Adenosine inhibits human astrocyte proliferation independently of adenosine receptor activation

Marcelino, Helena; Nogueira, Vanda; Santos, Cecília R. A.; Quelhas, Patrícia; Carvalho, Tiago Miguel Amaral; Fonseca-Gomes, João; Tomás, Joana; Diógenes, Maria José; Sebastião, Ana M.; Cascalheira, José F.

doi:10.1111/jnc.14937

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…Although Ado signaling ends upon intracellular incorporation of the purine via equilibrative nucleotide transporters, notably ENT1 and ENT2 (Eckle et al, 2013;Eltzschig et al, 2005;Griffiths et al, 1997), this transport of Ado across the cellular membrane marks the beginning of Ado salvage. Recent purine analyses of cultured T84 IECs and murine colon tissue extracts revealed relatively low Ado levels in general , suggesting that intracellular Ado is quickly metabolized, perhaps in an effort to minimize [Ado] to limit the inhibition of pyrimidine biosynthesis and ultimately proliferation (Hershfield et al, 1977;Ishii and Green, 1973;Marcelino et al, 2019). Interestingly, hypoxia, such as that associating with mucosal inflammation, represses adenosine kinase activity, leaving adenosine deaminase to metabolize the incorporated Ado into Ino (Morote- Garcia et al, 2008).…”

Section: Access Isciencementioning

confidence: 99%

Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function

et al. 2020

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The intestinal mucosa requires high levels of nucleotides for energy procurement, proliferation, and innate immunity. This need for nucleotide substrates substantially increases during injury, infection, and wound healing. In the present studies, we profile potential sources of purine nucleotides in murine mucosal tissue. This work reveals the gut microbiota as a prominent source of exogenous purines and that such microbiota-sourced purines (MSPs) are available to the intestinal mucosa. The MSPs are utilized for nucleotide genesis and promote energy balance. Further analyses reveal that colitic tissues lacking MSPs are proliferatively stunted, with notable energetic and endoplasmic reticulum stress to the detriment of mucous barrier integrity. Purine reconstitution either directly or through colonization of germ-free/antibiotic-treated mice with MSP-sufficient E. coli alleviates such deficits, establishing MSP as a critical source of substrate for tissue metabolism, wound healing, and mucous barrier sterile integrity.

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Section: Access Isciencementioning

confidence: 99%

Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function

et al. 2020

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“…Moreover, the blockade of A 2A receptor was also able to revert dipyridamole-mediated increase in mMP. We are confident that the concentration of each antagonist used in our experiments was sufficient to block each receptor; in fact, 15 µM DPCPX and 10 µM SCH58261 were already employed to block A 1 R and A 2A R in astrocytes [ 35 ] while A 2B R (500 nM PSB603) and A 3 R (1 μM MRS1334) antagonists were used at the highest concentration that was found non-toxic for cells. These data demonstrate that dipyridamole treatment of NPC1 fibroblasts increases extracellular levels of adenosine, which, in turn, stimulates the A 2A R subtype to reduce cholesterol accumulation and increase mMP.…”

Section: Discussionmentioning

confidence: 92%

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Pepponi

Simone

Nuccio

et al. 2022

IJMS

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Niemann Pick type C disease (NPC) is a rare disorder characterized by lysosomal lipid accumulation that damages peripheral organs and the central nervous system. Currently, only miglustat is authorized for NPC treatment in Europe, and thus the identification of new therapies is necessary. The hypothesis addressed in this study is that increasing adenosine levels may represent a new therapeutic approach for NPC. In fact, a reduced level of adenosine has been shown in the brain of animal models of NPC; moreover, the compound T1-11, which is able to weakly stimulate A2A receptor and to increase adenosine levels by blocking the equilibrative nucleoside transporter ENT1, significantly ameliorated the pathological phenotype and extended the survival in a mouse model of the disease. To test our hypothesis, fibroblasts from NPC1 patients were treated with dipyridamole, a clinically-approved drug with inhibitory activity towards ENT1. Dipyridamole significantly reduced cholesterol accumulation in fibroblasts and rescued mitochondrial deficits; the mechanism elicited by dipyridamole relies on activation of the adenosine A2AR subtype subsequent to the increased levels of extracellular adenosine due to the inhibition of ENT1. In conclusion, our results provide the proof of concept that targeting adenosine tone could be beneficial in NPC.

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“…Similarly, the adenosine concentration in the extracellular space was regulated and adenosine’s action on its membrane receptors was modified by ADA in human [ 39 , 40 ]. Moreover, the delay in cell growth before 24 h may result from events associated with the accumulation of extracellular adenosine, which inhibited cell proliferation, and resulted in the further deceleration of the nitrogen uptake [ 41 , 42 ]. Additionally, Hoshinoa et al revealed that the removal of endogenous adenosine by ADA resulted in an immediate rise in lipolytic activity [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Functional Characterization of Adenosine Deaminase in Mucor circinelloides: A Novel Potential Regulator of Nitrogen Utilization and Lipid Biosynthesis

Yang

Mohamed

et al. 2022

JoF

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Adenosine deaminase (ADA) is an enzyme distributed in a wide variety of organisms that cleaves adenosine into inosine. Since inosine plays an important role in nitrogen metabolism, ADA may have a critical function in the regulation of fatty acid synthesis. However, the role of ADA in oleaginous fungi has not been reported so far. Therefore, in this study, we identified one ada gene encoding ADA (with ID scaffold0027.9) in the high lipid-producing fungus, Mucor circinelloides WJ11, and investigated its role in cell growth, lipid production, and nitrogen metabolism by overexpressing and knockout of this gene. The results showed that knockout of the ada altered the efficiency of nitrogen consumption, which led to a 20% increment in the lipid content (25% of cell dry weight) of the engineered strain, while overexpression of the ada showed no significant differences compared with the control strain at the final growth stage; however, interestingly, it increased lipid accumulation at the early growth stage. Additionally, transcriptional analysis was conducted by RT-qPCR and our findings indicated that the deletion of ada activated the committed steps of lipid biosynthesis involved in acetyl-CoA carboxylase (acc1 gene), cytosolic malic acid enzyme (cme1 gene), and fatty acid synthases (fas1 gene), while it suppressed the expression of AMP-activated protein kinase (ampk α1 and ampk β genes), which plays a role in lipolysis, whereas the ada-overexpressed strain displayed reverse trends. Conclusively, this work unraveled a novel role of ADA in governing lipid biosynthesis and nitrogen metabolism in the oleaginous fungus, M. circinelloides.

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Adenosine inhibits human astrocyte proliferation independently of adenosine receptor activation

Cited by 8 publications

References 52 publications

Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function

Microbiota-Sourced Purines Support Wound Healing and Mucous Barrier Function

Repurposing Dipyridamole in Niemann Pick Type C Disease: A Proof of Concept Study

Identification and Functional Characterization of Adenosine Deaminase in Mucor circinelloides: A Novel Potential Regulator of Nitrogen Utilization and Lipid Biosynthesis

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