Tesis:

1

Alhawsawi, Sana Mahmoud. "β2m antibody is a suitable antibody to detect major histocompatibility complex class Ι as well as α chain antibody in healthy tissues and tissues infected with mouse parvovirus 1". Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1432738096.

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2

Carbone, Anna Lisa. "Engineering and functional characterisation of pentameric concatenated (α4)₂(β2)₃ and (α4)₃(β2)₂ nicotinic acetylcholine receptors". Thesis, Oxford Brookes University, 2009. https://radar.brookes.ac.uk/radar/items/6b5c0ace-ecf1-488d-95e6-b112bd79e252/1/.

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Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that influence neurotransmitter release, hence constituting a key component of the physiological mechanisms of neuronal signalling. This thesis is concerned with the properties of the a4P2 nAChR, the most abundant nAChR in the brain, and the major contributor to the central effects of nicotine. The a4P2 nAChR is made up of five subunits, which in heterologous systems can assemble into at least two different stoichiometries: the high sensitivity (HS) (a4h(P2)3 stoichiometry and the low sensitivity (LS) (a4)3(p2)2 stoichiometry, which might both exist in native tissues. Despite the attractiveness of the a.4P2 nAChR as a target for therapeutic intervention, progress in the development of a4P2 nAChR-selective drugs has been slowed, partly because of the lack of stoichiometric-specific receptor models. This study presents a strategy to express homogenous populations of a4P2 nAChRs with fixed stoichiometry. By using standard molecular biological techniques, pentameric concatenated (a4)2(P2)3 and (a4)3(P2)2 nAChRs were engineered. These receptors were expressed in Xenopus laevis oocytes and functional studies showed that their functional properties resembled those of their non-linked counterparts. Subsequent site-directed mutagenesis in combination with functional analysis allowed the identification of the agonist-binding subunits in both concatamers. Concatenated receptors proved to be suitable for comparative studies of the effects of receptor mutation linked to autosomal dominant nocturnal frontal lobe epilepsy. Studies carried out on non-linked receptors, showed that the properties of the (a4)3(p2)2 stoichiometry were affected more markedly than those of the (a4)2(p2)3 stoichiometry. Insertion of the mutation in concatenated receptors revealed that the mutation not only affected the functional properties of a.4P2 nAChRs but also altered the subunit composition of the receptor. These studies show that pentameric concatenated constructs are a powerful tool to study the function and structure of receptors that assemble in multimeric types in expression systems.

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3

Bohlin, Maria E. "Capillary electrophoresis of β2-glycoprotein I". Licentiate thesis, Karlstads universitet, Fakulteten för teknik- och naturvetenskap, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-3826.

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4

Jones, J. M. "β2 adrenergic receptor gene therapy during cardiopulmonary bypass". Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605686.

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5

Cross, Deborah Jane. "β2-adrenoceptor gene polymorphisms and hypertension in African Trinidadians". Thesis, University of Nottingham, 2004. http://eprints.nottingham.ac.uk/13194/.

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Background Essential hypertension remains a major risk factor for coronary heart disease (CHO) and stroke, and its prevalence is greater, more severe, occurs earlier, and is less well controlled among black individuals than among white individuals, at all ages after young adult hood (Comoni-Huntley et al, 1989). In Caucasians, studies have shown that β2-adrenoceptor polymorphism accounts for the variability in the vascular responsiveness to the agonist isoprenaline (Cockcroft et al, 1994 and Lang et al, 1995). Individuals homozygous for Gln 27 β2-adrenoceptor showed reduced responses due to chronic down regulation of β2-adrenoceptor in the vasculature. Therefore, variability in response to isoprenaline was determined by β2-adrenoceptor gene polymorphism. Aim and Objectives This study investigated whether there is a relationship between the ArglGly16 and Gln/Glu 27 β2-adrenoceptor polymorphisms by examining whether the incidence of occurrence is prevalent in African Trinidadians. In addition, comparison data of vascular responses with arterial compliance using pulse wave analysis (PWA) was correlated. The study aimed to give evidence if these polymorphisms contributed fully or in part, to determine the disease severity, or response to therapy in hypertensive individuals. It also aimed to prove that PWA is a reliable and therapeutic tool, in diagnosing and treating blood pressure, as reliance on brachial artery recording of blood pressure, alone, is becoming a poor indicator and predictor of risk. Methods The study genotyped 408 African Trinidadian subjects for the β2-adrenoceptor polymorphism and used the technique of applanation tonometry to analyse the central pulse wave, generating information on arterial compliance, left ventricular function and coronary perfusion. Blood pressure was measured in triplicate using a semiautomatic blood pressure meter after 15 minutes of supine rest and bloods lipids assessed using a validated portable lipid cartridge. This was achieved by subjects attending a nurse-led cardiovascular risk clinic. Results There is no significant association between the Arg-Glyl6 polymorphism and the Gln-Glu27 polymorphism and hypertension in African Trinidadians. Interestingly, the appearance of the Glu27 polymorphism was very uncommon in African Trinidadians and this is constant with findings by Candy et al, 2000. Conclusion There is no difference in the frequency of β2-polymorphisms between normotensive and hypertensive African Trinidadians, and are unlikely to be a contributing factor for essential hypertension. Therefore, hypertension would indicate that it is polygenic with complex gene to gene and gene environmental interactions, through multiple, indirect and intermediate phenotypes and interactions.

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6

Dropmann, Anne [Verfasser] y Steven [Akademischer Betreuer] Dooley. "TGF-β2 abundance in mice and men: A successful anti-TGF-β2 strategy in biliary-derived liver disease / Anne Dropmann ; Betreuer: Steven Dooley". Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177150050/34.

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7

Sweetman, Chlöe A. "TGF-β2 in human milk research: Exploration of a new field methodology and new findings of biosimilar TGF-β2 in non-human milk". Scholar Commons, 2018. http://scholarcommons.usf.edu/etd/7233.

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Objectives: There are three aims for this thesis: the first is to develop a field and laboratory protocol for the storage and analysis of transforming growth factor–beta 2 (TGF-β2) in human breastmilk; second, to validate this protocol and the immunoassay used to assess this new method; and lastly, to explore the ramifications of biosimilar TGF-β2 across multiple milks on human health, growth, and immunity through the review of laboratory findings and previous literature. Rational: Little anthropological research has been done on TGF-β2 in human milk. Anthropology as a discipline is well positioned to provide insight into TGF-β2, combining biocultural, evolutionary, and ecological approaches to holistically illustrate the effects this cytokine has on human immunity. This thesis provides an applied anthropological perspective and methodology on TGF-β2 in human milk. Methods: A protocol was developed for a new method of drying breastmilk on polystyrene microplates. Samples were then reconstituted using reagent diluent with 1% BSA and assayed using a Human TGF-beta 2 DuoSet enzyme-linked immunosorbent assay (ELIZA) assay kit from R&D Systems. Other mammalian milks and infant formula samples were also dried and tested for TGF-β2 concentrations. Validity of the assay and TGF-β2 concentrations were then statistically measured using linear regression analysis and Bland-Altman plots. Results: The results of the first objective in the development of a laboratory and field protocol for drying breastmilk on polystyrene plates for the extraction of TGF-β2 showed this method to hold promise for future application, but lacked statistical power in this study to confirm if this method is viable. The second objective of assay validation was unsuccessful, with the percent coefficient of variation for the intra-assay variation and inter-assay validation 38.28% and 17.70%, respectively indicating that this assay struggled to produce consistent and reliable results from the reconstituted samples. Results from the third objective suggest that biosimilar TGF-β2 in non-human milk can influence human growth and development, the extent of which, however, needs further study. Conclusions: Given these findings, more work with TGF-β2 in milk is required. TGF-β2 is a cytokine which could reveal a great deal about the developmental origins of human immunity and how it is maintained and altered across our life course and therefore an area of biology worth further research.

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8

Wagner, Ylva. "Conformational Change of β2-glycoprotein I : Evaluation of Difference in Binding Capacity of Autoantibodies to Open and Closed Forms of β2-glycoprotein I". Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-24838.

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Antiphospolipidsyndrome (APS) is one of the most common autoimmune diseases characterized bythrombosis, fetal loss and presence of antiphospholipid antibodies. In APS research the antibodies of biggestinterest are anti-β2-glycoprotein I antibodies (Aβ2GPIA). β2-glycoprotein I (β2GPI)is a plasma protein which becomes activated and obtains a open structure incontact with negative charged surface molecules such as phospholipids. Inactiveβ2GPI has a closed, circular shape which can’t bind autoantibodies. Thereis no golden standard for APS diagnosing and the methods used often giveinconsistent results. The purpose of this examination project work was toconvert β2GPI into the open and closed forms, respectively, by dialyzing againsthigh ionic strength, low and high pH and determine if there is any differencein binding capacity between the two forms and Aβ2GPIAon a microtiter plate. The binding capacity was tested inan ELISA (enzyme-linkedimmunosorbent assay) using purified IgG from patient sera and thedifferent conformational forms of β2GPI. An ELISA for measuring of Aβ2GPIAon several patient samples was also performed. No difference in binding capacitycould be detected which might be explained by that the conversion of β2GPI was unsuccessful.Perhaps no difference can be measured between the structures because the closedform is expected to open on microtiter plates. An unexpected result was thepresence of immune complexes of β2GPI-Aβ2GPIA found in the serum of one of the patients. In theory an ELISA based on theopen form of β2GPI would provide more reliable diagnoses and furtherresearch is needed in this area.

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9

COATTI, AURORA. "Heteromeric nicotinic receptors regulate developing and mature prefrontal circuits: interaction with other neuromodulators, and implications for sleep-related hypermotor epilepsy". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2018. http://hdl.handle.net/10281/199023.

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Il sistema colinergico proietta in modo diffuso alla corteccia prefrontale (PFC) matura e sostiene l’attivazione corticale durante la veglia e il sonno REM. Il ruolo dei recettori nicotinici (nAChRs) nel mediare questi processi è sempre più riconosciuto. Inoltre, i nAChRs regolano anche lo sviluppo dei circuiti corticali durante le prime settimane di vita. Innanzitutto abbiamo studiato topi esprimenti β2-V287L, una subunità mutata del nAChR associata all’epilessia notturna autosomica dominante del lobo frontale (ADNFLE). β2-V287L svolge la sua azione epilettogenica alterando la stabilizzazione sinaptica durante le fasi critiche della maturazione circuitale, infatti, la sua espressione durante le prime due settimane di vita è necessaria per lo sviluppo del fenotipo epilettico nel topo adulto. Questa fase critica, inoltre, coincide con lo switch del GABA da eccitatorio a inibitorio, determinato dalla diminuzione progressiva del rapporto tra l’espressione del cotrasportatore-1 Na+/K+/Cl- (NKCC1) e del cotrasportatore-2 (KCC2) K+/Cl-. La regolazione di questi trasportatori nella PFC e nel talamo è ancora largamente sconosciuta. Abbiamo indagato la distribuzione di NKCC1 e KCC2 in topi wild-type (WT) durante lo sviluppo. I livelli di entrambi i trasportatori aumentano progressivamente durante le prime due settimane di vita sia nella PFC che nella corteccia somato-sensoriale. Alla nascita, KCC2 è localizzato principalmente nei corpi cellulari neuronali e in seguito migra verso le membrane somato-dendritiche. In topi esprimenti β2-V287L, i livelli di KCC2 nel V strato della PFC a 8 giorni (P8) sono inferiori rispetto ai topi controllo, ma raggiungono livelli di espressione maggiori a P60. Anche la tempistica dello switch del GABA, misurato tramite patch perforato, risulta ritardato nel V strato della PFC nei topi mutati. Al momento della nascita NKCC1 e KCC2 sono molto espressi nel neuropilo dei nuclei talamici, indipendentemente dal genotipo. Il loro livello d’espressione rimane alto nei nuclei sensoriali nell’adulto, mentre KCC2 diminuisce significativamente nel nucleo reticolare a P40. Tale riduzione è più pronunciata nei topi esprimenti β2-V287L. Questi risultati indicano che i nAChRs contenenti la subunità β2 interagiscono con KCC2 durante la sinaptogenesi e questo può contribuire alla patogenesi dell’ADNFLE. In secondo luogo, abbiamo esplorato alcuni aspetti della complessa interazione tra i principali neurotrasmettitori che partecipano all’attivazione corticale, ovvero acetilcolina (ACh), noradrenalina (NE) e oressina A (OrxA), allo scopo di caratterizzare il loro effetto sull’eccitabilità del V strato della PFC. In particolare, tramite patch-clamp in topi WT adulti, abbiamo indagato il loro ruolo nel modulare il rilascio di glutammato sui neuroni piramidali del V strato. La somministrazione tonica di ACh stimola il rilascio di glutammato, principalmente attraverso i nAChRs contenenti la subunità α4. Inoltre, l’OrxA è in grado di stimolare il rilascio di glutammato sui neuroni piramidali attivando i recettori 1 dell’Orx (OrxR1). Anche basse concentrazioni di NE (10 nM) sono efficaci nell’aumentare il rilascio di glutammato. Possiamo concludere che questi neuromodulatori cooperano nel regolare la trasmissione glutammatergica nella PFC. Tale interazione potrebbe essere cruciale nella regolazione dei meccanismi cellulari alla base delle funzioni cognitive ed esecutive svolte da questa regione. Questo avviene sia in condizioni normali che patologiche, le quali sono spesso accompagnate da alterazioni dei ritmi theta, generati da dinamiche proprie dei neuroni piramidali. Questi risultati possono aiutare a comprendere la complessa regolazione dei microcircuiti della PFC, e pongono le basi per ulteriori indagini sui meccanismi patogenetici responsabili di anomalie corticali, tipiche di alcuni disordini legati al sonno, come l’epilessia frontale e la narcolessia con cataplessia.
The cholinergic system extensively innervates mature prefrontal cortex (PFC) and is critical to sustain cortical activation during wakefulness and REM sleep. The implication of nicotinic receptors (nAChRs) in these processes is increasingly recognized. Moreover, nAChRs regulate developing cortical circuits during the first postnatal weeks. First, we studied mice expressing β2-V287L, a mutant subunit of the nAChR linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). β2-V287L exerts the epileptogenic action by altering the synaptic stabilization during sensitive phases of network maturation, since its expression during the first two postnatal weeks is necessary to develop the epileptic phenotype. The peak of postnatal expression of nAChRs coincides with the excitatory to inhibitory GABAergic switch, which is determined by the progressive decrease in the ratio between the expression of the Na+/K+/Cl- cotransporter-1 (NKCC1) and the K+/Cl- cotransporter-2 (KCC2). How these transporters are regulated in PFC and thalamus is largely unknown. We first studied the distribution of NKCC1 and KCC2 in developing wild-type (WT) mice. The amount of NKCC1 and KCC2 in PFC and somatosensory cortex progressively increased during the first two postnatal weeks. NKCC1 was found in neurons as well as astrocytes. KCC2 was mainly localized in neuronal somata at birth, and subsequently migrated to the somatodendritic membranes. Next, in mice expressing β2-V287L, the KCC2 amount in PFC layer V was lower than in the control littermates at postnatal day 8 (P8), but reached higher amounts by P60. Consistently, the time course of the GABAergic switch was delayed in PFC layer V of mice carrying β2-V287L, as measured by perforated patch method. Irrespective of genotype, NKCC1 and KCC2 were highly expressed in the neuropil of thalamic nuclei at birth. Their amount remained high in the adult sensory nuclei, whereas a significant decrease of KCC2 was observed in the reticular nucleus by P40. Such a decrease was more pronounced in mice expressing β2-V287L. Our results indicate that β2-containing nAChRs interact with KCC2 during synaptogenesis as well as in mature circuits, which may contribute to the pathogenesis of ADNFLE. Second, we explored some aspects of the complex interplay between the main neurotransmitters involved in cortical arousal, i. e. acetylcholine (ACh), norepinephrine (NE) and orexin A (OrxA), in order to characterize their combined effect on the PFC layer V circuit. In particular, by patch-clamp methods, we investigated how these neurotransmitters regulate glutamate release onto pyramidal neurons in PFC layer V of adult wild-type mice. Tonic administration of ACh stimulated glutamate release, mainly through α4-containing nAChRs. Moreover, OrxA increased the glutamate release onto pyramidal neurons, through Orx Receptor 1 (OrxR1). Low concentrations of NE (10 nM) were also effective in increasing glutamatergic release. We conclude that these neuromodulators cooperate in regulating glutamatergic transmission in PFC. Such interaction may be crucial in the cellular mechanisms underlying the cognitive and executive functions in this area, in normal and pathological conditions, which are often accompanied by alterations in the theta rhythms, largely determined by pyramidal neurons dynamics. These results may yield new insights into the complex regulation of the PFC microcircuit and lay the basis for further investigations on the pathogenic mechanisms responsible of altered cortical activity in sleep-related disorders such as frontal epilepsy and narcolepsy with cataplexy.

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Haidar, Malak. "Rôle du facteur de croissance transformant (TGF-β2) dans la virulence des macrophages infectés par Theileria annulata". Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T044.

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Les parasites Theileria (Theileria. annulata and T. parva) sont des protozoaires intracellulaires qui font partie du phylum des Apicomplexa. Theileria infecte les leucocytes bovins et les transforment en cellules cancéreuses, induisant un genre de leucémie chez le bovin et conduisant à la mort de l’animal. Les cellules infectées par Theileria démontrent certaines caractéristiques de cellules cancéreuses telles qu’une importante capacité d’invasion et de migration cellulaire. Cependant, le traitement de cellules infectées avec une drogue Theiléricide spécifique (buparvaquone) permet l'élimination du parasite et la réversion du phénotype transformé. De plus, la virulence peut être atténuée par passages répétés sur culture cellulaire. La similitude entre les cellules transformées par Theileria et la leucémie humaine fait de Theileria un modèle très important permettant l’étude des mécanismes cellulaires induits par le parasite au cours de la transformation de la cellule hôte. Mon laboratoire d’accueil a publié une augmentation significative de TGF-β2 dans les cellules virulentes et a constaté que parmi les 1158 cibles de TGF-β, 68 gènes ont été reconnus d'avoir modifié leurs niveaux de transcription concomitante avec l'atténuation. Dans ce travail de thèse, nous avons étudié les voies de signalisations impliquées dans la régulation de l’adhésion et l’invasion des cellules infectées par Theileria. Nous nous sommes particulièrement intéressés à l’étude de la voie de signalisation TGF-β2 et ses effecteurs. Nos résultats montrent que l’activation de la voie de signalisation de TGF-β2 par Theileria entraîne une augmentation de l’invasion et de l’adhérence des cellules transformées par deux mécanismes différents, soit en activant la voie de signalisation PGE2/EP4/cAMP/PKA/EPAC/CREB, soit en stimulant la voie GRB2/PI3-K/AP-1. Les macrophages atténués infectés par Theileria sont plus stressés oxydativement ce qui diminue leur adhérence et leur invasion cellulaire. Ceci nous a amené à étudier en collaboration avec un autre doctorant (Mehdi Metheni) le rôle de TGF-β2 dans la régulation du stress oxydatif dans les macrophages infectés par Theileria. Nos données montrent que les niveaux élevés de TGF-β2 stimule l’expression de la catalase, une enzyme anti-oxydante qui convertit le H2O2 en H2O et la baisse de H2O2 favorise la virulence en augmentant l’invasion et l’adhésion des cellules infectées par Theileria (résultats supplémentaires). De plus, nous avons examiné le statut de stress oxydatif et le type de glycolyse utilisé par les cellules infectées par Theileria. Les cellules transformées par Theileria agissent comme des cellules cancéreuses, elles consomment énormément de glucose. La protéine BAD joue un rôle important dans l’apoptose ainsi que dans la voie de glycolyse. Son activité est régulée par phosphorylation en réponse à des facteurs de croissance et de survie. BAD peut être phosphorylée par la PKA sur le résidu sérine 155. Durant ma thèse, nous avons examiné le rôle de la phosphorylation de BAD par la PKA dans la régulation du métabolisme cellulaire des macrophages infectés par Theileria. Nos résultats montrent que l’abolition de la phosphorylation de BAD par la PKA dissocie le complexe mitochondrial formé entre BAD et HK2, ce qui induit l’ubiquitynation et la dégradation de HK2 par le protéasome. La baisse de HK2 stimule la voie de phosphorylation oxydative en faveur de l’effet Warburg dans les cellules infectées par Theileria
Theileria parasites (Theileria. annulata and T. parva) are intracellular protozoa and members of the phylum Apicomplexa. Theileria parasites are the only eukaryotes that possess the property of being able to transform another eukaryote, their leukocyte host cells. Transformed leukocytes show many characteristics of tumour cells such as heightened invasive capacity; however the tumour-like phenotype can be totally reversed upon drug induced parasite death and attenuated by multiple in vitro passages. Such multiple-passaged attenuated lines are used as live vaccines against tropical theileriosis. The similarities in tumour hyper-invasiveness between Theileria-transformed leukcocytes and human lymphomas imply that observations on Theileria-induced leukocyte transformation have the potential to give generally applicable insights into the mechanisms underpinning tumour virulence. My host laboratory described higher TGF-β2 levels in virulent infected macrophages and following microarray analysis of virulent compared to attenuated macrophages found that among the 1158 TGF-β-targets, 68 genes had altered transcript levels concomitant with attenuation. In this study, we investigate the signalling pathways involved in the regulation of cellular adhesion and invasiveness of Theileria-infected cells. We were especially interested in the study of TGF-β2 signalling in Theileria-transformed virulent versus attenuated macrophages. My results indicate that following Theileria infection of macrophages, the TGF-β2 signalling pathway is activated and induces an increase in adhesion of virulent transformed macrophages through two different mechanisms: either by activating a PGE2 / EP4 / cAMP / PKA / EPAC / CREB signaling pathway, or by stimulating a GRB2 / PI3-K / AP-1 pathway. As attenuated macrophages display heightened oxidative stress, which underpins their loss of adhesion and invasiveness, in collaboration with another PhD student (Mehdi Metheni) we investigated the role of TGF-β2 in the regulation of the oxidative stress status of Theileria-infected macrophages. Our data show that high levels of TGF-β2 increase the expression of catalase, an anti-oxidant enzyme that converts H2O2 into H2O and the drop in H2O2 output results in regain of the virulence trait heightened adhesion of Theileria-transformed macrophages to fibronectin. Theileria-transformed macrophages display many features of cancer cells such as their consumption of larger quantities of glucose. The BCL-2 family protein BAD has an alternative function in glucose metabolism separate from its role in apoptosis. The activity of BAD is regulated by phosphorylation in response to growth/survival factors. BAD can be phosphorylated on Ser155 by PKA. So during my thesis studies I examined the role of PKA mediated phosphorylation of BAD in the regulation of the cellular metabolism of Theileria-transformed macrophages. My results showed that ablation of BAD S155 phosphorylation dissociates the mitochondrial complex of BAD and HK2 and cytosolic HK2 becomes ubiquitinated and degraded by the proteasome. Loss of HK2 switches the metabolism of Theileria-transformed leukocytes from Warburg-like to OXPHOS-like glycolysis

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11

Whale, Christopher Ian. "Safety aspect of β2-agonists in chronic obstructive pulmonary disease". Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/10647/.

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Chronic Obstructive Pulmonary Disease (COPD) presents an enormous public health challenge. Cigarette smoking remains the most important aetiological factor and although legislation to reduce smoking has been introduced in parts of the more developed world, consumption is increasing in many of the poorest parts of the world. With the predicted rise in disease prevalence, COPD is expected to become the worlds third largest cause of death by 2020. COPD is a disease state characterised by airflow limitation that is not fully reversible. Inhaled bronchodilators can only produce a small improvement in the airflow obstruction, but despite this, patients with COPD frequently use high doses of beta-2-agonists as the disease progresses and they develop breathlessness and exercise limitation. Short-acting beta-2-agonists are generally used as required to reduce breathlessness and reduce airflow obstruction whereas long-acting beta-2-agonists are prescribed on a regular twice-daily basis to reduce symptoms and rescue medication use and because of a potential beneficial effect on quality of life and exacerbation rates. Although generally well tolerated, the safety of inhaled beta-2-agonists has been a source of some concern since the late 1960s, when an epidemic of asthma deaths was associated with the use of a high dose formulation of isoprenaline. Further controversy has followed and questions have extended to long-acting beta-2-agonists, most notably after a recent large-scale post marketing surveillance study identified an association between the regular use of inhaled salmeterol and asthma-related deaths. The safety of inhaled beta-2-agonists is also an important consideration for patients with COPD. Being older and likely to have a history of cigarette consumption means that they are at risk of having symptomatic, or subclinical, ischaemic heart disease. Beta-2-agonists cause a number of systemic effects including an increase in heart rate, transient hypoxaemia and hypokalaemia. Since many patients with COPD are already hypoxaemic and may be taking other drugs that stimulate the myocardium and cause hypokalaemia, the additional systemic effects from beta-2-agonists may be more likely to produce adverse cardiac events including dysrhythmia and ischaemia. This thesis is concerned with the safety of inhaled beta-2-agonists in the management of COPD. The introduction consists of an overview of the epidemiology, natural history and pathology of COPD (Chapter 1) and a review of human beta-2-adrenoceptor function and inhaled beta-2-agonist pharmacology (Chapter 2). This is followed by a systematic literature review of the results from long-term clinical studies of inhaled beta-2-agonists in subjects with COPD (Chapter 3). The original work consists of three clinical studies that have examined aspects of the effect of high dose inhaled beta-2-agonists in subjects with COPD and a discussion to place these findings in context. Most published studies of inhaled beta-2-agonists in subjects with COPD have focused on their efficacy, rather than safety. We were concerned that some individuals with COPD and limited bronchodilator reversibility may experience an increase in adverse systemic effects after inhaling high doses of beta-2-agonists, which could lead to detrimental outcomes in certain clinical situations. Apart from the cardiac effects mentioned above, beta-2-agonists increase tremor, which causes CO2 production, and cardiac output and tissue perfuson, which increases the transport of CO2 to the lungs. The increase in CO2 flux to the lungs will normally increase ventilation. We were concerned however that some subjects with severe COPD would not be able to increase ventilation appropriately in response to the beta-2-agonist and this would lead to an increase in PaCO2. Our hypothesis was that high dose inhaled beta-2-agonists could worsen respiratory failure in some subjects with severe COPD. The first two studies in the thesis examined the effect of high dose inhaled salbutamol on the partial pressure of arterial oxygen and carbon dioxide in subjects with severe COPD. We initially conducted a double blind, randomised study on subjects within 48 hours of being admitted to hospital with an acute exacerbation of COPD (Chapter 4). The study was designed to determine whether high dose salbutamol caused an increase in the partial pressure of arterial carbon dioxide. We randomised subjects at a ratio of 3:1 to receive either salbutamol or ipratropium bromide and studied the pharmacodynamic effect on heart rate, PaO2 and PaCO2 over five hours. Over eighteen months and despite extensive efforts I was only able to recruit ten subjects, of whom five completed the study. I found that subjects who required hospital admission with an acute exacerbation of COPD were either too unwell for the study, had co-morbidities that precluded participation or the individuals were unwilling to participate. Although the study was terminated prematurely and we were unable to perform statistical analysis, I have presented the findings from the five subjects who completed the study, of whom four were randomised to receive salbutamol. We used ascending doses of salbutamol (1.25mg, 1.25mg, 25mg, 5mg, 5mg) and found no consistent effect on PaCO2 or PaO2 and no dose response relationship. The subject with the highest baseline PaCO2 did however have a rise in PaCO2 with the highest 5mg doses of salbutamol. To test the hypothesis further we conducted a randomised, double blind, crossover study and examined the effect of salbutamol on the arterial blood gas tensions of fourteen patients with stable severe COPD and a history of chronic or intermittent hypercapnia. The study was designed to determine whether high dose salbutamol causes a rise in PaCO2 when inhaled by subjects with severe COPD and a history of alveolar hypoventilation. We compared the effect of two 5mg doses with two 200 microgram doses of salbutamol on PaO2 and PaCO2 and heart rate. The subjects had severe COPD with a mean FEV1 of 0.71 L (27% predicted) and a mean smoking history of 53 pack years. The mean baseline PaO2 was 7.9 kPa and the mean baseline PaCO2 was 7.0 kPa. The high dose of salbutamol caused a mean fall in both PaO2 and PaCO2 and a small increase in heart rate. There was some support for our hypothesis however as three subjects had a small rise in PaCO2 after high dose nebulised salbutamol (Chapter 5). The third study was a double blind, crossover, dose-response examination of the bronchodilator and systemic effects of inhaled formoterol in subjects with COPD (Chapter 6). The rapid onset and prolonged duration of action of formoterol offers potential for the drug to be used as rescue medication in addition to twice daily maintenance therapy, as is the case in the management of asthma. Our hypothesis was that high doses of formoterol would produce adverse systemic effects that would outweigh the beneficial bronchodilator effects in subjects with COPD and limited bronchodilator response to salbutamol. We studied 20 subjects, with a mean FEV1 of 1.32 L (47% predicted) and a mean smoking history of 42 pack years. Each subject was studied on five days and after receiving placebo, formoterol 6, 12, 24 and 48 mg in a random sequence, we examined the effect of each dose on FEV1, tremor, dyspnoea, heart rate, blood pressure, SpO2, walk distance, potassium and satisfaction. We found that all doses were well tolerated and although there was a small dose related increase in FEV1 and the mean satisfaction scores were higher with each dose of formoterol than placebo, there was no dose related improvement in measures that are important to the patient, including breathlessness and walk distance. Apart from a dose related increase in tremor, other systemic effects were limited. All three studies found that high dose inhaled beta-2-agonists produced relatively modest systemic effects in subjects with COPD.

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12

Найда, Вероніка Тарасівна, Лілія Олексіївна Зуб, Світла Іванівна Чередніченко, Лариса Осипівна Гавриш y Віталій Михайлович Гретчин. "Характеристика вмісту β2-мікроглобуліну у хворих на ревматоїдний артрит з ураженням нирок". Thesis, Матеріали науково-практичної конференції "АКТУАЛЬНІ ПИТАННЯ ВНУТРІШНЬОЇ МЕДИЦИНИ". - 2011. - С.115, 2011. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/1880.

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13

Зуб, Лілія Олексіївна, Мирослава Сергіївна Акентьєва, Антоніна Анатоліївна Ілюшина y Світлана Іванівна Чередніченко. "Значення β2 – мікроглобуліну у ранньому виявленні ураження нирок при діабетичній нефропатії". Thesis, Матеріали науково-практичної конференції "АКТУАЛЬНІ ПИТАННЯ ВНУТРІШНЬОЇ МЕДИЦИНИ". - 2011. - С.66, 2011. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/1868.

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14

Erraji, Loubna. "Caractérisation d'une lignée de souris transgéniques portant le gène du récepteur β2-adrenergique humain : étude des conséquences de la surexpression des β2-ARs dans le foie". Paris 5, 1997. http://www.theses.fr/1997PA05S028.

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Différents modèles de souris transgéniques surexprimant une des protéines du système -adrénergique (récepteur -ar, protéine gs ou -ark) dans le cur, ont été établis dans le cadre d'études des cardiomyopathies. Notre modèle de souris transgéniques (f28) porte le gène du 2-ar humain sous le contrôle de son promoteur naturel. Il a été produit dans le but d'avoir un modèle d'étude in vivo chez lequel on retrouve une distribution des 2-ars qui ressemble le plus possible a celle decrite chez l'homme. Dans une première partie de notre étude nous avons caractérisé chez les souris f28 l'expression du transgène dans plusieurs tissus cibles des catécholamines, en les comparants aux souris contrôles. Nous avons montré que le transgène est transcrit en messagers h2-ars spécifiques, dans le cur, le muscle, le poumon, le cerveau et le foie de souris f28, mais pas dans le rein et la rate. Leur profil de distribution tissulaire diffère de celui des arnm 2-ars de souris (m2-ars), et leur taille est supérieure à celle des messagers décrits chez l'homme et la souris. Ces messagers sont traduits en protéines, et les récepteurs transgéniques sont exprimés dans tous les organes de souris f28 exprimant les arnm transgéniques. L'expression la plus élevée est celle observée dans le foie ou les 2-ars représentent près de 95% des -ars totaux. Dans une deuxième partie de notre travail, nous avons montré dans le foie, que les récepteurs transgéniques sont capables d'interagir normalement avec les protéines gs de souris, et d'induire l'activation de l'adenylyl cyclase suite à la stimulation par l'agoniste -ar isoproterenol. Chez le rat, l'expression des 2-ars dans le foie varie en fonction de l'ontogenèse : elle est élevée chez le nouveau-né et faible chez l'adulte. Comme les 2-ars jouent un rôle physiologique très important dans cet organe, nous avons effectué une étude ontogénique du système -ar (-ars, protéine g, adenylyl cyclase). Nous avons montré que chez la souris contrôle on retrouve le même profil ontogénique d'expression des 2-ars et d'activité de l'adenylyl cyclase que ceux décrits chez le rat. En revanche, chez la souris f28, les 2-ars hépatiques sont fortement exprimes à tous les âges, tant chez le nouveau-né que chez l'adulte, et les réponses de l'adenylyl cyclase induites par l'agoniste, sont aussi fortement augmentées. Les souris f28 semblent présenter non seulement des altérations métaboliques mais aussi des altérations phénotypiques : une mortalité élevée des nouveau-nés, un déficit pondéral et un problème de coordination des mouvements des pattes arrière. Nous avons pu montrer que le phénotype de déficit pondéral est dû à l'expression du transgène, en particulier à la surexpression des 2-ars dans le foie. Finalement, nous avons utilise ce modèle de souris transgéniques pour mettre en évidence le rôle des 2-ars dans la régulation des phénomènes d'apoptose dans le foie. Il a été décrit que l'augmentation des taux d'ampc pouvait contrôler l'apoptose dans certains types cellulaires. Nous avons montre que les souris f28 qui surexpriment des 2-ars dans le foie, sont protégées contre l'apoptose induite par un anticorps anti-fas. Quant aux souris contrôles qui, normalement meurent suite à l'injection de cet anticorps, elles acquièrent une protection suite à l'administration de l'agoniste 2-ar clenbuterol. Le modèle de souris f28 est un outil de choix pour étudier l'impact physiopathologique de la modification de l'expression des 2-ars dans le foie, mais également dans d'autres tissus.

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15

Cortada, Almar Èric. "Trafficking and function of the voltage-gated sodium channel β2 subunit". Doctoral thesis, Universitat de Girona, 2020. http://hdl.handle.net/10803/671239.

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The sodium channel β2 subunit is a component of the voltage-gated sodium channel (NaV), a large multimeric protein complex. In the heart, NaV is mainly composed of a pore-forming α subunit, NaV1.5, and two associated β subunits. Deficient NaV plasma membrane localization underlies a subset of channelopathies with high incidence in sudden death. The precise role of β2 in the NaV complex is still a mystery. However, there have been described mutations in β2 linked to Brugada Syndrome (BrS) and Atrial Fibrillation, both deadly cardiac arrhythmias. We explore the polarized trafficking of β2 and describe its function in promoting the localization of NaV1.5 to the apical domain of Madin-Darby canine kidney cells. Overall, our findings support the idea that β2 promotes the functional localization of NaV1.5 to specific subdomains of the plasma membrane, thereby ensuring enough sodium channel density and decreasing arrhythmogenic potential
La subunitat β2 és un component del canal de sodi dependent de voltatge (NaV), un complex proteic multimèric. Al cor està compost principalment per una subunitat α, formadora del porus, i dues subunitats β associades. Les fallides en la correcte localització de NaV són la base d’un conjunt de canalopaties amb alta incidència de mort sobtada. Es desconeix el paper que juga β2 al cor. Tot i això, s’han descrit mutacions en β2 associades a fibril·lació atrial i síndrome de Brugada. Explorem el tràfic polaritzat de β2 i descrivim la seva funció en promoure la localització de NaV1.5 al domini apical de cèl·lules Madin-Darby canine kidney. Els nostres resultat donen suport a la idea que β2 promou la localització funcional de NaV1.5 a subdominis específics de la membrana plasmàtica. D’aquesta manera, β2 assegura una densitat de canals de sodi suficient i disminueix el potencial arritmogènic

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16

Lek, Hwee San. "Regulation of β2-integrins by signalling pathways and cytoplasmic interacting partners". Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/83ad1cce-151d-4526-897c-6fb4506df796.

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In the immune system, integrin-mediated adhesion is important for leukocyte trafficking, signalling, activation and effector functions, but how integrin-mediated adhesion is regulated in leukocytes is still incompletely understood. The main focus of this thesis was to investigate signalling pathways and mechanisms which regulate lymphocyte adhesion under flow conditions and integrin recycling and integrin-mediated phagocytosis in myeloid cells, respectively. Traditionally, cell adhesion assays have been carried out in static conditions using immobilized ligands. We have now developed shear flow assays to study integrin-mediated cell adhesion and signalling pathways involved in a physiologically-relevant manner. Integrin regulation in naïve T cells has been studied extensively in the past, and therefore the focus of this thesis was to investigate signalling pathways that regulate β2-integrins (particularly LFA-1, Lymphocyte Function-associated Antigen 1) in B cells and effector T cells. It was now shown that B cells do not require Protein Kinase C βeta or Protein Kinase D for integrin-mediated cell adhesion but inhibition of Phosphoinositide 3-kinase and Akt reduced chemokine-(Stromal cell-Derived Factor 1-) induced B cell adhesion to the LFA-1 integrin ligand ICAM-1 (Intracellular Adhesion Molecule 1) under shear stress. In contrast, integrin-mediated adhesion of CD4+ and CD8+ T cells was not affected by Akt inhibition under shear flow conditions, indicating that adhesion in different lymphocyte subtypes is regulated by different signalling pathways. I show here that effector cytotoxic T lymphocytes (CTLs) have high LFA-1 integrin expression and display high spontaneous binding to ICAM-1 under static conditions. Unlike B cells, these cells were able to adhere to ICAM-1 under shear stress in the absence of chemokines. However, cytotoxic T lymphocyte adhesion to ICAM-1 under shear flow was dependent on calcium/calmodulin signalling and an intact actin cytoskeleton. β2-integrins in myeloid cells are continuously recycled and mediate both cell trafficking and phagocytosis of complement (iC3b)-coated particles, but how these processes are regulated remain incompletely understood. I show here that a triple threonine-motif in the β2-integrin cytoplasmic domain is important for in integrin-mediated adhesion in primary mouse macrophages and dendritic cells. This motif also prevents integrin lysosomal degradation in primary myeloid cells, and is required for integrin-mediated phagocytosis of iC3b-coated particles. I also show that an R77H substitution in the extracellular domain of the Mac-1 integrin, which is associated with the inflammatory disorder systemic lupus erythematosus, leads to impaired cell adhesion to ICAM-1 and iC3b as well as impaired phagocytosis. In conclusion, in this thesis I have successfully developed methods to investigate integrin-mediated adhesion in leukocytes. In addition, I have investigated signalling pathways and mechanisms involved in regulation of β2-integrin-mediated functions in primary lymphocytes and myeloid cells. These studies have led to an increased understanding of how integrins in immune cells are regulated both in the presence and absence of shear stress.

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17

Magne, Sandrine. "L'acide arachidonique : second messager des effets cardiaques des agonistes β2 adrénergiques". Paris 6, 2002. http://www.theses.fr/2002PA066435.

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18

Faisy, Christophe. "Hyperréactivité bronchique provoquée par les β2-agonistes : mécanismes de signalisation intracellulaire". Paris 5, 2005. http://www.theses.fr/2005PA05S006.

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Ce travail montre qu'une incubation prolongée des bronches humaines isolées en présence de fénotérol à dose pharmacologique induit une hyperréactivité bronchique à l'endotheline-1. Ce phénomène intéresse trois éléments clés de l'hyperréactivité bronchique : la cellule musculaire lisse, les fibres neurosensorielles et la cellule épithéliale. Nous avons mis en évidence, en utilisant des techniques d'immuno-histochimie et de biologie moléculaire, que l'exposition prolongée au fénotérol induit la synthèse des récepteurs de l'endothéline-1 et celle de leur ARN méssager au niveau de l'épithélium du tonus musculaire bronchique. Nous avons également montré que l'hyperréactivité dépend d'une cascade d'évènements intracellulaires impliquant la stimulation des récepteurs vanilloïdes présents sur les fibres neurosensorielles ainsi que l'activation du NF-kB, du système des MAP-kinases et des protéines kinases C
Our result show that chronic fenoterol exposure induces hyperresponsiveness top endothelin-1 in human isolated bronchi. This effect involves three crucial factors implied in airways responsiveness : the epithelial cells, the sensory nerves, and the airway smooth muscle cells. Our immunohistochemical and biomolecular findings reveal that fenoterol-induced sensitisation of human isolated bronchi involves epithelial endothelin-1 receptors synthesis, which suggests perturbation of the epithelial regulation of airway smooth muscle contraction in response to endothelin-1. In addition, we highlighted the intracellular signalling pathways implied in fenoterol-sensitisation including sensory nerves by vanniloid receptors stimulation, and NF-kB, MAP-Kinases and protein kinases C activation

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19

Pavlov, Nikola. "Synthèse asymétrique d’analogues de β2-tryptophane et application en synthèse peptidique". Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20186/document.

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Le tryptophane est un acide aminé essentiel qui, en plus de son rôle dans la biosynthèse des protéines, est le précurseur biochimique de nombreux composés. Beaucoup de peptides biologiquement actifs, qui possèdent dans leurs séquences cet acide aminé contenant un substituant indole, ont des propriétés physiologiques importantes. On peut citer par exemple des dérivés comme la sérotonine, le tryptamine, le sumatriptan qui ont des effets neurophysiologiques. Les analogues de tryptophane sont aussi des « building block » important pour la synthèse de peptidomimétiques, d'analogues de produits naturels et de composés biologiquement actifs. Une autre propriété importante du tryptophane et de ses analogues concerne la fluorescence du noyau d`indole qui peut être utilisée par exemple pour l`étude de changements conformationnels d'une protéine et aussi l'étude des interactions protéine-membrane.Dans ce contexte, cette thèse est consacrée à la mise au point d'une nouvelle stratégie de synthèse asymétrique permettant d'accéder efficacement à d`analogues énantiopurs du tryptophane : les beta 2-tryptophanes (2-indolyl-beta-alanines) ainsi qu'à la synthèse et l'étude de nouveaux analogues de peptides à activité opioïdes contenant ces analogues. Nous avons développé une nouvelle stratégie de synthèse asymétrique permettant d'accéder efficacement à des analogues de beta 2-tryptophane (2-indolyl-beta-alanines) énantiopurs. - Nous avons effectué la synthèse d`un auxiliaire chiral le (R)-4-(3-hydroxy-4,4-diméthyl-2-oxopyrrolidin-1-yl) benzoate de benzyle ainsi que celle du dérivé nitroacrylate correspondant : le (R)-4-(3-(3-nitroacryloyloxy)-4,4-diméthyl-2-oxo pyrrolidin-1-yl) benzoate de benzyle ((R)-10). Les composés racémiques ont également été synthétisés pour préparer les témoins racémique des molécules cibles.- Nous avons mis au point des conditions optimisées de la réaction d`alkylation de Friedel-Crafts entre ce nitroacrylate chiral et divers indoles.- Nous avons également étudié pour chaque produit ainsi obtenu les meilleures conditions de transformation conduisant à la synthèse des analogues des N-Fmoc-beta 2-tryptophanes racémiques et optiquement purs.- Nous avons contrôlé l'absence d'épimérisation pouvant se produire pendant les réactions de transformation des produits optiquement purs et déterminé sans ambiguïté la configuration absolue des 2-indolyl-beta-alanines isolées.- Nous avons synthétisé sur support solide par stratégie-(Fmoc) 4 nouveaux peptides potentiellement biologiquement actifs et 2 peptides de référence - analogues raccourcis de la nociceptine
Tryptophan, an essential amino acid, both functions as a building block in protein biosynthesis and as a biochemical precursor. It is abundantly found in most biologically active peptides that exhibit various physiological properties in particular hormonal and antimicrobial activities. Some of its natural derivatives like serotonin, tryptamine, and also unnatural derivatives such as sumatriptan, have neurophysiologic effects. Tryptophan analogues are also important building blocks for the synthesis of peptidomimetics, natural products and biologically active compounds. Another important property of tryptophan and tryptophan analogues is related to the fluorescence of the indole ring that can be used to study conformational changes in protein and in protein-membrane interactions. The asymmetric Friedel-Crafts alkylation of various indoles with a chiral nitroacrylate provides optically active beta-tryptophan analogues after reduction of the nitro group and removal of the chiral auxiliary. This reaction generally occurs in good yield and high diastereoselectivity (up to 90:10). We have established a new route to prepare enantiopure beta-tryptophan analogues ((S)-2-indolyl-beta-alanines). We showed that beta-nitroacrylate (R)-2 is a good chiral auxiliary for asymmetric Friedel-Crafts alkylation of indoles. (R)-2-indolyl--alanines were obtained by the same synthetic route by using the chiral compound (S)-2. beta-tryptophan analogues are delivered in their N-Fmoc-protected form, ready to use for instance in solid phase peptide synthesis, which is one of the most popular method for peptide synthesis. This study provides a new example of asymmetric beta-tryptophan analogues preparation and further studies concerning their applications in medicinal chemistry and in organic synthesis are now in progress

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20

Cruz, Garcia Yiliam [Verfasser], Michaela [Gutachter] Kuhn y Thomas [Gutachter] Dandekar. "Interactome of the β2b subunit of L-type voltage-gated calcium channels in cardiomyocytes / Yiliam Cruz Garcia ; Gutachter: Michaela Kuhn, Thomas Dandekar". Würzburg : Universität Würzburg, 2021. http://d-nb.info/1237623189/34.

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21

Rosenborg, Johan. "Clinical-Pharmacokinetic Aspects of Prolonged Effect Duration as Illustrated by β2-Agonists". Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1399.

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Regularity is a key element of maintenance drug treatment; compliance is crucial for treatment success. Once- or twice-daily intake of a drug is always easier to comply with than regimens requiring more frequent dosing. Bronchodilating treatment was used as an example to illustrate how sustained duration of effect can be achieved by two different approaches: oral administration of the terbutaline prodrug bambuterol and inhalation of formoterol. Bioanalytical methods were employed to monitor the kinetic fate of bambuterol and formoterol in plasma, urine, or faeces. Generated terbutaline in plasma was used as a marker of effect for bambuterol. Established clinical laboratory tests were used to assess local and systemic effects of inhaled formoterol compared with salbutamol. Recommended doses of bambuterol, 10-20 mg once daily in adults, normally produced plasma concentrations of the active moiety terbutaline within therapeutically relevant limits. Dose proportionality for terbutaline makes dosing with bambuterol predictable. Compared with adults, children should be given higher doses than indicated by their lower body weight. Pharmacokinetic analysis indicated that absorption of bambuterol was slow and multi-phasic and that slow biotransformation to terbutaline occurred both presystemically and systemically. Systemically circulating formoterol was rapidly eliminated, the inactive (S;S)-formoterol more rapidly than the active (R;R)-formoterol. An inactive phenol glucuronide was the main metabolite, and a previously unknown sulphate metabolite was discovered. Duration of systemically mediated cardiovascular or metabolic side-effects of inhaled formoterol seemed not to differ from those of an inhaled systemically equieffective dose of salbutamol. There was a trend suggesting that the magnitude of systemic side-effects may be less pronounced after inhalation of formoterol compared with a locally equieffective dose of inhaled salbutamol. Both approaches to sustaining stimulation of β2-adrenoceptors have their pros and cons. Bambuterol can be dosed orally once daily, but full effect is reached slowly. The effect of formoterol is reached within a few minutes, but administration must occur via the lungs, often twice daily. Both treatments, however, give 24-h symptom relief during regular treatment.

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22

Brodin, Patcha Veronika. "Pro- and anti-inflammatory regulation of β2 integrin signalling in human neutrophils". Doctoral thesis, Linköpings universitet, Medicinsk mikrobiologi, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-9661.

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The body is under constant attack from pathogens trying to slip by our immune defence. If the barrier is breached, invading pathogens enter the tissues and cause inflammation. During this process neutrophils, constituting the first line of defence, leave the bloodstream and seek out and kill the invading pathogens. The mechanisms leading to activation of receptors on neutrophils must be closely orchestrated. Pro- and anti-inflammatory substances can influence the outcome of the inflammation process by affecting the involved players. If not well balanced, inflammatory diseases, such as atherosclerosis and rheumatoid arthritis, can be the outcome. The aim of this thesis was to elucidate the effect of pro- (fMLP, Leukotriene B4, and Interleukin-8) and anti- (lipoxins, aspirin and statins) inflammatory substances on the β2 integrins, mediating adhesion of neutrophils both under “normal” conditions and during coronary artery disease. More specifically, the effect of these substances on the β2 integrins were studied in regard to: i) the activity (i.e. affinity and avidity) of β2 integrins, ii) the signalling capacity of β2 integrins (i.e. detected as release of arachidonic acid, and the production of reactive oxygen species, and iii) the signal transduction mediated by the β2 integrins (i.e. phosphorylation of Pyk2). The pro-inflammatory substances belong to the family of chemoattractants that induces transmigration and chemotaxis. A hierarchy exists between the different family members; the end-target chemoattractants (e.g. fMLP) being more potent than intermediary chemoattractants (e.g. IL-8 and LTB4). It was found that intermediary chemoattractants regulate β2 integrins by mainly affecting the avidity of β2 integrins. End-target chemoattractants on the other hand, affected the β2 integrins by increasing the avidity and the affinity, as well as their signalling capacity. The anti-inflammatory substances used in this study were the exogenous aspirin and statins, and the endogenous lipoxins. In the presence of aspirin, stable analogues of lipoxin (i.e. epi-lipoxins) are formed in a trans-cellular process. Lipoxin inhibited the signalling capacity of β2 integrins mediated by intermediary chemoattractants, as well as the signal transduction induced by end-target chemoattractants. Moreover, the signalling capacity of β2 integrins in neutrophils from patients suffering from coronary artery disease (CAD) was impaired. Arachidonic acid, the precursor for both pro- and anti-inflammatory eicosanoid, induced an increase in the β2 integrin activity (both affinity and avidity), but had no effect on the signal transduction. In conclusion, different “roles” were observed for end-target and intermediary chemoattractants in the regulation of β2 integrins. The inhibitory effects of the anti-inflammatory lipoxins support earlier studies suggesting that these agents function as “stop signals” in inflammation. This is also confirmed by our findings in CAD patients, who have elevated levels of epi-lipoxins due to aspirin treatment. Moreover, Pyk2 was identified as a possible target for the inhibitory effect of anti-inflammatory drugs.

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23

Campbell, Gaynor Anne. "In vitro investigations of transforming growth factor-β2 induced airway wall remodelling". Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/in-vitro-investigations-of-transforming-growth-factor2-induced-airway-wall-remodelling(788cb4e3-e92d-419f-bef2-ebd01887eb8b).html.

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Airway wall remodelling contributes to decreased lung function in asthma. Key features of the remodelling process are thickening of the reticular basement membrane, differentiation of fibroblast-like cells with contractile properties termed myofibroblasts and sub-epithelial deposition of extracellular matrix. The pro-fibrogenic cytokine transforming growth factor-β2 (TGF-β2) is purported to drive remodelling responses. TGF-β2 may be upregulated in asthmatic epithelium, and is secreted by bronchial epithelial cells following injury. In this study significant increases in reticular basement membrane thickening and myofibroblast differentiation were identified by histology and immunohistochemistry of mild asthmatic and healthy human bronchial biopsy tissue, although no significant differences in TGF-β2 expression were identified. It was hypothesised that the proteolytic action of house dust mite (HDM) allergens would lead to increased activation of latent TGF-β2 secreted by bronchial epithelial cells. A transformed cell line, 16HBE14o-, did not show increased activation or expression following HDM extract challenge, however TGF-β2 activation and expression was increased following exposure of primary human bronchial epithelial cells to a HDM extract. Myofibroblast differentiation and matrix deposition by healthy and mild asthmatic- derived primary bronchial fibroblasts were assessed by α-smooth muscle actin expression and soluble collagen production, following challenge with exogenous TGF-β2. Results presented here show asthmatic bronchial fibroblasts are more sensitive to the myofibroblast priming effects of TGF-β2. Bronchial epithelial cell conditioned media challenge of healthy fibroblasts led to greater increases in matrix deposition and myofibroblast differentiation than was attributable to TGF-β2, with greatest increases seen following asthmatic epithelial cell conditioned media exposure. Responses were greater than suggested by the epithelial TGF-β2 levels, so it is suggested that additional soluble mediators play a part in airway wall remodelling responses. Further work is required to identify the soluble mediators secreted by bronchial epithelial cells that control the responses of the underlying fibroblasts.

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24

Soppa, Gopal Krishna Ranganathan. "Mechanical unloading and β2-adrenoceptor stimulation for the treatment of heart failure". Thesis, Imperial College London, 2009. http://hdl.handle.net/10044/1/5287.

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Background & Introduction: Heart transplantation is the most effective treatment for end-stage heart failure (HF) but is hindered due to an inadequate availability of donor organs. Left ventricular assist devices (LVADs) have been shown to be a suitable alternative and primarily used as a ‘bridge to transplantation’ wherein the failing heart can be supported by mechanical circulatory assistance until a suitable donor organ becomes available. In 4-9% of patients, the LVAD also acts as ‘bridge to recovery’, since it induces substantial functional improvement that allows LVAD explantation, without the need of transplantation. The rate for explantation of the LVAD remains low and the functional improvement observed, a transient phenomenon. LVADs cause mechanical unloading, which produces functional, structural, signalling and molecular changes in HF. Development of myocardial unloading-induced atrophy, time- dependent myocyte contractile dysfunction and excitation-contraction (EC) coupling changes may have detrimental consequences. However, when mechanical unloading is combined with pharmacological therapy, including the β2-AR agonist clenbuterol, an improved ‘bridge to recovery’ rate of 75% can be achieved. The effects of clenbuterol on functional, structural, signalling and molecular changes in a normal and failing hearts, during mechanical unloading, are unknown. This thesis investigates some of the key effects of mechanical unloading and β2-AR agonist stimulation with clenbuterol for HF treatment, based on the following hypotheses which have been individually addressed in Chapters 3, 4 and 5 respectively. • Chronic administration of clenbuterol alters myocardial structure and function and affects calcium handling in normal rat hearts. • Mechanical left ventricular unloading and the consequent left ventricular atrophy results in altered whole-heart and cellular function in non- failing/normal rat hearts. • Clenbuterol treatment during mechanical unloading of a normal rat heart normalises whole-heart and cellular function. • Clenbuterol has an additional benefit when combined with mechanical unloading in the treatment of failing rat hearts. Methods: Clenbuterol was administered by osmotic minipumps. Mechanical un- loading was achieved by heterotopic abdominal heart transplantation. Heart failure was induced by left coronary artery ligation in rats. In-vivo whole heart function was assessed by echocardiography and ex-vivo function by pressure- volume relationship. Only LV myocytes were isolated and studied using optical, fluorescence and electrophysiological techniques. Calcium handling protein expression was assessed by Western blotting. Theory and methodology of the single-cell studies is outlined, together with validation experiments and the necessary assumptions. Results: Data obtained and their interpretations are presented in three chapters according to the proposed hypotheses. The results show that clenbuterol with, without mechanical unloading, or on its own can affect both whole-heart and cellular function in normal hearts. The treatment of failing hearts with clenbuterol, alone or in combination with mechanical unloading, improves LV function at whole-heart and cellular level by effects on cell morphology, EC coupling and myofilament sensitivity to calcium. The details of individual experiments and their interpretation are discussed in the respective chapter. General Discussion: This thesis supports the use of clenbuterol in the strategy to improve recovery in HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function. The questions remaining unanswered are discussed and possible future experiments that could be performed to address them are described.

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25

Kondo, Takeshi. "β2-Adrenoreceptor Agonist Inhalation During Ex Vivo Lung Perfusion Attenuates Lung Injury". Kyoto University, 2016. http://hdl.handle.net/2433/215382.

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Bonicelli, Jana. "In-vitro-Untersuchungen zu antifibrotischen Wirkungen von β-Adrenozeptoragonisten und Glucocorticoiden in primären equinen Bronchialfibroblasten". Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-189393.

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Einleitung: Die Pathogenese chronisch entzündlicher Atemwegserkrankungen ist mit zunehmender Schädigung und fibrotischen Umbauvorgängen und daraus resultierenden Einschränkungen physiologischer Funktionen verbunden. Bei der Recurrent Airway Obstruction (RAO) des Pferdes sind solche strukturellen Veränderungen häufig assoziiert mit Verdickung der Atemwegswand, subepithelialer Fibrose und Obstruktion der Atemwege. Bei RAO besteht die Standardtherapie darin, die Bronchokonstriktion mit β2-Agonisten und die Entzündung mit Glucocorticoiden aufzuhalten. In den letzten Jahrzehnten konnte jedoch gezeigt werden, dass nicht alle Patienten mit der empfohlenen Therapie ausreichend behandelt werden können und neue Ansatzpunkte der Therapie gefunden werden müssen. Daher konzentrieren sich neuere Forschungsarbeiten auf strukturelle Alterationen in den Atemwegen, das sogenannte Airway-Remodelling. Zielsetzung: In der vorliegenden Arbeit sollen zunächst primäre equine Bronchialfibroblasten (EBF) isoliert, charakterisiert und kultiviert werden. Im nächsten Schritt sollen in diesen Zellen die β2-Rezeptorexpression und –eigenschaften charakterisiert werden. Anschließend soll die Eignung dieser Zellen als Zellmodell zur Untersuchung der zellulären Proliferation und Transformation sowie der Regulation der de-novo-Synthese von extrazellulärer Matrix und deren Beeinflussung durch β2-Agonisten und Glucocorticoide allein oder in Kombination sowie TGF-β überprüft werden. Material und Methoden: Mittels enzymatischer Verdauung mit 0,25 % Trypsin werden die EBF aus den Bronchien von 10 gesunden Schlachtpferden isoliert und in DMEM kultiviert. Diese Zellen werden morphologisch, immunzytochemisch und funktionell in deren Eigenschaften in An- oder Abwesenheit von fetalem bovinem Serum (FBS) oder Pferdeserum (HS) charakterisiert. Die Dichte und Subtypverteilung von β-Adrenozeptoren wird mittels Radioligandbindungsstudien mit [125I]-(-)-Iodocyanopindolol in Gegenwart von Rezeptorsubtyp-selektiven β-Antagonisten (β2: ICI 118,551 und β1: CGP 20712A) in EBF untersucht. Der Einfluss von β2-Agonisten auf die Proliferation und Differenzierung der EBF sowie die Kollagensynthese wird mittels [3H]-Thymidineinbauassay, Bestimmung von Gesamtprotein und α-Smooth Muscle Aktin (α-SMA) mit Lowrymethode und Western Blot-Analyse bzw. [3H]-Prolininkorporationsassay ermittelt. Die statistische Signifikanz wird über einen t-Test für verbundene Stichproben oder eine One-Way-ANOVA mit nachfolgendem Dunnett’s Test ermittelt und das Signifikanzniveau wird P ≤ 0,05 festgelegt. Ergebnisse: EBF können im DMEM-Medium nur in Gegenwart von Serum langfristig wachsen und kultiviert werden. In serum-freiem Medium und unter vorübergehendem Serumentzug können EBF nicht anhaften bzw. lösen sie sich ab. Die Effekte von FBS und HS auf EBF sind allerdings unterschiedlich. FBS fördert die Zellproliferation und -verdopplungsrate sowie die Zellpassage bis zur Passage 20 signifikant besser als HS (max. 9 Passagen). Unter FBS entwickeln EBF eine für Fibroblasten charakteristische spindelförmige Morphologie aber eine schwache α-SMA-Expression, während unter HS die Zellen eine atypische, polygonale Morphologie zeigen, jedoch mit signifikant hohem α-SMA und Proteingehalt. Radioligandenbindungsstudien zeigen, dass EBF lediglich den β2-Adrenozeptorsubtyp mit einer maximalen Rezeptorendichte (Bmax) von 5037 ± 494 Bindungsstellen/Zelle exprimieren. Die Behandlung der EBF mit β-Agonisten (Clenbuterol, Salbutamol, Isoproterenol) führt konzentrationsabhängig zur Abnahme dieser Anzahl der Rezeptoren mit unterschiedlicher Wirkungsstärke (Clenbuterol > Salbutamol > Isoproterenol), wobei Dexamethason diese nicht verändert. Diese Agonisten sowie auch Dexamethason hemmen die Proliferation der EBF, und dies kann in Gegenwart von ICI 118,551 aber nicht von CGP 20712A gehemmt werden, was auf den Einfluss des β2-Adrenozeptors hinweist. β2-Agonisten und Dexamethason gemeinsam resultieren in einer verstärkten Hemmung der EBF-Proliferation. Transforming Growth Factor-β1 (TGF-β1) stimuliert die Transformation von EBF zu Myofibroblasten mit einer erhöhten Expression von α-SMA in EBF, welches eher durch Dexamethason als durch Clenbuterol gehemmt wird. Die Kollagensynthese wird nur durch Dexamethason signifikant gehemmt. Schlussfolgerung: Das erstmalig etablierte EBF-Kulturmodell dient der Erforschung von Signalwegen und neuen Arzneimitteltargets im Zusammenhang mit der Pathogenese der equinen RAO insbesondere dem Atemwegs-Remodelling. So kann gezeigt werden, dass die Verwendung von β2-Agonisten allein oder in Kombination mit Glucocorticoiden eine Hemmung der Proliferation und Transformation von EBF in vitro bewirkt. Dies deutet auf einen zusätzlichen therapeutischen Nutzen von Clenbuterol und Glucocorticoiden hin und impliziert die Notwendigkeit eines frühzeitigen Einsatzes dieser Pharmaka bei der RAO des Pferdes.

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27

Зуб, Л. О. "Роль трансформуючого фактора росту β та β2- мікроглобуліну у прогресуванні хронічної хвороби нирок". Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18613.

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28

Joassard, Olivier. "Mécanismes moléculaires du contrôle de la masse musculaire sous l'action du β2-agoniste formotérol". Phd thesis, Université Jean Monnet - Saint-Etienne, 2013. http://tel.archives-ouvertes.fr/tel-01001862.

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Les β2-agonistes sont couramment utilisés pour prévenir et réduire les symptômes de l'asthme et de la bronchoconstriction induite par l'exercice. Mais, pris en quantités supérieures aux doses thérapeutiques, les β2-agonistes ont un effet anabolisant qui a été clairement démontré in vivo. Un certain nombre d'acteurs sont mis en jeu dans la réponse biologique du tissu musculaire aux β2-agonistes. L'un de ces acteurs est la voie de signalisation PI3K/Akt/mTOR, voie d'initiation de la traduction, ayant un rôle majeur dans la synthèse protéique. Dans ce contexte, notre première étude avait pour objectif de déterminer la cinétique des événements moléculaires responsables de l'hypertrophie du muscle squelettique de rat après administration de formotérol pendant 1 jour (J1), 3 jours (J3) et 10 jours (J10). Nous avons montré que l'administration de formotérol induisait une hypertrophie musculaire à J3 et J10 associée à l'activation transitoire de la voie de signalisation PI3K/Akt/mTOR (J1 et J3), et à une diminution de l'expression de l'E3 ubiquitine ligase MAFbx/Atrogin-1 (J3). La voie autophagie lysosome ne semblait pas être affectée. Ainsi, l'ensemble de ces résultats suggère que l'activation de la voie PI3K/Akt/mTOR est associée à la voie ubiquitine-protéasome mais pas à la voie autophagie-lysosome. La régulation transitoire de la voie PI3K/Akt/mTOR suggère que d'autres voies de signalisation sont impliquées dans l'hypertrophie musculaire induite par le formotérol. Le 007-AM, analogue de l'AMPc, a été décrit comme pouvant stimuler la voie de signalisation PI3K/Akt/mTOR via l'activation de la protéine Epac, suggérant que le 007-AM puisse constituer une molécule de substitution à l'utilisation des β2-agonistes. Notre seconde étude avait pour but de déterminer si le 007-AM avait une action anabolisante sur le tissu musculaire, mais également de déterminer si la 007-AM était une molécule stable permettant d'envisager son usage dans un cadre pharmacologique. L'administration de 007-AM pendant 7 jours chez des souris n'engendrait pas d'hypertrophie musculaire. En revanche, in vitro sur cellules C2C12, le 007-AM activait la voie de signalisation PI3K/Akt/mTOR comme en témoignait l'augmentation de la phosphorylation des protéines rpS6 et 4E-BP1. Nos résultats montraient également que le 007-AM était instable dans le plasma alors que son produit de dégradation, le 007 était plus stable. Pris ensembles, ces résultats suggèrent qu'un traitement de 7 jours au 007-AM n'est pas suffisant pour induire une hypertrophie musculaire et que l'absence d'hypertrophie musculaire pourrait provenir de l'instabilité du 007-AM dans le plasma. Toutefois, des études supplémentaires seront nécessaires pour confirmer ces résultats

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29

Skrentny, Thomas y Brittany Traylor. "Influence of Genetic Variation of the β2 Adrenergic Receptor in Patients with Cystic Fibrosis". The University of Arizona, 2010. http://hdl.handle.net/10150/623791.

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Class of 2010 Abstract
OBJECTIVES: Cystic fibrosis (CF) is a disease that adversely affects the lung resulting in a reduction of lung diffusion. Stimulation of the β2 adrenergic receptors results in mucocilliary clearance, and therefore, lung diffusion. We sought to determine the influence of an inhaled β-‐agonist on the diffusing capacity of the lungs for carbon monoxide (DLCO), alveolar-‐capillary membrane conductance (DM), pulmonary capillary blood volume (Vc), and peripheral oxygen saturation (SaO2) in subjects with CF and compare the data to matched healthy subjects. METHODS: To determine this we recruited 20 healthy subjects and 18 subjects with CF (age=23±7 vs. 24±4years, ht=168±8 vs. 174±12cm. wt=64±16 vs. 70±13kg, BMI= 23±4 vs. 23±3kg/m2, FEV1= 72±27 vs. 92±12%pred., VO2peak = 45±25 vs. 99±24%pred., P<0.05 for FEV1 and VO2peak, mean±SD) for the study and measured DLCO, DM, Vc and SaO2 before and 30, 60, and 90 minutes following the administration of inhaled albuterol. RESULTS: Within the healthy subjects, there were no differences in DLCO, DM, Vc, DM/Vc at baseline or in response to albuterol according to genetic variation of the ADRB2 at amino acid 27. Within the CF group, the Glu27Glu/Gln27Glu group had higher DM/Vc when compared to the Gln27Gln group at baseline. Both genotype groups had a significant decline in Vc and a significant improvement in DM/Vc and SaO2 in response to albuterol, but not in DLCO or DM. CONCLUSIONS: These results suggest that there are differences in lung diffusion and peripheral SaO2 according to genetic variants of the ADRB2 at position 27 and could play a potential role in treatment options.

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30

Chen, Fengshi. "Protective effect of a nebulized β2-adrenoreceptor agonist in warm ischemic-reperfused rat lungs". Kyoto University, 2007. http://hdl.handle.net/2433/135902.

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31

Salvat, Éric. "Traitements précoces et tardifs des douleurs neuropathiques et β2-agonistes : études thérapeutiques précliniques et cliniques". Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ104/document.

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Les douleurs neuropathiques sont secondaires à une maladie ou à une lésion affectant le système nerveux somatosensoriel et sont mal soulagées par les antalgiques usuels. Dans notre travail préclinique, nous avons étudié l’effet de différentes molécules, dont des antidépresseurs et antiépileptiques recommandés dans le traitement des douleurs neuropathiques. Dans un modèle murin de neuropathie traumatique, nous avons étudié l’influence de la période de traitement, précoce ou tardif, sur l’allodynie mécanique. Un traitement précoce par gabapentine ou par carbamazépine permet d’observer un effet préventif sur la chronicisation de l’allodynie. Dans un modèle murin de neuropathie diabétique, nous avons caractérisé l’action anti-allodynique d’un traitement par nortriptyline et par terbutaline. En clinique, nous avons réalisé un travail d’enquête rétrospective sur des patients opérés par thoracotomie. L’analyse des résultats montre une diminution significative du risque de présenter des douleurs chroniques avec des caractéristiques neuropathiques chez les patients traités par β2-agonistes au long cours
Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and is badly relieved by usual antalgics. In our preclinical work, we studied the effect of various molecules, in particular antidepressant and anticonvulsant drugs wich are recommended in the treatment of neuropathic pain. In a murine model of traumatic neuropathy, we studied the influence of the period of treatment, early or late, on the mechanical allodynia. An early treatment with gabapentin or carbamazepine leads to a preventive effect on sustained allodynia. In a murine model of diabetic neuropathy, we characterized the antiallodynic action of nortriptyline and terbutaline. In our clinical work, we realized a retrospective survey on patients operated by thoracotomy. The analysis of the results show a significant decrease of the risk to suffer from chronic pain with neuropathic characteristics in patients treated with long-term β2- agonists

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32

Fong, Sitt Wai. "The effects of transforming growth factor-β2 on synaptic transmission at the mammalian neuromuscular junctions". Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=133996.

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Transforming growth factor-βs (TGF-βs) are highly expressed in neural development but why the adult nervous system continues to express them is unclear. TGF-β2 is concentrated at mature neuromuscular junctions (NMJs) of mammalian skeletal muscle fibres, and the nerve terminal expresses TβR-II receptors. To test the role of TGF-β2 at mammalian NMJs, I performed four experiments. The first study tested whether TGF-β2 acutely modulates synaptic transmission at mature mammalian NMJs. Second, I asked if chronically reduced TGF-β2 expression disrupts synaptic transmission. Third, I asked if TGF-β2’s effects differ in terminals adapted to different activity patterns in vivo. Lastly, I asked whether TGF-β1, a related peptide to TGF-β2, is distinct in terms of its effects on transmitter release. Using single electrode potential recording, I found TGF-β2 significantly increased the amplitude of spontaneous released single neurotransmitter vesicles (miniature endplate potentials, MEPPs) and nerve stimulation evoked multi-vesicular release (endplate potentials, EPPs). These effects were blocked by L-vesamicol, a vesicular acetylcholine transporter inhibitor, and bafilomycin, a proton pump inhibitor, suggesting the increase in MEPP/EPP amplitude is due to increased vesicle filling presynaptically. These effects were also blocked by the MARK inhibitors, UO126 and PD98059, suggesting TGF-β2 acts via a MARK-dependent pathway. Postsynaptically, two electrode recording showed postsynaptic potential amplitude was enhanced by an increased fibre input resistance, suggesting TGF-β2 also acts postsynaptically. TGF-β2 reduced the number of vesicles released per stimulus (quanta content, QC) but this was blocked by atropine, showing this was indirect through autoreceptor negative feedback. Voltage clamp recording showed TGF-β2 significantly increased the miniature end plate currents (MEPCs), but not the end-plate currents (EPCs), supporting my initial hypothesis that TGF-β2 acts mainly presynaptically to increase vesicle filling. In TGF-β2+/- mice, I found greater MEPP amplitude variability. This supports my previous findings that TGF-β2 modulates vesicle filling. Unexpectedly, there was an excess in larger MEPP sizes (>0.88 mV), perhaps reflecting upregulation of either presynaptic signalling or another synaptic mediator. Two MEPP amplitude populations were induced in TGF-β2-treated TGF-β2+/- mouse NMJs, similar to the bimodal vesicle population in electroplaques. The extensor digitorum longus (EDL, ~95% fast fibres) and soleus (SOL, ~95% slow fibres) were used to investigate whether the TGF-β2-mediated effect differed between fibre types. Overall, TGF-β2 increased the quantal size (MEPP amplitude) in NMJs of both muscles, suggesting this effect is not fibre-type specific and, together with results in mice, that the TGF-β2-mediated increase in vesicle filling is common to all mammalian neuromuscular terminals. With respect to EPP amplitude and QC, the results differed between muscles. In EDL, the EPP amplitude was not significantly changed, whereas it increased in SOL. In EDL, QC was reduced but not in SOL. These difference compared to diaphragm perhaps do reflect muscle fibre-type dependent differences. TGF-β1, at 0.1 ng/ml, significantly reduced quantal size – the opposite of TGF-β2 at any concentration. One explanation would be that a receptor inhibition by TGF-β1 at low concentration interferes with endogenous TGF-β2 binding/receptor activation at the NMJ. However, when the TGF-β1 concentration was raised to 1 ng/ml, like TGF-β2, it significantly increased MEPP amplitude. This suggests that perhaps sufficient binding of TGF-β1 results in the receptor activation of TGF-β2 like signalling. Overall, I conclude that TGF-β2 enhances the size of spontaneous synaptic potentials in all types of muscle fibres, and this is much more rapid (1 hr vs 1 day) than at central neurone synapses in culture. Detailed study in the rat diaphragm shows it increased the evoked EPP amplitude, reduced QC and increased postsynaptic input resistance. Together, TGF-β2 would therefore enhance the postsynaptic depolarisation increasing synaptic strength, and by reducing QC, increase the efficiency of neurotransmission at mammalian NMJs. While unimportant for single stimuli in healthy terminals, by conserving vesicle use, it may help maintain release during stimulus trains, especially during neuromuscular disease.

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33

Jin, Jiqin y 金冀琴. "The role of protein kinase C beta 2 (PKC β2) in myocardial ischaemia-reperfusion injury". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208597.

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34

Skawran, Stephan Martin [Verfasser], Stefan [Akademischer Betreuer] Engelhardt, Stefan [Gutachter] Engelhardt y Antonio [Gutachter] Sarikas. "Oligomerisierung von β2-Adrenozeptoren / Stephan Martin Skawran ; Gutachter: Stefan Engelhardt, Antonio Sarikas ; Betreuer: Stefan Engelhardt". München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1160381127/34.

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35

Di, Bernardini Elisabetta. "Endothelial lineage differentiation from iPS cells is regulated by miRNA-21/AKT and TGF-β2 pathways". Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/endothelial-lineage-differentiation-from-ips-cells-is-regulated-by-mirna21akt-and-tgf2-pathways(ae3d9fe0-a3cf-41ea-a524-172716384971).html.

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Endothelial death/dysfunction is a critical process in the development of cardiovascular diseases. Finding a source of endothelial cells (ECs) for regenerative medicine is a challenging yet fundamental issue. Induced pluripotent stem cells (iPSCs) constitute an attractive source of cells for transplantation because of their high proliferation and differentiation potential

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36

Supekar, Vinit Mark. "Stress stimuli and pro-inflammatory kinases : structural studies of p38-α, -β2, -δ and IKK-α". Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619692.

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37

Приступа, Людмила Никодимівна, Людмила Никодимовна Приступа, Liudmyla Nykodymivna Prystupa, Анна Миколаївна Бондаркова, Анна Николаевна Бондаркова y Anna Mykolaivna Bondarkova. "Level of bronchial asthma control with regard to GLN27GLU polymorphism in the β2-adrenergic receptor gene". Thesis, Sumy State University, 2017. http://essuir.sumdu.edu.ua/handle/123456789/64795.

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The aim of our research was to identify asthma control level with regard to Gln27Glu polymorphism in the ADRB2 gene. Materials and methods. We examined 195 with bronchial asthma patients and 95 apparently healthy individuals. Patients with BA were divided into 3 groups depending on the genotypes for Gln27Glu polymorphism in the ADRB2 gene. Asthma control was assessed by means of Asthma Control Questionnaire-5 (ACQ-5) and respiratory function evaluation. Gln27Glu (rs1042714) polymorphism in the ADRB2 gene was detected using polymerase chain reaction. Statistical analysis was performed using SPSS– 21 program.

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38

Moumné, Roba. "Développement d' une nouvelle voie de synthèse d' acides β2[Bêta 2]-amines et application industrielle". Paris 6, 2005. http://www.theses.fr/2005PA066447.

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39

Cousin, Céline. "Préparation et caractérisation de fractions enrichies en transforming growth factor-β2 à partir de colostrum bovin". Lille 1, 2006. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2006/50376_2006_27.pdf.

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Le colostrum bovin est le "premier lait" produit dans les 24 à 48 heures suivant le vêlage. C'est un mélange complexe d'éléments qui agissent en synergie. Parmi eux, se trouvent les immunoglobulines G (IgG) et les facteurs de croissance tels que le Transforming Growth Factor-β2 (TGF-β2), qui intervient notamment dans la régulation du système immunitaire, la cicatrisation et la protection du tube digestif. L'objectif était de préparer des fractions colostrales ayant une activité facteur de croissance, ou des fractions immunopréventives hypoallergéniques. Les recherches ont donc été orientées vers la purification des immunoglobulines et des TGF-β2 latents, beaucoup plus stables sous cette forme, car protégés par une protéine de liaison. Dans un premier temps, l'utilisation de diverses chromatographies (exclusion stérique, interactions hydrophobes, échange de cations) a permis de mieux caractériser les propriétés physico-chimiques des TGF-β2 latents. Dans un second temps, deux types de procédés de fabrication ont été mis en place : - Une chromatographie d'exclusion stérique optimisée, permettant l'obtention d'une fraction hypoallergénique très riche en IgG et en TGF-β2 latents. - Une chromatographie de pseudo-affinité sur Cibacron Blue, qui a permis la préparation d'une fraction hypoallergénique très enrichie en TGF-β2. Enfin, les différents TGF-β2 latents du sérocolostrum bovin ont été mis en évidence par des électrophorèses mono et bidimensionnelles et par des techniques de marquage immunologique. Ces travaux ont également conduit à la mise en évidence d'interactions entre les IgG et les TGF-β2, et à identifier un certain nombre de protéines minoritaires du colostrum.

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40

Breitenbücher, Barbara [Verfasser], Thorsten [Akademischer Betreuer] Bach y Thomas [Akademischer Betreuer] Kiefhaber. "Studien zur Totalsynthese von Bioxalomycin β2 / Barbara Breitenbücher. Gutachter: Thorsten Bach ; Thomas Kiefhaber. Betreuer: Thorsten Bach". München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1054753164/34.

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41

Villard, Vanessa. "Effets anti-amnésiants et neuroprotecteurs de quelques dérivés aminotétrahydrofuraniques, ligands mixtes sigma1/muscariniques, dans un modèle non-transgénique de la maladie d'Alzheimer". Montpellier 2, 2009. http://www.theses.fr/2009MON20243.

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La maladie d'Alzheimer (MA) est une pathologie neurodégénérative pour laquelle, à l'heure actuelle, aucun traitement curatif ne peut être proposé aux patients. Les traitements actuels sont symptomatiques et n'ont qu'un effet ralentisseur modéré sur la progression de la pathologie. Il apparaît ainsi fondamental d'identifier de nouvelles voies de traitement pharmacologique, possédant notamment une activité neuroprotectrice efficace. Les candidats médicaments développés par Anavex Life Sciences présentent une affinité plus ou moins sélective pour le récepteur sigma1 qui est impliqué dans la modulation de multiples voies de signalisation cellulaire. Il est ainsi capable d'induire des effets anti-amnésiants et neuroprotecteurs dans de nombreux modèles pathologiques notamment le modèle non-transgénique de MA reposant sur l'injection centrale de peptide β25-35 amyloïde (Aβ25-35) chez la souris. Nous avons caractérisé les effets anti-amnésiants et neuroprotecteurs de différents composés mixtes sigma1/muscarinique dans ce modèle validé et prédictif de la MA sur les différents paramètres histologiques, moléculaires et comportementaux de la toxicité amyloïde. Nos résultats ont montré que sur les six composés testés, les ANAVEX1-41 et ANAVEX2-73 bloquent l'amnésie induite par l'injection de peptide Aβ25-35 via leur composante sigma1. Ils présentent une activité neuroprotectrice dans ce modèle pathomimétique de la MA en prévenant le stress oxydant, l'inflammation mais aussi la perte cellulaire induits par le peptide Aβ25-35. Ces effets s'accompagnent du blocage de l'apparition des déficits comportementaux. En conclusion, les composés ANAVEX1-41 et ANAVEX2-73 présentent des intérêts évidents dans le traitement de la MA
Alzheimer disease (AD) is a neurodegenerative disorder for which there is no curative treatment. The treatments proposed to patients are purely symptomatic and have only transitory effect on the disease progression. It thus appears essential to identify new ways of pharmacological treatment, with particularly effective neuroprotective activity. The drug candidates developed by Anavex Life Sciences have different affinities for the sigma1 receptor involved in the modulation of multiple cellular pathways. The sigma1 receptor is able to induce antiamnesic and neuroprotective effects in many pathological models including non-transgenic model of AD based on central injection of β25-35 amyloid peptide (Aβ25-35) in mice. Using this validated and predictive AD model, we have characterized the antiamnesic and neuroprotective effects of six mixed sigma1/muscarinic compounds on different amyloid toxicity parameters at the histological, molecular and behavioral levels. Our results showed that ANAVEX1-41 and ANAVEX2-73 compounds block the amnesia induced by injection of peptide Aβ25-35 via their component sigma1. They have a neuroprotective activity in this pathomimetic model of AD by preventing the oxidative stress, inflammation but also the cell loss induced by the peptide Aβ25-35. These effects are accompanied by blocking the onset of behavioral deficits. In conclusion, ANAVEX1-41 and ANAVEX2-73 are promising compounds for treatment of AD

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42

Then, Cornelia. "Die Bedeutung der Tyrosinkinase Syk für die Aktivierung der PI3-Kinase bei der β2-Integrin-abhängigen Leukozytenmigration". Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-86071.

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43

Frunza, A. V. "The role of urinary β2-microglobulin in predicting tubular damage in premature infants of different gestational ages". Thesis, БДМУ, 2022. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/19798.

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44

Ben, Ounis Wassef. "Évaluation du potentiel des interactions protéine-polysaccharide pour l'extraction du TGF-β2 à partir de substrats laitiers". Doctoral thesis, Université Laval, 2010. http://hdl.handle.net/20.500.11794/21397.

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Le TGF-β2 (Transforming Growth Factor-β2) est un facteur de croissance dont les activités biologiques sont nombreuses et que l'on retrouve en concentration relativement élevée dans certains isolats de protéines de lactosérum (IPLs). Bien que plusieurs travaux aient démontré le potentiel nutraceutique d'extraits laitiers enrichis en TGF-β2, peu d'études ont porté sur la concentration du TGF-β2 à partir d'IPLs. Ce projet visait donc à développer de nouvelles approches d'extraction du TGF-β2 à partir d'IPLs en se basant sur la formation de complexes protéine-polysaccharide. La chromatographie d'affinité ayant comme ligand le sulfate d'héparine a été utilisée pour concentrer les facteurs de croissance à partir d'un IPL. Des dosages immunologiques ont démontré que cette approche permettait de concentrer le TGF-β2, l'IGF-I (Insulin-like Growth Factor-I) et la lactoferrine par des facteurs de 10, 23 et 31, respectivement. Une analyse en électrophorèse sur gel 2D a aussi permis de détecter la présence de nombreuses protéines mineures reconnues pour leur bioactivité. La microfiltration a ensuite été étudiée en vue de séparer le TGF-β2 d'un IPL suivant sa complexation avec du carraghénane-[delta]. Pour ces essais, trois pH et deux forces ioniques ont été comparés en mode recirculation. Les résultats ont montré qu'à pH 7, sans l'ajout de sel ou de carraghénane-[delta], la transmission des protéines était de 72%, alors que celle du TGF-β2 était de 26%. Avec cette approche, le TGF-β2 a été concentré par un facteur inférieur à 2. La dernière approche consistait plutôt à complexer les protéines anioniques d'un IPL avec du chitosane, un polysaccharide cationique, puis à séparer les complexes par centrifugation en vue d'obtenir un surnageant enrichi en TGF-β2. Toutefois, la majorité des protéines sont demeurées dans le surnageant en présence du TGF-β2. Dans le culot, le TGF-β2 a été concentré par un facteur de seulement 1,14. Une analyse par SDS-PAGE a révélé que la p-lactoglobuline et le glycomacropeptide semblaient interagir avec le chitosane. Ces résultats supportent l'hypothèse que les interactions protéine-polysaccharide pourraient permettre de produire des fractions enrichies en TGF-β2. Toutefois, les approches et conditions évaluées dans cette étude ont mené à des taux d'enrichissement en TGF-β2 relativement faibles, limittant ainsi leur potentiel de mise à l'échelle industrielle.

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45

Pereira, Carolina Ruivo 1986. "Genomic profile of tumorgrafts identifies B2M as a novel tumor suppressor gene in lung cancer". Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/482055.

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El cáncer de pulmón es la forma más mortal de cáncer en el mundo. Recientemente, el estudio del perfil genómico a larga escala de tumores humanos ha impulsado el desarrollo de drogas que tienen como diana terapéutica genes alterados. Dado que las terapias dirigidas son escasas, el descubrimiento de nuevos genes implicados en cáncer de pulmón con relevancia clínica es crucial. Por eso, este proyecto tuvo como base la secuenciación de exomas y transcriptomas de xenotransplantes de pulmón. La pureza tumoral alcanzada durante el injerto fue fundamental, sobre todo para identificar delecciones homocigóticas y amplificaciones génicas. El gen B2M (β2-microglobulina), encontrado inactivado en 5% de los tumores pulmonares, se caracterizó. Su pérdida genética se correlacionó con bajos niveles de infiltración intratumoral por linfocitos T citotóxicos. Además, la β2-microglobulina se asoció a supervivencia en pacientes tratados con agentes anti-PD1/PD-L1, evidenciando su rol potencial el predecir respuestas a inmunoterapias en neoplasias pulmonares.
Lung cancer is the deadliest form of cancer worldwide. Recently, the large-scale genomic profiling of human tumors has fueled the development of efficient anticancer agents that target the activity of mutated genes. Given that directed therapies are still very scarce, the discovery of novel lung cancer-related genes with potential relevance within the clinical context is imperative. Thus, this project consisted on coupling high-throughput sequencing strategies (exomes and transcriptomes) with the use of lung tumorgrafts. The high tumor purity achieved through the engraftment was crucial, particularly to identify homozygous deletions and gene amplifications. The B2M gene (β2-microglobulin), found to be mutated in 5% of lung tumors, was characterized. Its genetic loss was correlated to lower cytotoxic T-cell intratumoral infiltration, probably impairing the immune-mediated tumor eradication. Moreover, β2-microglobulin was associated with survival in patients treated with anti-PD-1/PD-L1 agents, highlighting a potential role in predicting response to immunologically-based therapies in lung cancer.

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46

Rumzhum, Nowshin Nowaz. "TLR2 Receptor Activation and COX-2 Upregulation in Airway Smooth Muscle Cells: Uncovering the Molecular Mechanisms". Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15194.

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Asthma is a chronic pulmonary diseases characterized by airway inflammation, airway hyperresponsiveness and airway remodelling.The importance of airway smooth muscle cells (ASM) in asthma pathophysiology is well documented. Research has demonstrated that expression of toll like receptor-2 (TLR2) in ASM cells is responsible for the amplification of airway inflammatory responses during infectious exacerbation. Further, under various conditions of stimulation, ASM cells release several inflammatory mediators, including cyclooxygenase-2 (COX-2).In this thesis we aim to investigate the underlying molecular mechanisms of TLR2 receptor activation and upregulation of COX-2 protein levels in ASM cells in the context of airway inflammation induced by exacerbated bacterial infection. We show that activation of TLR2 receptor in ASM cells though didn’t upregulate NLRP3 inflammasome but did upregulate COX-2. β2-agonists are the most commonly used therapy for asthma. Research has revealed that β2-agonists lose bronchodilatory efficacy because the receptor-mediated molecular pathways responsible for their beneficial actions are desensitized by infection.Our studies show that in ASM cells, COX-2 induced by not only TLR2 activation but also by some other inflammatory mediators, is responsible for β2-AR desensitization via producing PGE2. This new knowledge may pave the way for novel pharmacotherapeutic strategies to treat asthma in near future.

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47

Hartmann, Eva [Verfasser]. "Fusionsproteine aus β2-adrenergem [Beta-2-adrenergem] Rezeptor und GFP als pH-sensible Sensoren / eingereicht von Eva Hartmann". Giessen : VVB Laufersweiler, 2006. http://d-nb.info/988662132/34.

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48

Artschwager, Raik. "Basic side chain containing amino acid derived peptido sulfonyl fluorides : an approach to future β2 selective proteasome inhibitors". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8534/.

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Peptido sulfonyl fluorides are a relatively new class of protease inhibitors which have undergone considerable development in recent years. Due to the right balance of reactivity and chemical stability, the sulfonyl fluoride moiety is denoted as a “privileged warhead” in chemical biology nowadays. This thesis describes the development of basic side chain containing amino acid derived sulfonyl fluorides and their incorporation into peptide inhibitor sequences which were unavailable until this point. The resulting peptido sulfonyl fluoride inhibitors (PSFs) are designed to target proteases which require a basic side chain at the P1 position. The synthesis of the sulfonyl fluoride derived from arginine was accomplished applying the standard synthetic route for the introduction of the sulfonyl fluoride warhead previously developed in the LISKAMP group. A slight modification of this synthetic route by masking the former N-terminus with an azido functionality led to the successful synthesis of lysine, 4-amino- and 4-aminomethyl phenylalanine derived sulfonyl fluorides. The challenging incorporation of the sulfonyl fluoride warhead molecules into peptide inhibitor sequences resulted in a library of 14 different PSF inhibitors to target the 20S proteasome trypsin-like site. Structure-activity relationship studies showed that the synthesised PSFs were highly potent (IC50 values ranges from 119 nM - 1.5 µM) and highly selective for the proteasome trypsin-like site (up to ~1000-fold). Furthermore, the results indicated that a free N-terminus in a PSF inhibitor is crucial for selectivity towards the trypsin-like site over the chymotrypsin-like site. Additionally, as an attempt to overcome the limitation of installing the SF moiety only at the C-terminus in an amino acid, cysteine derivatives ontaining the sulfonyl fluoride moiety in the side chain were synthesised, allowing the incorporation of these molecules at any desired position of a peptide sequence. Finally, to further explore the potential of the sulfonyl fluorides and as a proof of concept, a potentially fluorescent probe exhibiting the sulfonyl fluoride was synthesised.

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49

Molphy, John. "The impact of acute and chronic administration of short-acting β2-agonists on urinary pharmacokinetics and athletic performance". Thesis, Liverpool John Moores University, 2015. http://researchonline.ljmu.ac.uk/4330/.

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Exercise Induced Bronchoconstriction (EIB) is common amongst elite athletes. Short-acting β2-agonists represent the first-line treatment of EIB, however; limited data currently exists examining the ergogenic and pharmacokinetic impact of chronic short-acting β2-agonist administration. Furthermore, the ergogenic impact of acute and chronic administration of short-acting β2-agonists in asthmatic individuals is unknown. Whilst the short-acting β2-agonist salbutamol is permitted in and out of competition due to a known pharmacokinetic response, no urinary threshold has been established for the use of the alternative short-acting β2-agonist terbutaline. The purpose of study 1 was to investigate the ergogenic potential of the WADA upper daily limit of 1600 μg·day-1 salbutamol every day for 6 weeks versus placebo, alongside combined resistance and endurance training. Findings highlighted improvements in; 1 repetition maximum (1RM) bench press (Baseline: 65.6 ± 5.4 kg vs. 64.3 ± 4.9 kg – 6 weeks: 70.3 ± 4.9 vs. 72.5 ± 5.4 kg) and leg press (Baseline: 250 ± 26.9 vs. 217.9 ± 19 kg – 6 weeks: 282.5 ± 22.5 vs. 282.8 ± 18.3 kg); vertical jump test (Baseline: 53.5 ± 4.1 vs. 50.4 ± 2.1 cm – 6 weeks: 55 ± 3.5 vs. 52.4 ± 1.7 cm); 3 km running time-trial performance (Baseline: 988.7 ± 68.7 vs. 1040.5 ± 66.3 s – 6 weeks: 947.5 ± 54.9 vs. 1004.3 ± 70.5 s); isokinetic dynamometry (Baseline: 196.1 ± 47.3 vs. 184.6 ± 35.0 n.m. – 6 weeks: 179.5 ± 48.9 vs. 195.2 ± 28.9 n.m.); and body composition (Baseline: 32.1 ± 13.9 vs. 34.9 ± 10.4 mm – 6 weeks: 32.4 ± 14.5 vs. 34.5 ± 10 mm) for both the salbutamol group and the placebo group, respectively, over the 6 week period, with no difference observed between groups, indicating long-term therapeutic use of salbutamol at the WADA upper daily limit has no ergogenic effect. Of note, one participant exceeded the urinary threshold, presenting with an adverse 3 | P a g e analytical finding (AAF) showing that the upper daily limit can lead to AAF’s in susceptible individuals. Athletes who respond poorly to salbutamol treatment are able to apply for the use of the short-acting β2-agonist terbutaline via a therapeutic use exemption (TUE) certificate. Urinary upper limits are unknown for terbutaline and as such it is prohibited at all times without the presentation of a TUE. The purpose of study 2 was to investigate the urinary excretion of terbutaline following single and repeated use of inhaled or oral terbutaline. The aim of the study was to establish a differential distinction between routes of administration which could assist the WADA with regard to anti-doping policy and procedure. Results demonstrated a significant difference in urine concentration of terbutaline between inhaled and oral administration for female Caucasian (670.1 ± 128.3 vs. 361.8 ± 43.8 ng·ml-1; P=0.019; 680.8 ± 91 vs. 369.9 ± 41.9 ng·ml-1; P=0.006), male Afro-Caribbean (343.18 ± 45 vs. 231.3 ± 32.95 ng·ml-1; P=0.044; 389.73 ± 67.4 vs. 212.4 ± 50.3 ng·ml-1; P=0.008) and male Asian (266.4 ± 23.7 vs. 143.3 ± 22 ng·ml-1; P=0.004; 379.5 ± 50.4 vs. 197.5 ± 38.6 ng·ml-1; P=0.000) groups for single (5 mg oral vs. 2 mg inhaled) and repeated (4 x 5 mg oral vs. 8 x 1 mg inhaled) administration trials, respectively. No difference was observed in male Caucasians. High intra- and inter-individual variability between samples meant that a clear distinction between routes of administration could not be established. The study was able to identify an upper urinary threshold following inhaled administration of 1284.3 ng·ml-1 and an upper urinary threshold following oral use of 2376.3 ng·ml-1 which may inform the process of distinguishing between inhaled and oral use. Athletes are permitted to use inhaled terbutaline therapeutically through the TUE process. The purpose of study 3 was to investigate the ergogenic effect of terbutaline at high (2 mg and 4 mg) therapeutic inhaled doses on 3 km running time-trial performance in males and females. The 4 | P a g e study found that inhaled terbutaline, when used at the highest therapeutic dose, has no impact upon 3 km time-trial performance in males (956.3 s vs. 982 s) and females (1249 s vs. 1214.7 s) for placebo vs. 4 mg inhaled terbutaline, respectively. The majority of studies investigating the ergogenic potential of salbutamol have been in healthy individuals. It is not yet understood whether the exercise response differs in asthmatic individuals. The purpose of study 4 was to investigate the use of inhaled salbutamol (400 μg) during a 3 km running time-trial in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals, in a low humidity environment. Results demonstrated increased FEV1 in both groups following salbutamol inhalation, which did not translate to improved performance. No performance differences were found between salbutamol and placebo (Sal: 1012.7 ± 50 vs. 962.1 ± 37.5 s – Pla: 1002.4 ± 46.5 vs. 962 ± 28.8 s) in the EVH+ve group vs. the EVH-ve group, respectively. This thesis is the first to investigate the effects of long-term use of salbutamol at the WADA upper daily limit on exercise performance. It is also the first study to establish upper urinary thresholds for terbutaline use, and the effects of therapeutic inhaled terbutaline on exercise performance. The effect of salbutamol on exercise performance at low humidity in asthmatic individuals has also never previously been investigated. Overall, the findings from this thesis support previous research that inhaled β2-agonist use does not provide any ergogenic potential. With β2-agonists being an essential therapy for the treatment of EIB their current position on the WADA List of Prohibited Substances and Methods is appropriate. Further research is warranted to fully elucidate the upper urinary threshold for terbutaline to inform WADA and support the re-introduction of terbutaline as a therapeutic tool in the treatment of EIB in athletes.

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50

Santu, L. T. "The design, synthesis and characterisation of subtype selective dipeptide-linked fluorescent ligands for human β1 and β2-adrenoceptors". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/40085/.

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Beta-adrenoceptors belong to the superfamily of G-protein coupled receptors (GPCR) and remain an important target for drug discovery. The complexity of GPCR pharmacology in terms of its signaling profile has led to a desire to further the study of receptor-ligand interaction and obtain more detailed information regarding ligand affinity and efficacy. Development of selective fluorescent ligands targeted at human β1 and β2–adrenoceptors may facilitate drug discovery programs in terms of understanding receptor pharmacology and receptor localisation in both recombinant and primary cells from healthy and diseased tissue. Fluorescent ligands are usually designed and synthesized by tethering the ligand to a fluorophore via a linker to form a conjugate. This thesis reports the synthesis of a series of novel dipeptide-linked congeners which, when coupled to commercially available fluorophore active esters (BODIPY-X-630/650 or BODIPY–FL), afford a series of seventeen red- and green-emitting dipeptide-linked fluorescent ligands for human β1 and β2–adrenoceptors. Pharmacological characterization of the dipeptide-linked fluorescent ligands was achieved using the NanoBRET assay, a novel proximity-based assay. The most promising synthesised compounds propranolol-Gly-Ala FL and propranolol-Gly-Ser-FL (both nanomolar range KD), showed a respective 87-fold and 26-fold selectivity for the β2–adrenoceptor versus the β1–adrenoceptor [pKD = 8.59 ± 0.11 and 7.74±0.03 (β2); 6.65±0.09 and 6.32±0.20 (β1)]. Additionally, these compounds were used in a NanoBRET displacement binding experiment as tracer ligands, with known unlabelled compounds (such as CGP20712a, cimaterol, propranolol (hydrochloride) and ICI 118551) and newly-synthesised acetylated ligands at the Nluc β2 AR in order to determine their KD in this system. The displacement binding data agreed with literature values obtained by whole-cell binding assay in both CHO-K1 and Nluc HEK cells. Furthermore, [3H]-CGP 12177 whole-cell binding experiments were conducted in Nluc HEK 293 and CHO-K1 β1 and β2-AR and the results show good correlation with the NanoBRET saturation data and data obtained from another assay, the CRE-SPAP reporter gene assay. In cells expressing β2-AR, confocal microscopy studies revealed specific membrane labelling with selected ligands which was inhibited by propranolol and ICI 118551. These novel ligands have potential as tools for exploring the pharmacology of β–adrenoceptors in native systems where more than one receptor subtype is present in terms of imaging and in providing a replacement for radioligands in binding studies.

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