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Effect of non-selective PDE inhibitors on histamine release. The effects of either IBMX (□) or theophylline (•) on the release of histamine from basophils (a) or HLMC (b) were determined. Cells were incubated for 15 min with a PDE inhibitor before challenge with anti-IgE (1: 3000, basophils; 1:300, HLMC) for a further 45 (basophils) or 25 (HLMC) min. Results are expressed as the % inhibition of the control releases which were 41 ± 8% (basophils) and 31 ± 5% (HLMC). Statistically significant (P < 0.05 at least) levels of inhibition are indicated by an asterisk. Values are means, n = 5 (basophils) and n = 7 (HLMC); vertical lines show s.e.mean.
Source publication
The non-hydrolysable cyclic AMP analogue, dibutyryl (Bu2)-cyclic AMP, inhibited the stimulated release of histamine from both basophils and human lung mast cells (HLMC) in a dose-dependent manner. The concentrations required to inhibit histamine release by 50% (IC50) were 0.8 and 0.7 mM in basophils and HLMC, respectively. The cyclic GMP analogue,...
Context in source publication
Context 1
... classical, non-speci®c PDE inhibitors, IBMX and theophylline, inhibited the IgE-mediated release of histamine from both basophils and HLMC (Figure 2). IBMX was a more potent inhibitor than theophylline of IgE-mediated histamine release in both cell types and the eects of both PDE inhibitors were more pronounced in basophils than in HLMC. ...
Citations
... This document is contrary to our results obtained by flow cytometry assessment, which showed inhibition of Th1 proliferation without a significant difference in the apoptosis percentage of PBMCs after treatment with M-Pre-A, compared to the DMSO group. Furthermore, investigating anti-proliferative effect of M-Pre in another autoimmune disease (32,33) showed that using different doses of M-Pre, at least 48% inhibition of PBMC proliferation was prohibited in Rheumatoid Arthritis (RA) patients. Additiotnally, by compring healthy people and RA patients, it was indicated that size of this prohibitory effect on PBMCs was not significant. ...
Objective:
In spite of the advances in therapeutic modalities, morbidity, due to multiple sclerosis (MS), still remains high. Therefore, a large body of research is endeavouring to discover or develop novel therapies with improved efficacy for treating MS patients. In the present study, we examined the immunomodulatory effects of apigenin (Api) on peripheral blood mononuclear cells (PBMCs) isolated from MS patients. We also developed an acetylated form of Api (apigenin- 3-acetate) to improve In its blood-brain barrier (BBB) permeability. Additionally, we compared its anti-inflammatory properties to original Api and methyl-prednisolone-acetate (a standard therapy), as a potential option in treating MS patients.
Materials and methods:
The current study was an experimental-interventional research. The half maximal inhibitory concentration (IC50) values for apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate were determined in healthy volunteers' PBMCs (n=3). Gene expressions of T-box transcription factor (TBX21 or T-bet) and IFN-γ, as well as proliferation of T cells isolated from MS patients' PBMCs (n=5), were examined in co-cultures of apigenin-3-acetate, Api and methyl-prednisolone-acetate after 48 hours of treatment, using quantitative reverse transcription polymerase chain reaction (qRT-PCR).
Results:
Our findings showed that apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate at concentrations of 80, 80, and 2.5 M could inhibit Th1 cell proliferation after 48 hours (P=0.001, P=0.036, and P=0.047, respectively); they also inhibited T-bet (P=0.015, P=0.019, and P=0.022) and interferon-γ (IFN-γ) gene expressions (P=0.0001).
Conclusion:
Our findings suggested that Api may have anti-inflammatory properties, possibly by inhibiting proliferation of IFN-producing Th1 cells. Moreover, comparative immunomodulatory effects were found for the acetylated version of apigenin-3-acetate versus Api and methyl-prednisolone-acetate.
... Cyclic-AMP is one of the most effective inhibitors of basophil function and can therefore inhibit the stimulated release of histamine. Leukotriene and histamine release were attenuated by PDE4-I (rolipram, denbufylline, Ro 20-1724 and RP 73401), however, not by PDE1-I (8methoxymethyl and IBMX), PDE3-I (siguazodan, SKF 94120 and SKF 95654) or PDE5-I (zaprinast) in human basophils [104]. Interestingly, human basophils express PDE4A and PDE4D, but little PDE4B or C mRNA or protein [105]. ...
The pleiotropic function of 3′,5′‐cyclic adenosine monophosphate (cAMP)‐dependent
pathways in health and disease led to the development of pharmacological phosphodiesterase inhibitors (PDE‐I) to attenuate cAMP degradation. While there are many isotypes of PDE, a predominant role of PDE4 is to regulate fundamental functions, including endothelial and epithelial barrier stability, modulation of inflammatory responses and cognitive and/or mood functions. This makes the use of PDE4‐I an interesting tool for various therapeutic approaches. However, due to the presence of PDE4 in many tissues, there is a significant danger for serious side effects. Based on this, the aim of this review is to provide a comprehensive overview of the approaches and effects of PDE4‐Ifor different therapeutic applications. In summary, despite many obstacles to use of PDE4‐I for different therapeutic approaches, the current data warrant future research to utilize the therapeutic potential of phosphodiesterase 4 inhibition.
... It is also expressed in the airways smooth muscle, brain, and cardiovascular tissues, being the most characterized PDE isoenzyme (Boswell-Smith et al., 2006). The first generation of PDE4 inhibitors showed effective reduction of a wide range of inflammatory cell functions in vitro observed in eosinophils, lymphocytes, basophils, and neutrophils (Nielson et al., 1990;Weston et al., 1997;Giembycz et al., 1996;Dent et al., 1991). Furthermore, they were highly effective at suppressing inflammation in animal models of respiratory disease (Torphy and Undem, 1991). ...
The respiratory tract is constantly exposed to environmental aggressions including allergens, infections, and pollution. The immune system is pivotal to fight potential invaders and prevent the establishment of infections in the respiratory tract; however, excessive, misplaced or altered immune responses contribute to increase tissue damage, impair lung function, and exacerbate respiratory diseases. Indeed, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis are respiratory diseases that have uncontrolled inflammation as a unifying severity factor. In addition, the acute inflammatory responses in pneumonia must be controlled to avoid progression to acute respiratory distress syndrome, which can be lethal. In this regard, immunomodulatory therapies are promising pharmacological strategies to treat important respiratory pathologies. Understanding the pathogenesis of respiratory disorders have paved the way for the development of cytokine-directed therapies, allosteric or non-allosteric inhibitors of inflammatory receptors and enzymes, agonists of resolution of inflammation and other anti-inflammatory compounds. A multitude of studies have evaluated the safety, pharmacokinetics, and pharmacodynamics of several molecules that target inflammation in the respiratory tract, yet only few have been translated to clinical use. This article will summarize important aspects of asthma, COPD, cystic fibrosis, and pneumonia focusing on the role of immune responses in disease development and novel immunomodulatory therapies.
... It was shown that hypothemycin blocked FcεRI-mediated activation of MCs and also cytokine production from MCs by inhibiting Kit kinase activity (41). Moreover, inhibitors of phosphodiesterases are considered to be chemical stabilizers of MCs due to the fact that they inhibit the activation of MCs (42). Recently, there is an emerging interest to plant-derived mast cell stabilizers, quercetin and luteolin. ...
SARS-CoV-2(COVID-19) leads to severe acute respiratory syndrome by settling the pulmonary system. Mast cells (MCs) are multifunctional immune cells that are extensively distributed throughout the body and mostly present in pulmonary system. MCs play a vital role in acquired and innate immunity, and to maintain immune homeostasis of the body through a wide range of mediators in their cytoplasmic granules. Severe acute respiratory syndrome with proinflammatory cytokine release and pneumonia during COVID-19 infection can result in the death, in particular in debilitated individuals or those suffering from related chronic disorders. In this review, we attempt to discuss potential relationship between COVID-19 symptoms and mast cells as well as potential use of mast cell stabilizers as a supportive therapeutic option in COVID-19 infection. MCs are main source of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α as well as bronchoconstrictor mediators such as histamine, prostaglandin-D2 and leukotriene-C4 that can lead to fatal inflammatory responses and pulmonary complications during COVID-19 infection. SARS-CoV-2 may activate MCs through toll-like receptors or by inducing the cross-linking of the IgE-FcεRI, thus leading to release of those mediators. SARS-CoV-2-induced abnormal production and release of these mediators from MCs can further exacerbate inflammation in respiratory system, consequently pulmonary complications.Therefore administration of MC stabilizers as a supportive therapy may be useful to alleviate inflammatory responses and pulmonary complications in order to reduce deaths from SARS-CoV-2 infection.
... En effet, l'IBMX possède une affinité pour les récepteurs à l'adénosine évaluée aux environs de 1 à 10 µM (Nicholson et al., 1989) et pourrait bloquer l'action autocrine de l'adénosine (Morgan et al., 1993). De plus, dans la mesure où l'IBMX a une capacité à inhiber les PDE quantifiée par son IC50 aux environs de 2 à 50 µM (Beavo, 1995;Weston et al., 1997), il ne semble pas justifié d'utiliser des concentrations d'IBMX aussi élevées que 1 mM. ...
Les opiacés demeurent des molécules incontournables dans le traitement des douleurs moyennes à sévères. Si leur efficacité dans le traitement de la douleur aiguë est incontestable, leur utilisation chronique est responsable de nombreux effets indésirables comprenant une hypersensibilité à la douleur et une tolérance à leurs effets analgésiques. Une partie de ces effets secondaires résulteraient de l’activation de systèmes anti-opioïdes endogènes, comme les neuropeptides RF-amide, dont des études précédentes suggèrent une complémentarité de fonctionnement dans la modulation de la douleur. Le premier axe de travail de cette thèse fut de développer les outils moléculaires afin d’étudier la possibilité d’interactions fonctionnelles et d’hétérodimérisation de ces récepteurs, en particulier GPR103 et NPFF1R. Nous avons ainsi pu générer et caractériser des lignées cellulaires exprimant les différents récepteurs à peptide RF-amide avec un fluorophore fusionné à leur extrémité amino-terminale. En parallèle, nous avons pu développer au cours d’une collaboration fructueuse avec deux équipes de chimistes un ligand à dualité d’action, agoniste opioïdergique et antagoniste des récepteurs NPFF1R et NPFF2R. Chez la souris, nous avons montré que l’administration sous-cutanée de ce composé produit une analgésie longue durée, qui n’est pas atténuée par le développement de tolérance analgésique ou d’hyperalgésie après une semaine d’administration quotidienne. Le syndrome de sevrage, précipité par la naltrexone est plus faible après l’administration chronique de ce composé qu’avec l’agoniste opioïdergique de référence. De plus, grâce à ses caractéristiques d’agoniste biaisé sur le récepteur MOR, cette molécule induit une plus faible dépression respiratoire chez la souris.
... This method generated approximately 6 x 10 5 mast cells per g of tissue. Mast cells of enhanced purity 10-69% purity; median 35%) were generated by flotation over discontinuous Percoll gradients (Weston et al., 1997). Mast cells were further purified using a MACS magnetic cell sorting system (Miltenyi Biotec, Surrey, UK) according to the manufacturer's instructions and as described in detail elsewhere (Havard et al., 2011). ...
Mast cells are an exceptionally rich source of prostaglandin D2 (PGD2). PGD2 is pro-inflammatory and can cause bronchoconstriction. The enzyme cyclooxygenase (COX) is central to the generation of prostanoids such as PGD2. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX. COX exists as two isoforms, COX-1 and COX-2. The principal aim of this study was to establish whether COX-1 and/or COX-2 mediates PGD2 generation from human lung mast cells. Mast cells were isolated from human lung tissue and purified by flotation over Percoll and immunomagnetic bead separations. The cells were activated with anti-IgE or Stem Cell Factor (SCF). The generation of PGD2 was determined by ELISA. The effects of NSAIDs (aspirin, ibuprofen, diclofenac, naproxen, indomethacin), COX-1 selective (FR122047), and COX-2 selective (celecoxib) inhibitors on PGD2 generation were determined. The expression of COX-1 and COX-2 in mast cells was determined by Western blotting. All the NSAIDs tested abrogated stimulated PGD2 generation from mast cells except aspirin which was only weakly effective. FR122047 was an effective inhibitor of PGD2 generation (EC50 ~25 nM) from mast cells whereas celecoxib was ineffective. Immunoblotting indicated that COX-1 was strongly expressed in all mast cell preparations while COX-2 expression was weak. No induction of COX-2 was observed following activation of mast cells. These findings indicate that COX-1 is the principal isoform involved in generating PGD2 from human lung mast cells. These studies provide insight into the potential behaviour of NSAIDs in the context of respiratory diseases.
... 10,11 Later studies have shown that these same compounds can inhibit the stimulated generation of eicoanoids and cytokines from these cells. [12][13][14][15][16] These inhibitory effects of IBMX and theophylline are likely to be mediated by cAMP rather than cGMP as non-hydrolysable analogues of cAMP, but not analogues of cGMP, inhibit mast cell and basophil activity. 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. ...
... [12][13][14][15][16] These inhibitory effects of IBMX and theophylline are likely to be mediated by cAMP rather than cGMP as non-hydrolysable analogues of cAMP, but not analogues of cGMP, inhibit mast cell and basophil activity. 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. 13,14 The effects of selective inhibitors of PDE1 (8-methoxy-methyl-IBMX), PDE3 (siguazodan), PDE4 (rolipram), and PDE5 (zaprinast) on human basophil and mast cell function demonstrate that, of these selective inhibitors, only inhibitors of PDE4 are effective at preventing the stimulated release of histamine, eicosanoids, and cytokines from basophils. ...
... 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. 13,14 The effects of selective inhibitors of PDE1 (8-methoxy-methyl-IBMX), PDE3 (siguazodan), PDE4 (rolipram), and PDE5 (zaprinast) on human basophil and mast cell function demonstrate that, of these selective inhibitors, only inhibitors of PDE4 are effective at preventing the stimulated release of histamine, eicosanoids, and cytokines from basophils. By contrast, none of the isoformselective inhibitors, including several PDE4selective inhibitors, has any effect on mediator release from human lung mast cells. ...
Cyclic nucleotide phosphodiesterase (PDE) exists as multiple molecular forms. Of the 11 families of PDE identified so far, PDE4, a cAMP-specific PDE, has been identified as the major isoform regulating inflammatory activity. The principle aim of the present study was to determine whether human basophils and human lung mast cells express PDE4. Four sub-classes of PDE4 (A, B, C, and D) have been identified and expression of these was determined by RT-CPR and by western blotting. In basophils, prominent expression of mRNA for PDE4A and PDE4D was observed whereas little if any expression of PDE4B and PDE4C was detected. These findings were paralleled by immunoblotting experiments as human basophils were found to express PDE4A and PDE4D with little evidence for the presence of either PDE4B or PDE4C. By contrast, human lung mast cells expressed very little, if any, mRNA for PDE4 sub-classes although, in some preparations, some modest levels of mRNA for PDE4D were detected. However, there was no evidence, at the protein level, that mast cells express PE4. Overall, these data indicate that basophils express PDE4 (4A and 4D) whereas human lung mast cells do not.
... 10,11 Later studies have shown that these same compounds can inhibit the stimulated generation of eicoanoids and cytokines from these cells. [12][13][14][15][16] These inhibitory effects of IBMX and theophylline are likely to be mediated by cAMP rather than cGMP as non-hydrolysable analogues of cAMP, but not analogues of cGMP, inhibit mast cell and basophil activity. 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. ...
... [12][13][14][15][16] These inhibitory effects of IBMX and theophylline are likely to be mediated by cAMP rather than cGMP as non-hydrolysable analogues of cAMP, but not analogues of cGMP, inhibit mast cell and basophil activity. 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. 13,14 The effects of selective inhibitors of PDE1 (8-methoxy-methyl-IBMX), PDE3 (siguazodan), PDE4 (rolipram), and PDE5 (zaprinast) on human basophil and mast cell function demonstrate that, of these selective inhibitors, only inhibitors of PDE4 are effective at preventing the stimulated release of histamine, eicosanoids, and cytokines from basophils. ...
... 14 Moreover, extracts of mast cells and basophils hydrolyze cAMP but neither cell contains any noteworthy cGMP hydrolytic activity. 13,14 The effects of selective inhibitors of PDE1 (8-methoxy-methyl-IBMX), PDE3 (siguazodan), PDE4 (rolipram), and PDE5 (zaprinast) on human basophil and mast cell function demonstrate that, of these selective inhibitors, only inhibitors of PDE4 are effective at preventing the stimulated release of histamine, eicosanoids, and cytokines from basophils. By contrast, none of the isoformselective inhibitors, including several PDE4selective inhibitors, has any effect on mediator release from human lung mast cells. ...
Cyclic nucleotide phosphodiesterase (PDE) exists as multiple molecular forms. Of the 11 families of PDE identified so
far, PDE4, a cAMP-specific PDE, has been identified as the major isoform regulating inflammatory activity. The principle
aim of the present study was to determine whether human basophils and human lung mast cells express PDE4. Four
sub-classes of PDE4 (A, B, C, and D) have been identified and expression of these was determined by RT-CPR and by
western blotting. In basophils, prominent expression of mRNA for PDE4A and PDE4D was observed whereas little if
any expression of PDE4B and PDE4C was detected. These findings were paralleled by immunoblotting experiments as
human basophils were found to express PDE4A and PDE4D with little evidence for the presence of either PDE4B or
PDE4C. By contrast, human lung mast cells expressed very little, if any, mRNA for PDE4 sub-classes although, in some
preparations, some modest levels of mRNA for PDE4D were detected. However, there was no evidence, at the protein
level, that mast cells express PE4. Overall, these data indicate that basophils express PDE4 (4A and 4D) whereas human
lung mast cells do not.
... The IC 50 (the concentration of inhibitor to inhibit 50% of substrate activity) value of rolipram against a particular isoform of PDE4 depends on the cellular environment in which the enzyme is expressed and the intracellular compartment to which it is targeted. [38,39] Unlike rolipram, the potency of other inhibitors such as piclamilast (RP 73401) against PDE4 is for more consistent, suggesting that the two inhibitors interact differently with the enzyme. [40] Consideration of these multiple conformations of PDE4 is relevant for drug design because it has been proposed that the low-affinity conformation is associated with therapeutic effects of PDE4 inhibitors, whereas the high-affinity conformation correlates with central nervous system and the gastric side effects of PDE4 compounds. ...
Cyclic nucleotide phosphodiesterases (PDEs) are known as a super-family of enzymes which catalyze the metabolism of the intracellular cyclic nucleotides, cyclic-3',5'-adenosine monophosphate (cAMP), and cyclic-3',5'-guanosine monophosphate that are expressed in a variety of cell types that can exert various functions based on their cells distribution. The PDE4 family has been the focus of vast research efforts over recent years because this family is considered as a prime target for therapeutic intervention in a number of inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and rheumatoid arthritis, and it should be used and researched by pharmacists. This is because the major isoform of PDE that regulates inflammatory cell activity is the cAMP-specific PDE, PDE4. This review discusses the relationship between PDE4 and its inhibitor drugs based on structures, cells distribution, and pharmacological properties of PDE4 which can be informative for all pharmacy specialists.
... Many selective PDE inhibitors have been designed, including the use of PDE2 inhibitors in sepsis; PDE4 inhibitors in asthma, allergic rhinitis, multiple sclerosis and psoriasis; and PDE5 inhibitors in sexual dysfunction, cardiovascular disease, and pulmonary hypertension. Some PDE inhibitors have been found to possess mast cell stabilising activity (Weston et al., 1997). Theophylline has been long used to treat asthma because of its antiinflammatory and bronchodilator activities, as well as its ability to increase diaphragm contractility. ...
Mast cells play a critical role in type 1 hypersensitivity reactions. Indeed, mast cell mediators are implicated in many different conditions including allergic rhinitis, conjunctivitis, asthma, psoriasis, mastocytosis and the progression of many different cancers. Thus, there is intense interest in the development of agents which prevent mast cell mediator release or which inhibit the actions of such mediators once released into the environment of the cell. Much progress into the design of new agents has been made since the initial discovery of the mast cell stabilising properties of khellin from Ammi visnaga and the clinical approval of cromolyn sodium. This review critically examines the progress that has been made in the intervening years from the design of new agents that target a specific signalling event in the mast cell degranulation pathway to those agents which have been developed where the precise mechanism of action remains elusive. Particular emphasis is also placed on clinically used drugs for other indications that stabilise mast cells and how this additional action may be harnessed for their clinical use in disease processes where mast cells are implicated.
Copyright © 2015. Published by Elsevier B.V.
