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Дисертації з теми "Syk Inhibitor"

Автор: Grafiati

Опубліковано: 11 березня 2023

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1

Yamamoto, Noriyuki. "Development of a selective inhibitor for Syk tyrosine kinase and investigation of its pharmacological activities." 京都大学 (Kyoto University), 2003. http://hdl.handle.net/2433/148369.

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2

Roders, Nathalie. "Régulation de l'activation de lymphocytes B / cellules plasmatiques pendant le rejet chronique : Le rôle de SYK dans la modulation de Mcl-1." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS439/document.

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L'insuffisance rénale est un problème majeur de santé publique et la transplantation rénale est l’option thérapeutique principale, mais elle comporte le risque de rejet d'organe. Les cellules B jouent un rôle important dans le rejet médié par les anticorps (AMR). Au cours de l'AMR chronique, les structures lymphoïdes tertiaires, semblables aux centres germinatifs (GC), apparaissent dans l'organe rejeté, associées à la production des plasmocytes et des lymphocytes B mémoires spécifiques du donneur. Ces populations de lymphocyte B sont souvent mal contrôlées par les traitements actuels. La myeloid cell leukemia 1 (Mcl-1), un membre anti-apoptotique de la famille de B-cell lymphoma 2 (Bcl-2), est essentiel pour maintenir l’organisation de GC et de la différenciation des cellules B. Nous rapportons ici l'infiltration de cellules B exprimant Mcl-1 dans le rein de patients atteints d'AMR chronique, comme cela a été observé pour les cellules (pré) GC. Suite à l’abrogation de la signalisation du récepteur des cellules B (BCR), par l'inhibition de la spleen tyrosine kinase (SYK) nous avons observé une diminution de la viabilité des cellules GC, par l'intermédiaire d'une régulation de Mcl-1. La régulation négative de Mcl-1 est coordonnée au niveau de la transcription, potentiellement par l'intermédiaire du transducteur de signal et de l'activateur de la transcription 3 (STAT3), comme cela a été observé par (1) une translocation altérée de STAT3 dans le noyau suivant l'inhibition de SYK, et (2) les niveaux inférieurs de transcription de Mcl-1. Par ailleurs, la surexpression de Mcl-1 inhibe l'apoptose après l'inhibition du SYK. Des études avec des cellules B primaires, issues d'amygdales, ont confirmé que l'inhibition de SYK a diminué la survie cellulaire. Nous avons également constaté que l'inhibition du SYK a diminué les niveaux de protéines Mcl-1 dans les cellules B primaire, et que l’activation de ces cellules a été inhibée, tel que déterminé par l'expression de CD80 et des taux inférieurs de sécrétion d'IgG dans les cellules B primaires activées in vitro. Nos travaux suggèrent que la voie SYK-Mcl-1 peut offrir de nouvelles opportunités pour le traitement et la prévention de l'AMR
Renal failure is a major public health concern and renal transplantation is the main therapeutic option, however it comes with the risk of organ rejection. B-cells play an important role in antibody-mediated rejection (AMR). During chronic AMR, tertiary lymphoid germinal center (GC)-like structures appear in the rejected organ, associated with de novo production of donor-specific plasma and memory B-cells. Which are B-cell populations that are often poorly controlled by current treatments. Myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic member of the B-cell lymphoma-2 (Bcl-2) family, is essential for maintaining the GC reaction and B-cell differentiation. We report here the infiltration of B-cells expressing Mcl-1 in the kidney of patients with chronic AMR, as observed for (pre-)GC cells. The impairment of B-cell receptor (BCR) signaling, by inhibition of spleen tyrosine kinase (SYK), reduced viability and Mcl-1 protein levels in GC like cells. This downregulation is coordinated at the transcriptional level, potentially via signal transducer and activator of transcription 3 (STAT3), as shown by (1) impaired translocation of STAT3 to the nucleus following SYK inhibition, and (2) the lower levels of Mcl-1 transcription upon STAT3 inhibition. Moreover, overexpression of Mcl-1 prevented cells from entering apoptosis after SYK inhibition. In vitro studies with primary tonsillar B-cells confirmed that SYK inhibition decreased cell survival. We also found that SYK inhibition decreased Mcl-1 protein levels in primary B-cells, and that B-cell activation was inhibited, as determined by CD80 expression and lower levels of IgG secretion in tonsillar B-cells activated in vitro. Overall, our data suggest that the SYK-Mcl-1 pathway may provide new opportunities for the treatment and prevention of AMR

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3

Abadleh, Mohammed Mustafa Mohammed. "Diarylisoxazole als Leitstruktur für Design und Synthese von Proteinkinase Inhibitoren = Diarylisoxazoles as lead for the design and synthesis of protein kinase inhibitors /." Tübingen, 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000276718.

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4

Xu, Mingming. "Discovery of inhibitors against a-synuclein aggregation." Thesis, Griffith University, 2020. http://hdl.handle.net/10072/392373.

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Abnormal protein aggregation has been linked to many neurodegenerative diseases, including Parkinson’s disease (PD). The main pathological hallmark of PD is the formation of Lewy bodies and Lewy neurites, both containing the pre-synaptic protein α-synuclein (α-syn). Native α-syn, under normal conditions, exists in a soluble unfolded state but undergoes misfolding and aggregation into toxic aggregates under pathological conditions. Toxic α-syn species can cause oxidative stress, membrane penetration, synaptic and mitochondrial dysfunction, leading to neuronal death and eventually neurodegeneration. Currently, early diagnosis and treatments targeting PD pathogenesis are urgently needed. Given its critical role in PD, α-syn is an attractive target for the development of both diagnostic tools and effective therapeutics. This thesis consists of a series of published and unpublished papers. In Chapter 1, which was published as a review, the progress towards discovering imaging probes and aggregation inhibitors for α-syn was summarized. Since a key property of such required therapeutic agents is specific binding to the target protein, relevant strategies and techniques in the discovery of α-syn-targeted drugs are discussed. As my PhD project aimed to screen small molecules capable of binding to α-syn specifically and then discover new α-syn aggregation inhibitors from the screened structures, relevant techniques were discussed at the end of Chapter 1. Mass spectrometry was chosen to discover specific α-syn binding molecules as this technique allows rapid detection of direct interactions between molecules and proteins. The materials and methods that were used in the included publications, were summarized in detail in Chapter 2. To provide sufficient protein for our study, the in-house α-syn having equally good quality as the commercial protein, was successfully generated in Chapter 3. Also, high yield of pure protein can be acquired from medium scale of bacteria culture, saving plenty of time and money for preparing proteins for large-scale screening. The protein expression and purification was a part of the supplementary data in the publication included in Chapter 4, where an automated screening system based on the connection of a mass spectrometer and the auto-sampler from a high performance liquid chromatograph was successfully established. This system allows computer-controlled sample loading and data acquisition with high stability and reproducibility. We first discovered a new inhibitor by screening over 4,300 pure molecules. The new compound, 3-[(3-methoxyphenyl)carbamoyl]-7-[(E)-2-phenylethenyl]-4,7- dihydropyrazolo [1,5-a]pyrimidine-5-carboxylic acid, not only significantly inhibited the misfolding and aggregation of α-syn, protected neuroblastoma cells from α-syn toxicity, but also has a more specific binding site compared with positive controls. The capability of the MS-based screening was further extended to the discovery of active components from natural products (manuscript in submission). A total of 29 marine fractions from our collaborators, were tested by MS and a new cholesterol derivative with significant inhibition of α-syn aggregation, was discovered and isolated from the active fraction. This MS-guided isolation of active components from natural products can also be applied to investigating traditional Chinese medicines with known therapeutic effects. Post-translational modifications (PTMs) of α-syn, especially enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the proteins hydroxylated amino acid residues, have been reported to affect the pathogenic self-assembly of α-syn. As such, manipulation of the proteins’ O-GlcNAcylation statuses has been proposed to offer a therapeutic route toward addressing PD. In Chapter 5, small peptides with different sequences and modification sites were synthesized by our collaborators. In the thioflavin-T assay, which is a golden standard for measuring α-syn aggregation, two peptides with O-GlcNAcylation at the serine site exhibited significant inhibition. Therefore, small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate α-syn aggregation (manuscript under review). Other sources of compounds including new analogs of anle138b, which is a well-studied α-syn aggregation modulator, were evaluated. Two derivatives of anle138b exerted promising effects on the aggregation of α-syn. Interestingly, these synthesized compounds and peptides did not form protein-ligand complexes in the mass spectra, indicating that these molecules, unlike the compounds we discovered in Chapter 4, may interact with α-syn aggregates instead of α-syn monomers. In the last chapter, general conclusions of the thesis were made and future directions were also discussed.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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5

Coombes, Susan. "Boards of directors and nonprofit entrepreneurial orientation Catalyst, inhibitor, or inconsequential /." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2008. http://wwwlib.umi.com/cr/syr/main.

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6

Bracht, Kathrin. "Neue Inhibitoren zellmembranständiger Proteinkinasen /." Konstanz, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252796.

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7

Cohen, Jason C. "Attention mechanisms and inhibition of return in the somatosensory system." Related electronic resource: Current Research at SU : database of SU dissertations, recent titles available full text, 2002. http://wwwlib.umi.com/cr/syr/main.

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8

Amanovic, Ilijana. "Ginkgo biloba extract inhibits tissue factor degradation /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000278514.

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9

Wollmann, Heike. "MiRNA targeting mechanisms - translation inhibition versus transcript cleavage /." Tübingen, 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000251923.

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10

Bühler, Nico Martin. "Selektive COX-2 Inhibitoren und Nierenschädigung bei salzsensitiver Hypertonie /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000297941.

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11

Grässlin, Anja. "Protein epitope mimetics as inhibitors of protein-protein interactions and in synthetic vaccine design /." Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254199.

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12

Eichenauer, Dennis Alexander. "ADAM10 als CD30-Sheddase und immuntherapeutische Möglichkeitenn durch ihre Inhibition /." Köln, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252839.

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13

Zhou, Bin. "Disentangling perceptual and motor components in inhibition of return (IOR) /." München, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253469.

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14

Haase, Ludwig Christoph Benedikt. "Effektivität und Interaktionen von Flavopiridol, einem Inhibitor cyclin-abhängiger Kinasen, mit Methotrexat, Adriamycin und Cisplatin beim Harnblasenkarzinom in vitro /." Bonn, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253878.

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15

Raithel, Kerstin. "Effekt von S-Lost in HaCaT-Zellkulturen : Induktion der Apoptose und Effekt eines PARP-Inhibitors /." München, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254372.

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16

Gisler, Fabian. "Effectiveness of angiotensin-converting enzyme inhibitors in pediatric patients with mid to severe aortic value regurgitation /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000281144.

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17

Schreml, Stephan. "Antiproliferative und antiinflammatorische Aktivität von mTOR-Inhibitoren : Untersuchung an humanen organspezifischen Endothelzellkulturen /." Regensburg, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254339.

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18

Sommer, Eeva. "Exploring the contribution of SGK isoforms to signalling and mediating resistance to Akt inhibitors in breast cancer cells." Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/675ced8f-7a4d-467c-b1f2-cc0796f08f6e.

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19

Eklund, Hans. "Inhibition : om verkställighetsförbud m.m. i judiciell process, inom förvaltningsrätten och i utsökningsförfarandet /." Uppsala : Iustus Förl, 1998. http://www.gbv.de/dms/spk/sbb/recht/toc/272701300.pdf.

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20

Koeberle, Andreas. "Identification and characterization of microsomal prostaglandin E₂ synthase-1 inhibitors = Identifizierung und Charakterisierung von Hemmstoffen der mikrosomalen Prostaglandin E₂ Synthase-1 /." Tübingen, 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000278394.

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21

Fink, Kerstin. "Intestinale kommensale Bakterien als potentielle Inhibitoren oder Aktivatoren einer CD4⁺ T-Zell-induzierten Kolitis in Rag1-/- Mäusen /." Tübingen, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253090.

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22

Ziegler, Katharina. "Tetrasubstituierte Imidazole als ATP-kompetitive p38 MAP Kinase Inhibitoren: Synthese, biologische Testung und Untersuchung zur metabolischen Stabilität /." Tübingen, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253679.

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23

Fertmann, Jan Michael. "Untersuchungen zu den Auswirkungen der Inhibition der No-Synthase in einem In-vivo-Modell des regionalen myokardialen Ischämie-/Reperfusionsschadens /." München, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253658.

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24

Maass, Elke. "Einfluss von selektiven und nicht-selektiven COX-2-Inhibitoren in Kombination mit Cisplatin auf das Wachstumsverhalten oraler Plattenpithelkarzinomzellen in vitro /." Köln, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000254550.

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25

Ampem, Prince Tuffour. "Mechanism Underlying the Inhibitory Effect of Nitrative Stress on the Sulfation of Dopamine and its Methylated Product by Human SK-N-MC Neuroblastoma Cells." University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1333675845.

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26

Forster, Laura. "Entwicklung eines Assays zur Bestimmung der Aktivität von Hemmstoffen der Fatty Acid Amide Hydrolase (FAAH) und Synthese neuartiger Inhibitoren des Enzyms /." Münster, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000252266.

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27

Wächter, Michael. "Herstellung von optisch aktiven Organophosphaten mit cis- und trans-Decalingerüst zur Untersuchung der Inhibition von Acetylcholinesterase mittels Enzymkinetik und ³¹P-NMR Spektroskopie /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000282906.

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28

Carlo, Zuddas. "Surface antigenic changes in P.falciparum infected erythrocytes following treatment with Syk inhibitors and Artemisinin." Doctoral thesis, 2020. http://hdl.handle.net/11562/1018318.

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The human Plasmodium falciparum (P.falciparum) parasite, currently infects more than 200 million people annually, causing about 500 000 deaths a year and imposes considerable morbidity on the surviving population. Since 2001, the WHO has recommended Artemisinin based combination therapies (ACTs) as treatment of choice for falciparum malaria. However the WHO has observed foci of suspected artemisinin resistance in South- east Asia. Because strains of P. falciparum are rapidly emerging that are resistant to all known antimalarial drugs, including artemisinin, quinine, chloroquine, piperaquine, and mefloquine and their derivatives, emphasis is currently laid on comprehension of new therapies with novel mechanisms of action that includes also the patient’s immune response. Delayed parasite clearance (DPC) has been identified as an useful indicator of artemisin resistance but it has been shown that parasite clearance suffers interindividual variability and reactivity to antimalarials may depend on host immunity. Recently, studies have demonstrated Syk Inhibitors (R406) as potentially useful new class of antimalarial drugs reducing parasitemia by two ways i) delaying P.falciparum growth and ii) suppressing merozoite egress. The latter is caused by interfering of Syk inhibitors with the membrane of the parasite harboring host RBC. Aim of this study is to understand whether the efficacy of new antimalarial combinations of Syk inhibitors and artemisinins (ARTs) is paralleled by enhanced immune responses of the host. I tried to identify a role of antimalarial drug treatment in the parasites clearance by host’s innate immunity. To reach the goal, I studied the activating effect of Syk inhibitor R406, dihydroartemisinin (DHA) and the combination of both on cellular immune functions in in vitro experiments with human monocytes. First line defense mechanism against the malaria parasite, such as phagocytosis and oxidative burst were assessed in cultured primary phagocytes using ring-stage parasitized RBC as phagocytosis target without and with previous DHA and R406 treatment. The molecular basis for observed functional changes was investigated studying DHA- and R406-dependent opsonin-binding to ring-stage pRBCs. by flow cytometry, Western blotting and immune-precipitation. Monocytes show an increased phagocytosis level after treatment of parasitized Ring-PRBC with DHA and R406 and highest phagocytosis values when DHA and R406 were supplemented together at concentrations of 0.1uM and 0.5.uM, respectively. Membrane-bound autologous IgG and C3c complement factor were remarkably increased on Ring-PRBC surface after treatment with DHA and R406 as judged by flow cytometry. Immunoprecipitation confirmed Band 3 as main protein that is labelled by IgG in Syk-inhibitor treated pRBC and the decreased IgG/band 3 ratio in treated cells vs. untreated ones supports the band 3 aggregation model as signal for IgG flagging. Enhanced phagocytosis of PRBCs may represent the common mechanism for innate malaria protection in nonimmune individuals. Modifications on band 3 of host cell membranes accumulate by the oxidative challenge of the growing parasite accompanied by binding of haemichromes to the cytoplasmic tail of band 3. At the moment when a threshold of modifications is exceeded mainly at trophozoite stage PRBC are recognized by phagocytes and ingested. We hypothesize Syk kinase inhibitors to anticipate the moment of recognition by an early accumulation of modified band 3 and bound haemichromes already at ring stage. Syk inhibitors are described to specifically inhib phosphorylation used by PRBC to shed off band 3 – rich microparticles from their membrane. Consequently, DHA as radical producing molecule enhances the oxidative challenge in PRBC. In conclusion, my data support the hypothesis that Syk inhibitors are a promising class of antimalarial drugs that can suppress parasitemia by increasing also the antiparasitic immune defense. Particularly, R406 should not lead to the selection of resistant strains, as it targets host cell molecules and will likely avoid immunosuppressive effects of hemozoin due to the anticipated phagocytosis of Ring stage-PRBC. Therefore, Syk inhibitors may represent a strategic partner drug for artemisinin therapies for counteracting artemisinin resistance.

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29

Tsamesidis, Ioannis. "Mechanism of synergic interaction of Syk inhibitors on antimalarial artemisinin activity." Doctoral thesis, 2018. http://hdl.handle.net/11562/978967.

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The primary objective of malaria treatment is to eradicate the disease, which involves rapid and complete elimination of the Plasmodium parasite from the patients’ blood. Artemisinin combination therapies (ACTs) are the mainstay of recommended treatment for P. falciparum malaria and as no alternatives to artemisinin derivatives are expected to enter the market for several years, their efficacy must be preserved. Unfortunately, the resistance to ACTs, is a major thread for the control and elimination of malaria due to P. falciparum. The need for new antimalarial drugs is more urgent than ever before, with emerging strains of the parasite now showing resistance against the best available drugs. Recently it has been demonstrated that Syk inhibitors represent a new class of antimalarial drugs which suppress merozoite egress by inhibiting the host target, a factor that cannot be mutated by the parasite to evolve drug resistance. In this study, our aim is to evaluate the in vitro combination activity of Syk inhibitors with artemisinins and understand their mechanistic interaction. The results showed a high synergistic combination activity between all tested Syk inhibitors with artemisinins against P. falciparum. The combination index analysis indicated the following Syk inhibitors as the most synergistic with Artemisinins: P505-15, R406 and Imatinib. Furthermore, we observed that Syk inhibitors produce a massive accumulation of hemichromes in the parasitized erythrocytes, this in turn triggers the activation of artemisinins and causes a marked synergistic effect when administered in combination. The synergic effect of Syk inhibitors is based on a novel mechanism of action acting selectively on the parasitized erythrocytes which allows the artemisinins to be activated quicker and more efficiently. The concentrations of Syk inhibitors needed to synergize artemisinins is 5-20 fold lower than the IC50 measured as a direct effect on parasite growth. These concentrations correspond to very well tolerated dosages and can be rapidly reached after oral administration. In conclusion, our results potentially suggest Syk inhibitors as a strategic class of partner drugs for a new ACT.

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30

Castellanos, Penton Patricia. "Syk Inhibition Attenuates Airway Hyperresponsiveness in a Murine Model of Asthma and Exacerbation by Air Pollution." Thesis, 2012. http://hdl.handle.net/1807/33357.

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Airway hyperresponsiveness (AHR) is a cardinal feature of asthma that is aggravated by environmental air pollution (EAP). Splenocyte tyrosine kinase Syk has been associated with asthma pathogenesis. Therefore, we sought to investigate the effect of Syk inhibition on AHR and its exacerbation by EAP. For this purpose, we examined Syk protein expression in lung homogenates from three murine models of ovalbumin (OVA)-induced asthma expressing different pathophysiological features of the disease: airway inflammation, AHR and remodeling. Increased Syk expression was observed only in the chronic model of airway inflammation and remodeling. In vivo Syk inhibition attenuates AHR in this model, and further augmentation induced by EAP without affecting the underlying airway inflammation. We demonstrated, for the first time, that Syk inhibition effectively reverted AHR in an already established chronic model of asthma. These findings highlight the therapeutic potential of targeting Syk for the treatment of asthma and its exacerbations by EAP.

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31

Chen, Ching-Wen, and 陳菁雯. "PART I. Inhibition of interferon-gamma-mediated JAK-STAT signaling pathways by endonuclease inhibitor aurintricarboxylic acid and PPARg agonist 15dPGJ2 PART II. Signaling pathways of vanilloid receptor-independent inhibition of inducible nitric oxide syn." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/66451291613409478132.

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Анотація:

碩士
國立臺灣大學
藥理學研究所
90
Inducible nitric oxide (iNOS) is thought to involve in host defense and tissue damage in inflammatory loci. In previous study, we have found that the endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from cell death induced by bacterial lipopolysaccharide. This action is through the interruption with signaling pathways for NF-kB and AP-1 activation, and thus iNOS expression. In this study we have addressed the effects of ATA on JAK-STAT signaling pathways. In murine RAW 264.7 macrophages, IFN-g-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3-100 mM ATA. IFN-g-induced STAT1 activation, as assessed from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA response element and evoked IRF-1 reporter gene assay, was concomitantly inhibited by ATA. The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signaling in response to IFN-g, were also reduced by ATA. Moreover, IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5 and/or STAT6 in macrophages were diminished by the presence of ATA. Taken together, we conclude that ATA can interfere JAK-STAT signaling pathways in response to cytokines. This action contributes to the inhibition of IFN-g-induced iNOS expression. These data together with previously identified anti-apoptotic action raise the potential use of ATA in the therapy of inflammatory diseases. PPARs are transcription factors belonging to the nuclear receptor superfamily. PPARg ligand 15dPGJ2 has been reported to exert anti-inflammatory activities in macrophages by competition for transcriptional coactivators with some transcriptional factors. In the present study, the influences of PPARg activators on IFN-g-elicited macrophage stimulation and signalling cascades involving JAK/STAT are investigated. The results show that IFN-g-induced iNOS expression and NO production are more sensitive to the inhibition by 15dPGJ2 than by other two PPARg agonists, GW1929 and ciglitazone. Delayed addition of 15dPGJ2 for two hours results in a reduced inhibition, suggesting the action of 15dPGJ2 on the upstream signaling cascades. Immunoblotting, DNA binding and reporter gene assays consistently reveal the inhibitory abilities of 15dPGJ2, but not GW1929 or ciglitazone, on IFN-g elicited tyrosine phosphorylation of JAK2 and STAT1, as well as DNA binding activity and IRF-1 transactivation ability of STAT1. Not only inhibiting the signaling of IFN-g, 15dPGJ2 also attenuates IL-6-induced tyrosine phosphorylation of STAT1 and STAT3 in Hep3B hepatoma cells. Consistent with the inhibitory effect of ROS on STAT1 signaling, STAT1 inhibition by 15dPGJ2 is abrogated by antioxidants, NAC and GSH. Furthermore, 15dPGJ2-induced inhibition of STAT1 phosphorylation and NO production still occur in the presence of orthovanadate. This rules out the action mechanism of 15dPGJ2 on tyrosine phosphatase. Taken together, in this study, we for the first time demonstrate that 15dPGJ2 can inhibit cytokine-stimulated JAK-STAT signaling through a PPARg-independent, but ROS-dependent mechanism. These data provide a novel molecular mechanism of iNOS inhibition by 15dPGJ2, and reinforce its physiological role in anti-inflammation. Compounds related to capsaicin and its ultrapotent analog, resiniferatoxin (RTX), collectively referred to as vanilloids, interact at a specific membrane recognition site (vanilloid receptor, VR). To date, the major and well-known role of VR in nociception and neurogenic inflammation relies on its extremely abundant expression in primary sensory neurons. In this study, the effects of capsaicin analogs on early signalling related to iNOS and COX-2 expression in RAW 264.7 macrophages were investigated. Capsaicin and RTX concentration-dependently inhibited lipopolysaccharide (LPS)- and interferon-g (IFN-g)-mediated NO production, with similar IC50 value of 7-10 mM. Accompanied with NO inhibition, iNOS protein and mRNA expression were attenuated by capsaicin and RTX. Capsaicin also transcriptionally inhibited LPS- and/or PMA-induced COX-2 expression and PGE2 production. Moreover, this COX-2 inhibition by capsaicin exhibited 30-fold higher potency than for iNOS/NO inhibition, while RTX failed to change COX-2/PGE2 response at 10 mM. To address the role of VR in these actions of vanilloid agonists, we tested capsazepine, a competitive VR antagonist. The results revealed that capsazepine did not prevent the inhibition elicited by capsaicin or RTX; however, it mimicked vanilloids to inhibit iNOS/NO and COX-2/PGE2 responses of LPS with IC50 value of 3 mM. NO reduction by these three agents was not completely washable, and not relevant to Ca2+ influx, but displayed a mutual additivity. RT-PCR analysis and immunoblotting further excluded the expression of VR in RAW 264.7 macrophages. Consistent with the reduction of iNOS and COX-2 gene expression, DNA binding assay revealed the abilities of vanilloid agents to inhibit LPS-elicited NF-kB and AP-1 activation as well as IFN-g-elicited STAT1 activation. Kinase assay indicated that ERK and IKK activation by LPS was inhibited by vanilloid analogs. In conclusion, vanilloids not only regulate nociception, but also modulate the expression of inflammatory genes iNOS and COX-2 in macrophages. This action is unrelated to VRs, and provides new insight on the potential benefits of hot chilli peppers in inflammatory conditions.

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VANÍČKOVÁ, Martina. "Detekce a kvantifikace inhibitorů proteáz v klíštěti \kur{Ixodes ricinus} pomocí monoklonálních protilátek." Master's thesis, 2017. http://www.nusl.cz/ntk/nusl-381504.

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Inhibitors of proteases in tick saliva play an important role during tick feeding. Tick saliva contains a wide range of bioactive components which are able to modulate host imunity. Therefore, ticks are able to feed for a long time and transfer tick-borne diseases pathogens. The risk of transfer can be significantly reduced by deactivation of theese protease inhibitors. In this study I made monoclonal antibodies for detection and quantification of two serine protease inhibitors in tick saliva and other tick-body parts.

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(10716546), Panae Noomuna. "INHIBITION OF ERYTHROCYTE BAND 3 TYROSINE PHOSPHORYLATION: CHARACTERIZATION OF A NOVEL THERAPY FOR SICKLE CELL DISEASE AND MALARIA." Thesis, 2021.

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While the molecular defect that cause sickle cell disease has well been established, the cause of vaso-occlusive crisis remains elusive and largely debated upon. Majority of studies have linked the painful episodes to polymerization of sickle hemoglobin following its deoxygenation. The variability of the disease symptoms among patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator of Hb F induction and a widely used treatment, has ameliorated the complication of SCD but it is only effective in 50% of the patients. Expression of Hb F lowers the content of Hb S in blood and hence reduces oxidative stress caused by Hb S denaturation. Sickle cell disease severity depends on several factors. Most importantly, the ability of red cell to sickle dominates all other determinants. While deoxygenation of sickle hemoglobin may be inevitable, the duration with which the red cell remains in the deoxygenated state can be manipulated. Deoxygenation is a transient process that when compared to the time taken to develop the long filaments of deoxyhemoglobin to causes severe sickling, the red cell would have been cycled back to the lungs and re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle cells would flow as fast as healthy erythrocytes, the detrimental impacts of sickling such as vaso-occlusive crisis, would not be a concern for this disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation through auto-oxidation, which imposes oxidative stress to the cells. The oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which subsequently impair their constitutive action against the tyrosine kinases. In the end, a net tyrosine phosphorylation state in the red cell membrane proteins, most notably the transmembrane protein band 3, succeeds. Band 3 tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage to the membrane thus engendering membrane destabilization. A destabilized erythrocyte sheds membrane fragments in form of microvesicles/microparticles and discharges free hemoglobin into the extra cellular matrix. In consequence, the microparticles power initiation of coagulation cascade through activation of thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is necessary for vasodilation and induces further oxidative stress within the microvasculature, and activates expression of adhesion receptors on the endothelium. Taken together, these events culminate in entrapment of red cells (not naming leucocytes and platelets) in the microvasculature, blockade of blood vessels and further damage of erythrocytes through prolonged deoxygenated state thus terminating in tissue injury, strokes, and organ damage, amid vaso-occlusive episodes which always require hospitalization and extensive medical care for survival. Band 3 tyrosine phosphorylation and membrane weakening is not unique just to SCD, but also a druggable target for malaria. Malaria, a disease that is touted as the evolutionary cause of sickle cell disease, surprisingly thrives through the same mechanism. Briefly, malaria parasite consumes hemoglobin for its DNA synthesis, and in the process generate reactive oxygen species from denatured hemoglobin that feeds into the oxidative stress which triggers band 3 tyrosine phosphorylation. In this case however, a destabilized membrane offers perfect conditions for merozoites’ (malaria daughter parasites) egress/exit out of the cell to begin infecting other red cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s death. Treatment of diseased cells with imatinib and other Syk inhibitors effectively reversed membrane weakening. A stabilized membrane not only survives longer in circulation to alleviate SCD symptoms but also traps and starves malaria parasite leading to termination of the parasitic infection. With band 3 tyrosine phosphorylation at center stage, this dissertation explores the above events in an effort to unveil a novel therapy for sickle cell and malaria diseases. First, the therapeutic strategy regarding SCD is discussed in detail beginning with non-transfused patients and ending in additional mechanistic study on inactivation of the principal erythrocyte’s protein tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial proof of concept on efficacy of imatinib in treatment of malaria as a monotherapy and its efficacy when used in a triple combination therapy with the standard of care treatment. Finally, I outline an alternative possible mechanism of action of quinine against malaria.

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"Prevention of inorganic scale formation in off-shore oil exploration: applications of the ppca inhibitor." Tese, MAXWELL, 2002. http://www.maxwell.lambda.ele.puc-rio.br/cgi-bin/db2www/PRG_0991.D2W/SHOW?Cont=3663:pt&Mat=&Sys=&Nr=&Fun=&CdLinPrg=pt.

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Font, Haro Albert. "Modulace funkce plazmacytoidních dendritických buněk: role immunoreceptorů TIM-3 a BDCA-2." Doctoral thesis, 2021. http://www.nusl.cz/ntk/nusl-447158.

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Albert Font Haro ABSTRACT Modulation of plasmacytoid dendritic cell function: role of immunoreceptors TIM-3 and BDCA-2 Plasmacytoid dendritic cells (pDCs) are key players in the antiviral response as well as in linking innate and adaptive immune response. They express endosomal toll-like receptors 7 and 9, which can detect ssRNA and unmethylated CpG DNA, respectively. Due to the constitutive expression of the transcription factor IRF7, pDCs are able to rapidly produce massive quantities of type I (α, β, ω) and type III (1, 2, 3, 4) interferons (IFN-I and IFN-III) as well as pro- inflammatory cytokines such as IL-1, IL-6 and TNF-α. After maturation, they also function as antigen-presenting cells. Despite intense research, the mechanisms of IFN and pro-inflammatory cytokines production and regulation are still poorly understood. Using the pDC cell line GEN2.2 and also primary human pDCs, we shed light on the role of kinases MEK and SYK in IFN-I production and regulation. We found that SYK is not only involved in the regulatory receptor (RR)-mediated BCR-like pathway that represents the negative regulation of IFN-I and IFN-III secretion but also in the positive TLR7/9-mediated signal transduction pathway that leads to IFN-I production, representing the immunogenic function. We also found that MEK plays a...

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