The potential of methylxanthine-based therapies in pediatric respiratory tract diseases

Oñatibia-Astibia, Ainhoa; Martínez‐Pinilla, Eva; Franco, Rafael

doi:10.1016/j.rmed.2016.01.022

Cited by 48 publications

(51 citation statements)

References 92 publications

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“…This is in contrast to studies reporting a reduction of TNF-α expression via nonselective PDE inhibition in monocytes, lymphocytes, and whole blood at lower caffeine concentrations [80–82]. The promoter of TNF-α contains a cAMP response element [83] and we found an induction of CTGF mRNA by cAMP which could have subsequently been provoked via caffeine-mediated increase of cAMP [53]. Thus, one may speculate that caffeine might have also induced TNF-α mRNA expression via cAMP in our setting, although we still observed unmodified TNF-α mRNA levels after exogenous cAMP, which is again questioning this assumption.…”

Section: Discussioncontrasting

confidence: 99%

“…We may further attribute the caffeine-mediated induction of CTGF expression, observed at very early time points, to caffeine-mediated increases in cytosolic cAMP [53]. Moreover, an indirect induction of short-lived CTGF mRNA-degrading proteins by caffeine in consequence of this initial induction could be jointly responsible for the long-term reduction of CTGF.…”

Section: Discussionmentioning

confidence: 99%

“…Such short-lived proteins have been suggested to be induced after upregulation of CTGF mRNA to prevent uncontrolled CTGF expression [14]. As far as cAMP is concerned, it is possible that its early rising levels provoked by caffeine [53] mediated an induction of CTGF mRNA which may be later antagonized by TNF-α.…”

Section: Discussionmentioning

confidence: 99%

“…At higher concentrations, caffeine may act as an unspecific inhibitor of PDEs increasing intracellular levels of cAMP. At lower concentrations, predominantly nonselective antagonism on adenosine receptors but also roles in histone acetylation and deacetylation have been reported [50–53]. …”

Section: Introductionmentioning

confidence: 99%

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Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

Fehrholz¹,

Glaser²,

Speer³

et al. 2017

Respir Res

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BackgroundAlthough caffeine and glucocorticoids are frequently used to treat chronic lung disease in preterm neonates, potential interactions are largely unknown. While anti-inflammatory effects of glucocorticoids are well defined, their impact on airway remodeling is less characterized. Caffeine has been ascribed to positive effects on airway inflammation as well as remodeling. Connective tissue growth factor (CTGF, CCN2) plays a key role in airway remodeling and has been implicated in the pathogenesis of chronic lung diseases such as bronchopulmonary dysplasia (BPD) in preterm infants. The current study addressed the impact of glucocorticoids on the regulation of CTGF in the presence of caffeine using human lung epithelial and fibroblast cells.MethodsThe human airway epithelial cell line H441 and the fetal lung fibroblast strain IMR-90 were exposed to different glucocorticoids (dexamethasone, budesonide, betamethasone, prednisolone, hydrocortisone) and caffeine. mRNA and protein expression of CTGF, TGF-β1-3, and TNF-α were determined by means of quantitative real-time PCR and immunoblotting. H441 cells were additionally treated with cAMP, the adenylyl cyclase activator forskolin, and the selective phosphodiesterase (PDE)-4 inhibitor cilomilast to mimic caffeine-mediated PDE inhibition.ResultsTreatment with different glucocorticoids (1 μM) significantly increased CTGF mRNA levels in H441 (p < 0.0001) and IMR-90 cells (p < 0.01). Upon simultaneous exposure to caffeine (10 mM), both glucocorticoid-induced mRNA and protein expression were significantly reduced in IMR-90 cells (p < 0.0001). Of note, 24 h exposure to caffeine alone significantly suppressed basal expression of CTGF mRNA and protein in IMR-90 cells. Caffeine-induced reduction of CTGF mRNA expression seemed to be independent of cAMP levels, adenylyl cyclase activation, or PDE-4 inhibition. While dexamethasone or caffeine treatment did not affect TGF-β1 mRNA in H441 cells, increased expression of TGF-β2 and TGF-β3 mRNA was detected upon exposure to dexamethasone or dexamethasone and caffeine, respectively. Moreover, caffeine increased TNF-α mRNA in H441 cells (6.5 ± 2.2-fold, p < 0.05) which has been described as potent inhibitor of CTGF expression.ConclusionsIn addition to well-known anti-inflammatory features, glucocorticoids may have adverse effects on long-term remodeling by TGF-β1-independent induction of CTGF in lung cells. Simultaneous treatment with caffeine may attenuate glucocorticoid-induced expression of CTGF, thereby promoting restoration of lung homeostasis.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

Fehrholz¹,

Glaser²,

Speer³

et al. 2017

Respir Res

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“…Methylxanthines are phytochemicals found in plants such as coffee, tea, mate, kola nuts and cacao beans [2]. Thus far, seven natural methylxanthines have been identified: aminophylline, caffeine, IBMX, paraxanthine, pentoxifylline, theobromine and theophylline [3]. Plants containing methylxanthines are often used to produce beverages such as coffee, tea, cacao, tejate and several other methylxanthine containing foods, which have been consumed on a daily basis [2].…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Embryo as an In Vivo Model for Behavioral and Pharmacological Characterization of Methylxanthine Drugs

Basnet

Guarienti

Memo

2017

IJMS

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Zebrafish embryo is emerging as an important tool for behavior analysis as well as toxicity testing. In this study, we compared the effect of nine different methylxanthine drugs using zebrafish embryo as a model. We performed behavioral analysis, biochemical assay and Fish Embryo Toxicity (FET) test in zebrafish embryos after treatment with methylxanthines. Each drug appeared to behave in different ways and showed a distinct pattern of results. Embryos treated with seven out of nine methylxanthines exhibited epileptic-like pattern of movements, the severity of which varied with drugs and doses used. Cyclic AMP measurement showed that, despite of a significant increase in cAMP with some compounds, it was unrelated to the observed movement behavior changes. FET test showed a different pattern of toxicity with different methylxanthines. Each drug could be distinguished from the other based on its effect on mortality, morphological defects and teratogenic effects. In addition, there was a strong positive correlation between the toxic doses (TC 50 ) calculated in zebrafish embryos and lethal doses (LD 50 ) in rodents obtained from TOXNET database. Taken together, all these findings elucidate the potentiality of zebrafish embryos as an in vivo model for behavioral and toxicity testing of methylxanthines and other related compounds.

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Health benefits of methylxanthines in neurodegenerative diseases

Oñatibia-Astibia¹,

Franco

Martínez‐Pinilla

2017

Molecular Nutrition Food Res

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Methylxanthines (MTXs) are consumed by almost everybody in almost every area of the world. Caffeine, theophylline and theobromine are the most well-known members of this family of compounds; they are present, inter alia, in coffee, tea, cacao, yerba mate and cola drinks. MTXs are readily absorbed in the gastrointestinal tract and are able to penetrate into the central nervous system, where they exert significant psychostimulant actions, which are more evident in acute intake. Coffee has been paradigmatic, as its use was forbidden in many diseases, however, this negative view has radically changed; evidence shows that MTXs display health benefits in diseases involving cell death in the nervous system. This paper reviews data that appraise the preventive and even therapeutic potential of MTXs in a variety of neurodegenerative diseases. Future perspectives include the use of MTXs to advance the understanding the pathophysiology of, inter alia, Alzheimer's disease (AD) and Parkinson's disease (PD), and the use of the methylxanthine chemical moiety as a basis for the development of new and more efficacious drugs.

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The potential of methylxanthine-based therapies in pediatric respiratory tract diseases

Cited by 48 publications

References 92 publications

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

Caffeine modulates glucocorticoid-induced expression of CTGF in lung epithelial cells and fibroblasts

Zebrafish Embryo as an In Vivo Model for Behavioral and Pharmacological Characterization of Methylxanthine Drugs

Health benefits of methylxanthines in neurodegenerative diseases

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