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1
Mareux, Elodie. "Pharmacothérapie ciblée des déficits en ABCB11." Electronic Thesis or Diss., université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL083.
Повний текст джерелаАнотація:
ABCB11/BSEP (Bile Salt Export Pump) est exprimé à la membrane canaliculaire des hépatocytes. Sa fonction de transport d’acides biliaires dans la bile est essentielle à la sécrétion biliaire. Près de 400 variations du gène ABCB11 ont été identifiées et sont associées à des maladies hépatobiliaires rares, la plus sévère étant la cholestase intrahépatique progressive familiale de type 2 (PFIC2). L’efficacité des traitements médicaux est limitée. Par conséquent, une transplantation hépatique est indiquée avant l’âge adulte pour près de deux tiers des patients. Dans ce contexte, l’identification de thérapies alternatives est un enjeu capital.Cette thèse s’intéresse à la recherche de stratégies thérapeutiques personnalisées permettant de corriger les conséquences pathologiques de certaines variations d’ABCB11 identifiées chez des patients. Dans le cadre d’une stratégie de traitement par des molécules potentiatrices, nous avons étudié les variations A257V, G562D et T463I d’ABCB11 par modélisation moléculaire 3D. L’étude de l’expression et de la fonction de ces variants dans différents modèles cellulaires a confirmé que ces variations étaient responsables d’un défaut de fonction du transporteur Abcb11. L’ivacaftor (VX 770, Kalydeco®), approuvé cliniquement pour le traitement de la mucoviscidose, corrigeait le défaut d’activité de ces trois variants.Des effets similaires ont été observés avec les molécules GLPG1837, SBC040 et SBC219, connues comme potentiateurs de CFTR (Cystic Fibrosis Transmembrane conductance Regulator). Dans une optique de thérapie combinatoire, nous avons également mis en évidence la capacité de ces potentiateurs à corriger le défaut de fonction des variants R1090C et R1090W, produits potentiels de la translecture du variant non-sens R1090X. Nous avons également évalué les molécules correctrices elexacaftor (VX-445) et tezacaftor (VX-661). Ces correcteurs, en monothérapie ou en combinaison, permettaient de restaurer l’adressage du variant R1128C, s’accompagnant d’une augmentation significative du transport de taurocholate. De façon intéressante, l’addition de molécules potentiatrices réduisait ces effets.L’ensemble de ces travaux constitue une preuve de concept que les défauts de certains variants d’ABCB11 peuvent être corrigés par ces molécules potentiatrices à haut potentiel thérapeutique. Ce type de traitements pourrait être envisagé pour les patients atteints de déficit en ABCB11 et permettrait ainsi d’augmenter la pharmacopée disponible pour traiter ce genre de pathologies et ainsi repousser voir palier à la transplantation hépatique pour les cas les plus sévèresABCB11/BSEP (Bile Salt Export Pump) is expressed at the canalicular membrane of hepatocytes. It ensures bile acids secretion into bile which is essential for biliary secretion. Nearly 400 variations of the ABCB11 gene have been identified and are associated with rare hepatobiliary diseases, the most severe being progressive familial intrahepatic cholestasis type 2 (PFIC2). The effectiveness of medical treatments is limited. Consequently, liver transplantation is required before adulthood for almost 2/3 of PFIC2 patients. In this context, the identification of alternative therapies is a major challenge.This thesis focuses on personalized therapeutic strategies to correct the pathological consequences of some ABCB11 variations identified in patients. The A257V, G562D and T463I variations of ABCB11 were studied by 3D molecular modelling. These variations were responsible for a defect in Abcb11 transport function. Ivacaftor (VX-770, Kalydeco®), a clinically approved cystic fibrosis treatment, corrects the activity defect of the three variants.Similar effects were observed with GLPG1837, SBC040 and SBC219, known as potentiators of CFTR (Cystic Fibrosis Transmembrane Conductance Regulator).From a combinatory therapy perspective, we also demonstrated the ability of these potentiators to correct the transport defect of the R1090C and R1090W variants, potential readthrough products of the R1090X nonsense variant. We also evaluated the ability of Elexacaftor (VX-445) and Tezacaftor (VX 661) correctors of CFTR. These correctors, alone or in combination, restored trafficking of the R1128C missense variant, leading to a significant increase in the transport function. Interestingly, the addition of potentiators abolishes this effect.Altogether, this thesis constitutes a proof of concept that molecules with high therapeutic potential can correct the molecular defects of ABCB11 variants. These treatments could increase the pharmacopoeia available for patients with ABCB11 deficiency and thus delay or even suppress the need for liver transplantation
2
Hanoteau, Aurélie. "Chemotherapy potentiates immune responses against murine tumors." Doctoral thesis, Universite Libre de Bruxelles, 2016. https://dipot.ulb.ac.be/dspace/bitstream/2013/231745/5/Thesis.pdf.
Повний текст джерелаАнотація:
There is increasing evidence that the effect of chemotherapy on tumor rejection is not cell autonomous but relies on the immune system. Indeed, several reports have shown that human and murine tumors respond to chemotherapeutic agents more efficiently when the host immune system is intact. In particular, we have shown that cyclophosphamide treatment of DBA/2 mice bearing P815 mastocytoma induces rejection and long term protection in a CD4- and CD8-dependent manner. We used this tumor model, as it is poorly immunogenic, expresses tumor-associated P1A and tumor-specific P1E antigens, encoded by germline and mutated genes, respectively, and allows the identification of some tumor-specific CD8+ T cells.We have previously reported that tumor regression correlates with selective infiltration of CD8+ T cells specific for P1E/H-2Kd antigen in tumor bed upon cyclophosphamide treatment. Unexpectedly, the proportion of CD8+ T cells specific for the tumor-associated antigen P1A in the context of H-2Ld decreases concomitantly, indicating that cyclophosphamide alters the repertoire of CD8+ T cells recognizing tumor antigens. Using P1A KO mice, we found that preferential activation of CD8+ T cells to P1E is not solely due to thymic negative selection. The major role of “mutated” antigens in tumor resistance has been recently highlighted in humans and raises an interesting question about the immune mechanisms of tumor rejection. Additionally to its effect on the specific immune response, cyclophosphamide promotes tumor infiltration by effector memory (P1E/H-2Kd)+ CD8+ T cells which are characterized by higher expression of KLRG1 and Eomes. Our data point to a role of IL-15 and type 1 IFNs for their development, as increased levels of IL-15 and IRF7 were measured in tumor after cyclophosphamide. IFNAR1 blockade interferes with the tumor rejection in 50% of mice and decreases the (P1E/H-2Kd)+ CD8+ T cell infiltration induced by cyclophosphamide, suggesting a role of this cytokine in the expansion and/or recruitment of (P1E/H-2Kd)+ CD8+ T cells in vivo.Altogether, our results suggest that type 1 IFNs and IL-15 induced after cyclophosphamide promote the reprogramming of CD8+ T cells specific for the “mutated” P1E/H-2Kd antigen into effector memory lymphocytes.Option Biologie moléculaire du Doctorat en Sciences
info:eu-repo/semantics/nonPublished
3
Khalil, Dayekh. "Novel Combination Therapy: Monensin Potentiates Erlotinib-Induced Cytotoxicity." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24405.
Повний текст джерелаАнотація:
Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced
in the past decade as a promising therapeutic option in Head and Neck Squamous Cell
Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result,
RTK inhibitors require a combination based therapeutic approach with other treatment
modalities. To uncover such a combination of agents, we performed a high throughput
Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC
cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the
cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of
Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous
protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis
suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol
biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.
4
Lortie, Karine. "The growth-arrest-specific protein gas7 potentiates neuronal differentiation." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/26701.
Повний текст джерелаАнотація:
The growth-arrest-specific gas7 protein is involved in neuronal development. Its role in neuronal differentiation and its potential neuroprotective activity were investigated in PC 12 and NT2 cells. gas7 overexpression in PC12 cells promoted neurite outgrowth and potentiated nerve growth factor-induced expression of the neuronal markers betaIII-tubulin, synaptotagmin, alpha7 subunit of the acethylcholine receptor, and dihydropyrimidinase related protein-3. This effect was exerted independently of cellular proliferation, as gas7 did not affect cell cycle progression. Endogenous gas7 expression was induced during neuronal differentiation of NT2 cells with retinoic acid, suggesting a role for gas7 in neuronal development. Finally, gas7 overexpression in PC 12 cells did not protect against toxicity triggered by oxygen-glucose deprivation, the calcium ionophore A23187 or sodium nitroprusside. The ability of gas7 to potentiate neuritogenesis and neuronal differentiation makes it a potential therapeutic target to promote re-establishment of neuronal connections in the injured or diseased brain, such as following stroke.
5
Ho, Wing-tak, and 何永德. "Glycyrrhizic acid potentiates dsRNA-induced nitric oxide generation inalveolar macrophages." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31971799.
Повний текст джерела
6
Ho, Wing-tak. "Glycyrrhizic acid potentiates dsRNA-induced nitric oxide generation in alveolar macrophages." Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31971799.
Повний текст джерела
7
Nakamura, Takanori. "Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity." Kyoto University, 2011. http://hdl.handle.net/2433/142112.
Повний текст джерела
8
Liang, Xiaoting, and 梁小婷. "Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208584.
Повний текст джерелаАнотація:
Mesenchymal stem cell (MSC) transplantation has achieved only modest success in the treatment of ischemic heart disease due to poor cell viability in the diseased microenvironment. Genetic manipulation on the MSCs holds promising prospects in enhancing cell tolerance against adverse environmental conditions.
Recent studies demonstrate that the activation of the NRG1 (neuregulin 1) - ERBB4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) pathway can enhance pro-survival signaling, stimulate mature cardiomyocyte cell cycle re-entry and cell division. In this study, I aimed to determine whether activating NRG1-ERBB4 in MSCs can enhance their cardioprotective effects following myocardial infarction.
In chapter 3, I determined that MSC endogenously expresses NRG1, but not ERBB4. Considering the absence of ERBB4 in the MSCs might lead to mute response to its ligand NRG1, I exogenously manipulated ERBB4 into MSCs.
In chapter 4, MSCs, with or without ERBB4 overexpression were transplanted into mice following myocardial infarction. The transplantation of MSCs with ERBB4 expression considerably improved left ventricular ejection fraction and reduced infarctsize, compared to unmodified MSCs and direct NRG1 injection. ERBB4 overexpression induced greater MSC survival following infarction. The transduction of ERBB4 in MSCs increased cell mobility and apoptotic resistance via a PI3K/Akt pathway under hypoxic conditions in the presence of NRG1. The transplantation of MSCs with ERBB4 expression induced cardiomyocyte division and protected them against apoptosis during early phase of infarction.
In chapter 5, a novel autocrine loop regarding to NRG1-ERBB4-NRG1 signaling was identified. MSCs with ERBB4 overexpression in turn increased NRG1 synthesis and secretion. Conditioned medium of ERBB4-expressing MSCs containing elevated NRG1, promoted cardiomyocyte growth, division and anti-senescence, whereas neutralization of NRG1 blunted these effects. Injecting ERBB4-expressing MSCs restored NRG1 in the infarcted myocardium to a level comparable with that of the normal myocardium.
These findings collectively suggest overexpressing ERBB4 in MSCs enhances the effectiveness of MSCtherapy following myocardial in farction through potentiating MSC survival and revitalizing endogenous repair and regeneration. The combination of ERBB4 and MSC is more efficient than naïve MSC or solely recombinant NRG1 injection, emerging as potential target for developing novel strategy in treating myocardial diseases.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
9
Taylor, Marlon D., and Marlon D. Taylor. "Sulforaphane Potentiates Non-Melanoma Skin Cancer in UVB-Treated Nrf2 Knockout Mice." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/622859.
Повний текст джерелаАнотація:
Sulforaphane is a natural product found in cruciferous vegetables which is known to have many chemopreventive properties including the induction of apoptosis and the inhibition of inflammation, cellular proliferation, and reactive oxygen species (ROS) formation. The reduction of ROS activity by sulforaphane is likely linked to the activation of NF-E2 related factor-2 (Nrf2), a transcription factor involved in cytoprotection against ROS and electrophilic stress. The skin is particularly vulnerable to oxidative stress caused by ultraviolet (UV) light, which is an established complete carcinogen. Sulforaphane has been shown to reduce both chemical and UVB-induced skin carcinogenesis in mouse models. Suppression of DMBA/TPA-induced skin tumorigenesis by sulforaphane has been shown to be dependent upon Nrf2 activity. Additional studies have shown that genetic activation of Nrf2 can protect keratinocytes against UVB-induced ROS. Nrf2 has also been implicated in regulating inflammatory responses after UVB exposure in the skin. However, the role of Nrf2 in the antitumorigenic activity of sulforaphane in the context of UVB-induced skin tumors is not well understood. We therefore performed murine experiments in order to clarify whether sulforaphane requires Nrf2 in order to block UVB-induced non-melanoma skin cancer. Consistent with the literature, we observed that wildtype (WT) mice topically treated with sulforaphane were less susceptible to UVB-induced tumor incidence and tumor burden compared to the vehicle control WT group. However, Nrf2 KO mice treated with sulforaphane presented with significantly greater UVB-induced tumor incidence and burden compared to the WT sulforaphane group, suggesting that sulforaphane may potentiate tumorigenesis in the context of UVB exposure if Nrf2 is absent. We therefore performed acute in vivo and in vitro experiments using topical sulforaphane (as per the tumor experiment) to investigate why Nrf2 KO mice developed more tumors than WT mice during UVB and sulforaphane treatment. Topical treatment of SKH-1 mice with sulforaphane did result in slight reduction of UV-induced epidermal hyperplasia in wildtype mice which was not present in Nrf2 KO mice (trends were not significant). Surprisingly, while wildtype mice developed significantly more epidermal inflammation in our acute treatment model than did the Nrf2 KO strain (as measured by skin fold thickness), inflammation was not significantly influenced by topical sulforaphane treatment in either strain of mice. However, cell culture studies using primary mouse keratinocytes indicate that sulforaphane’s ability to block UVB-induced ROS is lost in Nrf2 KO cells. Taken together, our ROS data may strengthen the hypothesis that sulforaphane increases the oxidative stress of cells during UVB treatment in the absence of Nrf2.
10
Scarpa, Richard C. "Neurotensin potentiates the proliferative effects of growth factors in human embryonic lung fibroblasts /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2004.
Знайти повний текст джерелаАнотація:
Thesis (Ph.D.)--Tufts University, 2004.Adviser: David E. Cochrane. Submitted to the Dept. of Biology. Includes bibliographical references (leaves 137-165). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
11
Vono, Maria. "The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423482.
Повний текст джерелаАнотація:
Vaccines are the most effective agents to control infections [1]. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance the specific immune responses. Despite their effectiveness and their wide use, the mechanism of action of many adjuvants is poorly characterized [2]. Therefore, adjuvant research is crucial to better understand how they work and to exploit their full potential in vaccinology [3]. Release of endogenous danger signals has been linked to adjuvanticity, however the role of extracellular ATP during vaccination has never been explored. Extracellular ATP can work as "danger signal" and, as such is a strong modulator of immune responses [4-6]. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminium hydroxide, calcium phosphate (CaPi), incomplete Freund’s adjuvant (IFA) and the squalene-based oil in water emulsion MF59.
Experiments were performed ex vivo in excised mice muscles (tibialis anterior and quadriceps) and in vivo in live mice injected with the reporter system luciferase-luciferin that reports on ATP changes. We found that intramuscular injection in general is always associated to a weak transient release of ATP. In contrast, a greatly enhanced ATP release was found upon injection of MF59 but not by all other adjuvants tested.
Therefore, we wanted to dissect whether and how ATP release would contribute to the activity of MF59. The strong adjuvanticity of MF59 [7-8] has been ascribed to its capability to induce an immunocompetent environment in the muscle, characterized by a rapid and transient influx of a large number of immune cells participating in antigen uptake and transport to draining lymph nodes [9-11]. We found that the local injection of apyrase, an ATP-hydrolyzing enzyme, reduced the immune cells recruitment induced by MF59 but not by alum or IFA. These findings indicated that the ability of MF59 to induce migration of different immune cells into the injected muscle is partly due to induced ATP release. Moreover, co-injection of apyrase and MF59 at the muscle injection site reduces the number of antigen positive cells in the draining lymph nodes in a cell type-specific manner. Indeed, co-injection of apyrase negatively impacts the number of antigen positive B cells induced by MF59, suggesting that B cells could be a key component in ATP-mediated signaling during vaccination. Strong innate immune responses lead to enhanced adaptive immune responses [12]. Accordingly, we compared the impact of MF59-induced ATP release on T cells responses and antibody titers. Groups of mice were immunized with an experimental trivalent influenza vaccine (TIV) either as plain antigens or together with MF59 with or without apyrase. Apyrase strongly inhibited influenza specific T cell responses, total IgG and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link for the first time extracellular ATP to an enhanced response to vaccination.I vaccini rappresentano senza dubbio l’arma più efficace per combattere e tenere sotto controllo le infezioni [1]. In aggiunta agli antigeni del patogeno, i vaccini contengono adiuvanti utilizzati per potenziare le risposte immunitarie specifiche verso determinati antigeni. Nonostante la loro efficacia e il loro largo uso, il meccanismo di azione di molti adiuvanti è ancora scarsamente caratterizzato [2]. Pertanto, far luce sui meccanismi d’azione degli adiuvanti vaccinali è fondamentale per sviluppare prodotti nuovi, più efficienti e sicuri, e poter così sfruttare appieno il potenziale della vaccinologia [3]. Dopo la vaccinazione, è stato osservato al sito di iniezione il rilascio locale di molecole endogene con la capacità di segnalare “danno” al sistema immunitario, note come allarmine. Per esempio, un rilascio locale di acido urico e DNA è stato osservato nel modello murino dopo vaccinazione con alum, il più diffuso tra gli adiuvanti approvati per uso sull’uomo. Tuttavia, finora non è mai stato esplorato un potenziale ruolo dell’ATP durante la vaccinazione. L’ATP, tra le sue tante funzioni, quando rilasciato nell’ambiente extracellulare in concentrazioni opportune può fungere da allarmina e, come tale è un forte modulatore delle risposte immunitarie [4-6]. Pertanto, in questo lavoro abbiamo indagato se un rilascio di ATP è coinvolto nel meccanismo d’azione di quattro comuni adiuvanti vaccinali: idrossido di alluminio (alum), calcio fosfato (CaPi), adiuvante incompleto di Freund (IFA) e MF59. Sono stati condotti esperimenti ex vivo su muscoli murini isolati (tibiale anteriore e quadricipite) e in vivo in topi immunizzati intramuscolo con l’adiuvante da testare e il sistema reporter luciferina-luciferasi in grado di segnalare il livello di ATP al sito d’iniezione. Abbiamo osservato che l'iniezione intramuscolare è sempre associata a un debole e transitorio rilascio di ATP. Il rilascio basale di ATP è notevolmente potenziato dall’iniezione di MF59 ma non dagli altri adiuvanti testati. Pertanto, abbiamo esplorato se e come il rapido e transitorio rilascio di ATP indotto da MF59 al sito d’iniezione potesse contribuire al suo meccanismo d’azione. Il forte potere adiuvante di MF59 [7, 8] è stato attribuito alla sua capacità di istituire un ambiente immunocompetente al sito di iniezione nel muscolo, caratterizzato da un rapido e transitorio afflusso di un gran numero di cellule immunitarie che captano e assorbono l’antigene e lo trasportano ai linfonodi drenanti [9-11]. Abbiamo qui dimostrato, che la co-iniezione di apirasi, un enzima in grado di idrolizzare l’ATP, riduce fortemente l’afflusso di cellule immunitarie indotto da MF59 ma non quello indotto da alum o IFA. Questi risultati indicano che l’abilità di MF59 di indurre un forte afflusso di cellule immunitarie al sito di iniezione è in parte dovuta alla sua intrinseca capacità di rilasciare ATP. Inoltre, abbiamo osservato che la co-iniezione di apirasi e MF59 riduce il numero di cellule antigene-positive che dal muscolo raggiungono i linfonodi drenanti. Tale riduzione si è rivelata tipo cellulare-specifica, infatti il trattamento con apirasi impatta negativamente il numero di cellule B antigene-positive indotto da MF59 nei linfonodi drenanti, suggerendo che le cellule B potrebbero essere un elemento chiave nei “pathways” mediati da ATP durante la vaccinazione. Efficienti risposte immunitarie di tipo innato si traducono spesso in forti risposte adattative [12]. Pertanto, abbiamo analizzato un eventuale ruolo dell’ATP rilasciato da MF59 sull’attivazione delle cellule T e la produzione di titoli anticorpali antigene-specifici. Di conseguenza, gruppi di topi sono stati immunizzati con un vaccino influenzale trivalente, iniettato come tale o adiuvato con MF59 con o senza apirasi. L’apirasi ha fortemente ridotto la proliferazione delle cellule T vaccino-specifiche e i relativi titoli anticorpali. Questi dati dimostrano che un locale e transitorio rilascio di ATP a livello del sito d’iniezione è necessario per lo sviluppo di risposte immunitarie innate e adattative indotte da MF59 e associano per la prima volta un rilascio extracellulare di ATP a un potenziamento delle risposte immunitarie indotte dalla vaccinazione.
12
Bechtel, Cale. "Back squat potentiates both vertical and horizontal jump performance in collegiate ice hockey players." Thesis, California State University, Long Beach, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10638622.
Повний текст джерелаАнотація:
Back squats (BSQ) have been shown to effectively potentiate lower body power in a subsequent performance activity. There is a plurality of post activation potentiation (PAP) studies in which the BSQ and vertical jump (VJ) are used. To date, there is little information regarding BSQ and horizontal jump (HJ) performance. Nine collegiate ice hockey players from the California State University, Long Beach ice hockey team volunteered for the study. Participants performed five testing sessions separated by 96 hours. The first testing session was a one repetition maximum (1RM) BSQ to assign the athletes specific intensity. The intensity chosen was 87% of the athletes’ 1RM, which means they should complete five repetitions (87%) for the potentiated testing sessions. The four testing sessions were randomized consisting of a back squat followed by horizontal jump (BSQ-HJ), back squat followed by vertical jump (BSQ-VJ), horizontal jump only (CT-HJ) and vertical jump only (CT-VJ). During the potentiated conditions participants had a rest interval of 5 minutes between the BSQ and VJ or HJ. Alpha-level was set a priori at 0.05. The results indicate that both vertical (p = 0.017) and horizontal (p = 0.003) jump were significantly increased (VJ = +5.51cm, HJ = +11.55cm). The present study helps indicate that muscular power performance can be improved in VJ and HJ using the PAP training phenomenon in collegiate ice hockey players.
13
Miller, Laurence L. "A competitive NMDA receptor antagonist potentiates the effects of morphine on spatial and discrimination learning /." Electronic version (PDF), 2005. http://dl.uncw.edu/etd/2005/millerl/laurencemiller.pdf.
Повний текст джерела
14
Kuk, Raafat. "Lestaurtinib (CEP-701) Potentiates the Anticonvulsant Effect of Phenobarbital against Kainic Acid-induced Status Epilepticus." Thesis, The University of Arizona, 2018. http://hdl.handle.net/10150/626859.
Повний текст джерела
15
Chan, Hoi-ching, and 陳凱靜. "Heat shock protein 90 inhibitor 17-AAG potentiates anticancer activityof bortezomib in NK cell malignancies." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632025.
Повний текст джерела
16
Zhang, Wei. "LOSS OF MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 (MRP1/ABCC1) POTENTIATES DOXORUBICIN-INDUCED CARDIOTOXICITY IN MICE." UKnowledge, 2015. http://uknowledge.uky.edu/toxicology_etds/12.
Повний текст джерелаАнотація:
Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown.
The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and their C57BL (WT) littermates. Chronic DOX caused body weight loss and hemotoxicity, and these adverse effects were significantly exacerbated in Mrp1-/- vs WT mice. Importantly, loss of Mrp1 potentiated DOX-induced cardiotoxicity, presenting as worsened cardiac function and more cellular apoptosis in DOX treated Mrp1-/- mice. Mrp1 also protected neonatal mouse cardiomyocytes (CM) and cardiac fibroblasts (CF) culture against DOX cytotoxicity in vitro. This was demonstrated by the decreased cell survival, more apoptosis and more DNA damage in DOX treated Mrp1-/- vs WT cells.
In addition, the effects of deletion of Mrp1 was studied on glutathione (GSH)/glutathione disulfide (GSSG) homeostasis, glutathione conjugate of 4-hydroxy-2-nonenal (GS-HNE) accumulation, protein oxidative damage and expression of antioxidant enzymes. Loss of Mrp1 led to significantly higher GSH and GSSG basal levels in heart. Following DOX treatment, Mrp1-/- CM and CF showed increased GSH and GSSG levels vs WT cells. Meanwhile, DOX increased expression of the GSH synthesis enzymes in Mrp1-/- but not WT cells. Thus, increased GSH synthesis may contribute to the further increase in the GSH pool in DOX-treated Mrp1-/- cells. DOX induced comparable increases of GS-HNE concentration in WT and Mrp1-/- mice hearts. Finally, expression of extracellular superoxide dismutase (ECSOD/SOD3) was significantly lower in Mrp1-/- vs. WT CM treated with either saline or DOX.
In summary, this study is the first to document a protective role of Mrp1 in DOX-induced cardiotoxicity. It gives critical information regarding the potential adverse sequelae of introduction of MRP1 inhibitors as adjuncts to clinical chemotherapy of multidrug resistant tumors.
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Kahya, Hasan Faisal Hussein. "Removal of acetylation by pneumococcal esterases potentiates neuraminidase activity for mucin utilisation, colonisation and virulence." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/38750.
Повний текст джерелаАнотація:
The genome of pneumococcal strains contains 4 putative esterase genes (SPD_0534, estA; SPD_0932; SPD_1239; and SPD_1506, axe). Esterases have been reported to be important for bacterial physiology and virulence in other microorganisms but their role in S. pneumoniae is unknown. We hypothesised that esterases potentiate neuraminidase activity by removing acetylation in sialic acid. This hypothesis was tested using isogenic mutants and recombinant esterases in microbiological, biochemical and In vivo assays. The results showed that pneumococcal esterases are specific for short acyl chains, all gene contributed to overall esterase activity but SPD_0534 (EstA) was found to be responsible for main esterase activity. Both Axe and EstA could use acetylated xylan and Bovine Sub-maxillary Mucin (BSM), a highly acetylated substrate, but only EstA was active against tributyrin (triglyceride). Incubation of BSM with either Axe or EstA led to the acetate release in a time and concentration dependent manner, and pretreatment of BSM with either EstA or Axe increased sialic acid release by subsequent exposure to neuraminidase. qRT-PCR results showed that the expression level of estA and axe increased when exposed to BSM and in respiratory tissues. Mutation of either estA alone or in combination with nanA (codes for neuraminidase A), or the replacement of serine 121 to alanine in EstA, reduced the pneumococcal ability to utilise BSM as sole carbon source, sialic acid (Sia) release, colonisation and virulence in a mouse model of pneumococcal infection.
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Knoch, Megan E. "Short Term Exposure to Light Potentiates Phase Shifting to Nonphotic Stimuli in the Syrian Hamster." Kent State University / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=kent1117224927.
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Arendt, Kristina Anna Maria [Verfasser], and Rudolf [Akademischer Betreuer] Hatz. "An in vivo inflammatory loop potentiates KRAS blockade / Kristina Anna Maria Arendt ; Betreuer: Rudolf Hatz." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1213658829/34.
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Rowe, R. K., G. I. Ellis, J. L. Harrison, A. D. Bachstetter, G. F. Corder, Eldik L. J. Van, B. K. Taylor, F. Marti, and J. Lifshitz. "Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge." SAGE Publications, 2016. http://hdl.handle.net/10150/614986.
Повний текст джерелаАнотація:
Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
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Hassanieh, Sarah. "CO-ADMINISTRATION OF SILDENAFIL POTENTIATES DOXORUBICIN-INDUCED APOPTOSIS IN PROSTATE CANCER: THE ROLE OF NF-kappaB." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1655.
Повний текст джерелаАнотація:
Our recent studies have shown that that erectile dysfunction (ED) drugs including Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis) enhance killing of several types of cancer cells by anticancer drug, Doxorubicin (DOX). We observed increased cell death by apoptosis in response to the combined treatment with ED drugs and DOX. However, the mechanism of such enhancement of cell death by combined treatment of ED drugs and DOX is not fully understood. Nuclear factor-κB (NF-κB) is an oxidant-sensitive transcription factor that plays a critical role in the immediate-early activation of a multitude of genes that have been documented to play critical role in programmed cell death (apoptosis). NF-κB activation has been shown to block apoptosis and its inhibition improves existing anti-oncogenic therapy such as chemotherapy. In the present study, we tested the hypothesis whether combined treatment of prostate cancer cells, PC3, with Sildenafil plus DOX would attenuate the activation of NFκB by inhibiting translocation of the p65 and p50 subunits to the nucleus and by phosphorylation of cytosolic IκB In addition, we investigated the effect of DOX and DOX plus Sildenafil on the expression of BCL family of proteins which play critical role in apoptosis. We treated PC3 cells with 1.5 μM DOX with or without 10 µM Sildenafil for 6 hours and 72 hours. The nuclear translocation of p65 and p50 and expression of BCL family of proteins was determined by western blot analysis. Our results show that combined treatment of DOX and Sildenafil significantly reduced the nuclear translocation of p65 and p50 as compared with DOX alone (P < 0.05). This correlated with the significant reduction in the expression of Bcl-2, BclxL and phosphorylation of BAD. These data provide an important mechanism by which Sildenafil treatment augments the apoptotic potential of DOX in PC3 cancer cells.
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Leipert, Jenny, Franziska Kässner, Susanne Schuster, Norman Händel, Antje Körner, Wieland Kiess, and Antje Garten. "Resveratrol Potentiates Growth Inhibitory Effects of Rapamycin in PTEN-deficient Lipoma Cells by Suppressing p70S6 Kinase Activity." Taylor & Francis, 2016. https://ul.qucosa.de/id/qucosa%3A38595.
Повний текст джерелаАнотація:
Patients with phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome and germline mutations in PTEN frequently develop lipomatosis, for which there is no standard treatment. Rapamycin was shown to reduce the growth of lipoma cells with heterozygous PTEN deficiency in vitro, but concomitantly induced an upregulation of AKT phosphorylation. Since it was shown that resveratrol stabilizes PTEN, we asked whether co-incubation with resveratrol could suppress the rapamycin-induced AKT phosphorylation in PTEN-deficient lipoma cells.
Resveratrol incubation resulted in decreased lipoma cell viability by inducing G1-phase cell cycle arrest and apoptosis. PTEN expression and AKT phosphorylation were not significantly changed, whereas p70S6 kinase (p70S6K) phosphorylation was reduced in PTEN-deficient lipoma cells after resveratrol incubation. Rapamycin/resveratrol co-incubation significantly decreased viability further at lower doses of resveratrol and resulted in decreased p70S6K phosphorylation compared to rapamycin incubation alone, suggesting that resveratrol potentiated the growth inhibitory effects of rapamycin by reducing p70S6K activation. Both viability and p70S6K phosphorylation of primary PTEN wild-type preadipocytes were less affected compared to PTEN-deficient lipoma cells by equimolar concentrations of resveratrol. These results support the concept of combining chemopreventive natural compounds with mammalian target of rapamycin (mTOR) inhibitors to increase the efficacy of chemotherapeutic drugs for patients suffering from overgrowth syndromes.
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Mandrusiak, Lisa. "Transglutaminase potentiates proteasome dysfunction induced by polyglutamine-expanded androgen receptor : a potential pathogenic mechanism for spinobulbar muscular atrophy." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=79042.
Повний текст джерелаАнотація:
Research into CAG-triplet repeat expansion mutations responsible for human neurodegenerative disease is a rapidly expanding genetic field. The CAG repeat (encoding glutamine) expansion is thought to confer a novel, toxic gain of function to the protein that resulting in neuron-specific cell death. The mechanism of cytotoxicity in these diseases is unknown, but often centers on the shared pathological characteristic of protein aggregate formation. Recently, the calcium-dependent enzyme transglutaminase has been implicated in aggregate formation in several of these disorders. Cellular processes such as proteolysis, calcium homeostasis, gene transcription, and mitochondrial function are likely affected by polyglutamine-expanded proteins and contribute to pathogenesis.Expansion of the CAG repeat in the androgen receptor leads to the X-linked disorder spinobulbar muscular atrophy. To examine underlying disease mechanisms we investigated the link between polyglutamine-expanded androgen receptor and transglutaminase. We found N-terminal androgen receptor fragments to be a substrate for transglutaminase, and cells expressing polyglutamine-expanded androgen receptor exhibited ligand-depended proteasome dysfunction. This effect was prevented by the presence of cystamine, a transglutaminase inhibitor, suggesting involvement of a transglutaminase-catalyzed reaction in disease pathogenesis and providing a potential basis for the development of therapies for CAG-repeat expansion disorders.
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Pascal, Maud. "Innate Lymphoid Cells under Neuronal Control in the Small Intestine : vasoactive Intestinal Peptide potentiates ILC2 and ILC3 functions." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS318.
Повний текст джерелаАнотація:
L’intestin est une vaste surface de l’organisme constamment exposée aux substances ingérées et aux nombreux micro-organismes qui colonisent sa muqueuse. Afin d’assurer le maintien de son intégrité, plusieurs dispositifs de reconnaissance et de défense impliquent cellules immunitaires et neurones, faisant de lui un organe de choix pour l’étude des interactions neuroimmunes. La compréhension des éléments assurant un fonctionnement coordonné des Systèmes immunitaire (SI) et Nerveux (SN) dans l’intestin reste cependant partielle. Ce travail a porté sur l’étude des mécanismes régissant le fonctionnement intégré des SN et SI de l’intestin suite à une prise alimentaire. Nous démontrons que la libération de Peptide Intestinal Vasoactif (VIP) suite à une prise alimentaire impacte la fonction de cellules clés dans l’organisation de l’immunité intestinale, les cellules lymphoïde innées (ILC). Pour la première fois, on démontre qu’un neuropeptide modifie de manière anticipée la biologie des ILC2 et des ILC3 pour potentialiser l’effet de cytokines inductrices caractéristiques des immunités de type 2 ou de type 3, permettant une activation rapide et conséquente des ILC. Ce travail complexifie le réseau de régulation du fonctionnement des ILC et dévoile un nouveau rôle du VIP dans le maintien de l’homéostasie intestinale via sa capacité à anticiper et potentialiser les réponses immune de manière intégrée. La compréhension de ce nouveau mécanisme d’interactions neuroimmunes dans l’intestin ouvre la voie vers le développement de nouvelles stratégies thérapeutiques basées sur les propriétés du VIP pour prévenir et traiter des maladies infectieuses et inflammatoires de l’intestinThe intestine represents an extremely wide interface constantly exposed to substances that we ingest and to numerous micro-organisms that colonize its mucosae. Several mechanisms of recognition and defense involving both immune cells and neurons exist to ensure protection of the gut, setting the gut as a paradigm for neuroimmune interactions. However, how the nervous and immune systems coordinate and synchronize their action in the gut remain unclear. In this thesis, I aimed to elucidate the mechanisms underlying one type of neuroimmune communication occurring in the gut, during a physiological process: feeding. In this context, I demonstrated that the food-induced release of the Vasoactive Intestinal Peptide (VIP) impacts the function of the recently discovered “gatekeepers” of the gut immune system, Innate Lymphoid Cells (ILCs). For the first time, I showed that a neuropeptide induces an anticipatory priming of both ILC2 and ILC3, which could potentiate the effect of the canonical type 2 and type 3 inducer cytokines to lead a rapid and strong activation of ILCs. This work provides new insights in the highly complex regulatory network of ILCs and uncovers a new role for VIP in maintaining gut homeostasis through its ability to prime and eventually boost immune responses in an integrated and context dependent manner. The understanding of the neuroimmune interplay involving VIP in the small intestine opens the path toward the development of new therapeutic strategies based on VIP properties to treat infectious and inflammatory diseases of the gastrointestinal tract
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Yaseen, Alae Abod. "THE NATURAL POLYPHENOL RESVERATROL POTENTIATES THE LETHALITY OF HDAC INHIBITORS IN ACUTE MYELOGENOUS LEUKEMIA CELLS THROUGH MULTIPLE MECHANISMS." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/2519.
Повний текст джерелаАнотація:
This study examined the mechanisms underlying the interactions between the natural polyphenol Resveratrol and HDAC inhibitors in both U937 myelomonocytic leukemia cell line and blood samples from AML patients and normal cord blood. Simultaneous exposure to Resveratrol and HDAC inhibitors (Vorinostat-SAHA or Panobinostat-LBH589) resulted in potentiating the lethality caused by any single agent of the combination, this interaction found to be synergistic at multiple concentrations. Exposing U937 cells to minimal toxic doses of Resveratrol and HDACIs results in release of mitochondrial pro-apoptotic proteins AIF and cytochrome c, pro-apoptotic caspase activation especially caspase-8, and induction of DNA damage. These events were associated with increase deacetylation of NF-κB and reactive oxygen species generation, as well as G0-G1 cell cycle arrest. Genetic knockdown of SIRT1 (a deacetylator of NF-κB that is upregulated by Resveratrol) resulted in significant increase in NF-κB acetylation and activity. However, SIRT1 knock down failed to protect U937 cells against combination-induced cell death, implying the possibility of the involvement of other mechanisms in inducing cell death rather than NF-κB deactivation only. Co-incubation of the antioxidant vi MnTBAP significantly reduced Resveratrol/HDACIs induced cell death, and resulted in a marked decrease in caspase-8, caspase-3, and PARP activation. Finally, the combined treatment of Resveratrol/HDACIs induce cell cycle changes possibly through Resveratrol action of blocking cell cycle in S phase exposing more cells to HDACIs lethality. Collectively, these finding indicate that the combined regimen of Resveratrol and HDAC inhibitors promote lethality in U937 cells and primary AML cells by a variety of mechanisms. The approved use of both agents in clinical setting make future clinical studies for development of this drug regimen a potential option in the battle with leukemia.
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Shulak, Laura. "Vorinostat potentiates vesicular stomatitis virus oncolysis in prostate cancer cells by modulating autophagy in an NF-kB dependent manner." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121210.
Повний текст джерелаАнотація:
Vesicular stomatitis virus (VSV) replication and oncolytic potential is reversibly stimulated in combination with epigenetic modulators such as the histone deacetylase inhibitor (HDI) Vorinostat (SAHA). Based on this reversible effect of Vorinostat on viral oncolysis, we reasoned that critical host genes involved in oncolysis may be reversibly regulated in prostate cancer PC3 cells following removal of Vorinostat. A transcriptome analysis in PC3 cells identified a subset of NF- κB target genes that were reversibly regulated by Vorinostat and involved in regulation of inflammatory and stress-responses. Consistent with the induction of NF- κB target genes, Vorinostat-mediated enhancement of VSV oncolysis correlated with hyper-acetylation of the NF- κB transcription factor subunit RELA/p65; furthermore, VSV replication and cell killing were suppressed when NF- κB signaling was inhibited using pharmacological or genetic approaches. Additional bioinformatics analysis revealed that stimulation of NF- κB signaling also resulted in the increased expression of several autophagy-related genes. Inhibition of autophagy by 3-methyladenine led to an increase in expression of IFNβ-stimulated genes, and both 3-methyladenine treatment and genetic ablation of autophagy led to a decrease in VSV replication and oncolysis. Together, these data demonstrate that Vorinostat stimulates NF- κB activity in a reversible manner via modulation of RelA/p65 signaling, leading to induction of autophagy and enhancement of VSV replication and oncolysis. These studies thus positively correlate NF- κB signaling and autophagy with VSV replication and oncolysis.La réplication et l'activité oncolytique du virus de la stomatite vésiculaire (VSV) sont stimulées d'une manière réversible lorsque le VSV est combiné avec des modulateurs épigénétiques tels que le vorinostat (SAHA), un inhibiteur de l'histone déacétylase (IDH). En se basant sur cette observation, nous avons émis l'hypothèse que les gènes importants de l'hôte impliqués dans l'oncolyse peuvent-être eux aussi réversiblement régules dans les cellules du cancer de la prostate PC3 après le retrait du vorinostat. En effet, une analyse du transcriptome des cellules PC3 a identifié un set de gènes impliqués dans la voie NF-κB, plus précisément dans la réponse inflammatoire et aux réponses au stress, qui est régulé par le vorinostat. Conformément à l'induction des gènes cibles de la voie NF-κB, l'amélioration de l'effet oncolytique du VSV par le vorinostat corrèle avec une hyper-acétylation du NF-κB RELA/p65; En outre, la réplication du VSV et la mort des cellules ont été supprimées lorsque la voie signalétique NF-κB a été inhibée par des approches pharmacologiques et géniques. Nous avons également observé que l'expression de plusieurs gènes impliqués dans l'autophagie a été augmentée par la stimulation de la voie NF-κB. De plus, une analyse supplémentaire bioinformatique a révélé que l'expression de plusieurs gènes impliqués dans l'autophagie était également augmentée par la stimulation de NF-κB. En addition, l'inhibition de l'autophagie par le 3-méthyladénine a entrainé une amplification de l'expression des gènes stimulés par l'IFN-β. En outre, le traitement avec le 3-méthyladénine et l'inhibition génique de l'autophagie a résulté en une diminution de la réplication du VSV et de l'oncolyse. Ensemble, ces résultats démontrent que le vorinostat stimule l'activité du NF-κB de manière réversible via la modulation de RelA/p65, conduisant à l'induction de l'autophagie et à l'amélioration de la réplication du VSV et l'oncolyse. Ainsi, cette étude met en évidence le lien entre l'activation de l'axe NF-kB- autophagie et la réplication du VSV et son effet oncolytique.
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Braun, Floriane Claudia Maria [Verfasser]. "In vivo silencing of A20 via TLR9-mediated targeted siRNA delivery potentiates anti-tumor immune response / Floriane Claudia Maria Braun." Greifswald : Universitätsbibliothek Greifswald, 2016. http://d-nb.info/1088766536/34.
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Huang, Yu Hong. "Sustained release of prostaglandin E1 potentiates the impaired therapeutic angiogenesis by basic fibroblast growth factor in diabetic murine hindlimb ischemia." Kyoto University, 2009. http://hdl.handle.net/2433/126420.
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Usui, Ryota. "GPR40 activation initiates store-operated Ca²⁺ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells". Kyoto University, 2020. http://hdl.handle.net/2433/253196.
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King, Steven Bradley. "Chronic Stress Potentiates The Response To Intra-Bed Nucleus Of The Stria Terminalis (bnst) Pituitary Adenylate Cyclase Activating Peptide (pacap) Infusion." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/461.
Повний текст джерелаАнотація:
Chronic or repeated exposure to stressful stimuli can result in several maladaptive consequences, including increased anxiety-like behaviors and altered peptide expression in brain structures involved in emotion. Among these structures, the bed nucleus of the stria terminalis (BNST) has been implicated in emotional behaviors as well as regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. In rodents, chronic variate stress (CVS) has been shown to increase BNST pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate PAC1 receptor transcript, and BNST PACAP signaling may mediate the maladaptive changes associated with chronic stress. In order to determine whether chronic stress would potentiate the behavioral and/or endocrine response to subthreshold BNST PACAP infusion, rats were exposed to a 7 day CVS paradigm previously shown to upregulate BNST PAC1 receptor transcripts; control rats were not stressed. Twenty-four hours following the last stressor, stressed and control rats were bilaterally infused into the BNST with 0.5 µg PACAP. Startle response to intra-BNST PACAP infusion was assessed post-infusion in Experiment 1. In Experiments 2 and 3, blood was sampled via a tail nick 30 min following PACAP infusion to assess the corticosterone response to PACAP following CVS. We found an increase in startle amplitude and an increase in plasma corticosterone levels 30 minutes following BNST PACAP infusion only in rats that had been previously exposed to CVS. These results were likely mediated via PAC1 receptors, as equimolar infusion of the VPAC1/2 receptor ligand vasoactive intestinal polypeptide (VIP) had no effect on plasma corticosterone levels. These results suggest that repeated exposure to stressors sensitizes the neural circuits underlying the behavioral and endocrine responses to BNST PACAP infusion and BNST PACAP/PAC1 receptor signaling likely plays a critical role in mediating stress responses.
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Youssefian, Leena. "THE SMALL MOLECULE BCL-2 INHIBITOR HA14-1 POTENTIATES THE LETHALITY OF A REGIMEN COMBINING MEK1/2 AND CHK1 INHIBITORS IN MULTIPLE MYELOMA CELLS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1799.
Повний текст джерелаАнотація:
Previously, we have found that the co-administration of MEK1/2 inhibitors and Chk1 inhibitors synergistically induce multiple myeloma cell apoptosis through upregulation of the BH3-only pro-apoptotic protein Bim. However, these apoptotic events were largely blocked by the characteristic over-expression of Bcl-2 of Bcl-xL in multiple myeloma cells. HA14-1, a small molecule Bcl-2 inhibitor, may therefore circumvent this resistance to apoptosis by blocking Bcl-2 and Bcl-xL anti-apoptotic protein actions. In our project, we hypothesize that the co-administration of HA14-1 with MEK/Chk1 inhibitors will enhance apoptosis in multiple myeloma (MM) cells. To test this hypothesis, we exposed MM cells U266 and RPMI8226, or those cells with Bcl-2 over-expressing stable clones to minimally toxic concentrations of MEK1/2 inhibitor (PD184352) with Chk1 inhibitor (CEP3891) for 24 hours, followed by the Bcl-2 inhibitor (HA14-1). To date, our data indicates that co-administration of HA14-1 with the PD184352/CEP3891 regimen significantly enhances apoptotic death in U266/Bcl-2 multiple myeloma cells compared with the PD184352/CEP3891 regimen. Future studies are designed to elucidate mechanisms underlying Bcl-2 and Bcl-xL anti-apoptotic protein interactions with the Bak and Bim apoptotic proteins, focusing release of Bak and Bim from Bcl-2/Bcl-xL, and subsequent Bax/Bak activation.
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Leuillier, Matthieu. "Rôle de l'activité phosphatase de l'époxyde hydrolase soluble dans la régulation de l'homéostasie métabolique et cardiovasculaire. In vivo inactivation of the phosphatase activity of soluble epoxide hydrolase potentiates brown adispose thermogenesis and protects against cardiovascular damage and remodeling Discovery of the first in vivo active inhibitors of the soluble epoxide hydrolase phosphatase domain Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR150.
Повний текст джерелаАнотація:
Près de 40 ans après sa découverte initiale en 1972, il a été montré en 2003 que l'époxyde hydrolase soluble (sEH), codée par le gène EPHX2, est une protéine bifonctionnelle qui présente non seulement une activité époxyde hydrolase au niveau de sa partie C-terminale mais également une activité lipidophosphatase sur son domaine N-terminal. En effet, au niveau de sa partie C-terminale, l’activité hydrolase métabolise des époxydes d'acides gras polyinsaturés. Notamment, elle transforme les acides époxyeicosatriénoïques, facteurs vasodilatateurs et anti-inflammatoires biologiquement actifs générés par les cytochromes P450, en acides dihydroxyeicosatriénoïques qui sont des composés biologiquement moins actifs. Cette activité, est aujourd’hui la cible d’une nouvelle classe pharmacologique d’inhibiteurs. Contrairement à la fonction biologique de l’activité hydrolase, celle de l’activité phosphatase de la sEH reste, à ce jour, peu connue. Bien qu’à l’origine, il ait été montré que cette activité participait à la stabilisation de l’activité hydrolase ou à la dimérisation de l’enzyme, certaines données récentes révèlent que l’activité phosphatase de la sEH métabolise d'autres médiateurs lipidiques importants, comme les acides lysophosphatidiques intracellulaires, qui sont impliqués dans un large éventail de fonctions biologiques telles que le tonus vasculaire et l'inflammation, en monoacylglycérols. De plus, des études in vitro ont également suggéré que les deux activités de la sEH possèdent un rôle complémentaire dans la régulation du taux de cholestérol ainsi que dans l’homéostasie vasculaire. Même si les souris recombinantes qui n'expriment pas le gène EPHX2 existent depuis un certain temps, elles ne permettent pas d'étudier spécifiquement l’activité phosphatase car les deux activités de l’enzyme sont éliminées. Toutefois, des études portant sur les différences entre les effets de la délétion génétique de la sEH et ceux de l'inhibition pharmacologique de son activité hydrolase indiquent que l'activité phosphatase de la sEH possède probablement un rôle physiologique. Dans notre étude, afin de pouvoir étudier le rôle de l’activité phosphatase de la sEH et en raison de l’absence d’inhibiteur de cette activité utilisable in vivo, des rats transgéniques originaux exprimant une sEH sans activité phosphatase ont été générés grâce à la méthode CRISPR/Cas9. Un phénotypage métabolique et cardiovasculaire approfondi a été effectué sur ces animaux. Les résultats de cette étude ont mis en évidence que les rat Knock-In (KI) pour la sEH phosphatase présentent une diminution de leur poids corporel et de leur masse grasse comparativement à des rats sauvages du même âge. De plus, leur sensibilité à l’insuline est augmentée. Ce profil métabolique bénéfique est expliqué d’une part par une diminution de la consommation alimentaire et, d’autre part, par une augmentation de l'oxydation des graisses, potentialisant la thermogenèse dans le tissu adipeux brun, et de la dépense énergétique. Par ailleurs, lorsque les rats KI sont nourris avec un régime riche en graisses saturées, la prise de poids reste inférieure à celle des rats sauvages. De plus, ils ne développent pas d’insulino-résistance ou de stéatose hépatique. D’autre part, au niveau cardiaque, les rats KI présentent une activité mitochondriale basale plus élevée associée à une contractilité ventriculaire gauche accrue. Par ailleurs, les animaux KI sont protégés contre les lésions cardiaques d’ischémie-reperfusion et contre le développement de l'hypertension artérielle pulmonaire. Notre étude révèle ainsi que l’activité phosphatase de la sEH est un acteur clé du métabolisme lipidique et énergétique contribuant ainsi, comme l’activité hydrolase, à la régulation de l'homéostasie cardiométaboliqueNearly 40 years after its initial discovery in 1972, soluble epoxide hydrolase (sEH), encoded by the EPHX2 gene, was shown in 2003 to be a bifunctional protein that exhibits not only an epoxide hydrolase activity on its C-terminal domain but also a lipid phosphatase activity on its N-terminal domain. Indeed, the hydrolase activity metabolizes epoxides of polyunsaturated fatty acids. In particular, sEH converts the vasodilator and anti-inflammatory epoxyeicosatrienoic acids converts, generated by cytochromes P450, into dihydroxyeicosatrienoic acids, which are less biologically active. This activity is now the target of a new class of pharmacologicla inhibitors. Unlike the biological function of the hydrolase activity, the biological function of sEH phosphatase activity remains, this time, unknown. Although shown originally to contribute to the stabilization of hydrolase activity or dimerization of the protein, some recent data indicate that the sEH phosphatase metabolizes also important lipid mediators, such as intracellular lysophosphatidic acids, involved in a wide range of biological functions such as vascular tone and inflammation, into monoacylglycerols. In addition, in vitro studies also suggested that the two activities of sEH have a complementary role in cholesterol regulation and vascular homeostasis. Although recombinant mice that do not express the EPHX2 gene have been around for some time, they do not allow to specifically study the phosphatase activity because both activities are eliminated. However, studies examining the differences between the effects of the genetic deletion of sEH and those of the pharmacological inhibition of its hydrolase activity indicate that the phosphatase activity of sEH probably has also a distinct physiological role. In our study, to assess the role of sEH phosphatase activity in absence of an inhibitor of this activity usable in vivo, original transgenic rats expressing sEH without phosphatase activity were generated using the CRISPR/Cas9 method. A thorough metabolic and cardiovascular phenotyping was performed on these animals. The results of this study showed that Knock-In (KI) rats for the sEH phosphatase have a decrease in body weight and fat mass compared to wild type rats of the same age. In addition, their sensitivity to insulin is increased. This beneficial metabolic profile is explained on one hand by a decrease in food consumption and, on the other hand, by an increase in fat oxidation, potentiating thermogenesis in brown adipose tissue enhancing energy expenditure. In addition, when KI rats were fed a high fat diet, weight gain remains lower than that of the wild type rats. In addition, they do not develop insulin resistance or hepatic steatosis. Finally, at the cardiac level, KI rats have higher basal mitochondrial activity associated with increased left ventricular contractility. In addition, KI animals are protected against cardiac ischemia-reperfusion lesions and the development of pulmonary arterial hypertension. Our study thus reveals that the phosphatase activity of sEH is a key player in lipid and energy metabolism, thus contributing, like the sEH hydrolase activity, to the regulation of cardiometabolic homeostasis
33
Longpré-Lauzon, Ariane. "Étude moléculaire des mécanismes d’action de potentiateurs du canal CFTR sur le canal KCa3.1." Thèse, 2009. http://hdl.handle.net/1866/4054.
Повний текст джерелаАнотація:
Les cellules épithéliales des voies aériennes respiratoires sécrètent du
Cl- via le canal CFTR. La fibrose kystique est une maladie génétique fatale
causée par des mutations de ce canal. La mutation la plus fréquente en
Amérique du Nord, ∆F508, met en péril la maturation de la protéine et affecte
les mécanismes d’activation du canal. Au cours des dernières années,
plusieurs molécules ont été identifiées par criblage à haut débit qui peuvent
rétablir l’activation de protéines CFTR mutées. Ces molécules sont nommées
potentiateurs. Les canaux K+ basolatéraux, dont KCa3.1, jouent un rôle bien
documenté dans l’établissement d’une force électromotrice favorable à la
sécrétion de Cl- par CFTR dans les cellules épithéliales des voies aériennes
respiratoires. Il a par exemple été démontré que l’application de 1-EBIO, un
activateur de KCa3.1, sur des monocouches T84 résulte en une augmentation
soutenue de la sécrétion de Cl- et que cette augmentation était réversible suite
à l’application de CTX, un inhibiteur de KCa3.1(Devor et al., 1996). Dans le
cadre d’une recherche de potentiateurs efficaces en conditions physiologiques
et dans un contexte global de transport trans-cellulaire, il devient essentiel de
considérer les effets des potentiateurs de CFTR sur KCa3.1. Une
caractérisation électrophysiologique par la méthode du patch clamp et
structurelle via l’utilisation de canaux modifiés par mutagenèse dirigée de
différents potentiateurs de CFTR sur KCa3.1 fut donc entreprise afin de
déterminer l’action de ces molécules sur l’activité de KCa3.1 et d’en établir les
mécanismes.
Nous présentons ici des résultats portant sur les effets sur KCa3.1 de
quelques potentiateurs de CFTR possédant différentes structures. Un criblage
des effets de ces molécules sur KCa3.1 a révélé que la genisteine, le SF-03,
la curcumine et le VRT-532 ont des effets inhibiteurs sur KCa3.1. Nos résultats
suggèrent que le SF-03 pourrait agir sur une protéine accessoire et avoir un
effet indirect sur KCa3.1. La curcumine aurait aussi une action inhibitrice
indirecte, probablement via la membrane cellulaire. Nos recherches sur les
effets du VRT-532 ont montré que l’accessibilité au site d’action de cette
v
molécule est indépendante de l’état d’ouverture de KCa3.1. L’absence d’effets
inhibiteurs de VRT-532 sur le mutant constitutivement actif V282G indique que
cette molécule pourrait agir via l’interaction CaM-KCa3.1 et nécessiter la
présence de Ca2+ pour agir. Par ailleurs, un autre potentiateur de CFTR, le
CBIQ, a des effets potentiateurs sur KCa3.1. Nos résultats en canal unitaire
indiquent qu’il déstabilise un état fermé du canal. Nos travaux montrent aussi
que CBIQ augmente la probabilité d’ouverture de KCa3.1 en conditions
sursaturantes de Ca2+, ainsi que son affinité apparente pour le Ca2+. Des
expériences où CBIQ est appliqué en présence ou en absence de Ca2+ ont
indiqué que l’accessibilité à son site d’action est indépendante de l’état
d’ouverture de KCa3.1, mais que la présence de Ca2+ est nécessaire à son
action. Ces résultats sont compatibles avec une action de CBIQ déstabilisant
un état fermé du canal. Finalement, des expériences en Ba2+ nous ont permis
d’investiguer la région du filtre de sélectivité de KCa3.1 lors de l’action de CBIQ
et nos résultats pointent vers une action de CBIQ dans cette région. Sur la
base de nos résultats nous concluons que CBIQ, un potentiateur de CFTR,
aurait un effet activateur sur KCa3.1 via la déstabilisation d’un état fermé du
canal à travers une action sur sa ‘gate’ au niveau du filtre de sélectivité. De
plus, les potentiateurs de CFTR ayant montré des effets inhibiteurs sur KCa3.1
pourraient agir via la membrane ou via une protéine accessoire du canal ou sur
l’interaction CaM-KCa3.1.
Dans l’optique de traitements potentiels de la fibrose kystique, nos
résultats indiquent que le CBIQ pourrait être un potentiateur efficace pusiqu’il
est capable de trimuler à la fois KCa3.1 et CFTR. Par contre, dans les cas du
VRT-532 et du SF-03, une inhibition de KCa3.1 pourraient en faire des
potentiateurs moins efficaces.Airway epithelial cells are the site of Cl- secretion through CFTR. Cystic fibrosis is a fatal genetic disease caused by mutations in CFTR. The most frequent mutation in North America (∆F508) results in impaired maturation and altered channel gating of the protein. In the last years, several small molecules were identified by high throughput screening that could restore mutated CFTR function. Compounds addressing CFTR gating defects are referred to as potentiators. The basolateral K+ channel KCa3.1 has been documented to play a prominent role in establishing a suitable driving force for CFTR-mediated Clsecretion in airway epithelial cells. It has been shown, for example, that the application of 1-EBIO on T84 monolayers results in a sustained increase of Clsecretion and that this current can be reversed by application of CTX, a KCa3.1 inhibitor (Devor et al., 1996). Thus, in a global approach of transepithelial transport, the research for physiologically relevant CFTR potentiators should also consider their effects on the KCa3.1 channel. Electrophysiological patch clamp measurements and channel structural modification by site directed mutagenesis were used to characterize the action of CFTR potentiators on KCa3.1 and study their molecular mode of action. In this work we present results on the effects on KCa3.1 of several CFTR potentiators of different structures. We observed that the CFTR potentiators genistein, curcumin, SF-03 and VRT-532 could inhibit KCa3.1 activity at concentrations known to activate CFTR. Our results suggest that SF- 03 could act indirectly on KCa3.1 through a mechanism involving an accessory protein. Curcumin would also have an indirect inhibitory effect, probably mediated by the plasma membrane, as documented for other ion channels. A detailed study of VRT-532 revealed that this molecule has access to its binding site in a state independent manner, and is poorly effective on the V282G mutant of KCa3.1, which is constitutively active. These results suggest that VRT-532 could act through the CaM/KCa3.1 complex and require the presence of Ca2+ to inhibit channel activity. In contrast, CBIQ, another CFTR potentiator, succeeded to activate KCa3.1. Our results in single channel show that CBIQ vii destabilizes a non conducting state of the channel. We also showed that this molecule increases the apparent Ca2+ affinity as well as the channel open probability, even in saturating Ca2+ conditions. Experiences in which Ba2+ was used as a probe were also performed to determine if the action mechanism of CBIQ involves an effect on the selectivity filter. Our results showed that Ba2+ could displace CBIQ from its interacting site, suggesting that the increases in channel activity induced by CBIQ could result from a change in the energetics of the channel at the level of the selectivity filter. On the basis of our results, we conclude that CBIQ, a CFTR potentiator, could activate KCa3.1 by destabilizing a non conducting state of the channel, probably through an action near the selectivity filter region. Also, CFTR potentiators having an inhibitory effect on KCa3.1 are likely to act through the plasmic membrane, the CaM/KCa3.1 interaction or an accessory protein of the channel. In a perspective of future treatments for CF, our results indicate that CBIQ could be an efficient potentiator since this product stimulates KCa3.1 as well as CFTR. Conversly, the VRT-532 and SF-03 could be less efficient than on CFTR alone, due to their inhibition of KCa3.1.
34
wang and 王秀勻. "Rapamycin potentiates cAMP-induced differentiation in NG108-15 cells." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/69739597164108939347.
Повний текст джерелаАнотація:
碩士國防醫學院
生物化學研究所
97
NG108-15 cell line fused from N18TG-2 and C6-BU-1 is a good model for investgating neuronal development and differentiation. We found that cell proliferation would be inhibited by treating DMEM with only 1% serum. It has been already known that inhibiting cell proliferation and elevating concentration of cytosolic cyclic adenosine 3',5'-monophosphate (cAMP) would let NG108-15 cell differentiation through activating transcription factor, cAMP response element binding protein (CREB). There are three features when NG108-15 cell differentiate. (1) Neurite outgrowth and Formation of varicosity. (2) Activity of voltage sensitive calcium channel, VSCC, elevates. (3) Neuronal marker protein, Microtubule Associated Protein 2 (MAP2), formate. Rapamycin is an inhibitor of Mammalian Target of Rapamycin Complex 1 (mTORC1). mTOR is a protein kinase that control cell cycle from G1 to S phase, promote proliferation and inhibit autophagy. Therefore, rapamycin would arrest cell cycle in G0/G1 and promote autophagy. We found that treating dibutyryl cAMP (dbcAMP) and rapamycin at the same time would promote NG108-15 cell differentiation earlier than only treating dbcAMP. It would have higher neurite and varicosity number, VSCC activity and MAP2 content. Silencing mTOR would mimic the effect of rapamycin in NG108-15 cells. Furthermore, potentiating differentiation caused by cotreating dbcAMP and rapamycin would be inhibited by adding autophagic inhibitor or silencing Beclin1. Rapamycin could also induce differentiation in NG108-15 cells. Rapamycin would not change phosphorylatic level of ERK and CREB. Besides, dbcAMP would not induce autophagy. In sum, differentiation of NG108-15 cells would be potentiated through inducing autophagy by treating rapamycin or silencing mTOR.
35
Tsao, Chang-Chi, and 曹昌麒. "Bamboo mosaic potexvirus satellite RNA encoded P20 potentiates satellite RNA movement." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/47118094066401263582.
Повний текст джерелаАнотація:
碩士國立中興大學
農業生物科技學研究所
89
A satellite RNA of 836 nt depends on the bamboo mosaic potexvirus (BaMV) for its replication and encapsidation. The BaMV satellite RNA (satBaMV) contains a single open reading frame encoding a 20-kDa nonstructural protein (P20). The N-terminal arginine-rich motif of P20 is the RNA binding domain, which preferentially kinds at the 5’ and 3’ untranslated regions of satBaMV RNA. When the P20 open reading frame was replaced with sequence encoding chloramphenicol acetyltransferase (CAT), the accumulation level of BSCAT in systemic leaves of infected plants was only about 1/40-1/100 of that in inoculated leaves. Even though P20 is not required for satBaMV replication, the N-terminal or internal mutations of P20 caused a 21-50% decrease in the level of satBaMV accumulation in inoculated protoplasts when compared with the wild-type satBaMV. These results indicate that P20 may assist satBaMV replication, movement, or other functions. In this study, transgenic Nicotiana benthamiana plants that express the P20 were produced to investigate the effects of P20 on satBaMV movement. Complementary DNA of satBaMV that contains nt 59 to 836 was cloned in a plant expression vector, plasmid pKyLx7, and transformed to N. benthamiana by Agrobacterium-mediated transformation. R0 transformants selected were based on kanamycin resistance and verified by the PCR, Southern blot, Northern blot, and Western blot analyses. The ratio of kanamycin resistance in the F1 progenies was 3:1 which followed the Mendelian law. Transgenic lines which have homozygous satellite cDNA genotype were selected after analysis of F2 progenies. We have selected seedlings which have homozygous satellite cDNA genotype. The homozygous transgenic lines were challenged with BaMV and the virus titers were analyzed by indirect ELISA and western blots. The results showed that virus concentration in the transgenic lines was similar with the untransformed plants and the P20 level was not amplified by BaMV infection. Coinoculation of pCB and pCBSCAT onto untransformed plants, the BSCAT could move cell-to-cell in the inoculated leaves but failed to spread systemically. However, BSCAT could be detected in 16.6~80% of the upper uninoculated leaves of P20 transgenic plants 10 or 15 days after inoculation. Thses results indicat that the P20 transgenic plants can trans-complement the systemic movement of BSCAT. The ability that BSCAT spread from inoculated leaves to non-inoculation leaves was dependent upon the P20 protein in the transgenic plants. These results conclusively demonstrate that the P20 protein of satBaMV potentiates the movement of the satellite RNA.
36
Hsieh, Tsung-Hsiu. "Deltamethrin, a Pyrethroid Insecticide, Potentiates Lipid Accumulation in 3T3-L1 Adipocytes." 2016. https://scholarworks.umass.edu/masters_theses_2/359.
Повний текст джерелаАнотація:
Obesity is a growing concern in the world today. As we ponder about the many causes of this global epidemic, we are driven to look at our food and the environmental toxicants that may contribute to obesity. Deltamethrin, being a common synthetic pyrethroid used in agriculture for pest control, is the primary insecticide this study explores to connect with obesity in 3T3-L1 adipocytes. To investigate the relationship between deltamethrin and adipogenesis, various concentrations were tested, 1nM, 10nM, 100nM, 1μM, and 10μM. The result indicated that higher concentration of deltamethrin had a direct impact on fat accumulation. These experiment results indicate that deltamethrin may potentiate adipogenesis in this model. Further in vivo studies will be needed to validate these findings and confirm the effects of deltamethrin on obesity.
37
Mahmood, Hanan S. "Elucidating the Molecular Pathway through which L-Lactate potentiates NMDAR Signaling." Diss., 2019. http://hdl.handle.net/10754/660266.
Повний текст джерелаАнотація:
The role of L-Lactate has expanded from an energy metabolite to a signaling molecule in
neurons. Studies have shown that L-Lactate plays a role in neuroprotection and in
NMDAR-dependent long-term memory formation. The aim of this dissertation is to
characterize the role of L-Lactate as a signaling molecule and understand the molecular mechanism through which L-Lactate potentiates NMDAR signal. Using mass spectrometry, I monitored the time-dependent changes in the phosphoproteome of cortical neuronal cultures in response to Lactate. The phosphoproteomic analysis highlighted a number of cytoskeletal proteins involved in synapse remodeling as well as axon guidance that were regulated by L-Lactate. In addition, I found that L-Lactate
induced phosphorylation of proteins involved in the MAPK pathway, as reported in an earlier study. I hypothesize the involvement of CaMKII in this mechanism. CaMKII is one of the most abundant kinases in the brain and plays a role in learning and memory via interaction with NMDAR. Using CaMKII inhibitors and mutants of the NMDAR subunit GluN2B, the findings in this dissertation provide evidence for the involvement of CaMKII, specifically, the interaction between CaMKIIa and GluN2B, as a requirement for the L-Lactate mediated potentiation of NMDAR signal.
In addition, to gain insight into the evolution of lactate from a metabolite to a signaling
molecule, this study explores the evolution of glutamate as a signaling molecule in
multicellular organisms so it may serve as a model for evolution of metabolites like
lactate into signaling molecules. For this purpose, the model organism Hydra was used, since it belongs to phylum Cnidaria, evolutionarily one of the first phyla to have a
nervous system. In order to explore whether glutamate receptors, particularly, NMDAR
are functionally expressed in Hydra and are localized in neurons, a line of transgenic
Hydra expressing a calcium indicator (GCaMP6s) in neurons was generated. With the transgenic Hydra line, I attempted to measure the in vivo response of neurons in Hydra to glutamate. This study highlights several ground work experiments with an extensive discussion of implications and challenges and an outlook for future investigations.
38
Tu, Yu-Chen, and 涂榆晨. "Demethoxycurcumin nanocrystallite-chitosan nanocarrier potentiates cisplatin-induced apoptosis in non-small cell lung cancer." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/t8u587.
Повний текст джерела
39
Chia-Wei, Chu, and 朱嘉偉. "Propofol potentiates external ATP-activated cation currents in differentiated NG108-15 cells : a novel mechanism." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/95205236880162111394.
Повний текст джерелаАнотація:
碩士國防醫學院
藥理學研究所
86
ATP, a co-transmitter with catecholamines, can modulate nociceptive and non-no ciceptive functions of sensory neurons. Both increase in cytoplasmic Ca2+ and activation of a non-selective cation current (I(ATP)) by external ATP have been shown in various cells. Although propofol exerts its anesthetic action via GABA-A Cl- current, it may also interact with other neurotransmitters. In this paper, we demonstrated that propofol can interact with I(ATP) in Neuroblastoma-Glioma 108-15 hybrid cells. METHODS: Neuroblastoma-Glioma 108-15 hybrid cells were cultured. Transmembrane ionic currents were recorded using whole-cell patch clamp technique. Steady-state currents were registered with slow ramp voltage protocol, ranging from -100 mV to +100 mV at either hyperpolarizing or depolarizing direction. Pipette solution contained (in mM) : K-aspartate 130, MgATP 5, EGTA 5, Hepes 5, titrated to pH 7.2. Bath solution contained: NaCl 137, MgCl2 0.5, CaCl2 1.8, KCl 4, Hepes 10, glucose 5, titrated to pH 7.4. Drugs were applied into superfusate. RESULTS: External ATP (10 uM to 4 mM) activated a non-selective cation current. Propofol (5.6 to 560 uM), but not Intralipid, potentiated I(ATP) in a dose-dependent manner. Propofol (560 uM) potentiated Inward current induced by 0.5 mM ATP by 285.5 ± 127.9% (n = 17, p < 0.05). Inward currents induced by A1 agonists (adenosine) and various P2 agonists (AMP, ADP, GTP) could also be potentiated by propofol in different extent. The poten tiation action could be attenuated by P2 antagonists cibacron blue (30 uM), basilen blue (30 uM), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid tetrasodium (PPADS, 30 uM), but not by antagonist-- suramin (30 uM). Propofol did not show potentiation of I(ATP) when it was applied from cytoplasmic side. When I(ATP) was desensitized during exposure of high dose of ATP, propofol did not display any potentiation. Neither ketamine (1 mM) nor midazolam (0.1 mM) affected I(ATP). CONCLUSIONS: 1) Propofol suppressed voltage-dependent K+ outward current but potentiated ATP-activated non-selective cation current in NG108-15 cells. 2) The potentiation effects of propofol could be mimicked by variousnucleotides and attenuated by P2 antagonists.
40
Mongroo, Perry Satesh. "The adapter protein ParvB inhibits ILK oncogenic signaling and potentiates PPARG1 activation in breast cancer cells." 2007. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=479028&T=F.
Повний текст джерела
41
Wei, Chang Shih, and 張士偉. "Rosuvastatin Potentiates Vascular Function And Restores Blood Flow In The Arteriovenous Fistula Of Rats With Streptozotocin-Induced Diabetes." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/a2y5s5.
Повний текст джерелаАнотація:
碩士嘉南藥理大學
生物科技系
103
Blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in vascular endothelium and attenuate inflammatory responses. This study investigates the pathogenesis of AV fistula failure in subjects with diabetes mellitus, and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. Diabetes mellitus (DM) was induced in rats by a single injection of streptozotocin. Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. One week induction of diabetes, a fistula was created in descending aorta and the adjacent IVC (AC fistula). Blood flow in the aortic and venous segments of fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined using the flow cytometry. Vascular function of AC fistula was assessed by isometric force testing. The expression of pro-inflammatory genes and generation of superoxide anions in the fistula were examined. Number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased numbers of circulating EPC. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated following treatment with rosuvastatin. Rosuvastatin also attenuated the expression of iNOS and NADPH oxidase, generation of superoxide anions and proinflammatory cytokines (TNF-, IL-1 and IL-6) in the fistula tissues isolated from diabetic rats. We provide the first evidence demonstrating that rosovastatin improves blood flow and endothelial function of AC fistula in rats with diabetes mellitus by attenuating the activity of pro-inflammatory genes and generation of superoxide anions in the remodeled vasculature. These experimental findings serve as fundamental supportive evidences for conducting clinical testing of the protective effect of HMG-CoA reductase inhibitor (statins) in establishing a durable vascular access for hemodialysis in diabetic patients.
42
Chu, Chih-Sheng, and 朱志生. "Electronegative Low Density Lipoprotein Potentiates Vascular Endothelial Cell Toxicity via L5/LOX-1/CRP Cyclic Mechanism on Atherogenesis." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/45921231487731181797.
Повний текст джерелаАнотація:
博士高雄醫學大學
醫學研究所
102
OBJECTIVES Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. The series changes of TNF-a, the upstream mediator of CRP, and of nitrotyrosine were both examined in pre-diabetes patients for the association with coronary atherosclerosis. METHODS AND RESULTS Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5] = L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine. In 75g OGTT test, post-challenge changes of both TNF-a and nitrotyrosine in pre-diabetes were significantly increased in those with CAD. CONCLUSIONS Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5. Post-challenge changes of TNF-a and nitrotyrosine were both shown to be associated with the presence of coronary atherosclerosis in patients with pre-diabetes.
43
Huang, Shih-Huan, and 黃詩歡. "Demethoxycurcumin potentiates Cisplatin─induced apoptosis through down─regulation of ERCC1-related pathways in non-small cell lung cancer." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/wt3e7b.
Повний текст джерелаАнотація:
碩士中國醫藥大學
藥學系碩士班
102
Demethoxycurcumin (DMC) , a phenolic compound obtained from rhizome of Curcuma longa, is known to have antiproliferative and antitumor properties. Nucleotide excision repair (NER) is the primary DNA repair mechanism that removes platinum-DNA adducts from DNA. Excision repair cross-complementing 1 (ERCC1) is a critical protein in the NER mechanism. The aim of this study is to investigate whether DMC could potentiate Cisplatin–induced apoptosis through down regulation of ERCC1-related pathways in the NSCLC. First, the cell viability was determined by MTT assay. The data showed that DMC has cytotoxicity to A549 cells, but did not affect MRC-5 cell viability. Furthermore, to identify DMC-induced apoptotic pathway on A549, apoptotic protein levels were measured by western blotting. DMC treatment markedly increased Bax/Bcl-2 ratio, and Cytochrome c expression that were correlated with post-target Cisplatin resistance pathway. In addition, it was found that DMC also significantly inhibited on target protein, ERCC1, expression via PI3K- Akt- Snail pathway. Moreover, we also revealed that DMC alleviated ERCC1 protein through reducing TP expression. And, we created a model of short-term exposure to Cisplatin up-regulated ERCC1-related protein in A549 cells that we could continue the combination of DMC and Cisplatin. Importantly, it was found that, followed by CDDP treatment, DMC could inhibit ERCC1–related signalling pathways, which have been validated to reduce ERCC1 protein expression and which significantly increased apoptosis induced by the combination of CDDP and DMC. In conclusion, our results revealed that DMC can reduce both the on-target and post-target related proteins induced Cisplatin resistance.
44
Ahmadie, Roien. "Congenital absence of NOS3 potentiates left ventricular dysfunction in a murine model of diet induced obesity and chronic pressure overload." 2009. http://hdl.handle.net/1993/21391.
Повний текст джерела
45
Wang, Yi-Ya, and 王怡雅. "KMUP-1 Potentiates NO/cGMP Signaling Pathway in Hypertension and Inhibits ROCK/VEGF Signaling Pathway in Hypoxic Pulmonary Arterial Hypertension." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/61202971141379369865.
Повний текст джерелаАнотація:
碩士高雄醫學大學
藥理學研究所
96
The endothelial dysfunction resulting in vessel contraction observed in hypertension appears to be a consequence of high blood pressure. In normal endothelial cell, activation of endothelial nitric oxide synthase (eNOS), soluble guanylyl cyclase (sGC) and protein kinase G (PKG) resulted in vasodilation and anti-hypertension. Our previous studies have demonstrated that KMUP-1, a unique xanthine and piperazine derivative, activated the NO/ sGC/ cGMP pathway, and could lead to vascular relaxation. We used 8 week-old Spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rat for our experimental model. In the present study, the experimental rats were subdivided into five groups：(1) W1 (WKY group 1：control), (2) W2 [WKY group 2：treating with KMUP-1 (10 mg/kg)], (3) S1 (SHR group 1：control), (4) S2 [SHR group 2：treating with KMUP-1 (10 mg/kg)], (5) S3 [SHR group 3：treating with KMUP-1 (30 mg/kg)]. During 28 days of treatments, systolic blood pressure (SBP) was measured weekly to confirm whether KMUP-1 could ameliorate SBP in SHR. Furthermore, we used aorta to check eNOS, sGCα1, PKG protein expression by Western blotting.Our results showed that SBP of SHR elevated more than that of WKY with age. KMUP-1 (10 mg/kg) did not significantly decrease SBP of WKY. However, SBP of SHR by treating with KMUP-1 (10 mg/kg, 30 mg/kg) was significantly decreased as compared with SHR control. Moreover, eNOS, sGCα1 and PKG protein expression in SHR or WKY aorta by treating with KMUP-1 were significantly increased. In conclusion, KMUP-1 could active NO/cGMP pathway to improve SBP of SHR, suggesting that KMUP-1 could be a potential drug for hypertension. Hypoxia exposure induced impairment in the structure and function of cardiopulmonary circulation. The pathological changes of cardiopulmonary arteries included endothelial injury, vessel remodeling, and contraction. It has been confirmed that hypoxia promoted downregulation of endothelial nitric oxide synthase (eNOS), upregulation of Rho kinase (ROCK) and vascular endothelial growth factor (VEGF) expression resulting in vascular contraction and remodeling to induce pulmonary arterial hypertension. Furthermore, activation of eNOS, soluble guanylyl cyclase (sGC), and protein kinase G (PKG) protein expression resulted in pulmonary arterial vasodilation and anti-remodeling. Previous studies have demonstrated that KMUP-1, a unique xanthine and piperazine derivative, activated the NO/sGC/cGMP pathway, and could lead to vascular relaxation. In the present study, the Wistar rats were subdivided into four groups：(1) Normoxia, (2) Hypoxia (10% O2) for 21 days, (3) Hypoxia (10% O2) + KMUP-1 (5 mg/kg/day) for 21 days, (4) Hypoxia (10% O2) + Sildenafil (5 mg/kg/day) for 21 days. After 21 days of hypoxia, we measured pulmonary arterial pressure to evaluate the development of pulmonary arterial hypertension. Through method of Hematoxylin-Eosin staining, we investigated wall thickness of pulmonary artery and right ventricular hypertrophy. Moreover, molecular mechanism was analyzed by Western blotting and immunohistochemistry.Our findings indicated that hypoxia could increase pulmonary arterial pressure, wall thickness ratio of pulmonary artery, and right ventricular hypertrophy as well as downregulate eNOS, sGCα1 and PKG protein expression whereas upregulate ROCK II and VEGF protein expression in molecular mechanism. However, the above effects could be reversed by treating with KMUP-1 or Sildenafil. In conclusion, our study confirmed that KMUP-1 is involved in the expression of eNOS/sGCα1/PKG signaling pathway resulting in vessel relaxation and may be useful for the improvement of hypoxia-induced pulmonary arterial hypertension in the future.
46
Chang, Weng-Kei, and 曾詠琪. "17-Dimethylaminoethylamino-17-demethoxy-geldanamycin potentiates arsenic trioxide-induced mitotic arrest and apoptosis by facilitating Akt degradation in CGL-2 cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/68024061613367351398.
Повний текст джерелаАнотація:
碩士國立陽明大學
藥理學研究所
95
Arsenic trioxide (ATO) was effective in treatment of acute promyelocytic leukemia. Induction of mitotic apoptosis is a potential mechanism underlying the therapeutic effect of ATO. Numerous reports have demonstrated that the therapeutic efficacy of ATO can be enhanced by combined treatment of ATO with other anticancer drugs. Heat shock proteins, highly expressed in many tumors, can protect cells from ATO-induced injuries. 17-Dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG), a newly developed heat shock protein 90 (Hsp90) inhibitor, was shown to enhance the cytotoxicity of a variety of chemotherapeutic agents. In this report, the combined effect of 17DMAG and ATO was studied in CGL-2 cells. As compared to treatment with ATO alone, cotreatment of CGL-2 cells with 17DMAG and ATO significantly enhanced mitotic arrest, phosphorylation of BubR1 and accumulation of Pds1, mitotic abnormalities, and mitotic apoptosis. Akt, one of Hsp90 client proteins, plays important roles on regulation of G2/M cell cycle transition and involves in anti-apoptotic survival pathway. Western blot analysis showed that cellular Akt is dose-dependently reduced by cotreatment with 17DMAG and ATO. In addition, inhibition of phosphoinositide 3-kinase (PI3K)-Akt pathway by Akt inhibitor V or LY294002 also significantly increased ATO-induced mitotic arrest and apoptosis. Overexpression of constitutively active Akt reduced ATO-induced mitotic arrest and apoptosis, but decrease the expression of Hsp90 or Akt induced complicate effects and is different from the inhibition of 17DMAG. These results indicated that enhanced induction of mitotic arrest and apoptosis in cells cotreated with 17DMAG and ATO is mediated through 17DMAG-induced degradation of Akt protein.
47
KIMSENG, LAW, and 劉錦成. "Noncytotoxic and Sublethal Paclitaxel Treatment Potentiates the Sensitivity of Cultured Ovarian Tumor SKOV-3 Cells to Lysis by Lymphokine-activated Killer Cells." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/24703372721905313876.
Повний текст джерелаАнотація:
碩士長庚大學
臨床醫學研究所
95
The standard treatment of advanced epithelial ovarian cancer is tumor debulking by surgery, followed by six cycles of chemotherapy consisting of cisplatinum and paclitaxel. However, this therapy protocol is not satisfactory, since about 50% of the treated patients eventually experience recurrence within few years of follow-up. Thus, a more innovative treatment modality is urgently needed for patients with this malignancy. We hypothesized that pretreatment of ovarian cancer SKOV-3 cells at a noncytotoxic to sublethal dose range of paclitaxel would result in increased sensitivity to LAK-mediated killing. MTT and trypan blue dye exclusion were used to determine the noncytotoxic to sublethal range of paclitaxel against SKOV-3 cells. A 4-h 51Cr release cytotoxicity assay was used to evaluate the sensitivity of paclitaxel-treated and untreated SKOV-3 cells. Immunofluorescence/flow cytometric analysis was used for phenotypic changes of cells with or without paclitaxel treatment. Our results with trypan blue dye exclusion and MTT assays showed that the noncytotoxic to sublethal range was between 0.001 μM and 0.01 μM. Pretreatment of SKOV-3 cells with paclitaxel at these doses for 72 h revealed significantly enhanced LAK-mediated killing against SKOV-3 cells with the highest sensitivity achieved with cells treated with 0.001 μM paclitaxel, as compared with the baseline killing of untreated cells using LAK cell alone (p<0.05). The enhanced sensitivity of LAK-mediated killing appeared to be in part due to paclitaxel-induced expression of ICAM-1 on SKOV-3 cells. This treatment approach may be useful for further development of an effective therapeutic mode for patients with ovarian cancer.
48
Costello, Mary K. "Combined Treatment With Npy Y5 Antagonists and Nan-190 Attenuates Transients in Light-induced Phase Shifts and Potentiates Phase Shifts Only During the Late Subjective Night." 2008. https://scholarworks.umass.edu/theses/169.
Повний текст джерелаАнотація:
Circadian rhythms in physiology and behavior are synchronized by a central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Shift work, jet lag and sleep disorders can disrupt circadian rhythms, negatively impacting health and well-being. The SCN pacemaker resets rapidly in response to changes in the daily light cycle, however, adjustment of peripheral oscillators to changing time zones or work shifts is more gradual, leading to internal desynchrony. In addition, many diseases can impair the SCN’s ability to adjust to changes in the light cycle. My research investigated whether combined pharmacological inhibition of neuropeptide Y and serotonin could enhance resetting and attenuate transient cycles in locomotor activity following a sudden change in light exposure. I found that simultaneously blocking neuropeptide Y and serotonin receptors potentiated phase shifts during the late subjective night and significantly reduced transient cycles of locomotor activity in hamsters. Development of treatments that enhance the circadian system’s response to light may alleviate some of the negative health consequences experienced by travelers, shift workers and individuals with disease-related circadian desynchrony.
49
Bilodeau, Claudia. "Impact de l’hyperglycémie et de l’infection sur le transport ionique, la réparation épithéliale et l’action des correcteurs dans les voies aériennes en Fibrose kystique." Thèse, 2015. http://hdl.handle.net/1866/13400.
Повний текст джерелаАнотація:
La Fibrose kystique (FK), causée par des mutations du canal Cl- CFTR, entraîne une
dysfonction de la sécrétion de Cl- et un débalancement dans la sécrétion des fluides. La
diminution de la clairance mucociliaire qui s’en suit occasionne une accumulation du mucus.
Cet environnement est alors favorable à l’installation d’infections et d’inflammation
chroniques, responsables de lésions au niveau de l’épithélium respiratoire. Le vieillissement
de la population FK, suite à la prise en charge plus appropriée de la maladie, est accompagné
par l’émergence de pathologies associées, telles que le diabète. Celui-ci, ainsi que plusieurs
autres facteurs comme l’infection à Pseudomonas aeruginosa, contribuent au déclin progressif
de la fonction pulmonaire, principale cause de mortalité et de morbidité des patients FK. Le
maintien de la fonction pulmonaire est dépendant notamment du transport ionique et liquidien
régulant la clairance mucociliaire ainsi que de la réparation épithéliale nécessaire à la
génération d’un épithélium fonctionnel en réponse aux agressions. Nous avons donc évalué
l’impact de l’hyperglycémie et des exoproduits de P. aeruginosa sur ces deux mécanismes.
Nos résultats ont tout d’abord montré qu’un niveau de glucose élevé diminue les
courants Cl- CFTR et potassique et altère la réparation de l’épithélium bronchique FK et non
FK. Nous avons aussi observé que l’hyperglycémie limite l’impact bénéfique de la correction
de CFTR sur la réparation épithéliale. Dans un second temps, nous avons évalué l’impact de
l’infection à Pseudomonas aeruginosa sur le CFTR, qui tient un rôle important dans la
fonctionnalité de l’épithélium des voies aériennes non-FK. Nous avons noté que l’expression
du CFTR ainsi que sa fonction sont réduites par l’exposition aux produits bactériens dans les
cellules non-FK. De plus, ces exoproduits compromettent la maturation du CFTR muté par les
correcteurs ainsi que leur bénéfice sur la réparation de l’épithélium FK. Finalement, nous
avons testé différentes combinaisons de composés correcteurs et potentiateurs de CFTR afin
de déterminer quelle stratégie serait la plus efficace afin de favoriser la réparation épithéliale
bronchique FK malgré la présence d’infection.Cystic fibrosis (CF), caused by mutations in the CFTR gene, is characterized by dysfunctional Cl- secretion and an imbalance in ion/fluid transport resulting in a decrease in mucociliary clearance. Accumulation of mucus then occurs and this favors bacterial infection in the airways. Chronic infection and inflammation is then responsible for progressive injuries to the lung epithelium. These mechanisms are associated with a decline in lung function, the main cause of morbidity and mortality in CF. The recent improvement in clinical care of patients with CF has led to an increase in median life expectancy, which allows the emergence of comorbidities, such as CF-related diabetes (CFRD). Because Pseudomonas aeruginosa infection and CFRD have been associated with decreased lung function, we investigated their impact on ion transports and epithelial repair, two main functions of airway epithelia. First, our results showed a reduction in Cl- secretion by CFTR and total K+ currents through CF and non-CF airway epithelial cells in hyperglycemic conditions. Moreover, our data indicated a decrease in wound closure rates of airway cell monolayers after exposure to high glucose. We also demonstrated an impairment of the beneficial effect of CFTR correctors on repair rates. The second part of our studies reveals a deleterious impact of Pseudomonas aeruginosa diffusible material (PsaDM) on CFTR expression and function in non-CF airways cells. Importantly, we showed, for the first time, that the presence of PsaDM altered the functional rescue of mutated CFTR by correctors and dampened their beneficial effect on CF wound repair. Finally, we tested several different combinations of corrector and potentiators in order to identify the most efficient compounds to improve the repair rates of CF monolayers despite the presence of PsaDM. Overall, our research demonstrated a deleterious impact of CFRD and PsaDM on ion transports and wound closure. Moreover, the new therapies with correctors may also be impacted by these two components.