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N6-methyladenosine-modified circ_104797 sustains cisplatin resistance in bladder cancer through acting as RNA sponges.
Xu, C, Zhou, J, Zhang, X, Kang, X, Liu, S, Song, M, Chang, C, Lin, Y, Wang, Y
Cellular & molecular biology letters. 2024;(1):28
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Abstract
BACKGROUND Bladder cancer (BCa) ranks among the predominant malignancies affecting the urinary system. Cisplatin (CDDP) remains a cornerstone therapeutic agent for BCa management. Recent insights suggest pivotal roles of circular RNA (circRNA) and N6-methyladenosine (m6A) in modulating CDDP resistance in BCa, emphasizing the importance of elucidating these pathways to optimize cisplatin-based treatments. METHODS Comprehensive bioinformatics assessments were undertaken to discern circ_104797 expression patterns, its specific interaction domains, and m6A motifs. These findings were subsequently corroborated through experimental validations. To ascertain the functional implications of circ_104797 in BCa metastasis, in vivo assays employing CRISPR/dCas13b-ALKBH5 were conducted. Techniques, such as RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assays, and western blotting, were employed to delineate the underlying molecular intricacies. RESULTS Our investigations revealed an elevated expression of circ_104797 in CDDP-resistant BCa cells, underscoring its pivotal role in sustaining cisplatin resistance. Remarkably, demethylation of circ_104797 markedly augmented the potency of cisplatin-mediated apoptosis. The amplification of circ_104797 in CDDP-resistant cells was attributed to enhanced RNA stability, stemming from an augmented m6A level at a distinct adenosine within circ_104797. Delving deeper, we discerned that circ_104797 functioned as a microRNA reservoir, specifically sequestering miR-103a and miR-660-3p, thereby potentiating cisplatin resistance. CONCLUSIONS Our findings unveil a previously uncharted mechanism underpinning cisplatin resistance and advocate the potential therapeutic targeting of circ_104797 in cisplatin-administered patients with BCa, offering a promising avenue for advanced BCa management.
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Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy.
Augustin, RC, Leone, RD, Naing, A, Fong, L, Bao, R, Luke, JJ
Journal for immunotherapy of cancer. 2022;(2)
Abstract
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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Role of insulin, adenosine, and adipokine receptors in the foetoplacental vascular dysfunction in gestational diabetes mellitus.
Subiabre, M, Villalobos-Labra, R, Silva, L, Fuentes, G, Toledo, F, Sobrevia, L
Biochimica et biophysica acta. Molecular basis of disease. 2020;(2):165370
Abstract
Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal l-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A2A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/l-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and l-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.
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Prognostic Effect of Adenosine-related Genetic Variants in Metastatic Colorectal Cancer Treated With Bevacizumab-based Chemotherapy.
Tokunaga, R, Cao, S, Naseem, M, Lo, JH, Battaglin, F, Puccini, A, Berger, MD, Soni, S, Millstein, J, Zhang, W, et al
Clinical colorectal cancer. 2019;(1):e8-e19
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Abstract
BACKGROUND Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. PATIENTS AND METHODS We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed. RESULTS In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort. CONCLUSION Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.
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Functional insights into nucleotide-metabolizing ectoenzymes expressed by bone marrow-resident cells in patients with multiple myeloma.
Horenstein, AL, Morandi, F, Bracci, C, Pistoia, V, Malavasi, F
Immunology letters. 2019;:40-50
Abstract
Human myeloma cells grow in a hypoxic acidic niche in the bone marrow. Cross talk among cellular components of this closed niche generates extracellular adenosine, which promotes tumor cell survival. This is achieved through the binding of adenosine to purinergic receptors into complexes that function as an autocrine/paracrine signal factor with immune regulatory activities that i) down-regulate the functions of most immune effector cells and ii) enhance the activity of cells that suppress anti-tumor immune responses, thus facilitating the escape of malignant myeloma cells from immune surveillance. Here we review recent findings confirming that the dominant phenotype for survival of tumor cells is that where the malignant cells have been metabolically reprogrammed for the generation of lactic acidosis in the bone marrow niche. Adenosine triphosphate and nicotinamide-adenine dinucleotide extruded from tumor cells, along with cyclic adenosine monophosphate, are the main intracellular energetic/messenger molecules that serve as leading substrates in the extracellular space for membrane-bound ectonucleotidases metabolizing purine nucleotides to signaling adenosine. Within this mechanistic framework, the adenosinergic substrate conversion can vary significantly according to the metabolic environment. Indeed, the neoplastic expansion of plasma cells exploits both enzymatic networks and hypoxic acidic conditions for migrating and homing to a protected niche and for evading the immune response. The expression of multiple specific adenosine receptors in the niche completes the profile of a complex regulatory framework whose signals modify multiple myeloma and host immune responses.
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A Randomized Controlled Trial of Intra-Aortic Adenosine Infusion Before Release of the Aortic Cross-Clamp During Coronary Artery Bypass Surgery.
Ammar, A, Mahmoud, K, Elkersh, A, Kasemy, Z
Journal of cardiothoracic and vascular anesthesia. 2018;(6):2520-2527
Abstract
OBJECTIVES To assess the feasibility, safety, and potential useful effect of adenosine as a postconditioning agent in patients undergoing coronary artery bypass grafting surgeries. DESIGN Prospective randomized controlled study. SETTING University hospital. PARTICIPANTS The study comprised 60 patients scheduled for coronary artery bypass grafting surgery. INTERVENTIONS Adenosine (postconditioning group) or placebo (control group). Adenosine infusion (150 µg/kg/min) for 10 minutes via a cardioplegia needle into the aortic root was started 10 minutes before aortic cross-clamp removal. MEASUREMENTS AND MAIN RESULTS Compared with the control group, ejection fraction, fractional shortening, cardiac index (2.9 ± 0.3 v 2.2 ± 0.3 L/min/m2, p = 0.032 at 60 min postbypass) and diastolic function indices were significantly better in the postconditioning group at most time points in the postbypass period. Cardiac troponin I and creatine kinase-MB release and the inotropic score were significantly lower in the postconditioning group at most time points in the postoperative period. The need for intra-aortic balloon and epicardial pacing were comparable in both groups, whereas incidence of arrhythmia, duration of postoperative mechanical ventilation, and intensive care unit and total hospital stays were significantly lower in the postconditioning group. CONCLUSIONS Adenosine postconditioning provided cardiac protection as evidenced by a favorable outcome on systolic and diastolic function indices, less cardiac troponin I and creatine kinase-MB release, lower incidence of arrhythmia, lower inotropic score, and shorter duration of postoperative mechanical ventilation and intensive care unit stay.
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Impaired vasocontractile responses to adenosine in chorionic vessels of human term placenta from pregnant women with pre-existing and gestational diabetes.
Razak, AA, Leach, L, Ralevic, V
Diabetes & vascular disease research. 2018;(6):528-540
Abstract
BACKGROUND There is clinical and experimental evidence for altered adenosine signalling in the fetoplacental circulation in pregnancies complicated by diabetes, leading to adenosine accumulation in the placenta. However, the consequence for fetoplacental vasocontractility is unclear. This study examined contractility to adenosine of chorionic vessels from type 1 diabetes mellitus, gestational diabetes mellitus and normal pregnancies. METHODS Chorionic arteries and veins were isolated from human placenta from normal, gestational diabetes mellitus and type 1 diabetes mellitus pregnancies. Isometric tension recording measured responses to adenosine and the thromboxane A2 analogue U46619 (thromboxane A2 mediates fetoplacental vasoconstriction to adenosine). Adenosine and thromboxane prostanoid receptor protein expression was determined by immunoblotting. RESULTS Adenosine elicited contractions in chorionic arteries and veins which were impaired in both gestational diabetes mellitus and type 1 diabetes mellitus. Contractions to potassium chloride were unchanged. Adenosine A2A and A2B receptor protein levels were not different in gestational diabetes mellitus and normal pregnancies. Contractions to U46619 were unaltered in gestational diabetes mellitus arteries and increased in type 1 diabetes mellitus arteries. Overnight storage of vessels restored contractility to adenosine in gestational diabetes mellitus arteries and normalized contraction to U46619 in type 1 diabetes mellitus arteries. CONCLUSION These data are consistent with the concept of aberrant adenosine signalling in diabetes; they show for the first time that this involves impaired adenosine contractility of the fetoplacental vasculature.
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Neutrophils as sources of dinucleotide polyphosphates and metabolism by epithelial ENPP1 to influence barrier function via adenosine signaling.
Curtis, VF, Cartwright, IM, Lee, JS, Wang, RX, Kao, DJ, Lanis, JM, Burney, KM, Welch, N, Hall, CHT, Goldberg, MS, et al
Molecular biology of the cell. 2018;(22):2687-2699
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Abstract
Extracellular adenosine signaling is established as a protective component in mucosal inflammatory responses. The sources of extracellular adenosine include enzymatic processing from nucleotides, such as ATP and AMP, that can be liberated from a variety of cell types, including infiltrating leukocytes. Here we demonstrate that activated human neutrophils are a source of diadenosine triphosphate (Ap3A), providing an additional source of nucleotides during inflammation. Profiling murine enteroids and intestinal epithelial cell lines revealed that intestinal epithelia prominently express apical and lateral ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a member of the ENPP family of enzymes that metabolize diadenosine phosphates, especially Ap3A. Extensions of these studies demonstrated that intestinal epithelia metabolize Ap3A to ADP and AMP, which are further metabolized to adenosine and made available to activate surface adenosine receptors. Using loss and gain of ENPP1 approaches, we revealed that ENPP1 coordinates epithelial barrier formation and promotes epithelial wound healing responses. These studies demonstrate the cooperative metabolism between Ap3A and ENPP1 function to provide a significant source of adenosine, subserving its role in inflammatory resolution.
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Comparison of sodium nitroprusside and adenosine for fractional flow reserve assessment: a systematic review and meta-analysis.
Solernó, R, Pedroni, P, Mariani, J, Sarmiento, R
Expert review of cardiovascular therapy. 2018;(10):765-770
Abstract
BACKGROUND Fractional flow reserve (FFR) has become a useful tool in the assessment of physiological significance of coronary artery stenosis (CAS), and Adenosine (ADE) is associated with a high incidence of transient side effects. Sodium nitroprusside (NPS) has been proposed as an alternative vasodilator agent. A meta-analysis of studies comparing ADE and NPS for FFR assessment in the same coronary lesions was performed. METHODS Authors searched for articles comparing NPS and ADE for FFR assessment in intermediate coronary lesions published through January 2018. The following keywords were used: 'fractional flow reserve' AND 'nitroprusside'. Data were summarized using weighted mean differences for paired data. RESULTS Seven studies were identified comprising 342 patients and 401 lesions. Four studies evaluated intravenous ADE and 3 studies intracoronary ADE administration. Weighted means FFR values obtained with ADE and NPS were 0.8411 and 0.8445, respectively (weighted mean difference: 0.00, 95% confidence interval (CI) -0.01 to 0.01, p = 0,548). Adverse events were significantly reduced with IC NPS (RR = 0.08, 95%CI 0.02-0.30, P < 0.0001). CONCLUSIONS NPS produces similar FFR measurements compared to ADE with a significant reduction in adverse effects. These results may support its use as a suitable alternative to ADE for FFR assessment.
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Comparison between adenosine and magnesium sulphate as adjuvants for transversus abdominis plane block: a prospective randomized controlled trial.
Ammar, AS, Mahmoud, KM, Kasemy, ZA
Minerva anestesiologica. 2018;(3):304-310
Abstract
BACKGROUND Various adjuvants have been employed during different nerve blocks. We aimed to evaluate the effect of adding adenosine versus magnesium sulfate to bupivacaine on the quality and duration of transversus abdominis plane (TAP) block. METHODS Participants were randomized to TAP block using either 20 mL of bupivacaine hydrochloride 0.375% + 12 mg adenosine in 2 mL of saline 0.9% (adenosine group), 20 mL of bupivacaine hydrochloride 0.375% + 500 mg magnesium sulphate in 2 mL saline 0.9% (magnesium group) or 20 mL of bupivacaine hydrochloride 0.375% + 2 mL saline 0.9% (control group). Primary outcome measure included postoperative pain as assessed by Visual Analog Scale (VAS) for pain scoring on movement and secondary outcomes included analgesia duration, postoperative morphine need and any adverse effects. RESULTS VAS in adenosine and magnesium groups was significantly less than in control group at 6 and 12 hours postoperatively whereas it was comparable in adenosine and magnesium groups at all time points. Analgesia duration was significantly longer in adenosine and magnesium groups in comparison to the control group and it was relatively longer in the magnesium group when compared to adenosine group (401 vs. 447 vs. 320 minutes in adenosine, magnesium and control groups, respectively; P=0.003). CONCLUSIONS Both adenosine and magnesium improved the quality and duration of TAP block, but the duration was relatively longer with magnesium.