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#32531343   2020/06/10 To Up

ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain.

Effective analgesic treatment for neuropathic pain remains an unmet need, so previous evidence that epidermal growth factor receptor inhibitors (EGFRIs) provide unexpected rapid pain relief in a clinical setting points to a novel therapeutic opportunity. The present study utilises rodent models to address the cellular and molecular basis for the findings, focusing on primary sensory neurons because clinical pain relief is provided not only by small molecule EGFRIs, but also by the anti-EGFR antibodies cetuximab and panitumumab, which are unlikely to access the central nervous system in therapeutic concentrations. We report robust, rapid and dose-dependent analgesic effects of EGFRIs in two neuropathic pain models, matched by evidence with highly selective antibodies that expression of the EGFR (ErbB1 protein) is limited to small nociceptive afferent neurons. As other ErbB family members can heterodimerise with ErbB1, we investigated their distribution, showing consistent co-expression of ErbB2 but not ErbB3 or ErbB4, with ErbB1 in cell bodies of nociceptors, as well as providing evidence for direct molecular interaction of ErbB1 with ErbB2 in situ. Co-administration of selective ErbB1 and ErbB2 inhibitors produced clear evidence of greater-than-additive, synergistic analgesia; highlighting the prospect of a unique new combination therapy in which enhanced efficacy could be accompanied by minimisation of side-effects. Peripheral (intraplantar) administration of EGF elicited hypersensitivity only following nerve injury and this was reversed by local co-administration of selective inhibitors of either ErbB1 or ErbB2. Investigating how ErbB1 is activated in neuropathic pain, we found evidence for a role of Src tyrosine kinase, which can be activated by signals from inflammatory mediators, chemokines and cytokines during neuroinflammation. Considering downstream consequences of ErbB1 activation in neuropathic pain, we found direct recruitment to ErbB1 of an adapter for PI 3-kinase and Akt signalling together with clear Akt activation and robust analgesia from selective Akt inhibitors. The known Akt target and regulator of vesicular trafficking, AS160 was strongly phosphorylated at a perinuclear location during neuropathic pain in an ErbB1-, ErbB2- and Akt-dependent manner, corresponding to clustering and translocation of an AS160-partner, the vesicular chaperone, LRP1. Exploring whether neuronal ion channels that could contribute to hyperexcitability might be transported by this vesicular trafficking pathway we were able to identify Na1.9, (Na1.8) and Ca1.2 moving towards the plasma membrane or into proximal axonal locations - a process prevented by ErbB1 or Akt inhibitors. Overall these findings newly reveal both upstream and downstream signals to explain how ErbB1 can act as a signalling hub in neuropathic pain models and identify the trafficking of key ion channels to neuronal subcellular locations likely to contribute to hyperexcitability. The new concept of combined treatment with ErbB1 plus ErbB2 blockers is mechanistically validated as a promising strategy for the relief of neuropathic pain.
Rory Mitchell, Marta Mikolajczak, Christian Kersten, Sue Fleetwood-Walker

1919 related Products with: ErbB1-dependent signalling and vesicular trafficking in primary afferent nociceptors associated with hypersensitivity in neuropathic pain.

0.1mg100ug100 μg1 Set100 μg1 Set96 tests100ug

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#31980577   2020/01/24 To Up

LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages.

LETM1 domain-containing protein 1 (LETMD1), also known as HCCR-1, is a mitochondrial protein and is known to regulate p53 and STAT3 activities in cancer cells. In this study, we present, for the first time (to our knowledge), data indicating that LETMD1 suppresses multiple immune responses in monocyte/macrophage lineage cells and mouse primary macrophages. Attenuation of LETMD1 expression with specific small interfering RNA and short hairpin RNA constructs enhanced LPS-induced expressions of inflammatory mediators in macrophages. In addition, LETMD1 attenuation caused potentiation of phagocytosis as well as migration in a macrophage-like cell line, U937. These enhancing effects were associated with altered activation of signaling adaptors (such as NF-κB, MAPKs, p53, and JAK-STAT) involved in TLR4 signaling. Especially, LETMD1 selectively regulated TLR4-induced NF-κB activation via MyD88 but not via TIR-domain-containing adapter-inducing IFN-β (TRIF). Attenuation of LETMD1 expression caused mitochondrial hyperpolarization and subsequent decrease in ATP production and increase in mitochondrial/cellular reactive oxygen species (ROS) and intracellular calcium levels. LETMD1 attenuation also enhanced LPS-induced expression of NADPH oxidase (NOX) 2, the main producer of cellular ROS in phagocytes, through augmenting IFN regulatory factor 1. Accordingly, treatment with ROS scavenger, NOX2 suppressing agents, or calcium chelators resulted in suppression of LPS-induced cytokine production as well as NF-κB activation in cells with LETMD1 attenuation. These findings reveal a previously unknown function of LETMD1 and provide evidences showing LETMD1 negatively regulates macrophage functions by modulating mitochondrial function, subsequent ROS generation, and NF-κB activation.
Su-Geun Lim, Kyoungho Suk, Won-Ha Lee

1240 related Products with: LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages.

50 ug 50 ug 96T50 ug 10 mg100 100ul 100ul 5 G100 mg 100ul

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#28650772   2017/03/20 To Up

L'analyse de contribution pour évaluer l'impact de la démarche ÉIS sur les processus décisionnels municipaux : un choix méthodologique intéressant ?

La pertinence de l'évaluation d'impact sur la santé (ÉIS) pour promouvoir le développement de politiques publiques favorables à la santé au sein des municipalités est de plus en plus reconnue. L'appréciation des effets d'une démarche d'ÉIS sur les processus décisionnels d'acteurs municipaux peut toutefois être difficile en raison de la multitude d'influences sociales, économiques, géographiques et personnelles auxquels ils sont soumis. Dans un tel contexte, l'approche évaluative de l'analyse de contribution (AC) s'avère particulièrement intéressante puisqu'elle permet de documenter les facteurs menant à l'efficacité d'une intervention en tenant compte des éléments du contexte. Elle aide l'évaluateur à comprendre comment et pourquoi une intervention fonctionne. Le présent article utilise l'étude de cas pour explorer la faisabilité et l'efficacité de l'AC pour apprécier les effets de démarches d'ÉIS sur le processus décisionnel d'acteurs municipaux. Il décrit les stratégies de collecte et d'analyse de données utilisées auprès de trois municipalités de la Montérégie, au Québec. Cette analyse critique montre que l'AC est pertinente dans le contexte décrit. Elle permet d'établir des associations claires et transparentes entre l'intervention, soit la démarche d'ÉIS, et l'importance accordée à la santé par les acteurs municipaux. Elle assure la prise en compte des facteurs d'influence contextuels et offre la flexibilité nécessaire pour adapter la collecte de données à la réalité du terrain. Néanmoins, la lourdeur de l'approche peut en contraindre l'application et certaines limites méthodologiques ont été observées au niveau de l'analyse des données. Les stratégies mises de l'avant pour y remédier sont décrites.
Kareen Nour, Mariève M Lafontaine, Astrid Brousselle, Pernelle Smits, Jean-Marie Buregeya, Julie Loslier, Jean-Louis Denis

1009 related Products with: L'analyse de contribution pour évaluer l'impact de la démarche ÉIS sur les processus décisionnels municipaux : un choix méthodologique intéressant ?

1 Bottle/Unit25 mg30 Samples1 x 9630 mg100ug25 Bags/Unit100Tests10 mg1 Bag of 1000 Caps/Unit x

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#24308643   2013/12/05 To Up

Repeated open endotracheal suctioning causes gradual desaturation but does not exacerbate lung injury compared to closed endotracheal suctioning in a rabbit model of ARDS.

Although endotracheal suctioning induces alveolar derecruitment during mechanical ventilation, it is not clear whether repeated endotracheal suctioning exacerbates lung injuries. The present study aimed to determine whether repeated open endotracheal suctioning (OS) exacerbates lung injury compared to closed endotracheal suctioning (CS) during mechanical ventilation in an animal model of acute respiratory distress syndrome (ARDS).
Hideaki Sakuramoto, Nobutake Shimojo, Subrina Jesmin, Takeshi Unoki, Junko Kamiyama, Masami Oki, Ken Miya, Satoru Kawano, Taro Mizutani

1005 related Products with: Repeated open endotracheal suctioning causes gradual desaturation but does not exacerbate lung injury compared to closed endotracheal suctioning in a rabbit model of ARDS.

100 100ug Lyophilized100ug Lyophilized1 mL100ug Lyophilized100ug Lyophilized1 mL100ug100ug Lyophilized100ug Lyophilized100ug

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#19638216   2009/07/28 To Up

High-throughput retrotransposon-based fluorescent markers: improved information content and allele discrimination.

Dense genetic maps, together with the efficiency and accuracy of their construction, are integral to genetic studies and marker assisted selection for plant breeding. High-throughput multiplex markers that are robust and reproducible can contribute to both efficiency and accuracy. Multiplex markers are often dominant and so have low information content, this coupled with the pressure to find alternatives to radio-labelling, has led us to adapt the SSAP (sequence specific amplified polymorphism) marker method from a 33P labelling procedure to fluorescently tagged markers analysed from an automated ABI 3730 xl platform. This method is illustrated for multiplexed SSAP markers based on retrotransposon insertions of pea and is applicable for the rapid and efficient generation of markers from genomes where repetitive element sequence information is available for primer design. We cross-reference SSAP markers previously generated using the 33P manual PAGE system to fluorescent peaks, and use these high-throughput fluorescent SSAP markers for further genetic studies in Pisum.
Maggie Knox, Carol Moreau, James Lipscombe, David Baker, Noel Ellis

1725 related Products with: High-throughput retrotransposon-based fluorescent markers: improved information content and allele discrimination.

10x96, 2.0ml cultures10, 10ml whole blood Up to 200 ml cultures

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#15283702   // To Up

Glycoprotein VI/Fc receptor gamma chain-independent tyrosine phosphorylation and activation of murine platelets by collagen.

We have investigated the ability of collagen to induce signalling and functional responses in suspensions of murine platelets deficient in the FcRgamma (Fc receptor gamma) chain, which lack the collagen receptor GPVI (glycoprotein VI). In the absence of the FcRgamma chain, collagen induced a unique pattern of tyrosine phosphorylation which was potentiated by the thromboxane analogue U46619. Immunoprecipitation studies indicated that neither collagen alone nor the combination of collagen plus U46619 induced phosphorylation of the GPVI-regulated proteins Syk and SLP-76 (Src homology 2-containing leucocyte protein of 76 kDa). A low level of tyrosine phosphorylation of phospholipase Cgamma2 was observed, which was increased in the presence of U46619, although the degree of phosphorylation remained well below that observed in wild-type platelets (approximately 10%). By contrast, collagen-induced phosphorylation of the adapter ADAP (adhesion- and degranulation-promoting adapter protein) was substantially potentiated by U46619 to levels equivalent to those observed in wild-type platelets. Collagen plus U46619 also induced significant phosphorylation of FAK (focal adhesion kinase). The functional significance of collagen-induced non-GPVI signals was highlighted by the ability of U46619 and collagen to induce the secretion of ATP in FcRgamma chain-deficient platelets, even though neither agonist was effective alone. Protein tyrosine phosphorylation and the release of ATP were abolished by the anti-(alpha2 integrin) antibodies Ha1/29 and HMalpha2, but not by blockade of alphaIIbbeta3. These results illustrate a novel mechanism of platelet activation by collagen which is independent of the GPVI-FcRgamma chain complex, and is facilitated by binding of collagen to integrin alpha2beta1.
Gavin E Jarvis, Denise Best, Steve P Watson

1511 related Products with: Glycoprotein VI/Fc receptor gamma chain-independent tyrosine phosphorylation and activation of murine platelets by collagen.

1.00 mg0.1ml50 50ul (1mg/ml)100ug1 mg50 ug 5mg2 Pieces/Box96 wells (1 kit)100ug

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