Purinergic signaling during intestinal inflammation

Longhi, Maria Serena; Moss, Alan C.; Jiang, Z. Gordon; Robson, Simon C.

doi:10.1007/s00109-017-1545-1

Cited by 77 publications

(65 citation statements)

References 75 publications

(81 reference statements)

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“…CGS21680 (not shown) is an A 2A AR agonist in rat, but has substantial human (h) A 3 AR affinity (Alnouri et al, 2015). Potent A 2A AR agonist ATL-313 5 attenuates colitis in mice and reduces pro-inflammatory cytokines (Longhi et al, 2017). UK-432097 6 is a potent, selective A 2A AR agonist with limited oral bioavailability.…”

Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

“…Intestinal inflammation may cause downregulation of the ectonucleotidases CD39 (E-NTPDase1) and CD73 (5′-nucleotidase), leading to excess nucleotide-dependent proinflammatory effects and deficiency of adenosine-dependent anti-inflammatory effects in the immune and nervous systems (Longhi et al, 2017). CD39 hydrolyzes ATP and ADP to AMP, and CD73 hydrolyzes AMP to adenosine.…”

Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

“…CD39 hydrolyzes ATP and ADP to AMP, and CD73 hydrolyzes AMP to adenosine. Thus, soluble ectonucleotidases and selective A 2A AR agonists have been suggested as therapies for correcting an imbalance of purinergic signaling in inflammatory bowel disease (IBD) and gastrointestinal autoimmunity (Longhi et al, 2017). …”

Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

“…Purinergic receptors are key components of, and function at all levels of enteric neural reflexes and in both intrinsic and extrinsic neural pathways. Furthermore, purinergic signalling is an important regulator in activation and trafficking of immune/inflammatory cells (Cekic and Linden, 2016; Faas et al, 2017; Longhi et al, 2017). Activation of P2Rs generally boosts the immune response, while ARs tend to suppress it.…”

Section: Introductionmentioning

confidence: 99%

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Purinergic drug targets for gastrointestinal disorders

Burnstock

Christofi

2017

Current Opinion in Pharmacology

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Purinergic receptors are implicated in the pathogenesis of gastrointestinal disorders and are being explored as potential therapeutic targets. Gut inflammation releases ATP that acts on neuron, glial, epithelial and immune cells. Purinergic signalling in glia and neurons is implicated in enteric neuropathies. Inflammation activates glia to increase ATP release and alter purinergic signalling. ATP release causes neuronal death and gut motor dysfunction in colitis via a P2X7-dependent neural-glial pathway and a glial purinergic-connexin-43 pathway. The latter pathway also mediates morphine-induced constipation and gut inflammation that may differ from opioid-induced constipation (OIC). P2X7R antagonists are protective in inflammatory bowel disease (IBD) models, where as AZD9056 is questionable in CD, but is potentially beneficial for chronic abdominal pain. Drug targets under investigation for IBD, IBS and motility disorders include P2X7R, P2X3R, P2Y2R, A2A/A2BAR, enzymes and transporters.

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Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

Section: Medicinal Chemistry Of Purinergic Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Purinergic drug targets for gastrointestinal disorders

Burnstock

Christofi

2017

Current Opinion in Pharmacology

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“…Longhi et al focus on the potential role of IBD therapies based on influencing the purinergic signaling pathways [8]. Extracellular signaling mediated by purine nucleotides and nucleosides such as adenosine and adenosine triphosphate (ATP) predominantly associated with signaling in the circulatory system significantly gained attention in its immune response modulatory function.…”

mentioning

confidence: 99%

Novel therapeutic concepts for inflammatory bowel disease—from bench to bedside

2017

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Intestinal Nucleoside Transporters: Function, Expression, and Regulation

Pastor‐Anglada

Urtasun

Pérez-Torras

2018

Comprehensive Physiology

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The gastrointestinal tract is the absorptive organ for nutrients found in foods after digestion. Nucleosides and, to a lesser extent nucleobases, are the late products of nucleoprotein digestion. These metabolites are absorbed by nucleoside (and nucleobase) transporter (NT) proteins. NTs are differentially distributed along the gastrointestinal tract showing also polarized expression in epithelial cells. Concentrative nucleoside transporters (CNTs) are mainly located at the apical side of enterocytes, whereas equilibrative nucleoside transporters (ENTs) facilitate the basolateral efflux of nucleosides and nucleobases to the bloodstream. Moreover, selected nucleotides and the bioactive nucleoside adenosine act directly on intestinal cells modulating purinergic signaling. NT-polarized insertion is tightly regulated. However, not much is known about the modulation of intestinal NT function in humans, probably due to the lack of appropriate cell models retaining CNT functional expression. Thus, the possibility of nutritional regulation of intestinal NTs has been addressed using animal models. Besides the nutrition-related role of NT proteins, orally administered drugs also need to cross the intestinal barrier, this event being a major determinant of drug bioavailability. In this regard, NT proteins might also play a role in pharmacology, thereby allowing the absorption of nucleoside- and nucleobase-derived drugs. The relative broad selectivity of these membrane transporters also suggests clinically relevant drug-drug interactions when using combined therapies. This review focuses on all these physiological and pharmacological aspects of NT protein biology. © 2017 American Physiological Society. Compr Physiol 8:1003-1017, 2018.

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Purinergic signaling during intestinal inflammation

Cited by 77 publications

References 75 publications

Purinergic drug targets for gastrointestinal disorders

Purinergic drug targets for gastrointestinal disorders

Novel therapeutic concepts for inflammatory bowel disease—from bench to bedside

Intestinal Nucleoside Transporters: Function, Expression, and Regulation

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