Relevant bibliographies by topics / Targeted antagonist

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Academic literature on the topic 'Targeted antagonist'

Author: Grafiati
Published: 1 February 2023

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Journal articles on the topic "Targeted antagonist"

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Akbar, Mohammad J., Pâmela C. Lukasewicz Ferreira, Melania Giorgetti, Leanne Stokes, and Christopher J. Morris. "Bombesin receptor-targeted liposomes for enhanced delivery to lung cancer cells." Beilstein Journal of Nanotechnology 10 (December 19, 2019): 2553–62. http://dx.doi.org/10.3762/bjnano.10.246.

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Background: Gastrin-releasing peptide is a member of the bombesin family of peptides. Its cognate receptor, gastrin releasing peptide receptor (GRPR), is widely expressed in cancers of the lung, pancreas and ovaries. Gastrin releasing peptide (GRP) is an autocrine growth factor in small cell lung cancer, which has very poor patient outcomes. High affinity antagonist peptides have been developed for in vivo cancer imaging. In this report we decorated pegylated liposomes with a GRPR antagonist peptide and studied its interaction with, and accumulation within, lung cancer cells. Results: An N-terminally cysteine modified GRPR antagonist (termed cystabn) was synthesised and shown to inhibit cell growth in vitro. Cystabn was used to prepare a targeted 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000) lipid conjugate that was formulated into liposomes. The liposomes displayed desirable colloidal properties and good stability under storage conditions. Flow cytometric and microscopic studies showed that fluorescently labelled cystabn-decorated liposomes accumulated more extensively in GRPR over-expressing cells than matched liposomes that contained no cystabn targeting motif. Conclusion: The use of GRPR antagonistic peptides for nanoparticle targeting has potential for enhancing drug accumulation in resistant cancer cells.
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Marceau, François, and Hélène Bachelard. "A Robust Bioassay of the Human Bradykinin B2 Receptor That Extends Molecular and Cellular Studies: The Isolated Umbilical Vein." Pharmaceuticals 14, no. 3 (February 24, 2021): 177. http://dx.doi.org/10.3390/ph14030177.

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Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.
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Baghdadi, Neazar E., Benjamin P. Burke, Tahani Alresheedi, Shubhanchi Nigam, Abdu Saeed, Farooq Almutairi, Juozas Domarkas, Abid Khan, and Stephen J. Archibald. "Multivalency in CXCR4 chemokine receptor targeted iron oxide nanoparticles." Dalton Transactions 50, no. 5 (2021): 1599–603. http://dx.doi.org/10.1039/d0dt02626c.

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Tao, Haiyan, Emily Eastwood, Raymond G. Fox, Neil Raheja, Paul D. Crowe, and Scott M. Thacher. "Abstract LB144: Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB144. http://dx.doi.org/10.1158/1538-7445.am2022-lb144.

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Abstract Leydig cell tumors (LCT), originating from androgen-producing interstitial Leydig cells of the testis, represent about 3% of all testicular cancers. LCT belong to the family of sex cord stromal tumors (SCST), a collection of tumors formed in the supporting tissue within the ovaries or testes. Although 90% of LCT are considered benign and can be cured by orchiectomy, in adult patients about 10% of LCT are malignant and metastasis is common. Non-resectable metastatic disease is poorly responsive to radiation and chemotherapy and patients are advised to seek clinical trials. Steroidogenic Factor 1 (SF-1, or NR5A1) is a transcription factor that is essential for the development of the adrenal gland and gonads. SF-1 mutations result in disorders of sexual development, ovarian failure, and adrenal insufficiency. SF-1 is necessary for development of fetal and adult Leydig cells and is strongly expressed in LCT. Significant data support the role of SF-1 in adrenocortical cancer (ACC). To address the need for a targeted therapy in ACC and other SF-1-dependent malignancies, Orphagen has identified potent small molecule antagonists to SF-1*. Here, using R2C, a rat Leydig tumor cell line, we demonstrate that small molecule antagonists of SF-1 inhibit Leydig tumor cell proliferation in vitro and in vivo. OR-449, an orally available inhibitor of SF-1 transcriptional activity (SF-1 Luc IC50 = 16 nM) and OR-907S, a probe SF-1 antagonist (SF-1 Luc IC50 = 22 nM), exhibit striking anti-proliferative activity in R2C cell cultures, inhibiting DNA synthesis by >90% at 1 μM with estimated IC50’s of 0.068 μM and 0.074 μM, respectively. OR-907R, the ~100-fold less active stereoisomer of OR-907S (SF-1 Luc IC50 = 2 μM) was significantly less active in the R2C proliferation assay (estimated IC50 >10 μM). Moreover, in cell lines lacking SF-1 expression, such as HEK293, SF-1 antagonists have no anti-proliferative activity up to 20 μM, suggesting that the anti-proliferative effect on R2C is SF-1-mediated and not due to cytotoxicity. Furthermore, OR-449 completely blocks R2C xenograft tumor growth in immunocompromised mice at an oral dose of 30 mg/kg/day. OR-449 also dose-dependently regulates expression of SF-1 responsive genes, a mRNA signature first identified in R2C culture by comparison of the activity of OR-907S and OR-907R at 1 μM. OR-449 has excellent pharmacokinetic properties and is well-tolerated in repeat dosing toxicity studies in rodents and non-rodents*. These results highlight SF-1 antagonism as a novel targeted therapeutic approach with potential utility in the treatment of LCT and other SCST. OR-449 is currently in IND-enabling studies in order to enter the clinic by the end of 2022. * P. Crowe, et al. A novel steroidogenic factor-1 antagonist, OR-449, as a targeted therapy for adrenocortical cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010 Citation Format: Haiyan Tao, Emily Eastwood, Raymond G. Fox, Neil Raheja, Paul D. Crowe, Scott M. Thacher. Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB144.
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Bryant, Kelly G., Young Chan Chae, Rogelio L. Martinez, John C. Gordon, Khaled M. Elokely, Andrew V. Kossenkov, Steven Grant, Wayne E. Childers, Magid Abou-Gharbia, and Dario C. Altieri. "A Mitochondrial-targeted purine-based HSP90 antagonist for leukemia therapy." Oncotarget 8, no. 68 (December 11, 2017): 112184–98. http://dx.doi.org/10.18632/oncotarget.23097.

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Abouzayed, Ayman, Alisa Gorislav, Panagiotis Kanellopoulos, Vladimir Tolmachev, Theodosia Maina-Nock, Berthold A. Nock, and Anna Orlova. "Development of a stabilized GRPR antagonist for targeted cancer theranostics." Nuclear Medicine and Biology 114-115 (November 2022): S24. http://dx.doi.org/10.1016/s0969-8051(22)02142-4.

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Kwan, Byron H., Eric F. Zhu, Alice Tzeng, Harun R. Sugito, Ahmed A. Eltahir, Botong Ma, Mary K. Delaney, et al. "Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses." Journal of Experimental Medicine 214, no. 6 (May 4, 2017): 1679–90. http://dx.doi.org/10.1084/jem.20160831.

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Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti–PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.
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Pere, Helene, Yves Montier, Jagadeesh Bayry, Francoise Quintin-Colonna, Nathalie Merillon, Estelle Dransart, Cecile Badoual, et al. "A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens." Blood 118, no. 18 (November 3, 2011): 4853–62. http://dx.doi.org/10.1182/blood-2011-01-329656.

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Abstract Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8+ T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8+ T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8+ T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44high) and activated (ICOS+) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8+ T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.
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Bishayee, K., and A. R. Khuda-Bukhsh. "5-Lipoxygenase Antagonist therapy: a new approach towards targeted cancer chemotherapy." Acta Biochimica et Biophysica Sinica 45, no. 9 (June 9, 2013): 709–19. http://dx.doi.org/10.1093/abbs/gmt064.

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Roblek, Marko, Manuela Calin, Martin Schlesinger, Daniela Stan, Reiner Zeisig, Maya Simionescu, Gerd Bendas, and Lubor Borsig. "Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis." Journal of Controlled Release 220 (December 2015): 341–47. http://dx.doi.org/10.1016/j.jconrel.2015.10.055.

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Dissertations / Theses on the topic "Targeted antagonist"

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Mittal, Gayatri Arvind. "Development of a latent IL-17 antagonist for targeted therapy of rheumatoid arthritis." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8520.

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Cytokine based therapies can be targeted to the sites of active inflammation by modifying a given cytokine as a LAP-cytokine. IL-17A has been shown to directly contribute to pathogenesis of rheumatoid arthritis (RA). IL-17F, another member of the IL-17 cytokines family shares structural homology, receptor binding and biological properties with IL-17A but is 30-100 times less potent than IL-17A. (H161R) IL-17F mutant, a natural variant of IL-17F was shown to be protective against asthma in Japanese population. In vitro, IL-17F mutant competitively inhibited wild-type IL-17F and lacked the ability to activate downstream signaling pathways. I hypothesized that (H161R) IL-17F mutant is an additional inhibitor of IL-17A and if modified as LAP-IL-17F mutant, would be an effective targeted therapy for RA. (H161R) IL-17F mutant was created by substituting nucleotide A at position 485 in the wild type IL-17F by G. In vitro assays showed that the IL-17F mutant could bind to IL-17RC but lacked the ability to stimulate IL-6 secretion in HFFF2, 3T3 and HeLa cells and phosphorylate ERK1/2 in HeLa cells. IL-17F mutant also inhibited IL-17A induced secretion of IL-6 in all these cell lines. In order to assess in vivo therapeutic efficacy of LAP-IL-17F mutant in collagen induced arthritis mice, three mouse analogues of human IL-17F mutant were developed. Of these, (Q158R) IL-17F mutant displayed IL-17 agonistic properties, (H157R) IL-17F mutant could not be expressed in vitro and the truncated IL-17F mutant could not bind to mouse IL-17RC. Investigation of in vivo expression and pharmacokinetics of intravenous hydrodynamically delivered human full-length and LAP-IL-17 plasmid DNAs in naïve SCID and C57BL/6 mice showed that human IL-17 transgene expression was detectable in mouse serum at 48 hours post-delivery. The transgene expression however declined rapidly over the next two weeks. The local expression of transgene in C57BL/6 airpouch lavage fluid was less than 5% of its systemic levels. Taken together, the findings of the study warrant an investigation of in vivo therapeutic efficacy of human (H161F) IL-17F mutant in a suitable preclinical RA model, such as RA synovium/SCID mice.
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Ogor, Thomas. "Ciblage cellulaire spécifique de l'interféron α pour le contrôle des défenses immunitaires antitumorales." Thesis, Université de Montpellier (2022-….), 2022. http://www.theses.fr/2022UMONT001.

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Il est largement admis qu'un cancer se développe lorsque les cellules cancéreuses échappent au contrôle du système immunitaire et que l'exploitation des défenses immunitaires afin de réactiver les cellules T endogènes anti-tumorales pourrait être une option thérapeutique pour obtenir des réponses complètes et durables.L'interféron de type I est connu pour sa puissante activité antitumorale dans les tumeurs expérimentales de la souris. En outre, il s'est avéré être une cytokine clé nécessaire à l'efficacité de nombreux agents anticancéreux ciblant non seulement les cellules cancéreuses (radiations ionisantes, produits chimiques cytostatiques, AcM...) mais aussi le système immunitaire (vaccination, cellules CAR-T...). Cependant, son utilisation n'est plus envisagée par le clinicien en raison des effets secondaires subis par les patients. Pour répondre à cette préoccupation, une technologie très prometteuse permettant la conception de molécules d'interféron ciblées et spécifiques aux cellules a été développée et l'objectif de notre travail actuel est de générer et d'évaluer pré-cliniquement des composés principaux. Pour cela, il faut s'attaquer à un certain nombre de frontières de la recherche, notamment répondre aux questions fondamentales "où" et "quand" l'interféron doit agir pour exercer son activité antitumorale, seul ou en combinaison avec les stratégies thérapeutiques susmentionnées.La question "quand" est importante car on soupçonne fortement que le moment relatif de l'action de l'interféron et de la stimulation du TCR détermine si l'effet de l'interféron est immunostimulant ou immunosuppresseur. La question "où" est évidente car elle détermine le choix de la partie ciblée des interférons modifiés. Nous savons que l'action de l'interféron sur les cellules dendritiques est nécessaire à son activité antitumorale, mais est-elle suffisante ? Une action sur les cellules T est-elle également obligatoire ? L'action de l'interféron sur les cellules tumorales ou les cellules du stroma est-elle nécessaire pour attirer les cellules immunitaires effectrices ?
It is widely accepted that a cancer develops when cancer cells escape from the control of the immune system and that harnessing the immune defences in order to reactivate endogenous anti-tumor T cells could be a therapeutic option for full and durable responses.Type I interferon is known for its potent antitumor activity in experimental mouse tumors. Furthermore, it has been shown to be a key cytokine necessary for the efficacy of many anticancer agents targeting not only cancer cells (ionising radiations, cytostatic chemicals, mAbs…) but also the immune system (vaccination, CAR-T cells…). However, its use is no longer considered by the clinician owing to the side effects experienced by the patients. To address this concern, a highly promising technology allowing the design of cell-specific targeted interferon molecules has been developed and the objective of our present work is to generate and pre-clinically evaluate lead compounds. For this, a number of research frontiers must be tackled, these include to answer to the fundamental questions 'where' and 'when' interferon must act in order to exert its antitumor activity either alone or in combination with the above-mentioned therapeutic strategies.The question 'when' is important because it is highly suspected that the relative timing of interferon action and TCR stimulation determines whether the effect of interferon is immunostimulant or immunosuppressive. The question 'where' is evident since it determines the choice of the targeting moiety of the engineered interferons. We know that the action of interferon on dendritic cells is necessary for its antitumor activity but is it sufficient? Is an action on T cells also mandatory? Is an interferon action on tumor cells or stroma cells necessary for attracting effector immune cells?
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Pereira, Perpetual A. "Evaluation of methylenetetrahydrofolate reductase for targeted therapeutics in cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0018/MQ55085.pdf.

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Mayer, Bettina. "IAP antagonism as a novel approach to target endothelial activation." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-116846.

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Grant, Alesha. "Functional Conservation of Interferon Antagonism among Flaviviruses| Zika Virus Targets Human STAT2." Thesis, Icahn School of Medicine at Mount Sinai, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10270604.

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Flaviviruses are a diverse group of emerging arboviruses capable of infecting an extraordinarily broad range of vertebrate and invertebrate hosts. Nearly half of the viruses in this rapidly expanding genus have been reported to be pathogenic for humans, as well as other vertebrates. The spectrum of human disease includes asymptomatic and febrile illnesses, rash, arthralgia, encephalitis and hemorrhagic fever. The recent outbreak of Zika virus (ZIKV) has uncovered pathology in the form of microcephaly and Guillain-Barré syndrome, cementing the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) antiviral responses in order to replicate and cause disease in vertebrates. The non-structural protein NS5 is a potent and specific antagonist of IFN signaling for human pathogenic flaviviruses such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis viruses (TBEVs). Intriguingly, each of these viruses exhibits different mechanisms of IFN antagonism, highlighting the complicated evolutionary nature of flaviviruses. This thesis work presents novel insights into the NS5-mediated antagonism of IFN signaling for several underexamined flaviviruses. Notably, all NS5 proteins examined were able to inhibit IFN-induced gene expression in a mammalian system, indicating a functional conservation of IFN antagonism for flavivirus NS5 proteins. However, mechanistically NS5 function was diverse. Of great interest, ZIKV NS5 bound to the human, but not mouse, IFN-regulated transcriptional activator STAT2 and targeted it for proteasomal degradation. This phenomenon may explain the requirement for IFN deficiency in order to observe ZIKV pathogenesis in mice. Furthermore, the mechanism of ZIKV NS5 resembles that of DENV NS5, but not that of its closer relative Spondweni virus (SPOV). However, unlike DENV NS5, ZIKV NS5 did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Consequently, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. The potent antagonism of human IFN responses by neglected flaviviruses such as SPOV and Usutu virus (USUV), coupled with similar ecologies to that of known human flavivirus pathogens, suggests their potential for broad emergence into the human population.

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Mills, John Steven. "Interaction of calcium, metal ions, and calmodulin antagonist drugs and target proteins with calmodulin /." The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu148732574071875.

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Harmse, Rozanne. "Syntheses of 8-(phenoxymethyl)caffeine analogues and their evaluation as inhibitors of monoamine oxidase and as antagonists of the adenosine A2A receptor / Rozanne Harmse." Thesis, North-West University, 2013. http://hdl.handle.net/10394/9663.

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Background and rationale: Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system and is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The loss of functional dopamine in the striatum is thought to be responsible for the typical symptoms of PD. Cardinal features of PD include bradykinesia, muscular rigidity, resting tremor and impairment of postural balance. This study focuses on the inhibition of monoamine oxidase B (MAO-B) and antagonism of A2A receptors as therapeutic strategies for PD. Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing mitochondrial bound isoenzyme which consists of two isoforms namely MAO-A and MAO-B. The primary function of MAO is to catalyze the oxidative deamination of dietary amines, monoamine neurotransmitters and hormones. MAO-A is responsible for the oxidative deamination of serotonin (5-HT) and norepinephrine (NE), while MAO-B is responsible for the oxidative deamination of dopamine (DA). The formation of DA takes place in the presynaptic neuron where it is stored in vesicles and released into the presynaptic cleft. The released DA then either binds to D1 and D2 receptors which results in an effector response. The excess DA in the presynaptic cleft is metabolized by MAO-B which may result in the formation of free radicals and a decrease in DA concentrations. Under normal physiological conditions free radicals are removed from the body via normal physiological processes, but in PD these normal physiological processes are thought to be unable to remove the radicals and this may lead to oxidative stress. Oxidative stress is believed to be one of the leading causes of neurodegeneration in PD. The rationale for the use of MAO-B inhibitors in PD would be to increase the natural DA levels in the brain and also diminish the likelihood of free radicals to be formed. Adenosine is an endogenous purine nucleoside and yields a variety of physiological effects. Four adenosine receptor subtypes have been characterized: A1, A2A, A2B and A3. They are all part of the G-protein-coupled receptor family and have seven transmembrane domains. The A2A receptor is highly concentrated in the striatum. There are two important pathways in the basal ganglia (BG) through which striatal information reaches the globus pallidus, namely the direct pathway containing A1 and D1 receptors and the indirect pathway containing A2A and D2 receptors. The direct pathway facilitates willed movement and the indirect pathway inhibits willed movement. A balance of the two pathways is necessary for normal movement. In PD, there is a decrease in DA in the striatum, thus leading to unopposed A2A receptor signaling and ultimately resulting in overactivity of the indirect pathway. Overactivity of the indirect pathway results in the locomotor symptoms associated with PD. Treatment with an A2A antagonist will block the A2A receptor, resulting in the restoration of balance between the indirect and direct pathways, thus leading to a decrease in locomotor symptoms. Aim: In this study, caffeine served as a lead compound for the design of dual-targeted drugs that are selective, reversible MAO-B inhibitors as well as A2A antagonists. Caffeine is a very weak MAO-B inhibitor and a moderately potent A2A antagonist. Substitution on the C8 position of caffeine yields compounds with good MAO-B inhibition activities and A2A receptor affinities. An example of this behaviour is found with (E)-8-(3-chlorostyryl)caffeine (CSC), which is not only a potent A2A antagonist but also a potent MAO-B inhibitor. The goal of this study was to identify and synthesize dual-targeted xanthine compounds. Recently Swanepoel and co-workers (2012) found that 8-phenoxymethyl substituted caffeines are potent reversible inhibitors of MAO-B. Therefore, this study focused on expanding the 8-(phenoxymethyl)caffeine series and evaluating the resulting compounds as both MAO-A and -B inhibitors as well as A2A antagonists. Synthesis: Two series were synthesized namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines. The analogues were synthesized according to the literature procedure. 1,3-Dimethyl-5,6-diaminouracil or 1,3-diethyl-5,6-diaminouracil were used as starting materials and were acylated with a suitable substituted phenoxyacetic acid in the presence of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDAC) as an activating reagent. The intermediary amide was treated with sodium hydroxide, which resulted in ring closure to yield the corresponding 1,3-dimethyl-8-phenoxymethyl-7Hxanthinyl or 1,3-diethyl-8-phenoxymethyl-7H-xanthinyl analogues. These xanthines were 7-N-methylated in the presence of an excess of potassium carbonate and iodomethane to yield the target compounds. In vitro evaluation: A radioligand binding assay was performed to determine the affinities of the synthesized compounds for the A2A receptor. The MAO-B inhibition studies were carried out via a fluorometric assay where the MAO-catalyzed formation of H2O2 was measured. Results: Both series showed good to moderate MAO-B inhibition activities, while none of the compounds had activity towards MAO-A. Results were comparable to that of a known MAOB inhibitor lazabemide. For example, lazabemide (IC50 = 0.091 μM) was twice as potent as the most potent compound identified in this study, 8-(3-chlorophenoxymethyl)caffeine (compound 3; IC50 = 0.189 μM). Two additional compounds, 8-(4-iodophenoxymethyl)caffeine and 8-(3,4-dimethylphenoxymethyl) caffeine, also exhibited submicromolar IC50 values for the inhibition of MAO-B. The structure-activity relationships (SARs) indicated that 1,3-diethyl substitution resulted in decreased inhibition potency towards MAO-B and that 1,3-dimethyl substitution was a more suitable substitution pattern, leading to better inhibition potencies towards MAO-B. The compounds were also evaluated for A2A binding affinity, and relatively weak affinities were recorded with the most potent compound, 1,3-diethyl-7-methyl-8-[4-chlorophenoxymethyl]xanthine (compound 16), exhibiting a Ki value of 0.923 μM. Compared to KW-6002 (Ki = 7.94 nM), a potent reference A2A antagonist, compound 16 was 35-fold less potent. Comparing compound 16 to CSC [Ki(A2A) = 22.6 nM; IC50(MAO-B) = 0.146 nM], it was found that compound 16 is 31-fold less potent as an A2A antagonist and 21-fold less potent as a MAO-B inhibitor. Loss of MAO-B inhibition potency may be attributed to 1,3-diethyl substitution which correlates with similar conclusions reached in earlier studies. In addition, the replacement of the styryl functional group (as found with CSC and KW-6002) with the phenoxymethyl functional group (as found with the present series) may explain the general reduction in affinity for the A2A receptor. This suggests that the styryl side chain is more appropriate for A2A antagonism than the phenoxymethyl functional group. Conclusion: In this study two series of xanthine derivatives were successfully synthesized, namely the 8-(phenoxymethyl)caffeines and 1,3-diethyl-7-methyl-8-(phenoxymethyl)xanthines (11 compounds in total). Three of the newly synthesized compounds were found to act as potent inhibitors of MAO-B, with IC50 values in the submicromolar range. None of the compounds were however noteworthy MAO-A inhibitors. The most potent A2A antagonist among the examined compounds, compound 16, proved to be moderately potent compared to the reference antagonists, CSC and KW-6002. It may be concluded that the styryl functional group (as found with CSC and KW-6002) is more optimal than the phenoxymethyl functional group (as found with the present series) for A2A antagonism. 1,3-Diethyl substitution of the xanthine ring was found to be less optimal for MAO-B inhibition compared to 1,3-dimethyl substitution. These results together with known SARs provide valuable insight into the design of 8-(phenoxymethyl)caffeines as selective and potent MAO-B inhibitors. Such drugs may find application in the therapy of PD.
Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2013.
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Wachowius, Marco [Verfasser], and Klaus [Akademischer Betreuer] Förstemann. "The rabies virus phosphoprotein: novel targets and functions involved in interferon antagonism / Marco Wachowius ; Betreuer: Klaus Förstemann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1174142812/34.

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Waldeck, Kristian. "Targets for pharmacological intervention in the bladder and urethra." Lund : Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/68945055.html.

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Ragno, Daniele. "Sintesi di nuovi derivati tri-componente per target photodynamic therapy della neoplasia prostatica." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amslaurea.unibo.it/3875/.

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Therapies for the treatment of prostate cancer show several limitations, especially when the cancer metastasizes or acquires resistance to treatment. In addition, most of the therapies currently used entails the occurrence of serious side effects. A different therapeutic approach, more selective and less invasive with respect either to radio or to chemotherapy, is represented by the photodynamic therapy (PDT). The PDT is a treatment that makes use of photosensitive drugs: these agents are pharmacologically inactive until they are irradiated with light at an appropriate wavelength and in the presence of oxygen. The drug, activated by light, forms singlet oxygen, a highly reactive chemical species directly responsible for DNA damage, thus of cell death. In this thesis we present two synthetic strategies for the preparation of two new tri-component derivatives for photodynamic therapy of advanced prostate cancer, namely DRPDT1 and DRPDT2. Both derivatives are formed by three basic elements covalently bounded to each other: a specific ligand with high affinity for the androgen receptor, a suitably chosen spacer molecule and a photoactivated molecule. In particular, DRPDT2 differs from DRPDT1 from the nature of the AR ligand. In fact, in the case of DRPDT2 we used a synthetically engineered androgen receptor ligand able to photo-react even in the absence of oxygen, by delivering NO radical. The presence of this additional pharmacophore, together with the porphyrin, may ensure an additive/synergistic effect to the photo-stimulated therapy, which than may act both in the presence of oxygen and in hypoxic conditions. This approach represents the first example of multimodal photodynamic therapy for prostate cancer.
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Books on the topic "Targeted antagonist"

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A, Horton Michael, ed. Adhesion receptors as therapeutic targets. Boca Raton, Fla: CRC Press, 1996.

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Angerer, Erwin von. The estrogen receptor as a target for rational drug design. New York: Springer, 1995.

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Angerer, Erwin von. The estrogen receptor as a target for rational drug design. New York: Springer, 1995.

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K, Ghosh Arun. Aspartic acid proteases as therapeutic targets. Weinheim: Wiley-VCH, 2010.

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K, Ghosh Arun. Aspartic acid proteases as therapeutic targets. Weinheim: Wiley-VCH, 2010.

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1930-, Smith H. J., and Simons Claire, eds. Proteinase and peptidase inhibition: Recent potential targets for drug development. London: Taylor & Francis, 2002.

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1940-, Sanderson Colin J., ed. Interleukin-5: From molecule to drug target for asthma. New York: M. Dekker, 1999.

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Baldi, Elisabetta, and Corrado Bucherelli. Neuroscience. Florence: Firenze University Press, 2017. http://dx.doi.org/10.36253/978-88-6453-638-5.

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This bibliographic material is patrimony of our Laboratory of the Behavior Physiology. This research unit originated in 1972 by will of Aldo Giachetti (until 1990) and with the beginning of the activity of Corrado Bucherelli. In the early 1980s, with Carlo Ambrogi Lorenzini (until 2004), the cataloging became more capillary and systematic, to continue to this day. All the researchers who worked in our laboratory contributed to this collection (Giovanna Tassoni 1986-2000, Benedetto Sacchetti 1996-2002 and Elisabetta Baldi from 1991). The study of learning, memory and behavior requires to follow a broad spectrum of neuroscience topics, ranging from neuronal biochemistry to neuropsychology. The Authors’ idea of publishing this collection comes from believing that a such website, though not exhaustive, might be a useful and targeted tool for the selection of bibliographic material in the field of behavioral neuroscience. The bibliographic references present at the publication (29500), accompanied by a brief comment highlighting the contents, are organized in relation to the topics (represented by the 99 themes) constituting the publication itself. The intersection of several references will point out the topics that represent them simultaneously. Concerning neurotransmitters and neuromodulators, references to agonists, antagonists or molecules interfering with the activity of these synapses have been inserted in the pages of the implicated neurotransmitter (e.g. acetylcholine). The pages including topics that could have been dealt with separately (e.g. active and passive avoidance) are introduced by a short explanatory note. The comment of each publication highlights the animal species used. Each comment is intended to indicate the content rather than the experimental results of paper. This choice comes from wanting to provide the reader with a more objective and less speculative comment.
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Hendrickson, Rebecca C., and Murray A. Raskind. Pharmacological Treatment of Nightmares, Sleep Disturbance, and Daytime Hyperarousal in PTSD: The Role of Prazosin, Other Noradrenergic Modulators, and Sedative Hypnotics or Commonly Used Sedating Medications. Edited by Charles B. Nemeroff and Charles R. Marmar. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780190259440.003.0035.

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Disruption of stress-response systems contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Consistent with this, daytime hyperarousal and nighttime sleep disruption, including trauma-related nightmares, are core symptoms of the disorder, often requiring targeted pharmacologic treatment. Although a variety of medications that target sleep–wake and arousal mechanisms are commonly used for this purpose, there remains the best empirical support for prazosin, a brain-active antagonist of the α‎1 noradrenaline receptor, with emerging evidence for doxazosin, a longer-acting medication with the same mechanism of action. This chapter reviews the evidence for use of prazosin and doxazosin as well as for the sedative hypnotics (benzodiazepines, nonbenzodiazepine hypnotics, and related medications), antihistamines, and sedating antidepressants trazodone and nefazodone to address hyperarousal symptoms and trauma-associated nightmares in PTSD. Clinical recommendations for the use of prazosin in PTSD, as well as a discussion of emerging pharmacologic treatments, are also included.
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Budimirovic, Dejan B., and Megha Subramanian. Neurobiology of Autism and Intellectual Disability. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0052.

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Fragile X syndrome (FXS) is a neurodevelopmental disorder that manifests with a range of cognitive, behavioral, and social impairments. It is a monogenetic disease caused by silencing of the FMR1 gene, in contrast to autism spectrum disorder (ASD) that is a behaviorally-defined set of complex disorders. Because ASD is a major and growing public health concern, current research is focused on identifying common therapeutic targets among patients with different molecular etiologies. Due to the prevalence of ASD in FXS and its shared neurophysiology with ASD, FXS has been extensively studied as a model for ASD. Studies in the animal models have provided breakthrough insights into the pathophysiology of FXS that have led to novel therapeutic targets for its core deficits (e.g., mGluR theory of fragile X). Yet recent clinical trials of both GABA-B agonist and mGluR5 antagonist revealed a lack of specific and sensitive outcome measures capturing the full range of improvements of patients with FXS. Recent research shows promise for the mapping of the multitude of genetic variants in ASD onto shared pathways with FXS. Nonetheless, in light of the huge level of locus heterogeneity in ASD, further effort in finding convergence in specific molecular pathways and reliable biomarkers is required in order to perform targeted treatment trials with sufficient sample size. This chapter focuses on the neurobehavioral phenotype caused by a full-mutation of the FMR1 gene, namely FXS, and the neurobiology of this disorder of relevance to the targeted molecular treatments of its core symptoms.
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Book chapters on the topic "Targeted antagonist"

1

Blaschuk, Orest W., and Tracey M. Rowlands. "Cadherin Antagonists as Vasculature-targeting Agents." In Vascular-Targeted Therapies in Oncology, 195–204. Chichester, UK: John Wiley & Sons, Ltd, 2006. http://dx.doi.org/10.1002/0470035439.ch11.

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Bahl, Ash, Brian Springthorpe, and Rob Riley. "Chemokine CCR3 antagonists." In New Drugs and Targets for Asthma and COPD, 153–59. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320814.

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Hall, David, Alison Ford, and Simon Hodgson. "Therapeutic potential of CCR4 antagonists." In New Drugs and Targets for Asthma and COPD, 161–65. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320815.

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Dunford, Paul J., and Robin L. Thurmond. "Histamine H4 receptor antagonists." In New Drugs and Targets for Asthma and COPD, 187–91. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320818.

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Gavaldà, Amadeu, and Esther Garcia-Gil. "Aclidinium bromide, a novel long-acting muscarinic antagonist (LAMA)." In New Drugs and Targets for Asthma and COPD, 33–38. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320796.

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Vanderslice, Peter, and Darren G. Woodside. "Very late activation antigen-4 (VLA-4) antagonists." In New Drugs and Targets for Asthma and COPD, 169–73. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320816.

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Chwalisz, K., I. Gemperlein, C. P. Puri, S. Shao-Qing, and R. Knauthe. "Endometrial Contraception with Progesterone Antagonists: An Experimental Approach." In The Endometrium as a Target for Contraception, 223–58. Berlin, Heidelberg: Springer Berlin Heidelberg, 1997. http://dx.doi.org/10.1007/978-3-662-10323-4_11.

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Desaeger, Johan, Richard A. Sikora, and Leendert P. G. Molendijk. "Outlook: a vision of the future of integrated nematode management." In Integrated nematode management: state-of-the-art and visions for the future, 475–83. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789247541.0065.

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Abstract Integrated nematode management (INM) employs a diversity of management practices and focuses on key concepts such as targeted rotations, intercropping, advanced genetics for resistance breeding, remote sensing to monitor nematode distribution and densities, precision agriculture to target control treatments and molecular tools to measure soil suppressiveness. This chapter further discusses new building blocks of INM that could improve the future of nematode management. Outlooks on chemical control in the future; the growth of biological control; the need for resistance breeding; suppressive soil and its antagonistic potential for nematode management; climate change adaption; regional and site-specific approach in nematode management; loss of applied nematology positions at universities and plant protection agencies; and recommended INM programmes are described. For INM to become a reality, applied nematology needs to be at the forefront of the science of nematology again, and funded accordingly.
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Edwards, Dean P., and Paul Prendergast. "Facilitated Binding of Steroid Hormone Receptors to Target DNA by the Chromatin High-Mobility Group Protein-1: Protein Manipulation of DNA Structure." In Estrogens, Progestins, and Their Antagonists, 191–216. Boston, MA: Birkhäuser Boston, 1997. http://dx.doi.org/10.1007/978-1-4612-2004-6_8.

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Pettipher, Roy, and Trevor T. Hansel. "Antagonists of the prostaglandin D2 receptor CRTH2." In New Drugs and Targets for Asthma and COPD, 193–98. Basel: KARGER, 2010. http://dx.doi.org/10.1159/000320819.

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Conference papers on the topic "Targeted antagonist"

1

Rais, Rana, Jesse Alt, Ranjeet Dash, Lukáš Tenora, Pavel Majer, and Barbara S. Slusher. "Abstract 3620: Tumor targeted delivery of glutamine antagonist: Use of CES1-/-mice." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-3620.

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Rais, Rana, Jesse Alt, Ranjeet Dash, Lukáš Tenora, Pavel Majer, and Barbara S. Slusher. "Abstract 3620: Tumor targeted delivery of glutamine antagonist: Use of CES1-/-mice." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-3620.

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Rowan, Brian G., Tulasi Ponnapakkam, Murali Anbalagan, Yibin Kang, and Robert C. Gensure. "Abstract LB-259: Bone targeted parathyroid hormone antagonist for prevention of breast cancer bone metastases." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-lb-259.

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Cecchi, Fabiola, Deborah Pajalunga, Daniel Rabe, Andrew C. Fowler, Nicholas MacDonald, Davida K. Blackman, Stephen J. Stahl, Andrew R. Byrd, and Donald P. Bottaro. "Abstract B228: A hepatocyte growth factor antagonist engineered by targeted disruption of heparan sulfate binding." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-b228.

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Harmon, Tia L., Adriana Harbuzariu, Lily Yang, and Ruben R. Gonzalez-Perez. "Abstract 3909: Iron oxide nanoparticle-leptin receptor antagonist: A novel targeted adjuvant therapy for triple negative breast cancer." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3909.

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Soodgupta, Deepti, Dipanjan Pan, Grace Cui, Angana Senpan, Xiaoxia Yang, Samuel A. Wickline, Edward V. Prochownik, Katherine N. Weilbaecher, Michael H. Tomasson, and Gregory M. Lanza. "Abstract 5381: VLA-4 targeted nanoparticles deliver a cMYC-MAX prodrug antagonist extends survival a metastatic myeloma mouse model." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-5381.

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Engel, J., A. Schreiber, S. Seitz, F. Köster, T. Gaiser, U. Kämmerer, J. Dietl, and A. Honig. "Triple-Negative Breast Cancers Express Receptors for GnRH and Can Be Effectively Targeted by the Orally Active GnRH-Antagonist AEZS 115." In Abstracts: Thirty-Second Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 10‐13, 2009; San Antonio, TX. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.sabcs-09-6108.

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Hutcheson, Joshua D., Joseph Chen, Larisa M. Ryzhova, and W. David Merryman. "5-HT2B Antagonism Inhibits Strain- and Cytokine-Dependent Formation of Calcific Nodules by Aortic Valve Interstitial Cells." In ASME 2012 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/sbc2012-80496.

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The progression of aortic valve (AV) disease is often characterized by the formation of calcific nodules on thickened AV leaflets, limiting the biomechanical function of the valve. In these cases, the association of extracellular Ca2+ with phosphates remaining in cellular debris within the decellularized scaffolds has been proposed to lead to the nucleation and growth of calcific nodules. In native tissue, calcification is thought to be a more active process involving AV interstitial cells (AVICs). AVICs have been shown to form nodule-like structures in vitro through differentiation to a phenotype with osteogenic character. Additionally, in vitro nodules are characterized by activated smooth muscle α-actin (αSMA) positive AVICs and high levels of apoptosis [1–2]. Mechanical strain has also been shown to influence nodule formation in excised AV leaflets [3]. Our lab has recently developed a model system that recapitulates the formation of calcific nodules in vitro [4]. AVICs treated with TGF-β1 for 24 h prior to the addition of 15% cyclic strain in a Flexcell strain system form nodules that appear to be dependent upon the initiation of AVIC activation. These observations are consistent with previous studies that have shown that αSMA expression is required for nodule formation by AVICs in static culture, with statins shown to inhibit in vitro nodule formation [1]. However, retrospective epidemiological studies have shown that these drugs may not be as effective in preventing calcific valve disease in patients [5]. Additionally, the molecular target and relevant pathways for statins in AVICs remain largely unknown. Therefore, a therapeutically relevant target to prevent AVIC activation and subsequent nodule formation is greatly needed. In this study we investigated the ability of antagonists to 5-HT2B, a receptor known to be upstream of TGF-β1, to oppose strain- and TGF-β1-induced AVIC activation and nodule formation. We also assessed the efficacy of an antagonist to a receptor, the angiotensin II type I receptor (AT1R), known to crosstalk with both 5-HT2B and TGF-β1 signaling in other cell types in inhibiting AVIC nodule formation. Our results indicate that 5-HT2B antagonism inhibits AVIC activation and nodule formation by blocking non-canonical TGF-β1 signaling, whereas AT1R antagonism does not inhibit these outcomes. We believe that the results of this study may indicate novel therapeutic targets to prevent the progression of AV calcification.
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Souza, Felipe dos Santos, Matheus Furlan Chaves, and Antonio Marcos da Silva Catharino. "Rabbit syndrome induced by the use of Risperidone: a case report." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.013.

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Context: Risperidone is a selective monoaminergic antagonist, its main action as an antipsychotic is attributed to its affinity to dopamine D2 receptors. However, intervention in dopaminergic transmission by this medication can affect the motor control performed by the striatum, generating the so-called extrapyramidal syndromes. Among these syndromes, we have the rabbit syndrome (SC), which is manifested by the chronic use of antipsychotics and causes involuntary movements of the muscles of the jaw and tongue. Case report: E. B. L., a 89- year-old woman undergoing neurological follow-up due to dementia. He started using risperidone 1mg at night to treat behavioral changes and aggressions. However, 4 months after the start of the medication, he started to have a tremor of the chin and stiffness in the upper limbs. These symptoms improved after switching from risperidone to olanzapine 5mg at night. Conclusions: The present study emphasizes the importance of recognizing Rabbit Syndrome and the clinical repercussions of symptomatic variants, such as tardive dyskinesia, nocturnal bruxism and altered tongue motricity, in the differential diagnosis of drug-induced movement disorders. In this sense, neurological assessment includes an elucidating clinical history and targeted physical examination.
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"ARIPPRIPAZOLE AND ITS POTENTIAL EFFECT IN REDUCING COCAINE CRAVING IN SCHIZOPHRENIC PATIENTS WITH COCAINE-DEPENDENCE." In 23° Congreso de la Sociedad Española de Patología Dual (SEPD) 2021. SEPD, 2021. http://dx.doi.org/10.17579/sepd2021p062s.

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Goals: Non-systematic literature review of the role of aripiprazole in alleviating cocaine craving in schizophrenic patients with cocaine-dependence (CD). Material and methods: From the review performed, 2 studies outstand: In one study, 6 schizophrenic patients with CD completed 8 weeks of treatment with aripiprazole at a maximum dose of 15 mg/d. The Brief Psychiatric Rating Scale and the Brief Substance Craving Scale (BSCS) were used to measure psychosis and subjective cocaine and alcohol cravings and urine tests for cocaine were performed. In another study, 44 CD patients with schizophrenia or schizoaffective disorder were treated with aripiprazole or perphenazine during 8 weeks. The perphenazine group received the recommended dosage not exceeding 24 mg/d and the patients receiving aripripazole were started on 15 mg/d to a maximum of 30 mg/d or a minimum of 10 mg/d. Primary outcome targeted cocaine-free urine sample proportions, whereas secondary outcome focused on cocaine craving scores. BSCS was used to assess cocaine craving and the positive and negative symptom scale and the clinical global impression scale were used to monitor psychotic symptom severities. Results and conclusion: In the first study, positive urine tests dropped significantly after 2 weeks, mean cocaine and acohol craving scores declined significantly, and declining psychosis scores were associated with declining cocaine and alcohol craving. In the second study, the proportion of negative drug test results did not differ significantly between patients treated with aripiprazol or perphenazine. Regarding the anticraving effect, in the aripiprazol group during week 3 to 8, significant reductions in craving intensity, frequency and duration were seen, while no similar reduction was seen with perphenazine. In conclusion, although the results are still limited, studies suggest that aripiprazol may have a potential effect in dual diagnosis patients with schizophrenia and CD, possibly due to its dopamine activity as a partial agonist/antagonist.
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Reports on the topic "Targeted antagonist"

1

Keightley, Maria C. The Mechanism by Which Agonist and Antagonist Occupied Progesterone Receptors Regulate Target Genes. Fort Belvoir, VA: Defense Technical Information Center, June 1998. http://dx.doi.org/10.21236/ada350945.

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Fromm, A., Avihai Danon, and Jian-Kang Zhu. Genes Controlling Calcium-Enhanced Tolerance to Salinity in Plants. United States Department of Agriculture, March 2003. http://dx.doi.org/10.32747/2003.7585201.bard.

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The specific objectives of the proposed research were to identify, clone and characterize downstream cellular target(s) of SOS3 in Arabidopsis thaliana, to analyze the Ca2+-binding characteristics of SOS3 and the sos3-1 mutant and their interactions with SOS3 cellular targets to analyze the SOS3 cell-specific expression patterns, and its subcellular localization, and to assess the in vivo role of SOS3 target protein(s) in plant tolerance to salinity stress. In the course of the study, in view of recent opportunities in identifying Ca2+ - responsive genes using microarrays, the group at Weizmann has moved into identifying Ca2+-responsive stress genes by using a combination of aqeuorin-based measurements of cytosolic Ca and analysis by DNA microarrays of early Ca-responsive genes at the whole genome level. Analysis of SOS3 (University of Arizona) revealed its expression in both roots and shoots. However, the expression of this gene is not induced by stress. This is reminiscent of other stress proteins that are regulated by post-transcriptional mechanisms such as the activation by second messengers like Ca. Further analysis of the expression of the gene using promoter - GUS fusions revealed expression in lateral root primordial. Studies at the Weizmann Institute identified a large number of genes whose expression is up-regulated by a specific cytosolic Ca burst evoked by CaM antagonists. Fewer genes were found to be down-regulated by the Ca burst. Among the up-regulated genes many are associated with early stress responses. Moreover, this study revealed a large number of newly identified Ca-responsive genes. These genes could be useful to investigate yet unknown Ca-responsive gene networks involved in plant response to stress.
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Philosoph-Hadas, Sonia, Peter Kaufman, Shimon Meir, and Abraham Halevy. Signal Transduction Pathway of Hormonal Action in Control and Regulation of the Gravitropic Response of Cut Flowering Stems during Storage and Transport. United States Department of Agriculture, October 1999. http://dx.doi.org/10.32747/1999.7695838.bard.

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Original objectives: The basic goal of the present project was to increase our understanding of the cellular mechanisms operating during the gravitropic response of cut flowers, for solving their bending problem without affecting flower quality. Thus, several elements operating at the 3 levels o the gravity-induced signal transduction pathway, were proposed to be examined in snapdragon stems according to the following research goals: 1) Signaling: characterize the signal transduction pathway leading to the gravitropic response, regarding the involvement of [Ca2+]cyt as a mediator of IAA movement and sensitivity to auxin. 2) Transduction by plant hormones: a) Examine the involvement of auxin in the gravitropic response of flower stems with regard to: possible participation of auxin binding protein (ABP), auxin redistribution, auxin mechanism of action (activation of H+-ATPase) mediation by changes in [Ca2+]cyt and possible regulation of auxin-induced Ca2+ action b: calmodulin-activated or Ca2+-activated protein kinases (PK). b) Examine the involvement of ethylene in the gravitropic response of flower stems with regard to auxin-induced ethylene production and sensitivity of the tissue to ethylene. 3) Response: examine the effect of gravistimulation on invertase (associated with growth and elongation) activity and invertase gene expression. 4) Commercial practice: develop practical and simple treatments to prevent bending of cut flowers grown for export. Revisions: 1) Model systems: in addition to snapdragon (Antirrhinum majus L.), 3 other model shoe systems, consisting of oat (Avena sativa) pulvini, Ornithogalun 'Nova' cut flowers and Arabidopsis thaliana inflorescence, were targeted to confirm a more general mechanism for shoot gravitropism. 2 Research topics: the involvement of ABP, auxin action, PK and invertase in the gravitropic response of snapdragon stems could not be demonstrated. Alternatively, the involvement in the gravity signaling cascade of several other physiological mediators apart of [Ca2+]cyt such as: IP3, protein phosphorylation and actin cytoskeleton, was shown. Additional topics introduced: starch statolith reorientation, differential expression of early auxin responsive genes, and differential shoot growth. Background to the topic: The gravitropic bending response of flowering shoots occurring upon their horizontal placement during shipment exhibits a major horticultural problem. In spite of extensive studies in various aboveground organs, the gravitropic response was hardly investigated in flowering shoots. Being a complex multistep process that requires the participation of various cellular components acting in succession or in parallel, analysis of the negative gravitropic response of shoot includes investigation of signal transduction elements and various regulatory physiological mediators. Major achievements: 1) A correlative role for starch statoliths as gravireceptors in flowering shoot was initially established. 2) Differentially phosphorylated proteins and IP3 levels across the oat shoe pulvini, as well as a differential appearance of 2 early auxin-responsive genes in snapdragon stems were all detected within 5-30 minutes following gravistimulation. 3) Unlike in roots, involvement of actin cytoskeleton in early events of the gravitropic response of snapdragon shoots was established. 4) An asymmetric IAA distribution, followed by an asymmetric ethylene production across snapdragon stems was found following gravistimulation. 5) The gravity-induced differential growth in shoots of snapdragon was derived from initial shrinkage of the upper stem side and a subsequent elongation o the lower stem side. 6) Shoot bending could be successfully inhibited by Ca2+ antagonists (that serve as a basis for practical treatments), kinase and phosphatase inhibitors and actin-cytoskeleton modulators. All these agents did not affect vertical growth. The essential characterization of these key events and their sequence led us to the conclusion that blocking gravity perception may be the most powerful means to inhibit bending without hampering shoot and flower growth after harvest. Implications, scientific and agriculture: The innovative results of this project have provided some new insight in the basic understanding of gravitropism in flower stalks, that partially filled the gap in our knowledge, and established useful means for its control. Additionally, our analysis has advanced the understanding of important and fundamental physiological processes involved, thereby leading to new ideas for agriculture. Gravitropism has an important impact on agriculture, particularly for controlling the bending of various important agricultural products with economic value. So far, no safe control of the undesired bending problem of flower stalks has been established. Our results show for the first time that shoot bending of cut flowers can be inhibited without adverse effects by controlling the gravity perception step with Ca2+ antagonists and cytoskeleton modulators. Such a practical benefit resulting from this project is of great economic value for the floriculture industry.
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