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  1. Article ; Online: Identification of novel interacting partners of Sirtuin6.

    Oxana Polyakova / Satty Borman / Rachel Grimley / Jessica Vamathevan / Brian Hayes / Roberto Solari

    PLoS ONE, Vol 7, Iss 12, p e

    2012  Volume 51555

    Abstract: SIRT6 is a member of the Sirtuin family of histone deacetylases that has been implicated in inflammatory, aging and metabolic pathways. Some of its actions have been suggested to be via physical interaction with NFκB and HIF1α and transcriptional ... ...

    Abstract SIRT6 is a member of the Sirtuin family of histone deacetylases that has been implicated in inflammatory, aging and metabolic pathways. Some of its actions have been suggested to be via physical interaction with NFκB and HIF1α and transcriptional regulation through its histone deacetylase activity. Our previous studies have investigated the histone deacetylase activity of SIRT6 and explored its ability to regulate the transcriptional responses to an inflammatory stimulus such as TNFα. In order to develop a greater understanding of SIRT6 function we have sought to identify SIRT6 interacting proteins by both yeast-2-hybrid and co-immunoprecipitation studies. We report a number of interacting partners which strengthen previous findings that SIRT6 functions in base excision repair (BER), and novel interactors which suggest a role in nucleosome and chromatin remodeling, the cell cycle and NFκB biology.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Identification and characterization of PERK activators by phenotypic screening and their effects on NRF2 activation.

    Wensheng Xie / Marie Pariollaud / William E Wixted / Nilesh Chitnis / James Fornwald / Maggie Truong / Christina Pao / Yan Liu / Robert S Ames / James Callahan / Roberto Solari / Yolanda Sanchez / Alan Diehl / Hu Li

    PLoS ONE, Vol 10, Iss 3, p e

    2015  Volume 0119738

    Abstract: Endoplasmic reticulum stress plays a critical role to restore the homeostasis of protein production in eukaryotic cells. This vital process is hence involved in many types of diseases including COPD. PERK, one branch in the ER stress signaling pathways, ... ...

    Abstract Endoplasmic reticulum stress plays a critical role to restore the homeostasis of protein production in eukaryotic cells. This vital process is hence involved in many types of diseases including COPD. PERK, one branch in the ER stress signaling pathways, has been reported to activate NRF2 signaling pathway, a known protective response to COPD. Based on this scientific rationale, we aimed to identify PERK activators as a mechanism to achieve NRF2 activation. In this report, we describe a phenotypic screening assay to identify PERK activators. This assay measures phosphorylation of GFP-tagged eIF2α upon PERK activation via a cell-based LanthaScreen technology. To obtain a robust assay with sufficient signal to background and low variation, multiple parameters were optimized including GFP-tagged eIF2α BacMam concentration, cell density and serum concentration. The assay was validated by a tool compound, Thapsigargin, which induces phosphorylation of eIF2α. In our assay, this compound showed maximal signal window of approximately 2.5-fold with a pEC50 of 8.0, consistent with literature reports. To identify novel PERK activators through phosphorylation of eIF2α, a focused set of 8,400 compounds was screened in this assay at 10 µM. A number of hits were identified and validated. The molecular mechanisms for several selected hits were further characterized in terms of PERK activation and effects on PERK downstream components. Specificity of these compounds in activating PERK was demonstrated with a PERK specific inhibitor and in PERK knockout mouse embryonic fibroblast (MEF) cells. In addition, these hits showed NRF2-dependent anti-oxidant gene induction. In summary, our phenotypic screening assay is demonstrated to be able to identify PERK specific activators. The identified PERK activators could potentially be used as chemical probes to further investigate this pathway as well as the link between PERK activation and NRF2 pathway activation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Characterisation of a K390R ITK kinase dead transgenic mouse--implications for ITK as a therapeutic target.

    Angela Deakin / Graham Duddy / Steve Wilson / Steve Harrison / Judi Latcham / Mick Fulleylove / Sylvia Fung / Jason Smith / Mike Pedrick / Tom McKevitt / Leigh Felton / Joanne Morley / Diana Quint / Dilniya Fattah / Brian Hayes / Jade Gough / Roberto Solari

    PLoS ONE, Vol 9, Iss 9, p e

    2014  Volume 107490

    Abstract: Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells ... ...

    Abstract Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors. Consequently we have developed a transgenic mouse where the wild type Itk allele has been replaced by a kinase dead Itk allele containing an inactivating K390R point mutation (Itk-KD mice). We have characterised the immune phenotype of these naive mice and their responses to airway inflammation. Unlike Itk knockout (Itk-/-) mice, T-cells from Itk-KD mice can polymerise actin in response to CD3 activation. The lymph nodes from Itk-KD mice showed more prominent germinal centres than wild type mice and serum antibody levels were significantly abnormal. Unlike the Itk-/-, γδ T cells in the spleens of the Itk-KD mice had an impaired ability to secrete Th2 cytokines in response to anti-CD3 stimulation whilst the expression of ICOS was not significantly different to wild type. However ICOS expression is markedly increased on αβCD3+ cells from the spleens of naïve Itk-KD compared to WT mice. The Itk-KD mice were largely protected from inflammatory symptoms in an Ovalbumin model of airway inflammation. Consequently, our studies have revealed many similarities but some differences between Itk-/-and Itk-KD transgenic mice. The abnormal antibody response and enhanced ICOS expression on CD3+ cells has implications for the consideration of ITK as a therapeutic target.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen

    Anne L. Robertson / Nikolay V. Ogryzko / Katherine M. Henry / Catherine A. Loynes / Matthew J. Foulkes / Marco M. Meloni / Xingang Wang / Christopher Ford / Malcolm Jackson / Philip W. Ingham / Heather L. Wilson / Stuart N. Farrow / Roberto Solari / Roderick J. Flower / Simon Jones / Moira K. B. Whyte / Stephen A. Renshaw

    Disease Models & Mechanisms, Vol 9, Iss 6, Pp 621-

    2016  Volume 632

    Abstract: Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or ... ...

    Abstract Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well-regulated, persistent neutrophils can cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real time. Finally, our studies reveal that clinically available ‘cromones’ are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo. These findings could have implications for the therapeutic use of benzopyrones in inflammatory disease.
    Keywords Zebrafish ; Inflammation ; Neutrophil apoptosis ; Chromone ; Benzopyrone ; Medicine ; R ; Pathology ; RB1-214
    Subject code 610
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

    Aran Singanayagam / Nicholas Glanville / Jason L. Girkin / Yee Man Ching / Andrea Marcellini / James D. Porter / Marie Toussaint / Ross P. Walton / Lydia J. Finney / Julia Aniscenko / Jie Zhu / Maria-Belen Trujillo-Torralbo / Maria Adelaide Calderazzo / Chris Grainge / Su-Ling Loo / Punnam Chander Veerati / Prabuddha S. Pathinayake / Kristy S. Nichol / Andrew T. Reid /
    Phillip L. James / Roberto Solari / Peter A. B. Wark / Darryl A. Knight / Miriam F. Moffatt / William O. Cookson / Michael R. Edwards / Patrick Mallia / Nathan W. Bartlett / Sebastian L. Johnston

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 16

    Abstract: Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus ... ...

    Abstract Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

    Aran Singanayagam / Nicholas Glanville / Jason L. Girkin / Yee Man Ching / Andrea Marcellini / James D. Porter / Marie Toussaint / Ross P. Walton / Lydia J. Finney / Julia Aniscenko / Jie Zhu / Maria-Belen Trujillo-Torralbo / Maria Adelaide Calderazzo / Chris Grainge / Su-Ling Loo / Punnam Chander Veerati / Prabuddha S. Pathinayake / Kristy S. Nichol / Andrew T. Reid /
    Phillip L. James / Roberto Solari / Peter A. B. Wark / Darryl A. Knight / Miriam F. Moffatt / William O. Cookson / Michael R. Edwards / Patrick Mallia / Nathan W. Bartlett / Sebastian L. Johnston

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 16

    Abstract: Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus ... ...

    Abstract Corticosteroid therapy is frequently used for chronic obstructive pulmonary disease (COPD) but its use is associated with increased risk of pneumonia. Here the authors show that corticosteroid use impairs innate and adaptive immunity to rhinovirus infection, which is restored by exogenous IFNβ.
    Keywords Science ; Q
    Language English
    Publishing date 2018-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Over expression of wild type or a catalytically dead mutant of Sirtuin 6 does not influence NFκB responses.

    Rachel Grimley / Oxana Polyakova / Jessica Vamathevan / Joanne McKenary / Brian Hayes / Champa Patel / Janet Smith / Angela Bridges / Andrew Fosberry / Anshu Bhardwaja / Bernadette Mouzon / Chun-Wa Chung / Nathalie Barrett / Nicola Richmond / Sundip Modha / Roberto Solari

    PLoS ONE, Vol 7, Iss 7, p e

    2012  Volume 39847

    Abstract: SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB and HIF1α. Since it is possible to make small molecule activators and inhibitors of Sirtuins we wished to establish biochemical and cellular ... ...

    Abstract SIRT6 is involved in inflammation, aging and metabolism potentially by modulating the functions of both NFκB and HIF1α. Since it is possible to make small molecule activators and inhibitors of Sirtuins we wished to establish biochemical and cellular assays both to assist in drug discovery efforts and to validate whether SIRT6 represents a valid drug target for these indications. We confirmed in cellular assays that SIRT6 can deacetylate acetylated-histone H3 lysine 9 (H3K9Ac), however this deacetylase activity is unusually low in biochemical assays. In an effort to develop alternative assay formats we observed that SIRT6 overexpression had no influence on TNFα induced nuclear translocation of NFκB, nor did it have an effect on nuclear mobility of RelA/p65. In an effort to identify a gene expression profile that could be used to identify a SIRT6 readout we conducted genome-wide expression studies. We observed that overexpression of SIRT6 had little influence on NFκB-dependent genes, but overexpression of the catalytically inactive mutant affected gene expression in developmental pathways.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Correction

    Rachel Grimley / Oxana Polyakova / Jessica Vamathevan / Joanne McKenary / Brian Hayes / Champa Patel / Janet Smith / Angela Bridges / Andrew Fosberry / Anshu Bhardwaja / Bernadette Mouzon / Chun-Wa Chung / Nathalie Barrett / Nicola Richmond / Sundip Modha / Roberto Solari

    PLoS ONE, Vol 7, Iss

    Over Expression of Wild Type or a Catalytically Dead Mutant of SIRTUIN 6 Does Not Influence NFκB Responses

    2012  Volume 9

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Correction

    Rachel Grimley / Oxana Polyakova / Jessica Vamathevan / Joanne McKenary / Brian Hayes / Champa Patel / Janet Smith / Angela Bridges / Andrew Fosberry / Anshu Bhardwaja / Bernadette Mouzon / Chun-Wa Chung / Nathalie Barrett / Nicola Richmond / Sundip Modha / Roberto Solari

    PLoS ONE, Vol 7, Iss

    Over Expression of Wild Type or a Catalytically Dead Mutant of SIRTUIN 6 Does Not Influence NFκB Responses.

    2012  Volume 9

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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