Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?

Borea, Pier Andrea; Gessi, Stefania; Merighi, Stefania; Varani, Katia

doi:10.1016/j.tips.2016.02.006

Cited by 259 publications

(257 citation statements)

References 141 publications

(155 reference statements)

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“…Therefore, it seems reasonable to think that the variations in AR expression could occur during the early stages of lesion development. In this regard, the up-regulation of A 2A AR by TNF-a and Il-1b could play a protective anti-inflammatory role, as other researchers have suggested (Borea et al, 2016). Otherwise, IFN-a produced by plasmacytoid dendritic cells is one of the key and initial steps in psoriasis pathogenesis contributing to keratinocyte proliferation (Farkas and Kemeny, 2012).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Andrés

Terencio

Arasa

et al. 2017

Journal of Investigative Dermatology

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Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A 2B receptors, human epidermal keratinocytes also express A 2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A 2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A 2A receptors by CGS-21680 induces keratinocyte proliferation via p38emitogen-activated protein kinase activation. Adenosine and selective A 2A and A 2B agonists presented anti-inflammatory profiles independent of adenosine receptors but mediated by membrane phosphatase activation. Finally, keratinocyte exposure to diverse inflammatory cytokines altered adenosine receptor expression by reducing A 2B and increasing A 2A , a pattern also observed in psoriatic epidermis. Because increased epidermal turnover and inflammatory response are characteristics of psoriatic disease, further studies are needed to assess the role and consequences of the altered adenosine receptor expression in lesional and nonlesional psoriatic keratinocytes.

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Section: Discussionmentioning

confidence: 99%

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Andrés

Terencio

Arasa

et al. 2017

Journal of Investigative Dermatology

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“…It plays a major role in the regulation of immune homeostasis [7] . Adenosine inhibits endothelial cell adhesion and superoxide anion production by neutrophils and reduces the release of proinflammatory cytokines by dendritic cells, lymphocytes, and macrophages [8] . Additionally, adenosine A 2A and A 3 receptors are capable of modulating TNF-α release in the murine dendritic cell line XS-106 [9] .…”

mentioning

confidence: 99%

The Effects of Adenosinergic Modulation on Cytokine Levels in a Pentylenetetrazole-Induced Generalized Tonic-Clonic Seizure Model

Dede¹,

Karadenizli²,

Özsoy

et al. 2017

Neuroimmunomodulation

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Objective: It has been suggested that the adenosinergic system and cytokines play a role in the pathogenesis of epilepsy. Although the role of the adenosinergic system in the modulation of seizure activity is well known, the mechanism of this modulation needs to be described in detail. We performed this study to determine the contribution of the proinflammatory cytokines to the generalized seizure activity during adenosine and caffeine treatment. Methods: We induced generalized tonic-clonic seizures with the administration of 60 mg/kg pentylenetetrazole (PTZ) in male Wistar Albino rats. Adenosine (500 mg/kg) or caffeine (5 mg/kg) was administered before PTZ injection. We monitored seizure activity and then determined the TNF-α, IL-1β, and IL-6 levels in the cortical and thalamic brain regions of rats by ELISA. Results: Adenosine pretreatment significantly extended seizure latency (p < 0.05), but did not affect seizure duration and entry time to stage 4 seizure. Caffeine pretreatment did not change seizure latency and seizure duration. PTZ treatment did not change brain cytokine levels significantly (p > 0.05) compared to the control group. Whereas adenosine pretreatment decreased brain TNF-α, IL-1β, and IL-6 levels significantly (p < 0.05), caffeine pretreatment reduced brain cytokine levels slightly but nonsignificantly (p > 0.05). Conclusion: Our results show that there is a clear relation between adenosinergic system and brain tissue cytokine levels. Our findings indicated that TNF-α, IL-1β, and IL-6 participate in the pathogenesis of generalized seizures, and the inhibition of TNF-α, IL-1β, and IL-6 with adenosinergic modulation may decrease seizure severity.

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“…For example, gene therapy directed to ADK through an antisense oligonucleotide is being explored as a means of conserving adenosine by reducing ADK expression in animal models of epilepsy (Boison, 2010). Promisingly, adenosine has also been delivered directly to the brain ventricles of epileptic rats, thereby reducing DNA methylation and slowing disease progression (Borea et al, 2016).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Pharmacological targeting of adenosine receptor signaling

Peleli

Fredholm

Sobrevía

et al. 2017

Molecular Aspects of Medicine

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Please cite this article as: Peleli, M., Fredholm, B., Sobrevia, L., Carlström, M., Pharmacological targeting of adenosine receptor signaling, Molecular Aspects of Medicine (2017Medicine ( ), doi: 10.1016Medicine ( / j.mam.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractAdenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo. Moreover, we discuss several potential ways to overcome these obstacles (i.e., the use of partial agonists, indirect receptor targeting, allosteric enhancers, prodrugs, non-receptor-mediated effects, neoreceptors, conditional knockouts). It is important to address these concerns during development of new and successful therapeutic approaches targeting the adenosine system.

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Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?

Cited by 259 publications

References 141 publications

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis

The Effects of Adenosinergic Modulation on Cytokine Levels in a Pentylenetetrazole-Induced Generalized Tonic-Clonic Seizure Model

Pharmacological targeting of adenosine receptor signaling

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