin. To date, this is the most potent peptide inhibitor of plasmin that exhibits selectivity against plasma kallikrein, making this compound an attractive candidate for further therapeutic development.

Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

Science.gov (United States)

Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

2015-01-01

Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

Non-Specific Reactions during Immunomagnetic Separation of Listeria

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Iveta Zachová

2005-01-01

Full Text Available Problems occurring during the immunomagnetic separation (IMS of Listeria using immunomagnetic particles Dynabeads® anti-Listeria (Dynal Biotech, Norway were specified. Characteristics of these particles were compared with anti-Listeria spp. magnetite particles (Quantum Magnetics, USA. Pure cultures of Listeria innocua, Arthrobacter spp., Bacillus subtilis, Citrobacter braakii, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae and Staphylococcus aureus were used to evaluate non-specific reactions during IMS. Gram-positive microorganisms, especially Staphylococcus aureus and Arthrobacter spp., were found to be responsible for non-specific reactions in most cases. The capacity of Dynabeads® anti-Listeria particles was determined to be about 10 % of the initial pure cultures of Listeria spp., after 10 min of incubation. Non-specific reactions during IMS of Listeria were examined on the artificially inoculated food samples in which Gram-positive bacteria showed the highest percentage of capture. Influence of washing in two buffers was also studied.

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

Energy Technology Data Exchange (ETDEWEB)

Thomas, Ajit G.; Rojas, Camilo [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B.; Auld, Douglas S. [National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850 (United States); Ferraris, Dana V. [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tsukamoto, Takashi [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Slusher, Barbara S., E-mail: bslusher@jhmi.edu [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States)

2013-08-23

Highlights: •Ebselen, chelerythrine and apomorphine were identified as glutaminase inhibitors. •These had greater affinities and efficiency of inhibition than known prototypes. •Their previously reported biological activity could be due to glutaminase inhibition. -- Abstract: Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC{sup 1280})) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

International Nuclear Information System (INIS)

Thomas, Ajit G.; Rojas, Camilo; Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B.; Auld, Douglas S.; Ferraris, Dana V.; Tsukamoto, Takashi; Slusher, Barbara S.

2013-01-01

Highlights: •Ebselen, chelerythrine and apomorphine were identified as glutaminase inhibitors. •These had greater affinities and efficiency of inhibition than known prototypes. •Their previously reported biological activity could be due to glutaminase inhibition. -- Abstract: Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC 1280 )) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease

Cell-cycle inhibition by Helicobacter pylori L-asparaginase.

Directory of Open Access Journals (Sweden)

Claudia Scotti

Full Text Available Helicobacter pylori (H. pylori is a major human pathogen causing chronic gastritis, peptic ulcer, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. One of the mechanisms whereby it induces damage depends on its interference with proliferation of host tissues. We here describe the discovery of a novel bacterial factor able to inhibit the cell-cycle of exposed cells, both of gastric and non-gastric origin. An integrated approach was adopted to isolate and characterise the molecule from the bacterial culture filtrate produced in a protein-free medium: size-exclusion chromatography, non-reducing gel electrophoresis, mass spectrometry, mutant analysis, recombinant protein expression and enzymatic assays. L-asparaginase was identified as the factor responsible for cell-cycle inhibition of fibroblasts and gastric cell lines. Its effect on cell-cycle was confirmed by inhibitors, a knockout strain and the action of recombinant L-asparaginase on cell lines. Interference with cell-cycle in vitro depended on cell genotype and was related to the expression levels of the concurrent enzyme asparagine synthetase. Bacterial subcellular distribution of L-asparaginase was also analysed along with its immunogenicity. H. pylori L-asparaginase is a novel antigen that functions as a cell-cycle inhibitor of fibroblasts and gastric cell lines. We give evidence supporting a role in the pathogenesis of H. pylori-related diseases and discuss its potential diagnostic application.

Name agreement in picture naming : An ERP study

NARCIS (Netherlands)

Cheng, Xiaorong; Schafer, Graham; Akyürek, Elkan G.

Name agreement is the extent to which different people agree on a name for a particular picture. Previous studies have found that it takes longer to name low name agreement pictures than high name agreement pictures. To examine the effect of name agreement in the online process of picture naming, we

Chemical probing of the human sirtuin 5 active site reveals its substrate acyl specificity and peptide-based inhibitors.

Science.gov (United States)

Roessler, Claudia; Nowak, Theresa; Pannek, Martin; Gertz, Melanie; Nguyen, Giang T T; Scharfe, Michael; Born, Ilona; Sippl, Wolfgang; Steegborn, Clemens; Schutkowski, Mike

2014-09-26

Sirtuins are NAD(+)-dependent deacetylases acting as sensors in metabolic pathways and stress response. In mammals there are seven isoforms. The mitochondrial sirtuin 5 is a weak deacetylase but a very efficient demalonylase and desuccinylase; however, its substrate acyl specificity has not been systematically analyzed. Herein, we investigated a carbamoyl phosphate synthetase 1 derived peptide substrate and modified the lysine side chain systematically to determine the acyl specificity of Sirt5. From that point we designed six potent peptide-based inhibitors that interact with the NAD(+) binding pocket. To characterize the interaction details causing the different substrate and inhibition properties we report several X-ray crystal structures of Sirt5 complexed with these peptides. Our results reveal the Sirt5 acyl selectivity and its molecular basis and enable the design of inhibitors for Sirt5. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

On ‘lost’ indigenous etymological origins with the specific case of the name Ameiva

Directory of Open Access Journals (Sweden)

Nicole Frances Angeli

2018-04-01

Full Text Available Modern biology builds upon the historic exploration of the natural world. Recognizing the origin of a species’ name is one path to honor the historic exploration and description of the natural world and the indigenous peoples that lived closely with organisms prior to their description. While digitization of historic papers catalogued in databases such as the Biodiversity Heritage Library (BHL allows for searching of the first use and origin of names, the rapid pace of taxonomic publishing can occlude a thorough search for etymologies. The etymological origin of the genus name Ameiva is one such case; while unattributed in multiple recent works, it is of Tupí language origin. The first description was in the Historiae Rerum Naturalium Brasiliae by George Marcgrave (1648. Ameiva was the name used by Marcgrave’s Amerindian hosts in 17th century Dutch Brazil, where local people spoke the now extinct language Tupí. The Tupí origin was not lost, however, until as recently as the 2000s. Herein, the pre- and post-Linnaean use of the name Ameiva is traced and when the name is attributed to the Tupí language and to Marcgrave through time it is noted. The opportunity to discover and/or recover etymological origins, especially names from extinct and indigenous languages, provides insight into the early Western sciences. Careful study of etymology by naturalists is consistent with the idea that science is an evolving process with many predecessors to appreciate.

On ‘lost’ indigenous etymological origins with the specific case of the name Ameiva

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Angeli, Nicole Frances

2018-01-01

Abstract Modern biology builds upon the historic exploration of the natural world. Recognizing the origin of a species’ name is one path to honor the historic exploration and description of the natural world and the indigenous peoples that lived closely with organisms prior to their description. While digitization of historic papers catalogued in databases such as the Biodiversity Heritage Library (BHL) allows for searching of the first use and origin of names, the rapid pace of taxonomic publishing can occlude a thorough search for etymologies. The etymological origin of the genus name Ameiva is one such case; while unattributed in multiple recent works, it is of Tupí language origin. The first description was in the Historiae Rerum Naturalium Brasiliae by George Marcgrave (1648). Ameiva was the name used by Marcgrave’s Amerindian hosts in 17th century Dutch Brazil, where local people spoke the now extinct language Tupí. The Tupí origin was not lost, however, until as recently as the 2000s. Herein, the pre- and post-Linnaean use of the name Ameiva is traced and when the name is attributed to the Tupí language and to Marcgrave through time it is noted. The opportunity to discover and/or recover etymological origins, especially names from extinct and indigenous languages, provides insight into the early Western sciences. Careful study of etymology by naturalists is consistent with the idea that science is an evolving process with many predecessors to appreciate. PMID:29674919

A family of names : rune-names and ogam-names and their relation to alphabet letter-names

NARCIS (Netherlands)

Griffiths, Alan

2013-01-01

The current consensus is that vernacular names assigned to the runes of the Germanic fuþark and to Irish ogam characters are indigenous creations independent of Mediterranean alphabet traditions. I propose, however, that ogam-names are based on interpretations of Hebrew, Greek or Latin letter-names

Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice.

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Lueptow, Lindsay M; Zhan, Chang-Guo; O'Donnell, James M

2016-02-01

Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms. To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 μg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 μg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling. Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG). These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads.

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Mao, Wei; Daligaux, Pierre; Lazar, Noureddine; Ha-Duong, Tâp; Cavé, Christian; van Tilbeurgh, Herman; Loiseau, Philippe M; Pomel, Sébastien

2017-04-07

Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.

PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis

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Stephanie Schneider

2017-05-01

Full Text Available Objective: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. Setting: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks for non-small cell lung cancer. Results: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. Conclusions: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of ≥0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted.

Proteins in Soy Might Have a Higher Role in Cancer Prevention than Previously Expected: Soybean Protein Fractions Are More Effective MMP-9 Inhibitors Than Non-Protein Fractions, Even in Cooked Seeds

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Ana Lima

2017-02-01

Full Text Available The search for anticancer MMP-9 inhibitors (MMPIs in food products has become a major goal for research. MMPIs in soy have been related only to saponins and isoflavones, but recently, low specific protein fractions in soybeans were shown to reduce MMP-9 activity as well. The present work aimed at comparing the MMPI potential of protein fractions (P and non-protein fractions (NP isolated from soybean seeds, before and after soaking and cooking, mimicking dietary exposures. Reverse and substrate zymography, as well as a fluoregenic DQ gelatin assay were used to evaluate MMP-9 activities. Colon cancer cell migration and proliferation was also tested in HT29 cells. Regarding MMP-9 inhibition, proteins in soy presented IC50 values 100 times lower than non-protein extracts, and remained active after cooking, suggesting that proteins may be more effective MMP-9 inhibitors than non-protein compounds. Using the determined IC50 concentrations, NP fractions were able to induce higher inhibitions of HT29 cell migration and proliferation, but not through MMP-9 inhibition, whilst protein fractions were shown to specifically inhibit MMP-9 activity. Overall, our results show that protein fractions in soybeans might have a higher role in soy-related cancer prevention as MMPIs than previously expected. Being nontoxic and active at lower concentrations, the discovery of these heat-resistant specific MMPI proteins in soy can be of significant importance for cancer preventive diets, particularly considering the increasing use of soy proteins in food products and the controversy around isoflavones amongst consumers.

The bear in Eurasian plant names: motivations and models.

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Kolosova, Valeria; Svanberg, Ingvar; Kalle, Raivo; Strecker, Lisa; Özkan, Ayşe Mine Gençler; Pieroni, Andrea; Cianfaglione, Kevin; Molnár, Zsolt; Papp, Nora; Łuczaj, Łukasz; Dimitrova, Dessislava; Šeškauskaitė, Daiva; Roper, Jonathan; Hajdari, Avni; Sõukand, Renata

2017-02-21

Ethnolinguistic studies are important for understanding an ethnic group's ideas on the world, expressed in its language. Comparing corresponding aspects of such knowledge might help clarify problems of origin for certain concepts and words, e.g. whether they form common heritage, have an independent origin, are borrowings, or calques. The current study was conducted on the material in Slavonic, Baltic, Germanic, Romance, Finno-Ugrian, Turkic and Albanian languages. The bear was chosen as being a large, dangerous animal, important in traditional culture, whose name is widely reflected in folk plant names. The phytonyms for comparison were mostly obtained from dictionaries and other publications, and supplemented with data from databases, the co-authors' field data, and archival sources (dialect and folklore materials). More than 1200 phytonym use records (combinations of a local name and a meaning) for 364 plant and fungal taxa were recorded to help find out the reasoning behind bear-nomination in various languages, as well as differences and similarities between the patterns among them. Among the most common taxa with bear-related phytonyms were Arctostaphylos uva-ursi (L.) Spreng., Heracleum sphondylium L., Acanthus mollis L., and Allium ursinum L., with Latin loan translation contributing a high proportion of the phytonyms. Some plants have many and various bear-related phytonyms, while others have only one or two bear names. Features like form and/or surface generated the richest pool of names, while such features as colour seemed to provoke rather few associations with bears. The unevenness of bear phytonyms in the chosen languages was not related to the size of the language nor the present occurence of the Brown Bear in the region. However, this may, at least to certain extent, be related to the amount of the historical ethnolinguistic research done on the selected languages.

Phosphodiesterase inhibitors in clinical urology.

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Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

[A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy].

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Wang, Shan-Chun; Zeng, Li-Li; Ding, Yu-Yang; Zeng, Shao-Gao; Song, Hong-Rui; Hu, Wen-Hui; Xie, Hui

2014-01-01

Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.

In-vivo studies by positron emission tomography of the pharmacokinetics of L-6-F-18-fluorodopa

International Nuclear Information System (INIS)

Pate, B.D.; Calne, D.B.; Hewitt, K.A.; Ruth, T.J.; Adam, M.J.

1989-01-01

Positron emission tomography has been used to study the pharmacokinetics of fluorine-18-labelled L-6-fluorodopa in the brains of cynomolgus monkey subjects. The protocol for each experiment consisted of two series of twelve 10-minutes scans, conducted one after the other with the monkey in the same position, with an inhibitor acting at a specific stage of the kinetics, administered before the second series. Subtractions of the two scan series (following correction for activity residue in the second scans) then gave a quantitative measure of the effects produced by the inhibitor. The inhibitors studied include NSD 1015 (decarboxylase inhibitor), chlorgyline (MAO-A inhibitor), deprenyl (MAO-B inhibitor), pargyline (inhibitor of both MAO-A and MAO-B), U-0521 (COMT inhibitor), and reserpine (vesicular storage inhibitor). The results show that L-6-fluorodopa is a substrate for dopa decarboxylase, while fluorodopamine is a substrate for both MAO-A and MAO-B, and for COMT. Vesicular storage (inhibited by reserpine) was shown also to be essential for concentration of the activity into striatal images

An unusual helix-turn-helix protease inhibitory motif in a novel trypsin inhibitor from seeds of Veronica (Veronica hederifolia L.).

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Conners, Rebecca; Konarev, Alexander V; Forsyth, Jane; Lovegrove, Alison; Marsh, Justin; Joseph-Horne, Timothy; Shewry, Peter; Brady, R Leo

2007-09-21

The storage tissues of many plants contain protease inhibitors that are believed to play an important role in defending the plant from invasion by pests and pathogens. These proteinaceous inhibitor molecules belong to a number of structurally distinct families. We describe here the isolation, purification, initial inhibitory properties, and three-dimensional structure of a novel trypsin inhibitor from seeds of Veronica hederifolia (VhTI). The VhTI peptide inhibits trypsin with a submicromolar apparent K(i) and is expected to be specific for trypsin-like serine proteases. VhTI differs dramatically in structure from all previously described families of trypsin inhibitors, consisting of a helix-turn-helix motif, with the two alpha helices tightly associated by two disulfide bonds. Unusually, the crystallized complex is in the form of a stabilized acyl-enzyme intermediate with the scissile bond of the VhTI inhibitor cleaved and the resulting N-terminal portion of the inhibitor remaining attached to the trypsin catalytic serine 195 by an ester bond. A synthetic, truncated version of the VhTI peptide has also been produced and co-crystallized with trypsin but, surprisingly, is seen to be uncleaved and consequently forms a noncovalent complex with trypsin. The VhTI peptide shows that effective enzyme inhibitors can be constructed from simple helical motifs and provides a new scaffold on which to base the design of novel serine protease inhibitors.

Can the Pro-Drop Parameter Account for All the Errors in the Acquisition of Non-Referential "It" in L2 English?

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Antonova-Ünlü, Elena

2015-01-01

Numerous studies, examining the acquisition of non-referential it in [-pro-drop] English by learners of [+pro-drop] languages, have revealed that their participants omit non-referential subjects in English if their L1 allows null-subject position. However, due to the specificity of their focus, these studies have not considered other difficulties…

Medicinal Chemistry Insights into Novel HDAC Inhibitors: An Updated Patent Review (2012-2016).

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Zhan, Peng; Wang, Xueshun; Liu, Xinyong; Suzuki, Takayoshi

2017-01-01

Many laboratories have made intensive efforts to develop potent, selective, and orally bioavailable HDAC inhibitors (HDACIs). Novel HDACIs are being developed with the objective of improving potency and selectivity against specific types of cancers or non-cancer diseases. This updated patent review is an attempt to compile the work of various researchers of HDACIs from 2012 to mid 2016, and to enlighten and surprise both newcomers in this field and devoted medicinal chemists. According to the literature research and the writers' own research experience in the discovery of HDAC inhibitors. The inhibitors possessing new chemical scaffolds have attracted immense interest because they have the ability to improve HDAC isoform specificity and pharmaceutical properties. Focus is given to emerging medicinal chemistry principles and insights into the discovery and development of HDAC inhibitors. The development of effective HDACIs is shifting from trial-and-error approaches to sophisticated strategies. Effective profiling technologies will continue to have important utility. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Efficiency and corrosion rate analysis of organic inhibitor utilization from bawang dayak leaves (EleutherineamericanaMerr.) on API 5L steel

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Sari, Shaimah Rinda; Sari, Eli Novita; Rizky, Yoel; Sulistijono, Triana, Yunita

2018-05-01

This research studied the inhibition of corrosion by bawang dayak leaves extract (EleutherineamericanaMerr.) on API 5L steel in brine water environment (3.5% NaCl). The inhibitor was extracted using maceration process from bawang dayak leaves that was cultivated in Paser District, East Kalimantan. The test of antioxidant activity showed that bawang dayak leaves extract is a very powerful antioxidant with IC50 value of 27.30204. The results from FTIR test show the presence of electronegative atoms and double bonds of the alkenes groups that provide the potential of the extract as a corrosion inhibitor. Efficiency of inhibition reached up to 93.158% for the addition of inhibitor with 300 ppm concentration and 20 days of immersion time. This inhibitory behavior is also supported by polarization measurements where the lowest corrosion rate of 0.00128 mm/year is obtained at the same concentration and immersion time.

The use of dimethylsulfoxide as a solvent in enzyme inhibition studies: the case of aldose reductase.

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Misuri, Livia; Cappiello, Mario; Balestri, Francesco; Moschini, Roberta; Barracco, Vito; Mura, Umberto; Del-Corso, Antonella

2017-12-01

Aldose reductase (AR) is an enzyme devoted to cell detoxification and at the same time is strongly involved in the aetiology of secondary diabetic complications and the amplification of inflammatory phenomena. AR is subjected to intense inhibition studies and dimethyl sulfoxide (DMSO) is often present in the assay mixture to keep the inhibitors in solution. DMSO was revealed to act as a weak but well detectable AR differential inhibitor, acting as a competitive inhibitor of the L-idose reduction, as a mixed type of non-competitive inhibitor of HNE reduction and being inactive towards 3-glutathionyl-4-hydroxynonanal transformation. A kinetic model of DMSO action with respect to differently acting inhibitors was analysed. Three AR inhibitors, namely the flavonoids neohesperidin dihydrochalcone, rutin and phloretin, were used to evaluate the effects of DMSO on the inhibition studies on the reduction of L-idose and HNE.

Activity, specificity, and probe design for the smallpox virus protease K7L.

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Aleshin, Alexander E; Drag, Marcin; Gombosuren, Naran; Wei, Ge; Mikolajczyk, Jowita; Satterthwait, Arnold C; Strongin, Alex Y; Liddington, Robert C; Salvesen, Guy S

2012-11-16

The K7L gene product of the smallpox virus is a protease implicated in the maturation of viral proteins. K7L belongs to protease Clan CE, which includes distantly related cysteine proteases from eukaryotes, pathogenic bacteria, and viruses. Here, we describe its recombinant high level expression, biochemical mechanism, substrate preference, and regulation. Earlier studies inferred that the orthologous I7L vaccinia protease cleaves at an AG-X motif in six viral proteins. Our data for K7L suggest that the AG-X motif is necessary but not sufficient for optimal cleavage activity. Thus, K7L requires peptides extended into the P7 and P8 positions for efficient substrate cleavage. Catalytic activity of K7L is substantially enhanced by homodimerization, by the substrate protein P25K as well as by glycerol. RNA and DNA also enhance cleavage of the P25K protein but not of synthetic peptides, suggesting that nucleic acids augment the interaction of K7L with its protein substrate. Library-based peptide preference analyses enabled us to design an activity-based probe that covalently and selectively labels K7L in lysates of transfected and infected cells. Our study thus provides proof-of-concept for the design of inhibitors and probes that may contribute both to a better understanding of the role of K7L in the virus life cycle and the design of novel anti-virals.

Two-dimensional NMR studies of squash family inhibitors. Sequence-specific proton assignments and secondary structure of reactive-site hydrolyzed Cucurbita maxima trypsin inhibitor III.

Science.gov (United States)

Krishnamoorthi, R; Gong, Y X; Lin, C L; VanderVelde, D

1992-01-28

The solution structure of reactive-site hydrolyzed Cucurbita maxima trypsin inhibitor III (CMTI-III*) was investigated by two-dimensional proton nuclear magnetic resonance (2D NMR) spectroscopy. CMTI-III*, prepared by reacting CMTI-III with trypsin which cleaved the Arg5-Ile6 peptide bond, had the two fragments held together by a disulfide linkage. Sequence-specific 1H NMR resonance assignments were made for all the 29 amino acid residues of the protein. The secondary structure of CMTI-III*, as deduced from NOESY cross peaks and identification of slowly exchanging hydrogens, contains two turns (residues 8-12 and 24-27), a 3(10)-helix (residues 13-16), and a triple-stranded beta-sheet (residues 8-10, 29-27, and 21-25). This secondary structure is similar to that of CMTI-I [Holak, T. A., Gondol, D., Otlewski, J., & Wilusz, T. (1989) J. Mol. Biol. 210, 635-648], which has a Glu instead of a Lys at position 9. Sequential proton assignments were also made for the virgin inhibitor, CMTI-III, at pH 4.71, 30 degrees C. Comparison of backbone hydrogen chemical shifts of CMTI-III and CMTI-III* revealed significant changes for residues located far away from the reactive-site region as well as for those located near it, indicating tertiary structural changes that are transmitted through most of the 29 residues of the inhibitor protein. Many of these residues are functionally important in that they make contact with atoms of the enzyme in the trypsin-inhibitor complex, as revealed by X-ray crystallography [Bode, W., Greyling, H. J., Huber, R., Otlewski, J., & Wilusz, T. (1989) FEBS Lett. 242, 285-292].(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

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Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

2010-03-02

Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

What’s In Your Name? Associated Meanings of the Common Filipino Names Among Young Filipinos

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Shaira G. Castillo

2016-11-01

Full Text Available Name is important in knowing someone’s identity. By a person’s name someone can know his or her character. It is also possible that they bear a particular name because of their background and other factors that can lead to something important. This study aimed to find out the associative meanings of the most common Filipino male and female names among the Polytechnic University of the Philippines-Sta. Mesa students. Different factors such as character traits, physical appearance, and skills/talents were considered in determining meanings of the names. The study used quantitative and qualitative research approach, specifically the descriptive method, to analyze the gathered data. A selfadministered survey was distributed to 400 randomly selected respondents. General findings revealed that the respondents associated the most common Filipino male names in the same way regarding character traits and skills/talents. However, they have different associations to the male names in terms of physical appearance. On the other hand, the respondents associated the most common Filipino female names into similar character traits and physical appearance but associated them with different skills/talents. Results also revealed that the most common factors that influence the respondents’ associated meanings were relationships, experiences, popularity, and perception. The results imply that while young Filipinos associate similar character traits, physical appearances and skills to common Filipino names, they have different reasons in giving meanings to them.

Molecular cloning, characterization and functional analysis of a novel juvenile-specific cathepsin L of Fasciola gigantica.

Science.gov (United States)

Sansri, Veerawat; Changklungmoa, Narin; Chaichanasak, Pannigan; Sobhon, Prasert; Meemon, Krai

2013-10-01

Cathepsin L proteases are a major class of endopeptidases expressed at a high level in Fasciola parasites. Several isoforms of cathepsin L were detected and they may perform different functions during the parasite development. In this study, a complete cDNA encoding a cathepsin L protease was cloned from a newly excysted juvenile (NEJ) cDNA library of Fasciola gigantica and named FgCatL1H. It encoded a 326 amino acid preproenzyme which shared 62.8-83.1% and 39.5-42.9% identity to Fasciola spp. and mammalian cathepsins L, respectively. All functionally important residues previously described for cathepsin L were conserved in FgCatL1H. Phylogenetic analysis demonstrated that FgCatL1H belonged to a distinct group, clade 4, with respect to adult and other juvenile Fasciola cathepsin L genes. FgCatL1H expression was detected by RT-PCR, using gene specific primers, in metacercariae and NEJ, and the expression gradually decreased in advanced developmental stages. A recombinant proFgCatL1H (rproFgCatL1H) was expressed in the yeast Pichia pastoris, affinity purified, and found to migrate in SDS-PAGE at approximately 47.6 and 38.3kDa in glycosylated and deglycosylated forms, respectively. The molecular mass of the activated mature rFgCatL1H in glycosylated form was approximately 40.7kDa. Immunoblotting and immunohistochemistry using rabbit antibodies against rproFgCatL1H showed that FgCatL1H was predominantly expressed in epithelial cells of the digestive tract of metacercariae, NEJs and juveniles of F. gigantica. FgCatL1H could cleave the synthetic fluorogenic substrate Z-Phe-Arg-MCA preferentially over Z-Gly-Pro-Arg-MCA at an optimum pH of 6.5. It also showed hydrolytic activity against native substrates, including type I collagen, laminin, and immunoglobulin G (IgG) in vitro, suggesting possible roles in host tissue migration and immune evasion. Therefore, the FgCatL1H is a possible target for vaccine and chemotherapy for controlling F. gigantica infection. Copyright �

Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer’s Disease

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Youssef Dgachi

2016-05-01

Full Text Available We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM, good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

Modulators of arginine metabolism support cancer immunosurveillance

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Freschi Massimo

2009-01-01

Full Text Available Abstract Background Tumor-associated accrual of myeloid derived suppressor cells (MDSC in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G nitro-L-arginine methyl ester (L-NAME and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity. Results We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response. Conclusion Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders [version 1; referees: 2 approved

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William Vainchenker

2018-01-01

Full Text Available JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non-BCR-ABL1 myeloproliferative neoplasms (MPNs. Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations (CALR and MPL also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft-versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and one JAK1/JAK3 inhibitor (tofacitinib in methotrexate-resistant rheumatoid arthritis. The non-approved compounds exhibited many off-target effects leading to neurological and gastrointestinal toxicities, as seen in clinical trials for MPNs. Ruxolitinib is a well-tolerated drug with mostly anti-inflammatory properties. Despite a weak effect on the cause of the disease itself in MPNs, it improves the clinical state of patients and increases survival in myelofibrosis. This limited effect is related to the fact that ruxolitinib, like the other type I JAK2 inhibitors, inhibits equally mutated and wild-type JAK2 (JAK2WT and also the JAK2 oncogenic activation. Thus, other approaches need to be developed and could be based on either (1 the development of new inhibitors specifically targeting JAK2V617F or (2 the combination of the actual JAK2 inhibitors with other therapies, in particular with molecules targeting pathways downstream of JAK2 activation or the stability of JAK2