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Ling, Chunyan, Liangcheng Shang, Xin Xie, Sudan Ye, Ningjing Wang, and Chun Chen. "AdoR-1 (Adenosine Receptor) Contributes to Protection against Paraquat-Induced Oxidative Stress in Caenorhabditis elegans." Oxidative Medicine and Cellular Longevity 2022 (December 22, 2022): 1–13. http://dx.doi.org/10.1155/2022/1759009.
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AdoR-1, the single adenosine receptor homolog in Caenorhabditis elegans, which belongs to the superfamily of G-protein coupled receptors (GPCRs), mediates most of the physiological effects of extracellular adenosine. Adenosine has been proved to improve the survival rate of C. elegans in oxidative stress conditions. However, the potential mechanism of adenosine’s protective effect against oxidative stress via AdoR-1 has not been studied. In this study, C. elegans were divided into three groups: two groups with paraquat treatment, one in the presence and one in the absence of adenosine, and an untreated control group. Results indicate that many differentially expressed genes were found to be enriched significantly in neural-related signaling pathways among transcriptome data of three groups. Further gene network analysis showed that some important genes well known to be involved in promoting the acetylcholine release pathway, such as dop-1, egl-30, and unc-13, and those involved in promoting the neuropeptide release pathway, such as kin-1, were upregulated by paraquat induction but downregulated after adenosine treatment. Meanwhile, a completely opposite trend was observed for the goa-1 gene that inhibits the acetylcholine-release and neuropeptide-release pathway. Additionally, some biochemical assays including SOD, GSSG, GSH, and AChE were measured to identify the potential protection of adenosine against oxidative stress between wild-type strain N2 and ador-1 gene knockout strain EG6890. Conclusively, our study revealed series of adenosine receptor-mediated genes in C. elegans that might act as regulators of paraquat-induced oxidative stress and may indicate adenosine’s promising protective effects.
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Jackson, Edwin K., and Raghvendra K. Dubey. "Role of the extracellular cAMP-adenosine pathway in renal physiology." American Journal of Physiology-Renal Physiology 281, no. 4 (October 1, 2001): F597—F612. http://dx.doi.org/10.1152/ajprenal.2001.281.4.f597.
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Adenosine exerts physiologically significant receptor-mediated effects on renal function. For example, adenosine participates in the regulation of preglomerular and postglomerular vascular resistances, glomerular filtration rate, renin release, epithelial transport, intrarenal inflammation, and growth of mesangial and vascular smooth muscle cells. It is important, therefore, to understand the mechanisms that generate extracellular adenosine within the kidney. In addition to three “classic” pathways of adenosine biosynthesis, contemporary studies are revealing a novel mechanism for renal adenosine production termed the “extracellular cAMP-adenosine pathway.” The extracellular cAMP-adenosine pathway is defined as the egress of cAMP from cells during activation of adenylyl cyclase, followed by the extracellular conversion of cAMP to adenosine by the serial actions of ecto-phosphodiesterase and ecto-5′-nucleotidase. This mechanism of extracellular adenosine production may provide hormonal control of adenosine levels in the cell-surface biophase in which adenosine receptors reside. Tight coupling of the site of adenosine production to the site of adenosine receptors would permit a low-capacity mechanism of adenosine biosynthesis to have a large impact on adenosine receptor activation. The purposes of this review are to summarize the physiological roles of adenosine in the kidney; to describe the classic pathways of renal adenosine biosynthesis; to review the evidence for the existence of the extracellular cAMP-adenosine pathway; and to describe possible physiological roles of the extracellular cAMP-adenosine pathway, with particular emphasis on the kidney.
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Jackson, Edwin K., Jin Ren, Dongmei Cheng, and Zaichuan Mi. "Extracellular cAMP-adenosine pathways in the mouse kidney." American Journal of Physiology-Renal Physiology 301, no. 3 (September 2011): F565—F573. http://dx.doi.org/10.1152/ajprenal.00094.2011.
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The renal extracellular 2′,3′-cAMP-adenosine and 3′,5′-cAMP-adenosine pathways (extracellular cAMPs→AMPs→adenosine) may contribute to renal adenosine production. Because mouse kidneys provide opportunities to investigate renal adenosine production in genetically modified kidneys, it is important to determine whether mouse kidneys express these cAMP-adenosine pathways. We administered (renal artery) 2′,3′-cAMP and 3′,5′-cAMP to isolated, perfused mouse kidneys and measured renal venous secretion rates of 2′,3′-cAMP, 3′,5′-cAMP, 2′-AMP, 3′-AMP, 5′-AMP, adenosine, and inosine. Arterial infusions of 2′,3′-cAMP increased ( P < 0.0001) the mean venous secretion of 2′-AMP (390-fold), 3′-AMP (497-fold), adenosine (18-fold), and inosine (adenosine metabolite; 7-fold), but they did not alter 5′-AMP secretion. Infusions of 3′,5′-cAMP did not affect venous secretion of 2′-AMP or 3′-AMP, but they increased ( P < 0.0001) secretion of 5′-AMP (5-fold), adenosine (17-fold), and inosine (6-fold). Energy depletion (metabolic inhibitors) increased the secretion of 2′,3′-cAMP (8-fold, P = 0.0081), 2′-AMP (4-fold, P = 0.0028), 3′-AMP (4-fold, P = 0.0270), 5′-AMP (3-fold, P = 0.0662), adenosine (2-fold, P = 0.0317), and inosine (7-fold, P = 0.0071), but it did not increase 3′,5′-cAMP secretion. The 2′,3′-cAMP-adenosine pathway was quantitatively similar in CD73 −/− vs. +/+ kidneys. However, 3′,5′-cAMP induced a 6.7-fold greater increase in 5′-AMP, an attenuated increase (61% reduction) in inosine and a similar increase in adenosine in CD73 −/− vs. CD73 +/+ kidneys. In mouse kidneys, 1) 2′,3′-cAMP and 3′,5′-cAMP are metabolized to their corresponding AMPs, which are subsequently metabolized to adenosine; 2) energy depletion activates the 2′,3′-cAMP-adenosine, but not the 3′,5′-cAMP-adenosine, pathway; and 3) although CD73 is involved in the 3′,5′-AMP-adenosine pathway, alternative pathways of 5′-AMP metabolism and reduced metabolism of adenosine to inosine compensate for life-long deficiency of CD73.
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Dorostkar, Parvin C., Macdonald Dick, Gerald A. Serwer, Sarah LeRoy, and Brian Armstrong. "Effect of adenosine on atrioventricular conduction in children and young patients with supraventricular tachycardia." Cardiology in the Young 6, no. 4 (October 1996): 308–14. http://dx.doi.org/10.1017/s1047951100003930.
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AbstractAdenosine, when given as an intravenous bolus, has been shown to produce atrioventricular nodal block in humans. To examine the effect of adenosine on conduction across both accessory pathways and the atrioventricular node in children, we reviewed our experience with adenosine administered during both atrial and ventricular pacing in 42 patients with atrioventricular resting tachycardia and in eight patients with atrioventricular nodal reentry tachycardia. Adenosine was administered as a mean bolus of 195 μg/kg/dose during both atrial and ventricular pacing, examining antegrade and retrograde conduction before and after radiofrequency ablation. In those patients with persistent or intermittent pre-excitation, anomalous ventricular activation was either unchanged (n=8) or increased (n=11). Retrograde conduction (either through the accessory pathway alone in three, or across both the accessory pathway and the atrioventricular node in 19) persisted in 92% of the 24 patients studied. Adenosine produced either first or third degree antegrade heart block in all patients studied without pre-excitation (those with either dual atrioventricular nodal pathways or concealed accessory pathways). Adenosine produced retrograde block in all of the eight patients with dual atrioventricular nodal pathways. In contrast, retrograde conduction persisted in 82% (14/17) of patients with concealed accessory pathways (p=0.001). When used to examine retrograde conduction, adenosine was a sensitive (82%) and highly specific (producing retrograde atrioventricular block in all patients with dual atrioventricular nodal pathways) predictor of tachycardia supported by a concealed accessory pathway. Adenosine yielded a sensitivity and specificity of 96% and a positive predictive value of 99.5% for the success of ablation of accessory pathways. These data indicate that the pattern of adenosine-induced changes in either antegrade or retrograde atrioventricular conduction, or conduction in both directions, in young patients with supraventricular tachycardia is related to the mechanism of the tachycardia. Adenosine, therefore, is a useful adjunct in the electrophysiologic evaluation of supraventricular tachycardia in children.
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LAPAGE, MARTIN J., MICHAEL J. WALSH, JOHN H. REED, and J. PHILIP SAUL. "Adenosine Mapping for Adenosine-Dependent Accessory Pathway Ablation." Pacing and Clinical Electrophysiology 37, no. 5 (December 20, 2013): 610–15. http://dx.doi.org/10.1111/pace.12324.
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Jackson, Edwin K. "The 2′,3′-cAMP-adenosine pathway." American Journal of Physiology-Renal Physiology 301, no. 6 (December 2011): F1160—F1167. http://dx.doi.org/10.1152/ajprenal.00450.2011.
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Our recent studies employing HPLC-tandem mass spectrometry to analyze venous perfusate from isolated, perfused kidneys demonstrate that intact kidneys produce and release into the extracellular compartment 2′,3′-cAMP, a positional isomer of the second messenger 3′,5′-cAMP. To our knowledge, this represents the first detection of 2′,3′-cAMP in any cell/tissue/organ/organism. Nuclear magnetic resonance experiments with isolated RNases and experiments in isolated, perfused kidneys suggest that 2′,3′-cAMP likely arises from RNase-mediated transphosphorylation of mRNA. Both in vitro and in vivo kidney experiments demonstrate that extracellular 2′,3′-cAMP is efficiently metabolized to 2′-AMP and 3′-AMP, both of which can be further metabolized to adenosine. This sequence of reactions is called the 2′,3′-cAMP-adenosine pathway (2′,3′-cAMP → 2′-AMP/3′-AMP → adenosine). Experiments in rat and mouse kidneys show that metabolic poisons increase extracellular levels of 2′,3′-cAMP, 2′-AMP, 3′-AMP, and adenosine; however, little is known regarding the pharmacology of 2′,3′-cAMP, 2′-AMP, and 3′-AMP. What is known is that 2′,3′-cAMP facilitates activation of mitochondrial permeability transition pores, a process that can lead to apoptosis and necrosis, and inhibits proliferation of vascular smooth muscle cells and glomerular mesangial cells. In summary, there is mounting evidence that at least some types of cellular injury, by triggering mRNA degradation, engage the 2′,3′-cAMP-adenosine pathway, and therefore this pathway should be added to the list of biochemical pathways that produce adenosine. Although speculative, it is possible that the 2′,3′-cAMP-adenosine pathway may protect against some forms of acute organ injury, for example acute kidney injury, by both removing an intracellular toxin (2′,3′-cAMP) and increasing an extracellular renoprotectant (adenosine).
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Cruz-Ramos, Marlid, Sara Aileen Cabrera-Nieto, Mario Murguia-Perez, and Fernanda Sarahí Fajardo-Espinoza. "The Role of Adenosine in Overcoming Resistance in Sarcomas." International Journal of Molecular Sciences 25, no. 22 (November 14, 2024): 12209. http://dx.doi.org/10.3390/ijms252212209.
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Resistance to systemic therapies in sarcomas poses a significant challenge to improving clinical outcomes. Recent research has concentrated on the tumor microenvironment’s role in sarcoma progression and treatment resistance. This microenvironment comprises a variety of cell types and signaling molecules that influence tumor behavior, including proliferation, metastasis, and resistance to therapy. Adenosine, abundant in the tumor microenvironment, has been implicated in promoting immunosuppression and chemoresistance. Targeting adenosine receptors and associated pathways offers a novel approach to enhancing immune responses against tumors, potentially improving immunotherapy outcomes in cancers, including sarcomas. Manipulating adenosine signaling also shows promise in overcoming chemotherapy resistance in these tumors. Clinical trials investigating adenosine receptor antagonists in sarcomas have fueled interest in this pathway for sarcoma treatment. Ultimately, a comprehensive understanding of the tumor and vascular microenvironments, as well as the adenosine pathway, may open new avenues for improving treatment outcomes and overcoming resistance in sarcoma. Further studies and clinical trials are crucial to validate these findings and optimize therapeutic strategies, particularly for osteosarcoma. This study provides a literature review exploring the potential role of the adenosine pathway in sarcomas.
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Acton, David, Matthew J. Broadhead, and Gareth B. Miles. "Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling." Journal of Neurophysiology 120, no. 3 (September 1, 2018): 998–1009. http://dx.doi.org/10.1152/jn.00783.2017.
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Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output. NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.
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Tofovic, Stevan P., Edwin K. Jackson, and Olga Rafikova. "Adenosine deaminase–adenosine pathway in hemolysis-associated pulmonary hypertension." Medical Hypotheses 72, no. 6 (June 2009): 713–19. http://dx.doi.org/10.1016/j.mehy.2008.12.043.
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TINT, DIANA, CSABA KUN, ILDIKO BEKE, and ZOLTAN CSANADI. "Adenosine-Dependent Concealed Accessory Pathway." Pacing and Clinical Electrophysiology 35, no. 4 (March 21, 2011): e91-e93. http://dx.doi.org/10.1111/j.1540-8159.2011.03063.x.
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Morales, Bernardo, Nelson Barrera, Pablo Uribe, Claudio Mora, and Manuel Villalón. "Functional cross talk after activation of P2 and P1 receptors in oviductal ciliated cells." American Journal of Physiology-Cell Physiology 279, no. 3 (September 1, 2000): C658—C669. http://dx.doi.org/10.1152/ajpcell.2000.279.3.c658.
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The presence of ATP and adenosine receptors and their role in controlling ciliary activity in oviductal ciliated cells was studied by measuring the ciliary beat frequency (CBF) in oviductal tissue cultures. ATP, adenosine, and related compounds increased the CBF in a dose-dependent manner. We established that P2 receptors of subtype 2Y2 and P1 receptors of subtype A2a mediated the responses to ATP and adenosine, respectively. We found evidence to suggest that stimulation of ciliary activity by ATP requires d- myo-inositol 1,4,5-trisphosphate [Ins(1,4,5) P 3] metabolism, intracellular Ca2+ mobilization, and protein kinase C activation. On the other hand, the adenosine effect is mediated by activation of a Gs protein-dependent pathway that enhances cAMP intracellular levels. To study the interaction between P2 and P1 receptors, cells were stimulated simultaneously with both agonists. We observed a synergistic increase of the CBF even at agonist concentrations (100 nM) that did not produce a significant response when added separately to the culture. Furthermore, a blocker of the cAMP pathway produced a reduction of the ATP response, whereas a blocker of the Ins(1,4,5) P 3 pathway also produced an inhibition of the adenosine response. Our evidence demonstrates that both ATP and adenosine receptors are present in a single ciliated cell and that a mechanism of cross talk could operate in the transduction pathways to control ciliary activity.
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Cekic, Caglar, Imran Akdemir, Altay Koyas, Merve Kayhan, and Ali Can Savas. "Adenosine regulation of danger signaling." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 222.14. http://dx.doi.org/10.4049/jimmunol.198.supp.222.14.
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Abstract Metabolic and immune related activities converge as main triggers of adenosine accumulation in extracellular space. Adenosine by engaging adenosine A2A and A2B receptors strongly suppresses innate and adaptive immune responses. Although adenosine receptors are being targeted in preclinical and clinical studies how different danger signals are regulated by adenosine is poorly understood. Here we showed that adenosine receptor stimulation strongly inhibited inflammatory responses while sparing type-I interferon responses downstream of different danger signals in dendritic cells and macrophages. Mechanistically, danger signals associated with MyD88-dependent inflammatory pathways such as LPS and CpG but not the danger signals associated with IRF3/Type-I interferon pathways such as pA:U and cGAMP increase the expression adenosine A2A and A2B receptors. Adenosine was shown to increase the expression of NR4A nuclear hormone receptors to inhibit NF-κB activation. Although adenosine did not influence NF-κB phosphoactivation expression of anti-inflammatory NR4A1 was increased after adenosine receptor stimulation in the presence of TLR ligands known to activate MyD88 pathway but not in the presence of cGAMP and pA:U. Overall these results indicate that there is a differential modulation of danger signaling by adenosine rather than overall supression. Our results have important implications for developing combinatorial approaches to target adenosine and danger signaling pathways to cure immune-related diseases.
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Lertsuwan, Kornkamon, Supathra Phoaubon, Nathapol Tasnawijitwong, and Jomnarong Lertsuwan. "Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway." International Journal of Molecular Sciences 21, no. 3 (January 27, 2020): 814. http://dx.doi.org/10.3390/ijms21030814.
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Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA.
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Kienleitner, Filip, and Kerstin Lenk. "A1 adenosine receptor evoked Ca2+ signals in astrocytes." Current Directions in Biomedical Engineering 10, no. 3 (October 1, 2024): 5–8. http://dx.doi.org/10.1515/cdbme-2024-1102.
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Abstract In addition to neurons, glial cells make up the nervous system. These glial cells are divided into macroglial cells - including astrocytes - and microglial cells. Astrocytes have several important functions in the central nervous system, such as synthesizing transmitters and releasing them, thereby activating the surrounding neurons and astrocytes. Astrocytes do not generate action potentials, but they can transmit information to neighboring cells and react to external stimuli by employing Ca2+ dynamics. Increased neuronal activity can lead to an increased extracellular level of adenosine, reflected by a change in the metabolic state. Adenosine is a naturally occurring nucleoside distributed throughout the body as a metabolic intermediary. Its action is mediated by binding to adenosine receptors, such as the G-protein coupled receptors (GPCRs) A1 adenosine receptor. The binding of adenosine to the specific receptor type activates different signaling pathways in astrocytes. In our work, we studied Ca2+ signals generated upon adenosine A1 receptor activation by adding the pathway to the computational astrocyte model by Oschmann et.al (2017). We investigated the influence of the high-affinity A1 adenosine receptor in various astrocyte domains on the regulated Ca2+ release from the endoplasmic reticulum (ER) of astrocytes and concluded that the receptor-dependent pathway contributes to Ca2+ signals mainly in the soma.
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Azambuja, Juliana Hofstätter, Nils Ludwig, Elizandra Braganhol, and Theresa L. Whiteside. "Inhibition of the Adenosinergic Pathway in Cancer Rejuvenates Innate and Adaptive Immunity." International Journal of Molecular Sciences 20, no. 22 (November 14, 2019): 5698. http://dx.doi.org/10.3390/ijms20225698.
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The adenosine pathway plays a key role in modulating immune responses in physiological and pathological conditions. Physiologically, anti-inflammatory effects of adenosine balance pro-inflammatory adenosine 5’-triphosphate (ATP), protecting tissues from damage caused by activated immune cells. Pathologically, increased adenosine monophosphatase (AMPase) activity in tumors leads to increased adenosine production, generating a deeply immunosuppressed microenvironment and promoting cancer progression. Adenosine emerges as a promising target for cancer therapy. It mediates protumor activities by inducing tumor cell proliferation, angiogenesis, chemoresistance, and migration/invasion by tumor cells. It also inhibits the functions of immune cells, promoting the formation of a tumor-permissive immune microenvironment and favoriting tumor escape from the host immune system. Pharmacologic inhibitors, siRNA or antibodies specific for the components of the adenosine pathway, or antagonists of adenosine receptors have shown efficacy in pre-clinical studies in various in vitro and in vivo tumor models and are entering the clinical arena. Inhibition of the adenosine pathway alone or in combination with classic immunotherapies offers a potentially effective therapeutic strategy in cancer.
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Jaen, Juan C. "Abstract IA04: New developments in drugging the adenosine pathway." Cancer Immunology Research 13, no. 2_Supplement (February 23, 2025): IA04. https://doi.org/10.1158/2326-6074.io2025-ia04.
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Abstract Adenosine is a pleiotropic immunosuppressive substance, produced mainly by the enzymes CD39 and CD73, from extracellular immunogenic ATP. Thus, CD73-rich tumors may experience decreased anti-tumor immune activity when treated with immunogenic chemotherapies (e.g., platinum-based drugs), relative to what might be possible in the absence of adenosine. From a therapeutic perspective, potential drugs that aim to interfere with the production or signaling of adenosine need to be potent and selective enough, under physiological conditions, to overcome the large amount of adenosine present in selected tumors. Recent results from several clinical studies are strongly supportive of the anti-cancer potential stemming from inhibition of the adenosine axis, when drug properties, tumor selection/setting, and combination backbones are taken into account. This presentation will briefly highlight key design elements for two such drugs, etrumadenant (a dual blocker of A2a and A2b adenosine receptors) and quemliclustat (a CD73 inhibitor), as well as recent clinical results with these agents in advanced colorectal cancer (CRC; ARC-9) and pancreatic cancer (PDAC; ARC-8), respectively. We will also describe how drug-related changes in markers of adenosine activity, as well as baseline levels of those markers, are associated with clinical outcomes in these trials. Citation Format: Juan C Jaen. New developments in drugging the adenosine pathway [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr IA04.
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Allard, Bertrand, David Allard, Laurence Buisseret, and John Stagg. "The adenosine pathway in immuno-oncology." Nature Reviews Clinical Oncology 17, no. 10 (June 8, 2020): 611–29. http://dx.doi.org/10.1038/s41571-020-0382-2.
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Harrison, Charlotte. "Adenosine pathway increases β-cell regeneration." Nature Reviews Drug Discovery 11, no. 8 (August 2012): 602. http://dx.doi.org/10.1038/nrd3815.
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Azumi, Junya, Tomoya Takeda, Shunya Shibata, Yasuhiro Shimada, Hisashi Aso, and Takashi Nakamura. "The Organogermanium Compound 3-(trihydroxygermyl)propanoic Acid Exerts Anti-Inflammatory Effects via Adenosine-NR4A2 Signaling." International Journal of Molecular Sciences 26, no. 6 (March 9, 2025): 2449. https://doi.org/10.3390/ijms26062449.
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We previously reported that 3-(trihydroxygermyl)propanoic acid (THGP) suppresses inflammasome activation in THP-1 cells following stimulation with lipopolysaccharide (LPS) and ATP (signals 1 and 2) by forming a complex with ATP, thereby inhibiting IL-1β secretion. Our findings also suggested that THGP inhibits inflammasome activation through mechanisms independent of ATP complex formation. This study investigated the anti-inflammatory effects of THGP on signal 1 (ATP-independent) of inflammasome activation. THGP suppressed NF-κB nuclear translocation in LPS-stimulated THP-1 cells, which reduced the mRNA expression of the proinflammatory cytokines TNF-α and IL-6, as well as IL-1β secretion. This mechanism was mediated by the formation of a THGP–adenosine complex, which inhibited adenosine degradation and subsequently activated adenosine–NR4A2 signaling. Thus, THGP exerts anti-inflammatory effects by forming a complex with adenosine, leading to adenosine–NR4A2 signaling pathway activation. This mechanism is distinct from the ATP-dependent pathway by which THGP was previously reported to function. By targeting both ATP-dependent and ATP-independent inflammasome activation pathways, THGP has potential as a broad-spectrum therapeutic agent for various inflammatory diseases.
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Yang, Rui, Samah Elsaadi, Kristine Misund, Pegah Abdollahi, Esten Nymoen Vandsemb, Siv Helen Moen, Anna Kusnierczyk, et al. "Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade." Journal for ImmunoTherapy of Cancer 8, no. 1 (May 2020): e000610. http://dx.doi.org/10.1136/jitc-2020-000610.
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BackgroundPD1/PDL1-directed therapies have been unsuccessful for multiple myeloma (MM), an incurable cancer of plasma cells in the bone marrow (BM). Therefore, other immune checkpoints such as extracellular adenosine and its immunosuppressive receptor should be considered. CD39 and CD73 convert extracellular ATP to adenosine, which inhibits T-cell effector functions via the adenosine receptor A2A (A2AR). We set out to investigate whether blocking the adenosine pathway could be a therapy for MM.MethodsExpression of CD39 and CD73 on BM cells from patients and T-cell proliferation were determined by flow cytometry and adenosine production by Liquid chromatograpy-mass spectrometry (HPCL/MS). ENTPD1 (CD39) mRNA expression was determined on myeloma cells from patients enrolled in the publicly available CoMMpass study. Transplantable 5T33MM myeloma cells were used to determine the effect of inhibiting CD39, CD73 and A2AR in mice in vivo.ResultsElevated level of adenosine was found in BM plasma of MM patients. Myeloma cells from patients expressed CD39, and high gene expression indicated reduced survival. CD73 was found on leukocytes and stromal cells in the BM. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine production and reduced T-cell suppression in vitro in coculture of myeloma and stromal cells. Blocking the adenosine pathway in vivo with a combination of Sodium polyoxotungstate (POM-1), anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased interferon gamma production, and reduced the tumor load in a murine model of MM.ConclusionsOur data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.
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Komoto, Yuki, Takahito Ohshiro, and Masateru Taniguchi. "Development of Single-Molecule Electrical Identification Method for Cyclic Adenosine Monophosphate Signaling Pathway." Nanomaterials 11, no. 3 (March 19, 2021): 784. http://dx.doi.org/10.3390/nano11030784.
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Cyclic adenosine monophosphate (cAMP) is an important research target because it activates protein kinases, and its signaling pathway regulates the passage of ions and molecules inside a cell. To detect the chemical reactions related to the cAMP intracellular signaling pathway, cAMP, adenosine triphosphate (ATP), adenosine monophosphate (AMP), and adenosine diphosphate (ADP) should be selectively detected. This study utilized single-molecule quantum measurements of these adenosine family molecules to detect their individual electrical conductance using nanogap devices. As a result, cAMP was electrically detected at the single molecular level, and its signal was successfully discriminated from those of ATP, AMP, and ADP using the developed machine learning method. The discrimination accuracies of a single cAMP signal from AMP, ADP, and ATP were found to be 0.82, 0.70, and 0.72, respectively. These values indicated a 99.9% accuracy when detecting more than ten signals. Based on an analysis of the feature values used for the machine learning analysis, it is suggested that this discrimination was due to the structural difference between the ribose of the phosphate site of cAMP and those of ATP, ADP, and AMP. This method will be of assistance in detecting and understanding the intercellular signaling pathways for small molecular second messengers.
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Lloyd, H. G., A. Deussen, H. Wuppermann, and J. Schrader. "The transmethylation pathway as a source for adenosine in the isolated guinea-pig heart." Biochemical Journal 252, no. 2 (June 1, 1988): 489–94. http://dx.doi.org/10.1042/bj2520489.
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In order to quantify adenosine production from the transmethylation pathway [S-adenosylmethionine (AdoMet)→S-adenosylhomocysteine (AdoHcy) in equilibrium adenosine + L-homocysteine] in the isolated guinea-pig heart under basal conditions (normoxic perfusion with 95% O2) and during elevated adenosine production (hypoxic perfusion with 30% O2), two methods were used. (1) Hearts were perfused with normoxic medium containing [2,5,8-3H]adenosine (5 microM) and L-homocysteine thiolactone (0.1 mM), which brings about net AdoHcy synthesis via reversal of the AdoHcy hydrolase reaction and labels the intracellular pool of AdoHcy. From the decrease in AdoHcy pool size and specific radioactivity of AdoHcy in the post-labelling period, the rate of transmethylation, which is equivalent to the rate of adenosine production, was calculated to be 0.98 nmol/min per g. Adenosine release from the hearts was 40-50 pmol/min per g. (2) Hearts were perfused with hypoxic medium containing [35S]homocysteine (50 microM). Owing to the hypoxia-induced increase in adenosine production, this procedure also results in expansion and labelling of the AdoHcy pool. From the dilution of the specific radioactivity of AdoHcy relative to that of [35S]homocysteine, the rate of AdoHcy synthesis from AdoMet (transmethylation) was calculated to be 1.12 nmol/min per g. It is concluded that in the oxygenated heart the transmethylation pathway is quantitatively an important intracellular source of adenosine, which exceeds the rate of adenosine wash-out by the coronary system by about 15-fold. Most of the adenosine formed by this pathway is re-incorporated into the ATP pool, most likely by adenosine kinase. The transmethylation pathway is essentially O2-independent, and the known hypoxia-induced production of adenosine must be derived from an increase in 5′-AMP hydrolysis.
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Saigí, Maria, Oscar Mesía-Carbonell, David A. Barbie, and Raquel Guillamat-Prats. "Unraveling the Intricacies of CD73/Adenosine Signaling: The Pulmonary Immune and Stromal Microenvironment in Lung Cancer." Cancers 15, no. 23 (December 4, 2023): 5706. http://dx.doi.org/10.3390/cancers15235706.
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CD73 and adenosine have gained prominence in lung cancer research. The NT5E gene encodes CD73, known as an ectonucleotidase, which plays a crucial role within tumor cells, with immune-suppressive properties. Beyond cancer, CD73 exerts an influence on cardiac, neural, and renal functions, affecting cardiac, neural, and renal functions. CD73’s significance lies in its production of extracellular adenosine. It is notably expressed across diverse cell types within the immune and stromal lung microenvironment. CD73 expression amplifies in lung tumors, especially non-small cell lung cancer (NSCLC), often aligned with key oncogenic drivers like mutant EGFR and KRAS. CD73/adenosine pathway seems to be involved in tumoral immunoevasion, hampering the use of the immune checkpoint inhibitor (ICI) and correlating with therapy resistance. Despite the partial success of current ICI therapies, the CD73/adenosine pathway offers promise in enhancing their effectiveness. This comprehensive review explores recent insights into lung cancer’s CD73/adenosine pathway. It explores roles within tumor cells, the lung’s stromal environment, and the immune system. Ranging from pre-clinical models to clinical trials, potential therapies targeting the adenosine pathway for lung cancer treatment are discussed below.
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Younis, Samaira, Casper E. Christensen, Nikolaj M. Toft, Thomas Søborg, Faisal M. Amin, Anders Hougaard, and Messoud Ashina. "Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil." Cephalalgia 39, no. 14 (November 4, 2019): 1776–88. http://dx.doi.org/10.1177/0333102419882474.
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Objective Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.
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Graziano, Vincenzo, Andreas Dannhorn, Heather Hulme, Kate Williamson, Hannah Buckley, Saadia A. Karim, Matthew Wilson, et al. "Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma." Journal for ImmunoTherapy of Cancer 11, no. 8 (August 2023): e006457. http://dx.doi.org/10.1136/jitc-2022-006457.
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BackgroundThe prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo).MethodsUsing genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC.ResultsWe demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.ConclusionsThe formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC.
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Augustin, Ryan C., Robert D. Leone, Aung Naing, Lawrence Fong, Riyue Bao, and Jason J. Luke. "Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy." Journal for ImmunoTherapy of Cancer 10, no. 2 (February 2022): e004089. http://dx.doi.org/10.1136/jitc-2021-004089.
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Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
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Cekic, Caglar, Imran Akdemir, Altay Koyas, Merve Kayhan, and Ali Can Savas. "Molecular mechanisms for adenosine regulation of helper T cell activation." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 52.22. http://dx.doi.org/10.4049/jimmunol.198.supp.52.22.
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Abstract Polarization of T helper subsets into different functional phenotypes strongly affects the progression of immune-related diseases. One of the hallmarks of immune cell activation and inflammation is the elevation of extracellular adenosine and increased expression of adenosine A2A receptors in activated immune cells. Adenosine strongly inhibits activation of helper T cells by elevating cAMP concentrations, which activate PKA and EPAC proteins to regulate cellular responses. Here we showed that adenosine strongly inhibits T cell accumulation rather than differentiating into functional subsets in the presence of polarizing conditions. Different aspects of adenosine mediated T cell suppression were phenocopied by specific activation of PKA and/or EPAC pathways. Adenosine can suppress phospho-activation of Akt pathway to promote T cell quiescence and to inhibit immediate downstream events after TCR stimulation. One of the targets for Akt is Foxo1. Foxo1 is known to suppress T cell proliferation. Our results showed that adenosine receptor stimulation reduced inhibitory phosphorylation of Foxo1 downstream of Akt. Foxo1 inhibitor, AS1842856, completely reversed the inhibition of T cell accumulation by adenosine signaling. Our results suggest that adenosine by activating PKA and/or EPAC pathways and by sustaining Foxo1 activation suppresses T cell activation and accumulation. These findings have important implications to develop novel interventions to regulate helper T cell responses in different pathological conditions.
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Spanoghe, Jeroen, Lars E. Larsen, Erine Craey, Simona Manzella, Annelies Van Dycke, Paul Boon, and Robrecht Raedt. "The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor." International Journal of Molecular Sciences 22, no. 1 (December 30, 2020): 320. http://dx.doi.org/10.3390/ijms22010320.
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Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A1 receptor, a G protein-coupled receptor with a wide array of targets. Activating A1 receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A1 receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A1 receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A1 receptor might have detrimental effects, which will need to be avoided when pursuing A1 receptor-based epilepsy therapies.
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Yu, Hua, Yangyang Xie, Zhendong Zhou, Zhou Wu, Xiaoyu Dai, and Binbin Xu. "Curcumin Regulates the Progression of Colorectal Cancer via LncRNA NBR2/AMPK Pathway." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381987078. http://dx.doi.org/10.1177/1533033819870781.
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Objective: To identify the effect of curcumin on tumor suppression and the possible molecular pathways involved. Methods: The expression of long noncoding RNA neighbor of BRCA1 lncRNA 2 (NBR2) was quantified using reverse transcription-polymerase chain reaction on cultured colorectal cancer cells. Next, we used Western blot to measure the activation of adenosine monophosphate-activated protein kinase and mechanistic target of rapamycin kinase (mTOR) signaling molecules. Both cell proliferation and viability were measured via MTT assay, and the cell ratio and S phase were detected by BrdU assay. Colorectal cancer cells were pretreated with curcumin or transfected with shNBR2 or adenosine monophosphate-activated protein kinase inhibitor Compound C to examine the molecular pathway involved. Results: Current data showed that glucose deficiency increased the expression of NBR2 in colorectal cancer cells, and NBR2 knockdown affected the progression of colorectal cancer cells under glucose starvation conditions. When NBR2 was silenced in the treated colorectal cancer cells, the proliferation, the clone formation, and the percentage of S-phase cells suppressed by glucose deprivation were compromised. Furthermore, NBR2 knockdown could suppress glucose deprivation-induced adenosine monophosphate-activated protein kinase activation plus mTOR inactivation. Similarly, when colorectal cancer cells were treated with curcumin, the expression of NBR2 was significantly increased. NBR2 knockdown reversed curcumin-suppressed proliferation, clone formation, and the percentage of S-phase colorectal cancer cells. Furthermore, NBR2 knockdown abolished curcumin-induced activation of adenosine monophosphate-activated protein kinase and inactivation of the mTOR signaling pathway. Conclusion: This study revealed a novel mechanism by which long noncoding RNA NBR2 mediates curcumin suppression of colorectal cancer proliferation by activating adenosine monophosphate-activated protein kinase and inactivating the mTOR signaling pathway.
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King, Brionna, Zhi Huang, Peter Hewins, Thomasina Cook, Oygul Mirzalieva, Kristina Larter, Dorota Wyczechowska, et al. "Adenosine analogs have immunomodulatory antiviral properties through the Adenosine A2A Receptor pathway." Journal of Immunology 212, no. 1_Supplement (May 1, 2024): 1299_4492. http://dx.doi.org/10.4049/jimmunol.212.supp.1299.4492.
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Abstract The COVID-19 pandemic has unveiled an urgent need for novel antivirals to control emerging infectious diseases. Classic antivirals are often insufficient to clear infections in the absence of an effective immune response. Immunotherapy could complement the use of antivirals; however, its application to infectious diseases remains largely unexplored. Adenosine analogs (AAs) are antiviral drugs which resemble the structure of adenosine, a metabolite which suppresses the immune response through activation of the Adenosine A2A Receptor (A2AR) in immune cells. We hypothesized that selected AAs have previously unrecognized immunomodulatory properties by acting as A2AR antagonists. In this study, we used molecular docking modeling to screen AAs for their capacity to bind to A2AR and test AAs for immunomodulatory properties in cell-based and in vivo assays. We found that selected AAs restored T-cell functions from adenosine-mediated immunosuppression in T-cells, suggesting that they are endowed with immunomodulatory properties through A2AR antagonism, in addition to their intrinsic antiviral properties. These immunomodulatory functions contribute to the antiviral activity of the AAs as we found that the analogs could restore antiviral T-cell responses in COVID-19 models. In conclusion, selected AAs could be used as novel dual – immunomodulatory and intrinsic – antiviral drugs and could represent effective therapies against emerging viral diseases and future pandemics.
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Liu, Qinghang, and Polly A. Hofmann. "Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: role for p38 MAPK." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 1 (July 2003): H97—H103. http://dx.doi.org/10.1152/ajpheart.00956.2002.
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Adenosine A1 receptor activation causes protein phosphatase 2a (PP2a) activation in ventricular myocytes. This attenuates β-adrenergic functional effects in the heart (Liu Q and Hofmann PA. Am J Physiol Heart Circ Physiol 283: H1314–H1321, 2002). The purpose of the present study was to identify the signaling pathway involved in the translocation/activation of PP2a by adenosine A1 receptors in ventricular myocytes. We found that N6-cyclopentyladenosine (CPA; an adenosine A1 receptor agonist)-induced PP2a translocation was blocked by p38 MAPK inhibition but not by JNK inhibition. CPA increased phosphorylation of p38 MAPK, and this effect was abolished by pertussis toxin and inhibitors of the cGMP pathway. Moreover, CPA-induced PP2a translocation was blocked by inhibition of the cGMP pathway. Guanylyl cyclase activation mimicked the effects of CPA and caused p38 MAPK phosphorylation and PP2a translocation. Finally, CPA-induced dephosphorylations of troponin I and phospholamban were blocked by pertussis toxin and attenuated by p38 MAPK inhibition. These results suggest that adenosine A1 receptor-mediated PP2a activation uses a pertussis toxin-sensitive Gi protein-guanylyl cyclase-p38 MAPK pathway. This proposed, novel pathway may play a role in acute modulation of cardiac function.
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Weisell, Janne, Jouko Vepsäläinen, and Petri A. Turhanen. "Two strategies for the synthesis of the biologically important ATP analogue ApppI, at a multi-milligram scale." Beilstein Journal of Organic Chemistry 11 (November 13, 2015): 2189–93. http://dx.doi.org/10.3762/bjoc.11.237.
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Two strategies for the synthesis of the ATP (adenosine triphosphate) analogue ApppI [1-adenosin-5’-yl 3-(3-methylbut-3-enyl)triphosphoric acid diester] (1) are described. ApppI is an active metabolite of the mevalonate pathway and thus is of major biological significance. Chemically synthezised ApppI was purified by using triethylammonium bicarbonate as the counter ion in ion-pair chromatography and characterized by 1H, 13C, 31P NMR and MS spectroscopical methods.
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Jackson, Edwin K., and Zaichuan Mi. "Preglomerular Microcirculation Expresses the cAMP-Adenosine Pathway." Journal of Pharmacology and Experimental Therapeutics 295, no. 1 (October 2000): 23–28. https://doi.org/10.1016/s0022-3565(24)38864-0.
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Hammami, Akil, David Allard, Bertrand Allard, and John Stagg. "Targeting the adenosine pathway for cancer immunotherapy." Seminars in Immunology 42 (April 2019): 101304. http://dx.doi.org/10.1016/j.smim.2019.101304.
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Dubey, Raghvendra K., Delbert G. Gillespie, Zaichuan Mi, and Edwin K. Jackson. "Cardiac Fibroblasts Express the cAMP-Adenosine Pathway." Hypertension 36, no. 3 (September 2000): 337–42. http://dx.doi.org/10.1161/01.hyp.36.3.337.
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Jackson, Edwin K., Lefteris C. Zacharia, Mingdi Zhang, Delbert G. Gillespie, Chongxue Zhu, and Raghvendra K. Dubey. "cAMP-Adenosine Pathway in the Proximal Tubule." Journal of Pharmacology and Experimental Therapeutics 317, no. 3 (March 9, 2006): 1219–29. http://dx.doi.org/10.1124/jpet.106.101360.
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Tejero, Adrián, David Agustín León-Navarro, and Mairena Martín. "Effect of Xanthohumol, a Bioactive Natural Compound from Hops, on Adenosine Pathway in Rat C6 Glioma and Human SH-SY5Y Neuroblastoma Cell Lines." Nutrients 16, no. 11 (June 6, 2024): 1792. http://dx.doi.org/10.3390/nu16111792.
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Xanthohumol (Xn) is an antioxidant flavonoid mainly extracted from hops (Humulus lupulus), one of the main ingredients of beer. As with other bioactive compounds, their therapeutic potential against different diseases has been tested, one of which is Alzheimer’s disease (AD). Adenosine is a neuromodulatory nucleoside that acts through four different G protein-coupled receptors: A1 and A3, which inhibit the adenylyl cyclases (AC) pathway, and A2A and A2B, which stimulate this activity, causing either a decrease or an increase, respectively, in the release of excitatory neurotransmitters such as glutamate. This adenosinergic pathway, which is altered in AD, could be involved in the excitotoxicity process. Therefore, the aim of this work is to describe the effect of Xn on the adenosinergic pathway using cell lines. For this purpose, two different cellular models, rat glioma C6 and human neuroblastoma SH-SY5Y, were exposed to a non-cytotoxic 10 µM Xn concentration. Adenosine A1 and A2A, receptor levels, and activities related to the adenosine pathway, such as adenylate cyclase, protein kinase A, and 5′-nucleotidase, were analyzed. The adenosine A1 receptor was significantly increased after Xn exposure, while no changes in A2A receptor membrane levels or AC activity were reported. Regarding 5′-nucleotidases, modulation of their activity by Xn was noted since CD73, the extracellular membrane attached to 5′-nucleotidase, was significantly decreased in the C6 cell line. In conclusion, here we describe a novel pathway in which the bioactive flavonoid Xn could have potentially beneficial effects on AD as it increases membrane A1 receptors while modulating enzymes related to the adenosine pathway in cell cultures.
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Hamoud, Abdul-Rizaq, Karen Bach, Ojal Kakrecha, Nicholas Henkel, Xiaojun Wu, Robert E. McCullumsmith, and Sinead M. O’Donovan. "Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?" International Journal of Molecular Sciences 23, no. 19 (October 5, 2022): 11835. http://dx.doi.org/10.3390/ijms231911835.
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For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.
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Yang, Ke-Ke, Yi Sui, Hui-Rong Zhou, and Hai-Lu Zhao. "Interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats." Tumor Biology 39, no. 5 (May 2017): 101042831769911. http://dx.doi.org/10.1177/1010428317699116.
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Renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin–angiotensin system and adenosine monophosphate–activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate–activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate–activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate–activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate–activated protein kinase signaling pathway resulted in hyperlipidemia and carcinogenesis in tubular epithelial cells, which may be largely attenuated by renin–angiotensin system blockade, implying the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.
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Luo, Wang, and Shuhua Zhang. "CD73/adenosine pathway-related gene signature for intratumor heterogeneity and immune infiltration in prognosis of lung adenocarcinoma." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e20524-e20524. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e20524.
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e20524 Background: Adenosine is an immunosuppressive molecule that can inhibit the activity of immune cells, particularly T cells, and promote tumor growth. CD73, also known as ecto-5'-nucleotidase, is a cell-surface enzyme that plays a role in the adenosine pathway can catalyzes the conversion of AMP to adenosine. Establish and evaluate a prognosis model based on CD73/ Adenosine pathway will help to understanding of the biological mechanisms in lung adenocarcinoma (LUAD) and providing more accurate predictions for patients' treatment. Methods: The RNA sequencing (RNA-seq), whole exome sequencing (WES) and clinical data were obtained from LUAD cohorts of the Cancer Genome Atlas (TCGA). CD73/ Adenosine pathway-related genes were identified by screening for genes that were in both the CD73 STRING network (confidence = 0.9, 1st shell ≤50 interactors) and the KEGG purine metabolism pathway gene list(map00230). Least absolute shrinkage and selection operator (LASSO) regression was conducted to develop a CD73/ Adenosine pathway-related risk score (CD73RS). Time-dependent ROC curve and survival analysis were conducted in LUAD-TCGA cohort to verify the predictive performance of CD73RS. The MATH (Mutant-Allele Tumor Heterogeneity) ITH scores were calculated to evaluate intratumor heterogeneity (ITH) in LUAD-TCGA WES "maf" files using the R package "maftools" and the "math.score" function. TIMER 2.0 database(http://timer.cistrome.org/) was conducted to estimation of tumor microenvironment to further understand the molecular features of CD73RS. An independent cohort (GSE72094) was used to verify the prognostic effect of CD73RS. Results: A prognosis prediction model based on 21 CD73/ Adenosine pathway-related genes was established using LASSO regression. Kaplan-Meier survival analysis of the risk model from LUAD-TCGA cohort showed that the high-risk group had a significantly worse prognosis (HR = 3.298, P = 1.26e-08). The area under the curve (AUC) in time-dependent ROC curve at 1, 3 and 5 years were turn out to be 0.794, 0.722 and 0.686, respectively. The validation set also showed worse prognosis in high-risk group(HR = 1.473,p = 0.0403). In the high-risk group, there was a higher ITH score compared to the low-risk group (p = 0.0094), along with lower infiltration levels of B cells(p = 7.23e-15), CD4+ T cells(p = 0.003), macrophage cells(p = 0.016), and myeloid dendritic cells(p = 0.037). Conclusions: We established and validated a CD73/ Adenosine pathway risk model that exhibits a robust predictive performance for the outcome of patients with LUAD. The CD73/Adenosine pathway has been shown to play a role in both self-driven genomic changes, such as intra-tumor heterogeneity (ITH), as well as non-autonomous processes, such as immune microenvironment adaptation, which contribute to tumor plasticity and development.
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Shi, Linsen, Zhaoying Wu, Ji Miao, Shangce Du, Shichao Ai, En Xu, Min Feng, Jun Song, and Wenxian Guan. "Adenosine interaction with adenosine receptor A2a promotes gastric cancer metastasis by enhancing PI3K–AKT–mTOR signaling." Molecular Biology of the Cell 30, no. 19 (September 1, 2019): 2527–34. http://dx.doi.org/10.1091/mbc.e19-03-0136.
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The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial–mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K–AKT–mTOR pathway signaling.
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Saini, Krishan K., Samanta Sarti, Chelsea L. Rahiman, Brian E. Ragaishis, Patrick J. McCann, Shruti Bansal, Jason Cham, et al. "Abstract B011: Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy." Clinical Cancer Research 31, no. 2_Supplement (January 26, 2025): B011. https://doi.org/10.1158/1557-3265.targetedtherap-b011.
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Abstract Introduction: Radiation therapy (RT) induces adenosine signaling by releasing ATP in the tumor microenvironment (TME), promoting immune suppression and tumor progression. This study investigates how RT impacts adenosine signaling and immune cell infiltration in a preclinical model of non-small cell lung cancer (NSCLC). Using immunophenotyping of tumor-infiltrating immune cells in LLC1 murine model, we aim to explore the potential of targeting the adenosine pathway in combination with RT to enhance antitumor immunity and clinical outcomes. Methods: LLC1 tumor cells (5 x 105) were implanted subcutaneously in the flanks of C57BL/6 mice. After 12 days, mice received RT (4 Gy x 3 or 8 Gy x 3). Tumor volumes were measured thrice a week and harvested 5- and 10-days post-RT. We performed immunophenotyping of tumor tissue to assess changes in immune (CD45+) and CD45- compartments. The expression of adenosine signaling pathway members was quantified in distinct immune cell populations. Results: RT caused significant inhibition in tumor growth in a dose- and time-dependent manner. 5-days post-RT, CD73 (P< 0.01) and CD39 expressions (P< 0.01) were significantly upregulated in the immune compartment, while A2BR (P< 0.01) and A2AR (P< 0.05) were decreased in the non-immune compartment. RT decreased T cell populations, including CD4+ and CD8+ T cells. Further, CD4+ T cells downregulate adenosine signaling markers, particularly CD73 (P< 0.05) and ENPP1 (P< 0.05), while CD8+ T cells decreased in CD73 expression (P< 0.01). Myeloid subtype abundance was unchanged, but A2AR, A2BR, CD39, and CD73 expressions increased in the M2-like macrophage compartment (F4-80+MHCII-). 10 days post-RT, all adenosine signaling pathway markers significantly increased in the immune compartment and significantly decreased in the non-immune compartment. T cells (TCRb+) and macrophages (F4-80+) increased in abundance, including immuno-suppressive Arg+ macrophages (P< 0.05). Macrophage population that expressed the adenosine signaling markers increased by 10-15% (P< 0.05). While the proportion of CD4+ T cells and Tregs (CD4+FoxP3+) that expressed CD39 and CD73 also increased (P< 0.05). Conclusions: Our study revealed that RT promotes an immunosuppressive TME, in part through adenosine signaling. 5 days post-RT, we observed lymphocyte depletion and upregulation of the adenosine signaling pathway in M2-like macrophages. 10 days post-RT, adenosine signaling significantly increased across the immune compartment and decreased in the non-immune compartment, suggesting that the increase in adenosine signaling post-RT is immunologically mediated and largely driven by the myeloid compartment. These data lead to the hypothesis that inhibition of the adenosine signaling pathway may partially mitigate RT-induced immune suppression and improve RT efficacy. Ongoing work includes quantification of adenosine by LC-MS, extension to a preclinical SCC model of NSCLC, and evaluating adenosine pathway inhibition in combination with RT as a therapeutic strategy to improve antitumor immune responses. Citation Format: Krishan K. Saini, Samanta Sarti, Chelsea L. Rahiman, Brian E. Ragaishis, Patrick J. McCann, Shruti Bansal, Jason Cham, Julia An, Rosa Martin, Ariel Chen, Catherine S. Spina. Adenosine signaling and immune modulation in the tumor microenvironment: insights from lung cancer murine model of radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B011.
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Jackson, Edwin K., and Delbert G. Gillespie. "Extracellular 2′,3′-cAMP-adenosine pathway in proximal tubular, thick ascending limb, and collecting duct epithelial cells." American Journal of Physiology-Renal Physiology 304, no. 1 (January 1, 2013): F49—F55. http://dx.doi.org/10.1152/ajprenal.00571.2012.
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In a previous study, we demonstrated that human proximal tubular epithelial cells obtained from a commercial source metabolized extracellular 2′,3′-cAMP to 2′-AMP and 3′-AMP and extracellular 2′-AMP and 3′-AMP to adenosine (the extracellular 2′,3′-cAMP-adenosine pathway; extracellular 2′,3′-cAMP → 2′-AMP + 3′-AMP → adenosine). The purpose of this study was to investigate the metabolism of extracellular 2′,3′-cAMP in proximal tubular vs. thick ascending limb vs. collecting duct epithelial cells freshly isolated from their corresponding nephron segments obtained from rat kidneys. In epithelial cells from all three nephron segments, 1) extracellular 2′,3′-cAMP was metabolized to 2′-AMP and 3′-AMP, with 2′-AMP > 3′-AMP, 2) the metabolism of extracellular 2′,3′-cAMP to 2′-AMP and 3′-AMP was not inhibited by either 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor) or 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor), 3) extracellular 2′,3′-cAMP increased extracellular adenosine levels, 4) 3′-AMP and 2′-AMP were metabolized to adenosine with an efficiency similar to that of 5′-AMP, and 5) the metabolism of 5′-AMP, 3′-AMP, and 2′-AMP was not inhibited by α,β-methylene-adenosine-5′-diphosphate (CD73 inhibitor). These results support the conclusion that renal epithelial cells all along the nephron can metabolize extracellular 2′,3′-cAMP to 2′-AMP and 3′-AMP and can efficiently metabolize extracellular 2′-AMP and 3′-AMP to adenosine and that the metabolic enzymes involved are not the classical phosphodiesterases nor ecto-5′-nucleotidase (CD73). Because 2′,3′-cAMP is released by injury and because previous studies demonstrate that the extracellular 2′,3′-cAMP-adenosine pathway stimulates epithelial cell proliferation via adenosine A2B receptors, the present results suggest that the extracellular 2′,3′-cAMP-adenosine pathway may help restore epithelial cells along the nephron following kidney injury.
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Jacintho, Bruna Cardoso, Guilherme Leonardi, Bruna Mazetto, José Oliveira, Fabiola Zakia Monica, Erich Vinicius De Paula, and Fernanda A. Orsi. "Exploration of Purinergic Signaling Pathways As a Mechanism of Platelet Activation in Antiphospholipid Syndrome." Blood 144, Supplement 1 (November 5, 2024): 2610. https://doi.org/10.1182/blood-2024-203900.
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Background: We have previously demonstrated hyperreactivity to ADP, overexpression of the P2Y12 receptor, and reduced intracellular levels of cAMP and cGMP in platelets from antiphospholipid syndrome (APS) patients, suggestive of purinergic signaling activation. A possible explanation could be impaired adenosine pathways, since adenosine limits platelet activation by increasing intracellular cAMP via its A2A and A2B receptors. Aims: To evaluate the action of adenosine receptors (AR) on platelet activity in thrombotic primary APS (t-PAPS). Methods: t-PAPS and healthy volunteers were included. Platelet-rich plasma was used to evaluate platelet aggregation (induced by ADP 3 uM and collagen 1 μg/ml). Washed platelets (1X10^8 platelets/mL) were used to assess platelet activity (CD62P expression and CD41/CD61) induced by thrombin 0.005U in flow cytometry. CD62P or P-selectin, plays a key role in cell adhesion during neutrophil rolling and interactions between platelets and neutrophils and monocytes. CD41/CD61 or PAC-1, is a ligand-binding site for fibrinogen, von Willebrand factor, fibronectin, and vitronectin. Adenosine, NECA (stable adenosine analogue), CGS21680 (A2A receptor agonist) were used to evaluate adenosine pathway signaling. These are potent inhibitors of ADP-induced platelet aggregation and enhance the effects of P2Y12 antagonists. Results: A total of 53 t-APS and 63 controls were included, women were 74% of t-PAPS and 71% of controls. The median age was 46 years (IQR 37-55) for t-PAPS and 43 years (IQR 32-51) for controls (p=0.16). Notably, 25% of t-PAPS patients were triple-positive for antiphospholipid antibodies. Adenosine 1 μM inhibited ADP-induced aggregation by 19% (IQR 7%-48%) in t-PAPS and 38% (IQR 17%-61%; P=0.04) in controls. Adenosine 10 μM inhibited 75% (IQR 64%-88%) of ADP-induced aggregation in t-PAPS and 84% (IQR 76%-92%; p=0.01) in controls. Adenosine 10 μM also inhibited collagen-induced platelet aggregation by 91% (IQR 73%-94%) in t-PAPS and 94% (IQR 88%-98%; p=0.03) in controls. CGS21680 1 μM inhibited ADP-induced aggregation by 50% (IQR 28%-73%) in t-PAPS and 67% (IQR 41%-83%; p=0.03) in controls. CGS21680 10 μM inhibited ADP-induced aggregation by 79% (IQR 69%-85%) in t-PAPS and 88% (IQR 79%-93%; p=0.02) in controls. In flow cytometry analysis, CGS21680 at 10 μM inhibited P-selectin expression by 12% (IQR 3%-18%) in t-PAPS and 18% (IQR 9%-30%, p=0.05) in controls. NECA at 10 μM inhibited P-selectin expression by 13% (IQR 6%-24%) in t-PAPS and 22% (IQR 11%-35%; p=0.04) in controls. CGS21680 at 10 μM also inhibited PAC-1 expression by 25% (IQR 17%-37%) in t-PAPS and 30% (IQR 23%-52%; p=0.02) in controls. NECA at 10 μM inhibited PAC-1 expression by 27% (IQR 18%-42%) in t-PAPS and 35% (IQR 27%-58%; p=0.01) in controls. Discussion: Platelets from patients with t-PAPS exhibited a resistance to the inhibition effects of adenosine, CGS21680 and NECA. This resistance was observed in two distinct functional assays: platelet aggregation and cytometry. This observation raises the hypothesis that the activation of purinergic signaling in platelets from APS patients may be explained by a reduction in the regulatory activity of adenosine pathway. Conclusion: Platelets from patients with t-PAPS display resistance to platelet inhibition via the adenosine pathway. The stimulation of adenosine pathway may form a potential therapeutic option to control hypercoagulability in APS. Acknowledgements: Sao Paulo Research Foundation FAPESP (2023/07899-0)
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Graeff, Richard, Alonso Guedes, Ruth Quintana, Erin Wendt-Hornickle, Caroline Baldo, Timothy Walseth, Scott O’Grady, and Mathur Kannan. "Novel Pathway of Adenosine Generation in the Lungs from NAD+: Relevance to Allergic Airway Disease." Molecules 25, no. 21 (October 27, 2020): 4966. http://dx.doi.org/10.3390/molecules25214966.
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Adenosine and uric acid (UA) play a pivotal role in lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). In the present experiments, we measured adenosine synthesis from nicotinamide adenine dinucleotide (NAD+) in membranes prepared from wild type (WT) and CD38 knockout (CD38KO) mouse lungs, from cultured airway smooth muscle and epithelial cells, and in bronchoalveolar lavage fluid after airway challenge with epidemiologically relevant allergens. Adenosine was determined using an enzymatically coupled assay that produces ATP and is detected by luminescence. Uric acid was determined by ELISA. Exposure of cultured airway epithelial cells to Alternaria alternata extract caused significant nucleotide (NAD+ and ATP) release in the culture media. The addition of NAD+ to membranes prepared from WT mice resulted in faster generation of adenosine compared to membranes from CD38KO mice. Formation of adenosine from NAD+ affected UA and ATP concentrations, its main downstream molecules. Furthermore, NAD+ and adenosine concentrations in the bronchoalveolar lavage fluid decreased significantly following airway challenge with house-dust mite extract in WT but not in CD38KO mice. Thus, NAD+ is a significant source of adenosine and UA in the airways in mouse models of allergic airway disease, and the capacity for their generation from NAD+ is augmented by CD38, a major NADase with high affinity for NAD+. This novel non-canonical NAD+-adenosine-UA pathway that is triggered by allergens has not been previously described in the airways.
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Nichols, Nicole L., Erica A. Dale, and Gordon S. Mitchell. "Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism." Journal of Applied Physiology 112, no. 10 (May 15, 2012): 1678–88. http://dx.doi.org/10.1152/japplphysiol.00060.2012.
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Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35–45 mmHg arterial Po2 (PaO2)] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by Gq protein-coupled metabotropic 5-HT2 receptors. An alternate pathway to pMF is induced by Gs protein-coupled metabotropic receptors, including adenosine A2A receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25–30 mmHg PaO2) and moderate (45–55 mmHg PaO2) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A2A (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P < 0.05). MSX-3 (28% ± 6%; n = 6; P < 0.05) attenuated pLTF following severe AIH, but enhanced pLTF following moderate AIH (86% ± 26%; n = 8; P < 0.05). Methysergide abolished pLTF after moderate AIH (12% ± 5%; n = 6; P = 0.035), but had no effect after severe AIH (66 ± 13%; n = 5; P > 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted.
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Guo, Mengyi, and Tianfu Li. "Adenosine Dysfunction in Epilepsy and Associated Comorbidities." Current Drug Targets 23, no. 4 (March 2022): 344–57. http://dx.doi.org/10.2174/1389450122666210928145258.
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: Epilepsy, a complex neurological syndrome with dominant symptoms and various comorbidities, affects over 70 million people worldwide. Epilepsy-related comorbidities, including cognitive and psychiatric disorders, can impede therapy for epilepsy patients, leading to heavy burdens on patients and society. Adenosine has an anti-epileptic and anticonvulsive function in the brain. Several studies have shown that, through adenosine receptor-dependent and -independent mechanisms, adenosine can influence the development and progression (epileptogenesis) of epilepsy and its associated comorbidities. As the key enzyme for adenosine clearance, adenosine kinase (ADK) can exacerbate epileptic seizures not only by accelerating adenosine clearance, but also by increasing global DNA methylation through the transmethylation pathway. Therefore, adenosine augmentation therapies for epilepsy can have dual functions in the inhibition of epileptic seizures and the prevention of its overall progress. This review has three main purposes. First, we discuss how maladaptive changes in the adenosine pathway affect the development and progress of epilepsy in both receptor-dependent and receptor-independent ways. Second, we highlight the important influence of associated comorbidities on the prognosis of epilepsy and explore the role of adenosine in these comorbidities. Finally, we emphasize the potential of adenosine augmentation therapies in restoring normal adenosine signaling in the epileptic brain. Such treatments could effectively improve the prognosis of patients who are resistant to most antiepileptic drugs (AEDs), and thus bring new challenges and opportunities in the treatment of epilepsy patients.
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Ortiz-Capisano, M. Cecilia, Douglas K. Atchison, Pamela Harding, Robert D. Lasley, and William H. Beierwaltes. "Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway." American Journal of Physiology-Renal Physiology 305, no. 8 (October 15, 2013): F1209—F1219. http://dx.doi.org/10.1152/ajprenal.00710.2012.
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Renin is synthesized and released from juxtaglomerular (JG) cells. Adenosine inhibits renin release via an adenosine A1 receptor (A1R) calcium-mediated pathway. How this occurs is unknown. In cardiomyocytes, adenosine increases intracellular calcium via transient receptor potential canonical (TRPC) channels. We hypothesized that adenosine inhibits renin release via A1R activation, opening TRPC channels. However, higher concentrations of adenosine may stimulate renin release through A2R activation. Using primary cultures of isolated mouse JG cells, immunolabeling demonstrated renin and A1R in JG cells, but not A2R subtypes, although RT-PCR indicated the presence of mRNA of both A2AR and A2BR. Incubating JG cells with increasing concentrations of adenosine decreased renin release. Different concentrations of the adenosine receptor agonist N-ethylcarboxamide adenosine (NECA) did not change renin. Activating A1R with 0.5 μM N6-cyclohexyladenosine (CHA) decreased basal renin release from 0.22 ± 0.05 to 0.14 ± 0.03 μg of angiotensin I generated per milliliter of sample per hour of incubation (AngI/ml/mg prot) ( P < 0.03), and higher concentrations also inhibited renin. Reducing extracellular calcium with EGTA increased renin release (0.35 ± 0.08 μg AngI/ml/mg prot; P < 0.01), and blocked renin inhibition by CHA (0.28 ± 0.06 μg AngI/ml/mg prot; P < 0. 005 vs. CHA alone). The intracellular calcium chelator BAPTA-AM increased renin release by 55%, and blocked the inhibitory effect of CHA. Repeating these experiments in JG cells from A1R knockout mice using CHA or NECA demonstrated no effect on renin release. However, RT-PCR showed mRNA from TRPC isoforms 3 and 6 in isolated JG cells. Adding the TRPC blocker SKF-96365 reversed CHA-mediated inhibition of renin release. Thus A1R activation results in a calcium-dependent inhibition of renin release via TRPC-mediated calcium entry, but A2 receptors do not regulate renin release.
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Zahavi, David, and James W. Hodge. "Targeting Immunosuppressive Adenosine Signaling: A Review of Potential Immunotherapy Combination Strategies." International Journal of Molecular Sciences 24, no. 10 (May 17, 2023): 8871. http://dx.doi.org/10.3390/ijms24108871.
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The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable clinical success, resistance is common, and there is an urgent need to identify additional targets. Extracellular adenosine, a metabolite of ATP, is found at high levels in the tumor microenvironment and has potent immunosuppressive properties. Targeting members of the adenosine signaling pathway represents a promising immunotherapeutic modality that can potentially synergize with conventional anti-cancer treatment strategies. In this review, we discuss the role of adenosine in cancer, present preclinical and clinical data on the efficacy adenosine pathway inhibition, and discuss possible combinatorial approaches.
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Li, Dimin, Yuan Wei, and Wen-Hui Wang. "Dietary K intake regulates the response of apical K channels to adenosine in the thick ascending limb." American Journal of Physiology-Renal Physiology 287, no. 5 (November 2004): F954—F959. http://dx.doi.org/10.1152/ajprenal.00183.2004.
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We used the patch-clamp technique to study the effect of adenosine on the apical 70-pS K channel in the thick ascending limb (TAL) of the rat kidney. Application of 1 μM cyclohexyladenosine (CHA), an adenosine analog, stimulated apical 70-pS K channel activity and increased the product of channel open probability and channel number ( NPo) from 0.34 to 0.7. Also, addition of CGS-21680, a specific A2a adenosine receptor agonist, mimicked the effect of CHA and increased NPo from 0.33 to 0.77. The stimulatory effect of CHA and CGS-21680 was completely blocked by H89, an inhibitor of protein kinase A (PKA), or by inhibition of adenylate cyclase with SQ-22536. This suggests that the stimulatory effect of adenosine analogs is mediated by a PKA-dependent pathway. The effect of adenosine analog was almost absent in the TAL from rats on a K-deficient (KD) diet for 7 days. Application of DDMS, an agent that inhibits cytochrome P-450 hydrolase, not only significantly increased the activity of the 70-pS K channel but also restored the stimulatory effect of CHA on the 70-pS K channel in the TAL from rats on a KD diet. Also, the effect of CHA was absent in the presence of 20-HETE. Inhibition of PKA blocked the stimulatory effect of CHA on the apical 70-pS K channel in the presence of DDMS in the TAL from rats on a KD diet. We conclude that stimulation of adenosine receptor increases the apical 70-pS K channel activity via a PKA-dependent pathway and that the effect of adenosine on the apical 70-pS K channel is suppressed by low-K intake. Moreover, the diminished response to adenosine is the result of increase in 20-HETE formation, which inhibits the cAMP-dependent pathway in the TAL from rats on a KD diet.