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1
Reid, Anne Marie. « Raf-1 kinase inhibitor protein modulation of the cellular response to chemotherapeutic drugs and PDE5 inhibitors ». Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2497/.
Texte intégralRésumé :
RKIP was initially discovered as an endogenous inhibitor of the ERK and NF-κB pathways,and was also shown to prolong the activation of GPCRs via inhibition of the GRK2 protein. Now increasing evidence has linked RKIP to a metastases suppressing and chemo-sensitising role in cancer cells.The chemo-sensitising effect of RKIP was investigated in a colon carcinoma cell line using a variety of chemotherapeutic agents from conventional agents to newer targeted therapies. Initial results suggested that role of RKIP in the modulation of chemotherapeutic drug response was at the level of apoptosis; there did not appear to be great observable effects in the cell proliferative response and the cell cycle distribution of the colon carcinoma cells after treatment with selected agents. Apoptosis modulation by RKIP occurred after treatment with doxorubicin, FasL, paclitaxel and TRAIL. TRAIL-treated colon carcinoma cells displayed increased cell death as the levels of RKIP within the cell were increased. In contrast, doxorubicin, FasL and paclitaxel-treated cells displayed a scaffold-like response as the levels of RKIP were increased in the cell; with WT RKIP-expressing cells being more sensitive to doxorubicin, FasL and paclitaxel-induced apoptosis than low or high RKIP-expressing colon carcinoma cells. There was no modulation of 5-FU, cisplatin and etoposide-induced apoptosis by RKIP. Indeed, these three agents did not appear to induce cell death in this colon carcinoma cell line. RKIP modulation of chemo-sensitivity has never been shown before in a colon carcinoma cell line and this is the first time that doxorubicin and FasL-induced apoptosis has been shown to be modulated by RKIP. Further, it is shown here, for the first time, that the modulation of chemotherapy-induced apoptosis by RKIP can change depending upon the cytotoxic drug employed as treatment. TRAIL and FasL, both members of the TNF super-family, were selected for further analysis due to the distinctive cell death responses observed as a consequence of the levels of RKIP within the cell. WT RKIP cells were sensitive to FasL treatment, and high RKIP cells were most sensitive to TRAIL administration. Increased sensitivity of high RKIP-expressing colon cells to TRAIL treatment appeared to involve up-regulation of the DR5 receptor; down-regulation of the anti-apoptotic molecule Bcl-xl; pIKK which activates the NF-κB pathway; and TRAF2 which has been shown to activate the NF-κB pathway. Whether RKIP directly interacts with these molecules is unknown however RKIP has been shown to bind upstream activators of the NF-κB pathway and another TRAF subtype TRAF6. YY1 expression was evident in the TRAIL-treated cells but the expression was unchanged as the levels of RKIP within the cell were altered. The FasL-treated cells also displayed decreased pIKK levels as the levels of RKIP were increased; it is possible that NF-κB was behaving as both pro- and anti-apoptotic within this cell line. Thus RKIP inhibition of the NF-κB pathway may have prevented FasL-induced apoptosis in the high RKIP-expressing colon carcinoma cells. The expression of TRAF6, which has been shown to bind RKIP, displayed a scaffold-like response with WT RKIP-expressing cells having the highest TRAF6 expression. This was also the case for the transcriptional regulator YY1, thus it is possible that both YY1 and TRAF6 were behaving in a pro-apoptotic-like manner in the WT RKIP-expressing cells. TRAF2 was also evident in the FasL-administered cells but the expression did not change regardless of the levels of RKIP within the cell. Overall, it appears that differential expression of TRAF adaptor proteins is responsible for the contrasting responses of TRAIL and FasL-treated cells with low, WT and high RKIP expression. Utilisation of particular TRAF adaptors or TRAF combinations by the TRAIL and Fas receptors may also account for the pro- and anti-apoptotic roles of the NF-κB pathway, and the recruitment or down-regulation of other proteins dependent upon the cell stimulus. How RKIP affects these proteins requires further investigation, however these results are exciting and novel, and strengthen evidence surrounding the role of RKIP in chemosensitivity. On another note, RKIP has been shown to bind the PDE5 inhibitor PF-3717842, therefore investigation of the effects of the PDE5 inhibitors sildenafil citrate and vardenafil citrate on RKIP inhibition of the ERK pathway in a colon carcinoma cell line were examined. The effects of the PDE5 inhibitors were compared to the cell migration inhibitor locostatin that has been shown to bind and inhibit RKIP, and prevent the RKIP-Raf-1 interaction. With TPA and EGF stimulation, locostatin appeared to act in a manner consistent with its known function as an RKIP inhibitor. The PDE5 inhibitors sildenafil citrate and vardenafil citrate displayed a similar trend to that of locostatin, although their effects on the ERK pathway were not as potent. It is possible that after EGF stimulation, the strong activation of B-Raf was over-shadowing the subtle effects of the drug treatments. Under growth conditions, the RKIP inhibitor locostatin did not appear to behave as an inhibitor of RKIP nor did the PDE5 inhibitors sildenafil citrate and vardenafil citrate. It is possible that the strong activation of various growth and proliferative cascades was impinging upon the ERK pathway, were overshadowing the drug effects, or resulting in off-target (RKIP-unrelated) effects of the drugs. In summary, the role of RKIP within the cell is becoming an increasingly exciting avenue of research and is consistently yielding new and interesting roles and interactions within the cell. Understanding and elucidating the roles of this intriguing protein within the cell will not only strengthen our knowledge of signal transduction regulation and modulation, but may also provide a new source of targeted therapy and means of manipulation in the treatment of cancer and chemotherapeutic drug resistance.
2
Kurian, Stefanie [Verfasser]. « Effects of combination therapy of PDE5 inhibitor sildenafil and multikinase inhibitors sorafenib and sunitinib in NSCLC / Stefanie Kurian ». Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1076760546/34.
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3
Wang, Guocheng. « Design, synthesis and development of PDE5 inhibitors ». Thesis, Aston University, 2009. http://publications.aston.ac.uk/15405/.
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This research project is concerned with the design, synthesis and development of new phosphodiesterase 5 (PDE5) inhibitors with improved selectivities and lower toxicities. Two series of a 5 member and a 6 member ring fused heterocyclic compounds were designed, and synthesized. By alteration of starting materials and fragments, two virtual libraries, each is consisted of close to hundred compounds, were obtained successfully. The screening of sexual stimulation activity with rabbits demonstrated both groups of compounds were able to stimulate rabbit penile erection significantly. The following toxicity studies revealed 2-(substituted-sulfonylphenyl)-imidazo [1,5-a]-1,3,5-triazine-4-(3H)-one group possessed an unacceptable toxicity with oral LD50 about 200mg/kg; while 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group showed an acceptable toxicity with oral LD50 over 2000mg/kg. The continued bioactivity studies showed yonkenafil, the representative of 2-(substituted-sulfonylphenyl)-pyrrolo[2,3-d]pyrimidin-4-one group, has a better selectivity towards PDE5 and PDE6 than sildenafil and a better overall profile of sexual stimulation on animals than sildenafil. Chronic toxicity studies of yonkenafil further confirmed yonkenafil did not cause any serious side effect and damage on animal models and most actions were explainable. Based on evidences of the above studies, yonkenafil were recommended to enter clinical trials by the regulation authority of China, SFDA. Currently yonkenafil has been through the Phase I clinical trials and ready to progress into Phase II. Hopefully, yonkenafil will provide an alternative to the ED patients in the future.
4
Strange, Julian William Nevill. « PDE5 inhibition in pulmonary arterial hypertension ». Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441986.
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NGUYEN, HOANG OANH. « ANTI-INFLAMMATORY PROPERTIES OF PDE4 INHIBITION IN SARS-COV-2-ACTIVATED HUMAN DENDRITIC CELLS ». Doctoral thesis, Università degli studi di Brescia, 2022. http://hdl.handle.net/11379/555422.
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È stato dimostrato che la risposta immunitaria disfunzionale e l’iper-infiammazione con conseguente tempesta citochinica giocano un ruolo chiave nello sviluppo di forme severe di malattia da Coronavirus 2019 (COVID-19). Tale condizione clinica suggerisce che l’eccessiva risposta immunitaria innata potrebbe scatenare una patologia immunitaria virus-dipendente. In questo lavoro, viene descritto un nuovo meccanismo di attivazione delle cellule dendritiche da parte del virus SARS-CoV-2. Nello specifico, sequenze di RNA del genoma virale sono in grado di attivare dei recettori endosomiali, in particolare il TLR7 e TLR8. L’attivazione di questi recettori da parte delle sequenze di RNA virale ha indotto in-vivo una forte infiammazione polmonare, come dimostrato dall’accumulo di mediatori pro-infiammatori e dall’infiltrato leucocitario, mentre in-vitro ha indotto una polarizzazione in senso Th1 ed un forte rilascio di interferoni e citochine pro-infiammatorie.
Tanimilast è un nuovo inibitore selettivo della fosfodiesterasi 4, che viene assunto per via inalatoria, ed è impiegato in avanzati studi clinici per il trattamento della broncopneumopatia cronica ostruttiva e che potrebbe potenzialmente rivelarsi utile nel trattamento della polmonite da COVID-19. In questo progetto abbiamo visto come la potente attivazione delle cellule dendritiche da parte di sequenze di RNA del SARS-CoV-2 è stata notevolmente inibita dal trattamento con Tanimilast. Il trattamento con Tanimilast ha infatti causato una diminuzione del rilascio di citochine pro-infiammatorie (TNF-α e IL6) e chemochine (CCL3, CXCL9 e CXCL10), nonché alla riduzione del rilascio di citochine associate alla polarizzazione in senso Th1 (IL-12 ed Interferoni di tipo I). Tuttavia, il trattamento con Tanimilast non ha influito sull’espressione dei marker di maturazione quali CD83, CD86, MHC-II e CCR7. Coerentemente con ciò, il trattamento con Tanimilast non ha compromesso la capacità delle cellule dendritiche attivate di attivare i linfociti T CD4+, ma ha deviato la loro polarizzazione preferenzialmente verso un fenotipo Th2. Inoltre, Tanimilast ha inibito l’espressione di molecole MHC di classe I, limitando di conseguenza l’attivazione e il differenziamento dei linfociti T citotossici CD8+. Gli effetti immunomodulatori di Tanimilast sono stati ulteriormente confermati dalla sua capacità di promuovere il rilascio di molecole immunosoppressorie cAMP-dipendenti come IDO1, TSP1, VEGF-A e anfiregulina in cellule dendritiche stimolate con LPS. Queste cellule hanno anche fortemente over-espresso il CD141 e mostrato un incremento nella fagocitosi di cellule morte.
Complessivamente, i nostri risultati indicano che Tanimilast promuove l’acquisizione di proprietà immunomodulatorie da parte delle cellule dendritiche mature, nonché un differente fenotipo semi-maturo associato ad una elevata sovra espressione del CD141. I dati permettono quindi di suggerire Tanimilast come un promettente farmaco immunomodulatorio per il trattamento di malattie immuno-mediate o infiammatorie, possibilmente includendo le polmoniti severe da COVID-19.Dysfunctional immune response and hyper-inflammation with subsequent cytokine storm were shown to play a key role in the development of severe and fatal forms of Coronavirus disease 2019 (COVID-19). This clinical condition suggests that an overactive innate immune response may unleash virus-dependent immune pathology. Here, we described a novel mechanism of SARS-CoV-2-dependent activation of dendritic cells (DCs), based on the recognition of sequences of viral genomic ssRNA (SCV2-RNA) by endosomal pattern recognition receptors, namely TLR7 and TLR8. Importantly, SCV2-RNA recapitulated potent lung inflammation in vivo as shown by accumulation of proinflammatory mediators and immune cell infiltration; and induced a strong release of pro-inflammatory cytokines and Th1 polarization in vitro. Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterases 4 that is in advanced clinical development for the treatment of chronic obstructive pulmonary disease and could prove beneficial in severe COVID-19 pneumonia. In our experimental setting, the potent activation of DCs by SCV2-RNA was severely blunted by Tanimilast, which decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). However, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86, HLA-DR and CCR7. Consistent with this, Tanimilast did not reduce the capability of activated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. In addition, Tanimilast blocked the increase of HLA class I molecules and restrained the proliferation and activation of cytotoxic CD8+ T cells accordingly. The immune-modulatory effects of Tanimilast were further demonstrated by its capacity to enhance cAMP-dependent immunosuppressive molecules such as IDO1, TSP1, VEGFA and Amphiregulin in LPS-stimulated DCs. These cells also strongly upregulated CD141 and displayed increased uptake of dead cells. Altogether, our results indicate that Tanimilast induce mature DCs to acquire immunomodulatory properties as well as a distinct semi-mature phenotype, associated with the prominent expression of CD141, thus proposing Tanimilast as a promising immunomodulatory drug for the treatment in inflammatory or immune-mediated diseases, possibly including severe COVID-19 pneumonia.
6
LI, HONGWU. « Phosphodiesterase 7(PDE7) inhibitors : a new target to treat drug addiction ». Doctoral thesis, Università degli Studi di Camerino, 2015. http://hdl.handle.net/11581/401772.
Texte intégralRésumé :
Drug addiction not only causes addicts health damage, but also leads serious social, economic and public health problems, which threaten our harmonious society. The neurobiological mechanism of drug addiction has not been fully elucidated that is still lack of ideal treatment and intervention models. Especially, relapse is a worldwide problem, the high relapse rate after detoxification treatment more than 95%. The nucleotide phosphodiesterase (PDE) type 7 family includes two members, PDE7A and PDE7B, which are cyclic-AMP-specific PDEs expressed in brain dopaminergic regions linked to addiction, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA). Here we assessed the role of PDE7 in addiction by evaluating selective PDE7 inhibitors (PDE7i) Compound A and Compound B in rat models of durg self-administration and relapse to drug seeking by behavior test. Our results showed that PDE7 inhibition by Compound A or Compound B significantly reduced fixed-ratio 3 and progressive ratio nicotine self-administration. In preclinical model of relapse we found that Compound A and Compound B also attenuated cue- and yohimbine-induced reinstatement of nicotine seeking. In rats implanted bilaterally with intracranial cannulas aimed at the VTA, we found that site specific injection of Compound A or Compound B into this brain area significantly reduced nicotine self-administration under both FR-3 and PR schedule of reinforcement suggesting a role of corticomesolimbic dapaminergic circuitries in PDE7i effects. In cocaine addiction experiments, the results showed that PDE7 inhibitor Compound B (low dose, intermediate dose and high dose) significantly reduced cue-induced relapse to cocaine seeking. The reinstatement experiments showed that PDE7 inhibitor exhibited significant effects in preventing stress-induced relapse to cocaine seeking behavior at the doses tested (low dose and high dose). The same results were found in heroin addiction test. The PDE7 inhibitor Compound A (intermediate dose and high dose) significantly reduced heroin-seeking behavior after extinction. The reinstatement experiments showed that PDE7 inhibitor Compound A exhibited significant effects in preventing cue-induced relapse to heroin seeking behavior at the doses tested (low dose, intermediate dose and high dose). Further, PDE7 inhibitor (intermediate dose and high dose) significantly reduced alcohol self-administration. The reinstatement experiments showed that PDE7 inhibitor exhibited significant effects in preventing stress- and cue-induced relapse to alcohol seeking behavior. These findings suggest that PDE7 could be a novel therapeutic target for drug addiction.
7
Tippelt, Sabine [Verfasser]. « Untersuchung der Pathogenese der möglicherweise speziesspezifischen toxikologischen Effekte von PDE4-Inhibitoren bei Ratten / Sabine Tippelt ». Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1037885198/34.
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Xu, Chenjia. « A Novel in vitro PDE7 Inhibitor Inhibits IL-2 Gene Expression in Activated T Cells and Induces Apoptosis in a B-cell Line and Monocytic Cell Line ». Thesis, Boston College, 2013. http://hdl.handle.net/2345/3935.
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Thesis advisor: Thomas C. ChilesElevating intracellular cAMP levels can result in a wide range of anti-inflammatory effects and growth arrest and apoptosis in cancer cells, marking phosphodiesterases (PDEs) as potential targets for inflammatory diseases and cancer treatment. PDE7A is proposed to be a new therapeutic target for its ubiquitous expression in proinflammatory and immune cells. A Barbituric acid based compound, BC12 was identified as an in vitro PDE7 inhibitor in fission-yeast-based high-throughput screen. Analysis of this compound on the activation of Jurkat T lymphocytes, mouse and human primary T cells reveals inhibition of IL-2 production, though cell viability is not significantly impacted. Real-time RT-PCR and mRNA stability assays indicate that the inhibition of IL-2 production by BC12 is attributable to transcriptional repression without accelerating IL-2 mRNA decay. By contrast, compounds of similar structure with that of BC12 exhibit varying effects on IL-2 production that does not correlate with their in vitro PDE7 inhibitory activity, suggesting that the in vivo target of BC12 responsible for these effects may not be PDE7. Our study further reveals that BC12 inhibits IL-2 transcription through targeting NFAT and NFkB-mediated pathways. Preliminary investigation on other T helper cell cytokine secretion indicates that BC12 has a potential to selectively inhibit Th2 cytokines. Our data suggest that BC12 may present a novel anti-inflammatory drug for its immunosuppressive and potential immunomodulatory effects. Analysis of BC12 on a human B-cell line and a monocytic cell line demonstrate its pro-apoptotic effects in a dose-dependent manner. Titration of BC12 on human diffuse large B-cell lymphoma (DLBCL), LY18 cells, and human primary B cells reveals that BC12 induces cell death more effectively in DLBCL LY18 cells than normal B cells, suggesting the anti-cancer potential of this compound
Thesis (PhD) — Boston College, 2013
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
9
Grommel, Sonja [Verfasser]. « Untersuchung möglicher positiver Effekte hinsichtlich der Aufrechterhaltung der Gravidität durch PDE4-Inhibitoren an Ratten / Sonja Grommel ». Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1037800826/34.
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Clapham, John Christopher. « Characterisation and structural studies on dog heart cyclic nucleotide phosphodiesterase ». Thesis, Birkbeck (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267913.
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Oliver, James John. « Inhibition of phosphodiesterase type 5 in cardiovascular disease ». Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/6581.
Texte intégralRésumé :
Nitric oxide is released from the endothelium and causes relaxation of vascular smooth muscle by stimulating guanylate cyclase to produce guanosine 3’,5’-cyclic monophosphate (cGMP) which, in turn, is degraded by phosphodiesterase type 5 (PDE5). Inhibition of PDE5, with drugs like sildenafil citrate, promotes NOstimulated relaxation of vascular smooth muscle. The overall aim of the work contained within this thesis was to further characterise the systemic vascular effects of PDE5 inhibition. Four clinical studies were performed. The aims of the first study were to investigate in healthy men the effect of smoking on endothelium-dependent vasomotor function measured as the change in peripheral arterial wave reflection with inhaled salbutamol, and the effect of acute sildenafil 100 mg on this response. Smokers (n=12) exhibited a reduced response to inhaled salbutamol compared to non-smokers (n=11) [mean(standard deviation) area under the curve of the change in central augmentation index following salbutamol 400 μg: -29(143) AU in smokers vs -159(124) AU in non-smokers, P=0.03]. In the smokers, there was a trend to an improvement in the response to salbutamol following sildenafil [-96(266) AU vs -29(143) AU with matched placebo; P=0.2]. The co-administration of glyceryl trinitrate (GTN) and sildenafil is absolutely contraindicated because of the potential for profound hypotension. The aim of the second study was to characterise the time course of this interaction. Twenty men with stable angina, maintained on their usual medicines, were administered sublingual GTN 400 μg 1, 4, 6 and 8 hours after sildenafil 100 mg or matched placebo. Compared to the combination of GTN and placebo, the combination of GTN and sildenafil resulted in greater mean maximum reductions from baseline in sitting systolic blood pressure (BP) at 1, 4 and 8 hours, and in sitting diastolic BP at all time points (all P<0.05). Compared to placebo, sildenafil alone reduced systolic BP at 1, 4, 6 and 8 hours (P<0.01 at 1 hour and P<0.05 at 4, 6, and 8 hours) and diastolic BP at 4, 6, and 8 hours (all P<0.01). Analysis of the change in BP from the measures taken before each GTN challenge suggested that the interaction on BP might be synergistic at 1 hour after sildenafil, but no more than additive at 6 and 8 hours after sildenafil. Symptoms consistent with hypotension occurred following GTN in 6 subjects at 1 hour and 3 subjects at 4 hours after sildenafil, but in no subjects at 6 and 8 hours after sildenafil or at any time after placebo. In the third study, 25 otherwise untreated hypertensives were given sildenafil 50 mg or matched placebo three times daily for 16 days and the effects on ambulatory BP, clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity and brachial artery flow-mediated dilatation were measured. Three subjects were withdrawn because of side effects and the data from the remaining 22 subjects were analysed. Sildenafil reduced ambulatory BP [change from baseline in average daytime BP: systolic -8(9) mmHg vs 2(9) mmHg with placebo, P<0.01; diastolic -6(5) mmHg vs 0(6) mmHg, P<0.01] and clinic BP [change from baseline to 1 hour after drug administration on day 16: systolic -5(11) mmHg vs 4(10) mmHg, P<0.01; diastolic -5(5) mmHg vs 2(7) mmHg, P<0.01]. Sildenafil, but not placebo, reduced arterial wave reflection [central augmentation index from 32(9)% at baseline to 30(10)% at 1 hour after administration on day 16, P<0.05; radial augmentation index from 88(13)% to 84(13)%, P<0.01], but the change in arterial wave reflection was not statistically significant compared to the change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The fourth study investigated the potential of combined PDE5 inhibition and organic nitrate for the management of treatment-resistant hypertension (TRH). In 6 patients with TRH, maintained on their usual antihypertensives sildenafil 50 mg alone, isosorbide mononitrate (ISMN) 10 mg alone and co-administered sildenafil and ISMN all acutely reduced systolic BP and diastolic BP compared to placebo (quantified as the area under the curve of the change from baseline to 4 hours after drug administration; all P≤0.01). The combination produced a greater reduction in systolic BP than did either sildenafil alone (P=0.03) or ISMN alone (P=0.01) and a greater reduction in diastolic BP than did sildenafil alone (P=0.02). Compared to placebo, from 1 to 3 hours after drug administration BP was on average 13/10 mmHg lower with sildenafil alone, 18/14 mmHg lower with ISMN alone and 26/18 mmHg lower with the combination. The following conclusions were made. (1) Smokers exhibit impaired vascular responsiveness to inhaled salbutamol, indicating systemic endothelial dysfunction, which may be improved by sildenafil. (2) In men with stable angina there is an interaction on BP reduction between sildenafil 100 mg and sublingual GTN 400 μg for at least 8 hours after sildenafil administration, but this interaction is no more than additive from 6 hours after sildenafil administration. (3) Regular sildenafil monotherapy reduces BP in hypertension. (4) In patients with TRH maintained on their usual antihypertensives sildenafil alone and ISMN alone both acutely reduce BP and there is additional BP reduction when these drugs are given in combination.
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Kaur, Gurpreet. « Synthesis of Boronic Acid Based Sensors for Glucose and Sialic Acid and Synthesis of Novel and Selective PDE4 Enzyme Inhibitors ». Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/9.
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The boronic acid functional group is known to bind compounds with the diol group tightly and reversibly in aqueous environment and has been used as a recognition moiety for the design of carbohydrate sensors. The first chapter of the dissertation studies the synthesis and substitution effect on the affinity and selectivity of a known boronic acid-based glucose sensor. In such a sensor design effort, the availability of a signaling event, whether it is fluorescence or UV, is crucial. The second chapter studies the detailed mechanism on how a well-known fluorescent boronic acid compound changes fluorescent properties upon binding. A new mechanism has been established which corrected a decade old mistake. In the third chapter, a series of boronic acid-based sensors were designed and synthesized for sialic acid, which is part of tetrasaccharide found on many cell surface carbohydrates. Such sialic acid sensors could be very useful for the development of new type of anti-influenza therapy. The fourth is on the design and synthesis novel and selective inhibitors for phosphodiesterase 4 (PDE4), which are potential anti-asthma agents.
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Demirbas, Cakici Didem. « Identification and Characterization of PDE8 Inhibitors Using a Fission Yeast Based High-throughput Screening Platform ». Thesis, Boston College, 2011. http://hdl.handle.net/2345/3051.
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Thesis advisor: Charles S. HoffmanIn this thesis, I describe the development of a screening platform for detecting PDE8A inhibitors using the cAMP-dependent glucose sensing pathway of the fission yeast Schizosaccharomyces pombe, which led us to discover several PDE8A selective inhibitors. In this system, the only PDE of the fission yeast is replaced with mammalian PDE8A1 in strains that have been engineered such that PDE inhibition is required to allow cell growth. Using this system, I screened 56 compounds obtained from PDE4 and PDE7 high throughput screens (HTSs) and identified a PDE4-PDE8 dual specificity inhibitor. Using this as a positive control, I developed a robust high-throughput screen (HTS) for PDE8A inhibitors and screened 240,267 compounds at the Harvard Medical School ICCB Screening Facility. Approximately 0.2 % of the screened compounds were potential PDE8A inhibitors with 0.03% displaying significant potency. Secondary assays of 367 of the most effective compounds against strains expressing PDE8A (both full length and catalytic domain), PDE4A and PDE7A or PDE7B led to the selection of structurally diverse compounds for further testing. To profile the selectivity of twenty-eight of these compounds, dose response assays were conducted using 16 yeast strains that express different PDE isoforms (representing all PDE families with the exception of the PDE6 family). These assays identified compounds with different patterns of inhibition, including structurally-distinct PDE8A-specific inhibitors. By evaluating the effects of these compounds for steroid production in mouse Leydig cells, biologically active compounds that can elevate steroid production were identified
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
14
Joseph, Emlyn Clive. « Pathogenesis of arteriopathy induced by PDE III inhibitors in the rat and dog ». Thesis, Queen Mary, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307684.
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Wan, Kah Fei. « Characterisation of phosphodiesterase inhibitory proteins (PDE#gamma#) signalling in human embryonic kidney 293 cells ». Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288596.
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Patel, Brijeshkumar Shantilal. « Exploring the mechanistic pathway of various phosphodiesterase inhibitors in airway smooth muscle cells ». Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16264.
Texte intégralRésumé :
Asthma is a chronic lung disease with complex inflammatory disorder. In asthma, airways are remodelled and narrowed, resulting into increased mucus production and contraction of muscles. It has been known that in asthma, airway smooth muscle (ASM) cells act as the primary effector and pivotal cell type involved in asthma. The current treatment suggests β2-agonists as drugs of choice for bronchodilation in ASM cells and long acting β2-agonists (LABA) combined with inhaled corticosteroid (ICS) are used as maintenance therapy in asthma. The mechanism of β2-agonists works via increased levels of cyclic adenosine mono phosphate (cAMP) in ASM cells. It is well established that a rapid increase in cAMP levels in ASM are critical for effective bronchial relaxation however, these intracellular cAMP levels is labile and reduced by phosphodiesterase (PDEs) enzymes. PDEs are intracellular regulators catalysing the breakdown of cAMP and/ cGMP (cyclic guanosine-5'-monophosphate) to their inactive forms. This makes β2-agonists less effective in relaxation of bronchial muscles. The molecular mechanism of PDE is still not clearly known and there are no approved PDE inhibitors in the market for asthma. Our hypothesis is that once we treat ASM cells with PDE inhibitors in addition to LABA and corticosteroid, the effectiveness of LABA and corticosteroid will enhance in airway inflammation. In addition to the bronchial relaxation effect of β2-agonists, also causes anti-inflammatory properties due, in part, to their ability to upregulate mitogen-activated protein kinase phosphatase 1 (MKP-1) in a cAMP-dependant manner. Given that MKP-1 is cAMP-dependant and inhibition of PDE acts to increase β2-agonist-induced cAMP, it is possible that the presence of PDE inhibitors may enhance β2-adrenoceptor-mediated responses. Additionally, it would enable us to understand the molecular mechanism of these PDE inhibitors as a possible additive therapy for asthma in the future. Among all PDE isoenzymes inhibition of PDE3 and PDE4 are the main targets for ASM cells. Utilizing primary cultures of ASM cells, we showed in chapter 3 that inhibitors of PDE4, but not PDE3, increase β2-agonist-induced cAMP, MKP-1 mRNA and protein upregulation. When cAMP was increased there was a concomitant increase in MKP-1 levels and significant inhibition of tissue necrosis factor α (TNFa) induced neutrophil chemoattractant cytokine, interleukin -8 (IL-8). This result was consistent with all PDE4 inhibitors examined but not for the PDE3 inhibitors. These findings reinforce cAMP-dependent control of MKP-1 expression in ASM cells. Since MKP-1 is an integral part of the anti-inflammatory effect of PDE4 inhibitors in ASM cells, we were keen to see the effect of a newer generation of PDE4 inhibitor, Roflumilast N-oxide (RNO) for anti-inflammatory repression. RNO is approved for use in chronic obstructive pulmonary disease (COPD) and has demonstrated anti-inflammatory impact in vivo and in vitro. Up to the present time, however, the effect of RNO on the synthetic function of ASM cells is unknown. We address this herein in chapter 6 and investigate the effect of RNO on β2-adrenoceptor-mediated, cAMP-dependent responses in ASM cells in vitro, and whether RNO enhances steroid-induced repression of inflammation. RNO (0.001-1000 nM) alone had no effect on cAMP production from ASM cells, and significant potentiation of the formoterol-induced cAMP could only be achieved at the highest concentration of RNO tested (1000 nM). At this concentration, RNO exerted a small, but not significantly different, potentiation of formoterol-induced expression of anti-inflammatory MKP-1. Consequently, TNFα induced IL-8 secretion was unaffected by RNO in combination with formoterol. However, as there was the potential for PDE4 inhibitors and LABA to interact with corticosteroids to achieve superior anti-inflammatory efficacy, we examined whether RNO, alone or in combination with formoterol, enhanced the anti-inflammatory effect of dexamethasone. While RNO alone did not significantly enhance cytokine repression achieved with steroids, RNO in combination with formoterol significantly enhanced the anti-inflammatory effect of dexamethasone in ASM cells. Once we had obtained reliable results from the PDE4 inhibitors we were intrigued to investigate the molecular mechanism of non-specific PDE inhibitors, mainly xanthine derivatives such as theophylline and doxophylline, for their formoterol-induced cAMP effect in ASM cells. We showed in chapter 4 and 5 that theophylline and doxophylline both did not potentiate cAMP release from ASM cells treated with formoterol. Moreover, theophylline (0.1-10 µM) did not increase formoterol-induced MKP-1 mRNA expression nor protein upregulation; consistent with the lack of cAMP generation. Similar trends observed for doxophylline (0.1-100 µM) where cAMP level was not enhanced. In asthma, adenosine receptor activates adenylate cylclase which leads to elevation of cAMP however doxophylline have lower affinity for adenosine receptor so does not induce cAMP. Theophylline (at 10 µM) was anti-inflammatory and repressed secretion of IL-8, produced in response to TNFa. Because theophylline’s effects were independent of PDE4 inhibition or anti-inflammatory MKP-1, we then wished to elucidate the novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase 2A (PP2A), a master controller of multiple inflammatory signalling pathways, and showed that theophylline increases TNFa induced PP2A activity in ASM cells. In spite of positive clinical data for doxophylline with exhibition of lesser side effects in recent studies, our results do not appear to have any significant repression of IL-8 in ASM cells. Further experiments with less variability in the results and tight control on cell plating techniques may provide better understanding of results and test our hypothesis more fully. Overall our study suggests that understanding the molecular mechanism of various PDE inhibitors in ASM cells offers an additive option as anti-inflammatory therapy in asthma.
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Maier, Christiane [Verfasser], et Michael [Gutachter] Stürzl. « Inhibition of Phosphodiesterase 4 (PDE4) Reduces Experimental Fibrosis by Interfering with the Release of Interleukin-6 from M2 Macrophages / Christiane Maier ; Gutachter : Michael Stürzl ». Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2017. http://d-nb.info/1128401576/34.
Texte intégral
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SILVA, Jessy Rosanily Tavares Landim. « In vitro characterization of the antimalarial activity and mode of action of new PDEs and DHODH inhibitors against Plasmodium falciparum ». Master's thesis, Instituto de Higiene e Medicina Tropical, 2019. http://hdl.handle.net/10362/75614.
Texte intégralRésumé :
A malária é uma das doenças parasitárias mais antigas e continua a ser a que mais mortes provoca mundialmente atualmente. Pode ser causada por cinco espécies distintas de protozoários do género Plasmodium (P. falciparum, P. ovale, P. vivax, P.malariae e P. knowlesi), sendo o P. falciparum a espécie mais letal. O parasita é transmitido ao ser humano pela picada do mosquito fêmea do gênero Anopheles. aquando da refeição sanguínea. Em 2017, a Organização Mundial da Saúde relatou 219 milhões de casos de malaria em todo o mundo, sendo a grande maioria na região subsaariana do continente africano. A doença pode ser classificada como: malária grave e não grave, afetando principalmente crianças com idade inferior a cinco anos. As resistências aos fármacos antimaláricos em uso, bem como a inexistência de uma vacina eficaz e o difícil controlo vectorial são os principais obstáculos no combate à doença. A disseminação das resistências torna imperativo a investigação e síntese de novos compostos com potencial ação antimalárica, capazes de atuar em diversos estádios do desenvolvimento do parasita, rapidamente.
Neste trabalho, procedeu-se à caracterização da atividade antimalárica e do modo de ação de compostos sintetizados. Compostos sintetizados para serem inhibidores de fosfodiesterases (PDEs) e de dihydroorotate dehydrogenase (DHODH) parasitárias (enzimas importantes para os diferentes estádios de desenvolvimento de P. falciparum).
Para a análise da atividade antimalárica, foi avaliado a velocidade de ação dos compostos, os estádios parasitários em que os compostos têm maior atividade, bem como a sua toxicidade nesses estádios. Foram também otimizados dois protocolos de modo a poder, posteriormente, avaliar a ação dos compostos na produção de espécies reativas de oxigénio (ROS) e na alteração do potencial da membrana mitocondrial do parasita.
Avaliando a atividades antimaláricas dos potenciais inibidores de PFPDE, um dos compostos demostrou ser de atuação rápida, com atividade nos dois estádios eritrocitários e ter um efeito citocida nos parasitas. O segundo composto com potencial ação contra os PFPDEs avaliado, demostrou ser de atuação mais lenta, com uma ação predominante nos parasitas no estádio de anel, mas tendo um efeito citocida. O composto com potencial ação contra os PFDHODH demostrou ser de atuação lenta, com uma ação predominante com um efeito citocida nos parasitas no estádio de anel e um efeito citostático nos parasitas no estádio de trofozoítos.Malaria is one of the oldest parasitic diseases and continues to be the one that causes the most deaths worldwide nowadays. It can be caused by five distinct species of Plasmodium (P. falciparum, P. ovale, P. vivax, P.malariae and P. knowlesi), with P. falciparum being the most lethal. The parasite is transmitted to humans by the bite of the female mosquito of the genus Anopheles during the blood meal. In 2017, WHO reported 219 million malaria cases worldwide, with the vast majority in the sub-Saharan region. The disease can be classified as: severe and non-severe malaria, mainly affecting children under five years old. Resistance to antimalarial drugs in use as well as the lack of a effective vaccine and the difficult vectorial control are the main obstacles in the fight against the disease. The dissemination of resistance makes it imperative to investigate and synthesize new compounds with potential antimalarial action, capable of acting at several stages of parasite development, rapidly. In this work, the antimalarial activity and the mode-of-action of synthesized compounds were studied. Compounds synthetized to be phosphodiesterase’s (PDEs) and dihydroorotate dehydrogenase (DHODH) inhibitors (important enzymes for Plasmodium falciparum different stages of development). For the analysis of the antimalarial activity, the speed of action of the compounds was evaluated, the stage-specific activity and toxicity of the compounds were determinate. Two protocols were also optimized, in order to evaluate, later, the action of the compounds, in the production of reactive oxygen species (ROS) and in the alteration of mitochondrial membrane potential. Evaluating the antimalarial activities of the potential inhibitors of PFPDE, one of the compounds was shown to be fast acting with activity in both erythrocyte stages studied and to have a cytocidal effect on the parasites. The second compound with potential action against the PFPDEs evaluated, showed to be of slower action, with a predominant action in the ring-stage parasites, but having a cytocidal effect. The compound with potential action against PFDHODH shown to be a slow acting compound, with a predominant action in the ring-stage parasite and to have a cytocidal effect on the ring-stage parasites and a cytostatic effect on trophozoite-stage parasites.
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Santos, Filho Hilton Oliveira dos 1956. « Estudo clínico fase I de carbonato de lodenafila, um novo tipo de inibidor de fosfodiesterase 5 (PDE5), em voluntários saudáveis do sexo masculino = A phase I clinical trial of lodenafil carbonate, a new phosphodiesterase type 5 (PDE5) inhibitor, in healthy male volunteers ». [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309461.
Texte intégralRésumé :
Orientador: Gilberto De NucciTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-22T19:42:28Z (GMT). No. of bitstreams: 1 SantosFilho_HiltonOliveirados_D.pdf: 1622141 bytes, checksum: 5f817cf4a04ee643bdf7e261e5861691 (MD5) Previous issue date: 2013
Resumo: Carbonato de Lodenafila é um novo tipo de inibidor de fosfodiesterase 5 (PDE5) utilizado no tratamento da disfunção erétil. O presente estudo foi realizado para avaliar a segurança, tolerabilidade e farmacocinética do carbonato de lodenafila após a administração de doses orais únicas ascendentes (de 1 a 100 mg) a voluntários saudáveis do sexo masculino (n = 33). O estudo foi um estudo clínico fase I, aberto, de escalonamento de dose, utilizando a administração de doses orais únicas de carbonato de lodenafila. Carbonato de Lodenafila foi administrado sequencialmente escalonado em doses únicas de 1 mg a 100 mg com um período sem uso do medicamento (washout) de pelo menos 1 semana, entre cada dose. A progressão para a próxima dose foi permitida se após a avaliação dos exames clínicos, laboratoriais e Monitorização Ambulatorial da Pressão Arterial (MAPA), não demonstrassem alterações e eventos adversos sem relevância clínica. As amostras de sangue foram coletadas na pré-dose e em intervalos determinados e 24 horas após a administração. As amostras de plasma para a mensuração de carbonato lodenafila e lodenafila foram analisadas por cromatografia líquida acoplada à espectrometria de massa. Não foram observados eventos adversos graves, e nenhum dos voluntários abandonou o estudo devido à intolerância. As medições do MAPA, exames clínicos e laboratoriais e ECG não revelaram alterações significativas mesmo em doses mais elevadas. Carbonato Lodenafila não foi detectado em qualquer amostra, indicando que ele atua como um pró-droga. Os parâmetros farmacocinéticos médios de lodenafila para tmax e t1 / 2 foram 1,6 (± 0,4) horas e 3,3 (± 1,1) horas, respectivamente. Este estudo demonstrou que o carbonato de lodenafila é bem tolerado e apresentou um bom perfil de segurança em voluntários saudáveis do sexo masculino
Abstract: Lodenafil carbonate is a new phosphodiesterase type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 to 100 mg) single oral doses to healthy male volunteers (n=33). The study was an open-label, dose-escalation, phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg to 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, determined intervals and 24h postdosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a pro-drug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 (±0.4) hr and 3.3 (±1.1) hr, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers
Doutorado
Clinica Medica
Doutor em Clínica Médica
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Adams, David. « Modulation of agonist-stimulated second messenger and contractile events in bovine tracheal smooth muscle with cyclic nucleotide PDE inhibitors ». Thesis, University of Leicester, 1994. http://hdl.handle.net/2381/33624.
Texte intégralRésumé :
The aim of this thesis was to investigate and characterize the effects of isoenzyme- selective phosphodiesterase (PDE) inhibitors on a range of biochemical and functional parameters in bovine airway smooth muscle in order to further our understanding of 'cross-talk' between different second messenger pathways in this tissue. Cyclic nucleotide levels were measured after selective or non-selective PDE isoenzyme inhibition under conditions of basal and stimulated adenylyl and guanylyl cyclase activity. These data led to the conclusion that PDE IV plays an important role in the regulation of agonist-stimulated increases in cAMP levels, since under conditions of isoprenaline stimulation, incubation with the PDE IV-selective inhibitor rolipram resulted in an increase in cAMP from a control level of 20 2.7 to 50.3 4.0 pmol/mg protein. This response was potentiated in a synergistic manner by simultaneously inhibiting PDE III with ORG 9935. Co-inhibition of PDE III/IV also resulted in a significant increase in basal cAMP levels in tracheal smooth muscle slices and a marked decrease in the rolipram EC50 for cAMP accumulation in isoprenaline-stimulated slices from 205 102 to 7.3 3.0 muM. This suggested that metabolism of cAMP by PDE III is also functionally important in this tissue at least when PDE IV activity is compromized. Evidence was also obtained to suggest that cGMP is metabolized by PDE V, since incubation with zaprinast resulted in a 47% increase in basal cGMP values; however, where cGMP levels were elevated a greater increase in cGMP accumulation was seen in the presence of the nonspecific PDE inhibitor, IBMX (24.3 1.6 pmol/mg protein) compared to that seen with zaprinast (15.2 1.6 pmol/mg protein) suggesting that cGMP metabolism by other PDEs plays a significant role under these conditions. The effects of selective PDE inhibition on agonist-stimulated inositol phosphate accumulation was then investigated. Stimulation with maximally-effective concentrations of carbachol and histamine for 30 min resulted in 36- and 10-fold increases in inositol phosphate accumulations. The response to carbachol (1-100 muM) was largely unaffected by increases in cAMP accumulation caused by isoprenaline or PDE inhibition, however both manipulations inhibited the response to histamine (100muM) by approximately 80%. Again the inhibitory effects of rolipram were potentiated by ORG 9935 such that the EC50 value for rolipram-mediated inhibition was decreased from 120 27 to 1.5 0.9 muM. Such results suggest that PDE III/IV inhibition may be effective in relaxing airway smooth muscle. Consequently it was established that whilst rolipram could inhibit smooth muscle contraction stimulated by histamine or sub-maximal concentrations of methacholine, co-inhibition of PDEs with rolipram and ORG 9935 resulted in a much more potent anti-spasmogenic action. Furthermore, in contrast with the effects of rolipram alone the PDE III/IV inhibitor combination also significantly inhibited phasic contractions generated by either agonist. For example rolipram/ORG 9935 completely abolished the ability of 30uM histamine to cause a phasic contractile response. In common with previous suggestions that the membrane hyperpolarizing actions of cAMP-elevating agents may be responsible, at least in part, for the relaxation of trachealis muscle, experiments reported here suggest that PDE inhibition causes membrane hyperpolarization, possibly through increasing the open-state probability of the high- conductance, calcium-activated potassium channel, and this action may account for the mechanism whereby selective PDE inhibitors can inhibit phosphoinositide turnover and possibly as a consequence relax airway smooth muscle.
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Tavallai, Mehrad. « INTRODUCING NOVEL COMBINATORIAL TARGETED THERAPIES IN MULTIPLE TYPES OF CANCER ». VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4088.
Texte intégralRésumé :
The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, a phosphodiesterase type 5 inhibitor, could enhance the toxicities of sorafenib and regorafenib in HCC and CRC cells, respectively. Our in vitro data indicated that the drugs interacted strongly to kill cancer cells via induction of ER stress, autophagy and apoptosis. In accordance with these findings, our in vivo data demonstrated a significant reduction in tumor growth.
The second study in this manuscript was conducted based on the growing body of evidence about the significant contribution of EGFR and JAK/STAT signaling to the breast tumorigenesis. Our preliminary in vitro data demonstrated that the concurrent inhibition of these two pathways by lapatinib, a dual ERBB1/2 inhibitor, and ruxolitinib, a JAK1/2 inhibitor, synergistically killed breast cancer cells of all types, including the resistant triple negative subtype. Our mechanistic studies showed that the combination of ruxolitinib and lapatinib triggered cytotoxic mitophagy, and autophagy-dependent activation of BAX and BAK leading to the mitochondrial dysfunction.
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Kreißelmeier, Klaus-Peter [Verfasser]. « Therapeutische Effekte von Iloprost und dem PDE 3/4-Inhibitor Tolafentrin im Modell der Monocrotalin-induzierten chronischen pulmonalen Hypertonie der Ratte / Klaus-Peter Kreißelmeier ». Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1062973119/34.
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Nickum, Elisa A. « Analysis of Regulated Drugs Using Chromatographic and Spectrophotometric Techniques Coupled with Spectroscopy An Orthogonal Approach to Protecting Public Health ». University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504799568245931.
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GALBIATI, ANDREA. « DESIGN AND SYNTHESIS OF NOVEL ENZYME INHIBITORS AS ANTIPROLIFERATIVE COMPOUNDS WITH ANTIPROTOZOAL AND ANTICANCER ACTIVITY ». Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827428.
Texte intégralRésumé :
This dissertation describes the research carried out as part of a PhD program in Chemistry
from the 1st October 2017 until 30th November 2020. The PhD project investigated the
development of inhibitors of enzymes involved in important metabolic pathways, with the
final aim to produce an antiproliferative effect. The present thesis combines the works
performed at the University of Milan and Vrije Universiteit of Amsterdam.
Part A describes the research performed in Amsterdam, NL during my period abroad from
January to September 2019 in the research group of Professor Rob Leurs, at the Division of
Medicinal Chemistry of the Amsterdam Institute for Molecules, Medicines and Systems,
Vrije Universiteit of Amsterdam. In particular, this part outlines the design, synthesis and
pharmacological evaluation of two novel series of potent antitrypanosomal agents,
identified through SAR exploration and scaffold hopping approach starting from cyclic
nucleotide Trypanosoma brucei phosphodiesterase (PDE) inhibitors. PDE enzymes provide
a fine control on several biochemical pathways and have recently been demonstrated to
be essential for parasite proliferation. Their disruption by RNA interference (RNAi)
dramatically increase intracellular cAMP and, consequently, causes complete mortal
trypanosome cell lysis.
Part B describes the research done at the Department of Pharmaceutical Sciences,
University of Milan, under the supervision of Professor Paola Conti, on the design and
synthesis of novel covalent inhibitors targeting the glycolytic enzyme Glyceraldehyde-3-
phosphate dehydrogenase (GAPDH). Due to its pivotal role in the glycolysis, GAPDH
represents a rate-limiting enzyme in those cells that mostly, or exclusively rely on this
pathway for energy production. In this context, GAPDH inhibition represents a valuable
approach for the development of anticancer and antiparasitic drugs. Due to the presence
of a druggable nucleophilic cysteine residue in the catalytic pocket of the target, I focused
my attention on the development of covalent GAPDH inhibitors, presenting an electrophilic
warhead with a finely tuned reactivity. In particular, Section B2 reportsthe work conducted
on the development of Plasmodium falciparum GAPDH inhibitors and the in vitro
antiplasmodial activity. Section B3 shows the work performed on the design and synthesis
of human GAPDH inhibitors, with in vitro antitumor activity.
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Kalsi, J. S. « The effect of soluble guanylate cyclase activators and a nitric oxide releasing PDE 5 inhibitor on cavernosal and anococcygeal smooth muscle function in conditions of nitric oxide deficiency ». Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1333229/.
Texte intégralRésumé :
Introduction: PDE5 inhibitors improve erections by potentiating nitric oxide (NO)- cyclic guanosine monophosphate system. However, long-term diabetic patients have reduced efficacy secondary to dysfunction of NO system. The aim of this thesis was to investigate in-vitro effects of a PDE5 inhibitor (sildenafil), a soluble guanylate cyclase (sGC) activator (BAY41-2272) and an NO-releasing PDE5 inhibitor (NCX-911) on urogenital smooth muscle in conditions of NO deficiency. Method: The effect of these compounds was investigated on tone and electrical field stimulation-induced nitrergic relaxation of cavernosal (human and rabbit) and anococcygeal (rat) smooth muscle and compared to an NO donor (spermine-NONOate) and non-specific sGC activator (YC-1) in the absence/presence of inhibitor of NO synthesis (L-NAME) or inhibitor of sGC (ODQ). In a diabetic rat model, these compounds were assessed in untreated and L-NAME-treated tissues from non-diabetic and diabetic animals. Results: BAY41-2272 was more potent than YC-1 and spermine-NONOate at relaxing rabbit/human cavernosum. ODQ significantly decreased the potency of BAY41-2272 whereas L-NAME did not. BAY41-2272 potentiated nitrergic responses and partially reversed the inhibition of nitrergic responses by L-NAME. NCX-911 and sildenafil were equally potent at relaxing rabbit and human cavernosum. In presence of L-NAME the potency of sildenafil decreased significantly. Both compounds potentiated nitrergic relaxations equally but failed to induce relaxation in the presence of ODQ. Nitrergic relaxation was significantly decreased in the diabetic rats but still potentiated by BAY41-2272 but not by sildenafil or NCX-911. The potencies of NCX-911 and BAY41- 2272 were unaltered but that of sildenafil was significantly reduced in the diabetic animals. Conclusion: The rank of potency in control tissues was BAY41-2272 > NCX-11 = sildenafil; whereas in NO deficiency BAY 41-2272 > NCX-911 > sildenafil. Endogenous NO derived from nitrergic nerves is significantly decreased in diabetes. NO-releasing PDE5 inhibitors and sGC activators may be effective in management of diabetic erectile dysfunction.
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Schaffner, Denise [Verfasser], et Irmgard [Akademischer Betreuer] Merfort. « Investigations of hepatic hemodynamics and alterations in the NO-cGMP pathway in an animal model of liver fibrosis / cirrhosis suggest PDE5 inhibitors as promising adjunct in portal hypertension therapy ». Freiburg : Universität, 2018. http://d-nb.info/1189583216/34.
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Capdeville, Marion-Justine. « Études des cycles biogéochimiques des contaminants organiques dits « émergents » dans les systèmes aquatiques ». Thesis, Bordeaux 1, 2011. http://www.theses.fr/2011BOR14304/document.
Texte intégralRésumé :
Les substances pharmaceutiques font partie du groupe des contaminants émergents du fait de leur intérêt récent dans les études environnementales comparativement à des polluants étudiés depuis plus longtemps tels que les pesticides. Elles correspondent aux principes actifs des médicaments et, à ce titre, sont responsables des propriétés pharmacologiques des médicaments. Ce sont donc des molécules biologiquement actives qui peuvent agir sur les organismes vivants présents dans les écosystèmes impactés. L’origine des substances pharmaceutiques dans l’environnement est variable mais les principales sources sont liées à leur utilisation en médecine humaine ou vétérinaire. Une fois consommées, les substances pharmaceutiques sont excrétées dans les urines ou les fèces et se retrouvent dans les eaux usées (consommation humaine) ou dans les déchets d’élevage (consommation vétérinaire). Dans le premier cas, elles peuvent être rejetées directement dans le milieu, ou indirectement, avec les eaux usées traitées ou les boues résiduaires, après traitement dans les stations d’épuration (STEP). Dans le deuxième cas, elles atteignent directement le milieu lorsque les animaux sont élevés en prairie ou indirectement lorsque les déchets d’élevage sont épandus sur les sols agricoles pour les fertiliser. Ces travaux de thèse se sont attachés à étudier l’origine et le devenir de ces substances dans ces 2 cas de figure. Ainsi en se basant sur des critères de consommation, de présence dans l’environnement par rapport à des études antérieures, de toxicité et d’écotoxicité, d’originalité et de disponibilité des composés standards de référence, 32 puis 78 molécules appartenant aux classes thérapeutiques des antibiotiques, des anticancéreux, des béta-bloquants, des anti-VIH et des inhibiteurs de phosphodiestérase de type 5 (PDE 5) ont été étudiées dans 2 continuums : i) effluents hospitaliers - eaux usées brutes et traitées – eaux de surface, et ii) eaux usées brutes et traitées - eaux de surface - eaux de captage souterraines. En s’appuyant sur les mêmes critères de sélection, le devenir de 7 antibiotiques a été étudié dans des lisiers porcins dans des filières simples de traitement du lisier (fosse de stockage), dans des filières complexes de traitement du lisier (système de traitement ressemblant à des mini STEP) et dans des mésocosmes en conditions contrôlées. Pour pouvoir réaliser l’ensemble de ces études, des protocoles analytiques mettant en œuvre une étape d’extraction par SPE (Solide Phase Extraction) ou d’extraction ASE (Extraction Accélérée par Solvant) puis de purification par SPE et d’analyse par LC/MS/MS (Chromatographie en phase liquide couplée à la spectrométrie de masse en tandem) ont été développés. Ces protocoles, en remplissant des critères de qualité tels que des limites de détection et de quantification compatibles avec des analyses environnementales (de l’ordre du ng/l à la dizaine de ng/l), une bonne linéarité, précision, justesse et performance, ont permis d’analyser la phase dissoute des échantillons d’eaux et la phase dissoute et solide des échantillons de lisiers. Il ressort des analyses des échantillons aqueux que : i) les béta-bloquants, les anti-VIH et les antibiotiques appartenant aux familles des macrolides, des fluoroquinolones et des sulfonamides, sont les molécules les plus représentatifs de la contamination du milieu naturel parmi les classes étudiées ; ii) les rejets de STEP sont une source majeure de la contamination des systèmes aquatiques ; iii) les eaux usées sont davantage contaminées en hiver qu’en été ; et iv) les eaux de surface sont davantage contaminées en été qu’en hiverPharmaceutical substances belong to the group of emerging contaminants due to their recent interest in environmental studies in comparison with pollutants who have been studied for a longer time like pesticides. They correspond to the active ingredient of drugs and by this mean are responsible for their pharmacological properties. Consequently they are biologically active molecules that can act on living organisms present in impacted ecosystems. The origin of pharmaceuticals in the environment is variable but the main sources are related to their use in human and veterinary medicine. Once consumed, pharmaceutical substances are excreted in urine or feces and are found in wastewater (human consumption) or animal manure (veterinary consumption). In the first case, they can be discharged directly in the environment, or indirectly, with treated wastewater or sludge from sewage treatment plants (SWTP). In the second case, they directly reach the environment when animals are bred on grassland or indirectly when livestock wastes are spread on agricultural soils as fertilizer. This PhD work has been focused on the study of the origin and fate of pharmaceutical substances in these 2 cases. Thus according to consumption data, occurrence in the environment reported in previous studies, toxicity and ecotoxicity data, originality and availability of reference standard compounds, 32 then 78 molecules belonging to 5 different therapeutic classes (antibiotics, antineoplastics, beta-blockers, anti-HIV, phosphodiesterase type 5 inhibitors (PDE 5 inhibitors)) were studied in 2 continuums : i) hospital wastewater effluents – raw and treated wastewater – surface water, and ii) raw and treated wastewater – surface water – ground water. Based on the same selection criteria, the fate of 7 antibiotics was studied in pig manure in simple manure storage facilities (storage tank), in aerobic manure treatment facilities (treatment system like in small SWTP) and in mesocosms under controlled conditions. In order to achieve all these studies, analytical protocols implementing an extraction step by SPE (Solid Phase Extraction) or an ASE extraction (Accelerated Solvent Extraction) followed by a SPE purification and an analytical step by LC / MS / MS (liquid chromatography tandem mass spectrometry) have been developed. These protocols, by filling out quality criteria such as limits of detection and quantification compatible with environmental analysis (ng/l to dozen of ng/l), good linearity, precision, accuracy and performance, were used to analyze the dissolved phase of water samples and dissolved and solid phases of pig manure samples. The water samples analysis shows : i) beta-blockers, anti-HIV and antibiotic belonging to the families of macrolides, fluoroquinolones and sulfonamides are the most representative molecules of the environmental contamination from the classes studied; ii) SWTP releases are a major source of aquatic systems’ contamination; iii) wastewaters are more contaminated in winter than in summer; and iv) surface water are more contaminated in summer than in winter. The pig manure samples analysis shows : i) the levels of contamination of manure by antibiotics are high, from a few µg/l to mg/l; ii) the manure level of contamination is not related to the physiological stage of pigs; iii) the interest to store manure before spreading in order to reduce the antibiotics contamination is not highlighted; iv) oxytetracycline, tetracycline, tylosin and marbofloxacin are mainly present in the solid phase whereas sulfadiazine, lincomycin and monensin are mainly present in the liquid phase of manure; v) the separation of solid and liquid phases reduce manure contamination in aerobic treatment facilities; and vi) antibiotics degradation is mainly aerobic.Key words:
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Sormes, Michael [Verfasser], et Stefan [Akademischer Betreuer] Ückert. « Funktionelle Effekte selektiver Phosphodiesterase (PDE)-Inhibitoren auf die glatte Muskulatur der humanen Prostata / Michael Sormes. Klinik für Urologie und Urologische Onkologie im Zentrum Chirurgie der Medizinischen Hochschule Hannover. Betreuer : Stefan Ückert ». Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2010. http://d-nb.info/1010308475/34.
Texte intégral
29
Lin, Yu-Yuan, et 林玉苑. « Regulation of LPS-induced inflammatory responses by PDE4 inhibitor in macrophages ». Thesis, 2010. http://ndltd.ncl.edu.tw/handle/09428785409479309990.
Texte intégralRésumé :
碩士國立中央大學
生命科學研究所
98
Type 4 cAMP-specific phosphodisterases (PDE4s), the enzymes that degrade the second messenger cAMP, play a critical role in regulation of intracellular cAMP concentration. It has been demonstrated that PDE4 isozymes are expressed at high levels in immune cells and PDE4 inhibitors exhibit anti-inflammatory effects. revious studies have shown that lipopolysaccharide (LPS) induced PDE4B expression and activity in macrophages, and this induction is associated with an increase in the production of TNF-?. This TNF-? responses was inhibited by the PDE4 inhibitor rolipram. Moreover, LPS stimulates an increase in src tyrosine kinase activity, while is involved in various function of macrophages. In this study, we observed that rolipram, db-cAMP, and the Src kinase inhibitor PP2 attenuate LPS-induced TNF-? production in Raw 264.7 cells. In PDE4B-deficient macrophages, LPS-induced TNF-? release was decreased and the level of the decrease was similar to that observed in the wild-type macrophages inhibited by rolipram or PP2, indicating the effects of PDE4B on the TNF-? release are mediated by regulating cAMP signaling pathway as well as src tyrosine kinase activity. Moreover, measurements of PDE enzymatic activity indicated that LPS-induced PDE4 activity in macrophages was not inhibited by PP2, ruling out the possibility that PP2 attenuated TNF-? response isn’t derived from the inhibition of PDE4 by PP2. We also found that LPS-induced ROS production in macrophages was inhibited by cAMP or PKA activation, but not by PP2. In Raw 264.7 cells, LPS did not alter Lyn-tyr396 phosphorylation while decreased Lyn-tyr507 phosphorylation. In addition, the effect of rolipram on Lyn tyrosine phosphorylation was not exhibited as predicted. Taken together, these findings showed that inhibition of PDE4B activity reduces LPS-induced TNF-? release and ROS production, but interupting Src tyrosine kinase only attenuates the TNF-? release. This difference indicates that cAMP signaling and Src tyrosine kinase activation have their unique and specific role in regulation of TLR signaling.
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Parola, Carmen. « New strategies to control dendritic cell activity ». Doctoral thesis, 2012. http://hdl.handle.net/11562/407939.
Texte intégralRésumé :
IDENTIFICAZIONE DEL LIGANDO NATURALE PER CLEC4C PER VALUTARE IL SUO RUOLO NEL RILASCIO DI IFN-I DA PARTE DELLE CELLULE DENDRITICHE PLASMACITOIDI.
Le cellule dendritiche plasmacitoidi sono specializzate nella produzione di interferone-I (IFN-I), citochina in grado di promuovere una risposta antivirale e antitumorale e che svolge un importante ruolo anche nelle malattie autoimmuni. L’attivazione della secrezione di IFN-I dipende dai recettori TLR7 e TLR9, in grado di riconoscere rispettivamente RNA e DNA microbici. La produzione di IFN-I è modulata da diversi recettori, incluso CLEC4C “C-type lectin domain family 4, member C”. Il ligando naturale di CLEC4C è sconosciuto. Per identificarlo, abbiamo utilizzato una forma solubile del dominio extracellulare di CLEC4C come sonda per rivelare un glycan array. Abbiamo trovato che CLEC4C riconosce zuccheri di tipo complesso con galattosi terminali. In aggiumta, CLEC4C solubile è in grado di legare leucociti da sangue periferico e cellule tumorali che esprimono glicani con residui di galattosio all’estremità non riducente. La modulazione positiva e negativa dei residui di galattosio sulla membrana cellulare è associata alla regolazione del rilascio dell’IFN-I da parte delle pDC negli esperimenti di co-cultura in vitro. Questi risultati suggeriscono che la modulazione nell’espressione di oligosaccaridi non-sialilati da parte dei patogeni o cellule tumorali può influenzare la secrezione di IFN-I e la sorveglianza immunitaria.
EFFETTO DEGLI INIBITORI DELLE FOSFODIESTERASI 4 SULLE CELLULE DENDRITICHE PLASMACITOIDI E CELLULE DENDRITICHE.
Le cellule dendritiche (DC) mettono in comunicazione l’immunità innata e adattativa e hanno un ruolo esclusivo nella presentazione dell’antigene ai linfociti T naive. Inoltre, dopo attivazione, le DC sono in grado di indurre la polarizzazione in senso Th1/Th2/Th17. L’attivazione, la migrazione e l’attività immunogenica e tolerogenica delle DC sono orchestrate dal rilascio delle citochine nel microambiente locale. E’ noto che il mancato equilibrio nella produzione di citochine è coinvolto nella rottura della tolleranza.
Il lupus eritematoso sistemico (LES), per esempio, è caratterizzato da una produzione aberrante di IFN-I, abbondantemente secreto da pDC attivate da immunocomplessi.
Nelle lesioni precoci psoriasiche, invece, il peptide antimicrobico LL-37, quando legato al selfDNA, induce un aumento del rilascio di IFNα da parte delle pDC. Elevati livelli di IFNα inducono l’attivazione delle DC mieloidi che a loro volta sono in grado di presentare gli antigeni del self alle cellule T, promuovendo l’ espansione dei cloni autoreattivi Th1/Th17.
Recentemente gli inibitori delle fosfodiesterasi (PDE4i) sono stati descritti come una efficace stategia per regolare la produzione di citochine. Le fosfodiesterasi sono enzimi fondamentali nel metabolismo del cAMP, un secondo messangero cruciale per regolare l’ infiammazione e la produzione di citochine. Le fosfodiesterasi 4 (PDE4) sono tra le più studiate poiché altamente espresse dalle cellule del sistema immunitario, cellule endoteliali e cheratinociti.
Questo lavoro descrive i risultati di una dettagliata analisi eseguita in vitro dell’effetto di PDE4-1, un nuovo inibitore a basso peso molecolare di PDE4, valutandone l’impatto su diversi aspetti chiavi del modello patogenetico della psoriasi. PDE4-1 riduce efficientemente la secrezione di IFN-I da parte delle pDC. Inoltre, quando somministrato alle DC mieloidi, questo farmaco è in grado di inibire il rilascio di IL12p70, un’importante citochina in grado di polarizzare i linfociti T in senso Th1, TNFα, IL-6 e IL-23, citochine di fondamentale importanza nella polarizzazione in senso Th17. In aggiunta il PDE4-1 è in grado di guidare la riduzione del rilascio della chemochina CXCL10/IP10 responsabile del richiamo dei linfociti Th1. In conclusione, abbiamo dimostrato che PDE4-1 è efficace nel modulare il rilascio di mediatori chiave implicati nella patogenesi della psoriasi.IDENTIFICATION OF THE NATURAL LIGAND FOR CLEC4C TO EVALUATE ITS ROLE ON THE RELEASE OF IFN-I BY PLASMACYTOID DENDRITIC CELLS. Plasmacytoid dendritic cells (pDC) are specialized in the production of interferon-I (IFN-I), which promotes antiviral and antitumor responses, as well as autoimmune disorders. Activation of IFN-I secretion depends on the pattern recognition receptors TLR7 and TLR9, which sense microbial RNA and DNA, respectively. IFN-I production is modulated by several receptors, including C-type lectin domain family 4, member C (CLEC4C). The natural ligand of CLEC4C is unknown. To identify it, here we probed a glycan array with a soluble form of the CLEC4C ectodomain. We found that CLEC4C recognizes complex type sugars with terminal galactose. Importantly, soluble CLEC4C bound peripheral blood leukocytes and tumor cells that express glycans with galactose residues at the non-reducing ends. The positive and negative modulation of galactose residues on cell membranes was paralleled by the regulation of IFN-I secretion by plasmacytoid dendritic cells in co-culture experiments in vitro. These results suggest that the modulation in the expression of non-sialylated oligosaccharides by invading pathogens or transformed cells may affect IFN-I response and immune surveillance. EFFECT OF PHOSPHODIESTERASE 4 INHIBITORS ON PLASMACYTOID DENDRITIC CELLS AND DENDRITIC CELLS. Dendritic Cells (DC) link innate and adaptive immunity and play a unique role in the presentation of antigens to naïve T cells. Moreover, upon activation, DC are able to induce Th1/Th2/Th17 polarization. Indeed, activation, migration, immunogenic and tolerogenic activities of DC are orchestrated by the release of cytokines by the local microenviroment. Deregulation of cytokine production is known to be involved in the breakdown of tolerance. Systemic Lupus Erythematosus (SLE), for example, is characterized by an aberrant production of IFN-I, abundantly secreted by immunocomplex-activated pDC. In early psoriatic lesions, instead, the anti microbial peptide LL-37, when bound to selfDNA, leads to an increased release of IFNα by pDC. Elevated levels of IFNα trigger myeloid DC activation that will better present self antigens to T cells and promote the expansion of autoreactive Th1/Th17 clones. Recently phosphodiesterase inhibitors (PDEi) were reported as an effective strategy to regulate cytokine production. Phosphodiesterases (PDEs) are unique enzymes metabolizing cAMP, a pivotal second messenger able to regulate inflammation and cytokine production. Phosphodiesterase 4 (PDE4) is one of the most studied since it is highly expressed by immune cells, endothelial cells and keratinocytes. The present work describes the results of a detailed in vitro analysis of the effect of PDE4-1, a new, low molecular weight inhibitor for PDE4 on several key aspects of the psoriasis pathogenetic model. We show that PDE4-1 efficiently reduce the secretion of IFN-I by activated plasmacytoid dendritic cells. On the other hand, when administered to in-vitro derived myeloid dendritic cells, this drug also inhibit the release of IL-12p70, an important Th1-driving cytokine, and of TNFα, IL-6 and IL-23, that are of fundamental importance for Th17 polarization, in addition to reducing the release of the Th1-attracting chemokine CXCL10/IP10. In summary, we demonstrate that PDE4-1 reduce the release of key pathogenetic mediators, involved in the current model of psoriasis.
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Chen, Shih-Yu, et 陳仕祐. « PDE4 and PDE3 Inhibitors Synergistically Inhibit Collagen-Induced Arthritis and IFN-γ and IL-17A Release in DBA/1 Mice ». Thesis, 2016. http://ndltd.ncl.edu.tw/handle/7x69w6.
Texte intégralRésumé :
碩士國立中央大學
生命科學系
104
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease. It targets multiple joints with complex pathological processes. To date, the etiology of RA is not fully understood. Accumulating evidence indicates that cAMP-elevating agents can negatively modulate many inflammatory responses in virtually all immune inflammatory cells and thereby ameliorate inflammatory diseases. Type 4 phosphodieasterases (PDE4s) are the predominant cAMP-hydrolyzing enzymes in most immune cells, hence being important in controlling the intracellular cAMP concentration and immune functions. So far, the PDE4 inhibitors Roflumilast and Apremilast are used in clinic to treat chronic obstructive pulmonary disease (COPD) and psoriasis and psoriatic arthritis, respectively. Using the animal models of RA, several studies have shown that the incidence and severity of arthritis as well as articular pannus formation and cartilage damage are significantly reduced by PDE4 inhibitors in experimantal animals. However, the molecular mechanisms of these effects still remain unclear. It is known that the helper Th1 and Th17 cells are involved in the pathogenesis of RA by secreting the cytokines IFN-γ and IL-17A, respectively. Thus, in this study we used collagen-induced arthritis (CIA) model to determine whether inhibition of PDE4 can regulate the IFN-γ and IL-17A release as well as the arthritic severity in CIA mice. Using type II collagen (CII) to immunize DBA/1 mice by two protocols (i.e., i.d./i.d. and i.d./i.p. models), we first observed that CII-induced IFN-γ and IL-17A release in local lymph node cells (by i.d./i.d. model) and spleen cells (by i.d./i.p. model) was dose dependently increased. The secretion of Th1 cytokine IFN-γ in both tissue cells was significantly decreased by dibutyryl-cAMP (cAMP analog) and forskolin (adenylyl cyclase activator), as well as by the PDE4 inhibitor rolipram, indicating that the inhibitory effect of rolipram was mediated by an increase of cAMP in Th1 cells. In addition, the release of IL-17A in the spleen cells, but not the lymph node cells also was suppressed by these cAMP-elevationg agents. Moreover, like rolipram, the PDE3 inhibitor cilostazol also significantly attenuated the secretion of IFN-γ and IL-17A while having less extent. In a CII-primed model, anti-CD3/CD28 antibody-induced IFN-γ release in the mouse local lymph node and spleen cells was also significantly reduced by rolipram, but not by cilostazol. As for IL-17A, inhibition of PDE4 caused a significant decrease in IL-17A release in the spleen cells but not the lymph node cells. It was noted that in all CIA models tested IFN-γ and IL-17A release was almost completely inhibited when the two tissue cells were treated with rolipram in combination with cilostazol. Thus, the two inhibitors were used together to treat CIA mice and the results showed that the inhibition of both PDE4 and PDE3 significantly attenuated the arthritic severity. Moreover, using the CIA model in the PDE4B null mice revealed that ablation of PDE4B did not affect the development of arthritis, while administration of cilostazol to PDE4B null mice appeared to reduce the disease severity when compared with the control wild type mice. Taken together, these results indicate that inhibition of PDE4 can effectively reduce the CII-induced Th1 and Th17 responses, and inhibition of PDE3 exerts synergistic inhibitory effects in CIA mice. Our findings provide an experimental basis for developing PDE3/4 dual inhibitors for RA therapy.
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Chang, Tsu-Ya, et 張慈雅. « Anti-asthmatic effects of hesperetin, a selective phosphodiesterase (PDE)4 inhibitor, potentiated by daidzein, a selective PDE3 inhibitor ». Thesis, 2006. http://ndltd.ncl.edu.tw/handle/88830513624619954883.
Texte intégralRésumé :
碩士臺北醫學大學
藥理學研究所
94
Selective PDE4 inhibitors increase cAMP level, therefore have bronchodilatory and anti-inflammatory effects, and is worth to develop for ameliorating asthma in the future. Selective PDE3 inhibitors also increase cAMP level. Whether addition or potentiation will be observed when they combine each other is the aim of the present study. Hesperetin (PDE4 inhibitor) at 100 μM dilated baseline tension of ovalbumin (OVA)-sensitized guinea pig trachealis. When combined with 100 μM of diadzein (PDE3 inhibitor), addition was observed. In addition, the relaxant effect of combination of these two on histamine (30μM)-induced precontraction in isolated non-sensitized guinea pig trachealis was 80.1 ± 3.3% of aminophylline (1 mM)-induced maximal relaxation, and significantly greater than that of either (300 μM) alone. However, hesperetin (300 μM) or diadzein (300 μM) did not displace a half of [3H]-rolipram binding from high affinity rolipram binding sites (HARBS) in brain particles. Combination of these two (300 μM, each) also did not increase the displacement ability from HARBS. Many pharmaceutical manufactories of the world are trying to develop selective PDE4 inhibitors as anti-asthmatic drugs, nowadays, but the side effects, such as nausea, vomiting, gastric acid hypersecretion, induced by these drugs constrict their development. In the sensitized and OVA-secondarily challenged BALB/c mice, an asthmatic animal model, daidzein (1 μmol/kg, i.p.) significantly potentiated the lowering effect by hesperetin (10 μmol/kg, i.p.) when they combine each other, but not singly applied daidzein (1 μmol/kg, i.p.), on methacholine (MCh, 50 mg/ml)-induced enhanced pause (Penh) in control group. The combination also significantly reduced total cells, lymphocytes, neutrophils, eosinophils, IL-5, TNF-α and OVA-specific IgE in BALF. In addition, it also significantly decreased total IgE in serum. The combination suppressed airway hyperresponsiveness (AHR) and had brochodilatory and anti-inflammatory effects with a benefit of decreasing side effects in the model of allergic asthma. The combination of daidzein (1 μmol/kg, i.p.) and hesperetin (10 μmol/kg, i.p.) seems the most appropriate, because other combination, such as daidzein (1 μmol/kg, i.p.) with hesperetin either at 3 or 30 μmol/kg (i.p.), only had less anti-asthmatic effects, in the present results.
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Fernandes, Diogo Miguel Pereira. « Inibidores seletivos e não seletivos da fosfodiesterase no tratamento da DPOC ». Master's thesis, 2018. http://hdl.handle.net/10316/82803.
Texte intégralRésumé :
Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaCOPD is nowadays the world’s 4th cause of death with a prevision that in 2020 it becames the 3rd. In Portugal the estimated prevalence is 14,2%, leading to 8000 annual deaths. It is an important public health issue that requires a lot of health resources. COPD is characterized by a progressive and irreversible airflow limitation, with a combination of lung destruction and small airways obstruction. Inflammation is one of the major mechanisms that induce the disease and tobacco is the major and preventable cause. The main goal of the treatment is to maintain the disease stable, preventing exacerbations. There are a lot of drugs approved (ICS, LABA, LAMA, SABA, SAMA), including the PDE inhibitors, selective (Roflumilast) and non-selective (Theophylline). PDE’s hydrolyse intracellular cyclic nucleotides (cAMP and cGMP), into inactive 5′ monophosphates and they are found in a variety of inflammatory and structural cells. PDE’s inhibitors allow the elevation of cAMP and cGMP which lead to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation. PDE4 inhibitors act by increasing intracelular concentrations of cAMP, associated with anti-inflammatory effects acting over various cells involved in COPD. The main goal of this study is to review the use of this type of drugs, their efficacy and safety, based only in clinical trials, obtained with a search in the PUBMED database. The data suggest that non-selective inhibitors (theophylline) are only used in a small group of patients (not a first-line option), and Roflumilast only shows efficacy and appears to be a reasonable treatment option to patients with very severe COPD, with frequent exacerbations and presence of chronic bronchitis, added to ICS + LABA or LAMA. It is not used alone in the stable disease and until now, the benefits in the quality of life remains undetermined. The safety profile is overall good, but the emesis and weight loss often leads to the discontinuation of the treatment. Safety and efficacy improvements should be attempted in new drug developments.
A DPOC é atualmente a 4ª causa de morte mundial, estimando-se que em 2020 possa ser a 3ª causa. Em Portugal tem uma prevalência de 14,2%, levando a cerca de 8000 mortes anuais. A DPOC é caracterizada por uma limitação progressiva e irreversível do fluxo aéreo, combinando a destruição do parênquima pulmonar, com a obstrução das vias aéreas, nomeadamente as de menor dimensão, sendo a inflamação um dos seus principais mecanismos e o tabaco a principal causa passível de prevenção. Com o tratamento pretende-se manter a doença estável, prevenindo as exacerbações. Estão aprovados diversos fármacos (ICS, LABA, LAMA, SABA, SAMA), onde se incluem os inibidores da PDE, seletivos (Roflumilast) e não seletivos (Teofilina). As PDE’s promovem a hidrólise dos nucleótidos cíclicos (cGMP e cAMP), nos seus 5-monofosfatos inativos, sendo encontradas em diversas células estruturais e inflamatórias. A sua inibição permite uma elevação das concentrações de cAMP e cGMP, com diversos efeitos, nomeadamente no relaxamento do músculo liso das vias aéreas e inibição da inflamação celular. Os inibidores da PDE4 atuam aumentando as concentrações intracelulares de cAMP, com efeitos anti-inflamatórios em diversas células envolvidas na DPOC. O principal objetivo deste trabalho foi rever o papel deste tipo de fármacos no tratamento da DPOC, com ênfase na sua eficácia e segurança, tendo apenas por base ensaios clínicos obtidos através de uma pesquisa na PUBMED. Os inibidores não seletivos (Teofilina) não são a primeira opção para o tratamento e relativamente ao Roflumilast, apenas mostrou ser vantajoso no tratamento de doentes com DPOC muito severa, com exacerbações frequentes e com bronquite crónica, associado ao ICS + LABA ou LAMA, não mostrando benefícios claros na melhoria da qualidade de vida. A segurança do medicamento é globalmente boa, com alguns efeitos adversos frequentes, alguns deles responsáveis pela descontinuação do tratamento (emese e perda de peso), pelo que a investigação se deverá centrar na melhoria do perfil de segurança desta classe.
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Chen, Bo-Guang, et 陳柏光. « Disposition of PDE5 Inhibitors in the Isolated Perfused Rat Liver ». Thesis, 2008. http://ndltd.ncl.edu.tw/handle/37594322795062623437.
Texte intégralRésumé :
碩士國立成功大學
臨床藥學研究所
96
Introduction： PDE5 inhibitors are used for the treatment of male erectile dysfunction and pulmonary arterial hypertension. The structures of PDE5 inhibitors are similar to cGMP and they are mainly metabolized by CYP3A and CYP2C9 isozymes in the liver. Currently, the interaction studies of PDE5 inhibitors are focused on the metabolic aspect and none of them has addressed on the transporter interactions. However, recent studies have demonstrated that sildenafil can inhibit the activity of MRP4, MRP5 and OATP. And it has beeen suggested that P-gp, in addition to CYP3A, was responsible for the increase of the concentration of PDE5 inhibitors when concomitant with ritonavir in clinical settings. In our previous study, we found that vardenafil underwent active biliary secretion in rats. Therefore, it is of great interest to investigate the role of drug transporters on the hepatobiliary disposition of PDE5 inhibitors. Purpose：The aim of this study was to investigate the hepatic disposition of PDE5 inhibitors, and to explore the role of drug transporters on their hepatobiliary transport in the isolated perfused rat liver. Results：All PDE5 inhibitors showed active biliary secretion during single-pass constant perfusion experiments. As the extent of secretion of sildenafil was greater than that of tadalafil and vardenafil, sildenafil was chosen as the model drug to further explore drug interactions of PDE5 inhibitors. Using the recirculated perfused rat liver preparation, the biliary secretion of sildenafil and its metabolite was found to decrease with increasing concentration of concomitant cyclosporine A, an inhibitor of OATP、MRP2、P-gp. When co-administered with rifampicin, an OATP and MRP2 inhibitor, the perfusate concentration of sildenafil increased slightly, yet the cumulative amount excreted in bile of sildenafil was increased appreciably. In the prescence of the MRPs inhibitor probenecid, both the perfusate concentration and the cumulative amount excreted in bile of sildenafil increased significantly. When concomitant with amisulpride, a P-gp substrate, the biliary secretion of sildenafil and its metabolite was found to decrease slightly. Conclusion：In this study, we found that all three PDE5 inhibitors underwent active biliary secretion. This study also demonstrated that the disposition of sildenafil was influenced by various inhibitors of membeane transporters. Sildenafil appeared to be a substrate for P-gp, and the role of OATP was limited for hepatic transport of sildenafil. Whether the transporters in sinusolidar membrane are involved in the hepatic disposition of sildenafil or not remains unclear.
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Lin, Pei-Jung, et 林佩蓉. « Phosphodiesterase(PDE)Inhibitors Modulated Spontaneous Action Potential of Snail Central Neurons ». Thesis, 2004. http://ndltd.ncl.edu.tw/handle/00006037855537775825.
Texte intégralRésumé :
碩士國立臺灣大學
藥理學研究所
92
The roles of phosphodiesterase (PDE) on the spontaneous action potentials and the effects of phosphodiesterase (PDE) inhibitors on bursts of potential elicited by d-amphetamine were studied on RP4 neuron of snail, Achatina fulica Ferussac in vitro. PDE inhibitors used include: vinpocetine (PDE1 selective), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, PDE2 selective), milrinone (PDE3 selective), rolipram (PDE4 selective), sildenafil (viagra) (PDE5 selective) and the non-selective inhibitor, caffeine. Vinpocetine, EHNA, milrinone, rolipram and caffeine but not sildenafil (viagra), did elicited bursts of potentials on the RP4 neuron. Calcium free solution or high magnesium solution or U73122 did not block the bursts of potential elicited by rolipram. However, the bursts of potential elicited by rolipram were blocked by KT5720. Similar effects were also found in vinpocetine, EHNA, milrinone and caffeine elicited bursts of potential. These results suggest that vinpocetine, EHNA, milrinone, rolipram or caffeine elicited bursts of potential through cAMP signalling pathways in central neuron of snail. The ionic currents of the RP4 neuron were measured under two electrode voltage clamping. Rolipram significantly decreased the amplitude of total inward currents and outward currents in a concentration-dependent manner, but did not elicit a negative slope resistance (NSR) in current-voltage relationships of steady-state outward currents. These results suggest that the effect was in associate with the phosphodiesterase activity in the neuron. It is concluded that the phosphodiesterase activity plays an important role on the modulation of potentials in the RP4 neuron. Oscillation of membrane potential and bursts of potential were elicited by d-amphetamine, vinpocetine, EHNA, milrinone, rolipram and caffeine in a concentration-dependent manner, while sildenafil (viagra) did not elicit bursts of potential on the RP4 neurons. Caffeine (10 mM), vinpocetine (160 μM), EHNA (300 μM), milrinone (100 μM), rolipram (100 μM) and forskolin (100 μM) potentiate the bursts of potential elicited by d-amphetamine. Sildenafil (Viagra, 1 mM) did not affect the bursts of potentials elicited by d-amphetamine. It is concluded that the bursts of potential elicited by d-amphetamine was associated with the phosphodiesterase activity in the neuron.
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Santos, Ana Isabel Reis dos. « Stimulation of neural stem cell proliferation by inhibition of phosphodiesterase 5 ». Master's thesis, 2011. http://hdl.handle.net/10316/25828.
Texte intégralRésumé :
Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de CoimbraO cGMP é uma molécula sinalizadora que actua como segundo mensageiro e os seus níveis são regulados por um equilíbrio entre a sua produção e a sua hidrólise. O cGMP é sintetizado numa reacção catalisada pela guanilil ciclase solúvel (sGC), cuja activação depende de alguns factores, em particular o óxido nítrico (NO•). O NO• e o cGMP são importantes numa grande variedade de processos biológicos e, nos últimos anos, tem sido dada atenção ao seu envolvimento na formação de novos neurónios – neurogénese. A neurogénese ocorre ao longo da vida adulta no cérebro dos mamíferos e é afectada por vários factores, incluindo o NO•. As fosfodiesterases são enzimas responsáveis pela degradação do cGMP. Em algumas condições, como o envelhecimento, os níveis de cGMP estão diminuídos, podendo estar envolvidos na neurodegeneração relacionada com a idade, na diminuição da neurogénese e no declínio cognitivo. A inibição da hidrólise de cGMP poderá ser uma estratégia para aumentar os níveis de cGMP e, consequentemente, reverter estes efeitos. A fosfodiesterase tipo 5 (PDE5) é específica para a degradação de cGMP e está presente no cérebro. Curiosamente, existem alguns estudos sobre o aumento da neurogénese pelo uso de inibidores da PDE5. Nesta perspectiva, testámos o efeito de três inibidores com diferentes selectividades e potências para a PDE5, o T0156, o sildenafil e o zaprinast, na proliferação de células da zona subventricular. Com este trabalho mostrámos que os inibidores da PDE5 aumentam a proliferação celular, um efeito que parece estar envolvido na activação das vias das MAPK e da sGC. Contudo, estas não parecem ser as únicas vias activadas, sendo necessários mais estudos de modo a esclarecer os possíveis mecanismos envolvidos. De acordo com os resultados obtidos, os inibidores da PDE5 podem tornar-se numa estratégia terapêutica interessante para estimular a neurogénese adulta.
cGMP is a second messenger signaling molecule, whose levels are regulated by an equilibrium between its production and hydrolysis. cGMP is produced in a reaction catalyzed by soluble guanylyl cyclase (sGC) and this enzyme can be activated by factors such as nitric oxide (NO•). NO• and cGMP are important in a wide array of biological processes, and in the last years increasing attention has been given to their involvement in the formation of new neurons – neurogenesis. Neurogenesis occurs during the entire adult life in the mammalian brain, and is affected by several agents, including NO•. Phosphodiesterases are the enzymes responsible for the degradation of cGMP. In several conditions, such as aging, cGMP levels are decreased and may be involved in age-related neurodegeneration, decreased neurogenesis and cognitive decline. The inhibition of cGMP hydrolysis could be a strategy to increasing the levels of cGMP and, consequently, reverse these effects. Phosphodiesterase type 5 (PDE5) is specific for cGMP degradation and is present in the brain. Interestingly, there are a few studies reporting the enhancement of neurogenesis by the use of PDE5 inhibitors. Within this background, we tested the effect of three inhibitors with different selectivity and potency for PDE5, T0156, sildenafil and zaprinast, in the proliferation of subventricular zone cells. With this work we show that PDE5 inhibitors increase cell proliferation, an effect that appears to involve the activation of the sGC and MAPK pathways. However, these do not seem to be the only pathways activated and further studies are needed in order to clarify the mechanisms involved. In agreement with the present results, PDE5 inhibitors may be an interesting therapeutic approach for enhancing adult neurogenesis.
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Wang, Bo-xiang, et 王柏翔. « Effects of phosphodiesterase 3 (PDE3) inhibition on protein expression in 3T3-L1 adipocytes ». Thesis, 2015. http://ndltd.ncl.edu.tw/handle/78146248394350565337.
Texte intégralRésumé :
碩士國立中央大學
生命科學系
103
Cyclic nucleotide phosphodiesterase 3B (PDE3B), a PDE3 family isozyme that hydrolyzes cAMP with high affinity, plays an important role in the regulation of energy homeostasis in adipocytes mainly through regulation of lipolysis, lipogenesis, gluconeogenesis, and glucose uptake. It is known that increasing intracellular cAMP concentration by inhibition of PDE3B triggers rapid lipid degradation, whereas decreasing cAMP level leads to antilipolytic action and lipogenesis. However, the proteins that are regulated by PDE3B in these lipid metabolic processes remain largely undefined. In this study, we used two-dimensional (2-D) gel electrophoresis and mass spectrometry to identify the proteins expressed in mouse 3T3-L1 adipocytes in the presence of the PDE3 inhibitor cilostazol. The initial results showed that three proteins were upregulated in 3T3-L1 cells after treatment with cilostazol and insulin for 18 h. Comparing to the 2-D gel results derived from the cells treated with insulin alone indicates that two of the three proteins were induced in expression by cilostazol. Following the mass spectrometry analysis, these proteins were identified as annexin a2 (ANX A2) and nucleoside diphosphate kinase b (NDPK-B). The third protein upregulated in the presence of cilostazol and insulin was not identified by the method. Further analysis by real-time PCR revealed that ANX A2 and NDPK-B mRNA expression was also upregulated by cilostazol. In a separate experimental setting, 3T3-L1 adipocytes were treated with cilostazol and the β-adrenergic receptor agonist isoproterenol (ISO) for 8 h, followed by 2-D gel analysis. The results showed that in the presence of ISO one protein was upregulated by cilostazol, and mass spectrometry identified it as thioredoxin-1 (TXN-1). This induction in TXN-1 protein also was associated with an increase in mRNA expression. Both TXN-1 and NDPK-B have been shown to inhibit lipogenesis in adipocytes. Thus, we rationalize that inhibition of PDE3B to induce TXN-1 and NDPK-B expression is a mechanism underlying the blockage of lipogenesis by cilostezol. In addition, ANX A2 is implicated in GLUT4 translocation in adipocytes, pointing to a potential role of PDE3 inhibitors in regulation of glucose transport via enhancing ANX A2 expression. This proposed effect, however, awaits further experimental attestation.
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Tseng, Pin Jung, et 曾品榕. « Investigating the interactions of MY-5445, a PDE5 inhibitor, and LY3023414, a PI3K/mTOR dual inhibitor, with MDR-linked ATP-binding cassette proteins ABCB1 and ABCG2 ». Thesis, 2019. http://ndltd.ncl.edu.tw/cgi-bin/gs32/gsweb.cgi/login?o=dnclcdr&s=id=%22107CGU05114084%22.&searchmode=basic.
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Bock, Katrin [Verfasser]. « Untersuchungen zu pharmakologischen Wirkungen des PDE4-Inhibitors Cilomilast und des β2-Agonisten [Beta-2-Agonisten] Isoxsuprin an bovinen Myometriumstreifen, isoliert perfundiertem Uterus und in vivo / vorgelegt von Katrin Bock ». 2004. http://d-nb.info/97392022X/34.
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Selige, Jens Ditmar [Verfasser]. « Pathophysiological relevance of PDE inhibition in lung fibroblasts for the treatment of pulmonary diseases / vorgelegt von Jens Ditmar Selige ». 2010. http://d-nb.info/1011541785/34.
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Yu, Pei-Ju, et 游佩茹. « PDE Inhibitors and cAMP Signaling Regulate IFN-g and IL-17A Release from CD4+ T Cells in Mouse Models of Rheumatoid Arthritis ». Thesis, 2013. http://ndltd.ncl.edu.tw/handle/8rt83f.
Texte intégralRésumé :
碩士國立中央大學
生命科學系
102
Rheumatoid arthritis (RA) is a complicated, chronic autoimmune disorder that affects 1-2% population worldwide. It primarily attacks cartilage and bone of joints. The etiology of the disease still remains to be defined. Accumulating evidence indicates that elevation of intracellular cAMP concentration can suppress a vast spectrum of inflammatory responses in most immune cells and, thereby ameliorate chronic inflammatory diseases, such as asthma, COPD, and atopic dermatitis. Type 4 phosphodiesterases (PDE4s) are the major cAMP-hydrolyzing enzymes in various inflammatory cells. Inhibition of PDE4, thus increasing intracellular cAMP, has been considered an attractive strategy for developing anti-inflammatory drugs. Using collagen-induced arthritis (CIA) models, previous studies show potential benefits of PDE4 inhibitors in RA, while the mechanism of the effect remains unclear. Moreover, the Th1 and Th17 cytokines IFN- and IL-17A, respectively, are known important in the pathogenesis of RA. Therefore, in this study we employed CIA models to access whether PDE4 or cAMP signaling is involved in regulation of Th1 and Th17 responses in RA. By immunization of C57BL/6 and DBA/1 mice with chick collagen II (CII), we found that the disease incidence for the two mouse strains were 45% and 91%, respectively, and the arthritic symptoms developed during 21-42 and 27-33 days, respectively, after collagen immunization. In addition, the C57BL/6 mice, considered genetically resistant to CIA in early studies, also developed severe arthritic conditions. Immunization of DBA/1 mice with CII by different protocols (i.e. the id./id. and id./ip. models) indicated that both models induced the activation of CII-specific Th1 and Th17 cells in the spleen and draining (inguinal) lymph nodes of these mice. In vitro stimulation with CII and/or -CD3 antibody revealed a significant increase in IFN-and IL-17A release in T cells of the two lymphoid tissues from the two models, and these responses were significantly inhibited by the PDE4 inhibitor rolipram except for the release of IL-17A in the inguinal lymph node cells. The non-selective PDE inhibitor IBMX also attenuated IFN- and IL-17A release in these T cells to an extent similar to that of rolipram, indicating PDE4 is the major PDE isozymes in regulation of the Th1 and Th17 responses. Studies with the cAMP-elevating agents dbcAMP and forskolin and with PKA and Epac activators and inhibitors further suggested that the inhibitory effect of rolipram was mediated by activation of the cAMP/PKA axis. The PDE3 inhibitor cilostazol and PDE7 inhibitor BRL 50481 mostly had no effect on the Th1 and Th17 responses, whereas cilostazol showed synergistic effect to the rolipram inhibition. In conclusion, these findings indicate that PDE4 selective inhibitors can efficaciously alleviate inflammation in RA, yet PDE3 and PDE4 dual inhibitors may be more beneficial to RA patients.