Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy

Loukovaara, Sirpa; Sandholm, Jouko; Aalto, Kristiina; Liukkonen, Janne; Jalkanen, Sirpa; Yegutkin, Gennady G.

doi:10.1007/s00109-016-1472-6

Cited by 26 publications

(27 citation statements)

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“…Soluble NTPDase/ADPase, e N/CD73, ADA, and AK were assayed by incubating the VF (or serum) with [ 3 H]ADP, [ 3 H]AMP, [ 3 H]adenosine, and [ 3 H]AMP plus ATP, as respective enzyme substrates. 3 H-labeled nucleotides and nucleosides were separated by thin-layer chromatography (TLC) and quantified by scintillation β-counting [17, 25] or developed by autoradiography, as described in the Supplementary Material. In competitive assays, the samples were pretreated for 30 min with inhibitors of NTPDases sodium polyoxotungstate-1 (POM-1) (Tocris Bioscience, Bristol, UK) and POM-144 [26], selective e N/CD73 inhibitors α,β-methylene ADP (APCP, Sigma) and its derivative N 6 -phenylethyl-[(phosphonomethyl)-phosphonic acid], (PSB-12379 [27]), inhibitor of AK diadenosine pentaphosphate (Ap 5 A), and ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, Tocris Bioscience).…”

Section: Methodsmentioning

confidence: 99%

“…A 2A and other subtypes of adenosine receptors were shown to be implicated in the modulation of the light responses of photoreceptors, retinal hyperemia, pathological retinal angiogenesis, protection of neurons from hyper-excitation and glutamate toxicity [3, 10–13]. Previous research from our and other laboratories revealed the ability of VF and aqueous humor to maintain ATP and adenosine at certain characteristic nanomolar levels, which increase in pathological conditions, such as dry eye disease [14], glaucoma [2, 12, 15], age-related macular degeneration with subretinal hemorrhage [4], and diabetic retinopathy (DR) [16, 17].…”

Section: Introductionmentioning

confidence: 99%

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Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage

et al. 2019

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ATP and adenosine are important signaling molecules involved in vascular remodeling, retinal function, and neurovascular coupling in the eye. Current knowledge on enzymatic pathways governing the duration and magnitude of ocular purinergic signaling is incompletely understood. By employing sensitive analytical assays, this study dissected ocular purine homeostasis as a complex and coordinated network. Along with previously characterized ecto-5′-nucleotidase/CD73 and adenylate kinase activities, other enzymes have been identified in vitreous fluids, including nucleoside triphosphate diphosphohydrolase (NTPDase), adenosine deaminase, and alkaline phosphatase. Strikingly, activities of soluble adenylate kinase, adenosine deaminase, ecto-5′-nucleotidase/CD73, and alkaline phosphatase, as well as intravitreal concentrations of ATP and ADP, were concurrently upregulated in patients suffering from diabetic retinopathy (DR) with non-clearing vitreous hemorrhage (VH), when compared to DR eyes without VH and control eyes operated due to macular hole or pucker. Additional histochemical analysis revealed selective distribution of key ecto-nucleotidases (NTPDase1/CD39, NTPDase2, ecto-5′-nucleotidase/CD73, and alkaline phosphatase) in the human sensory neuroretina and optic nerve head, and also in pathological neofibrovascular tissues surgically excised from patients with advanced proliferative DR. Collectively, these data provide evidence for specific hemorrhage-related shifts in purine homeostasis in DR eyes from the generation of anti-inflammatory adenosine towards a pro-inflammatory and pro-angiogenic ATP-regenerating phenotype. In the future, identifying the exact mechanisms by which a broad spectrum of soluble and membrane-bound enzymes coordinately regulates ocular purine levels and the further translation of purine-converting enzymes as potential therapeutic targets in the treatment of proliferative DR and other vitreoretinal diseases will be an area of intense interest. Key messages NTPDase, alkaline phosphatase, and adenosine deaminase circulate in human vitreous. Purinergic enzymes are up-regulated in diabetic eyes with vitreous hemorrhage. Soluble adenylate kinase maintains high ATP levels in diabetic retinopathy eyes. Ecto-nucleotidases are co-expressed in the human retina and optic nerve head. Alkaline phosphatase is expressed on neovascular tissues excised from diabetic eyes. Electronic supplementary material The online version of this article (10.1007/s00109-018-01734-0) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage

et al. 2019

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“…thus, affected patients are often included as a control group in analyses of in ammation-related ocular diseases [9]. However, after onset of IMHs, tissue damage and reparation often lead to local in ammatory reactions, which affect cytokine levels in the aqueous humor.…”

Section: Discussionmentioning

confidence: 99%

Analysis of multiple cytokines in aqueous humor of patients with idiopathic macular hole

Wang

Han

et al. 2020

Preprint

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Background: Idiopathic macular holes are common ophthalmic manifestations with unknown pathogenesis. Thus far, there has been minimal research regarding the causes of idiopathic macular holes, especially with respect to the underlying immune mechanism. To provide clarity regarding the treatment and prognosis of idiopathic macular holes, specifically regarding the levels of cytokines in affected patients, this study examined and analyzed multiple cytokine levels in aqueous humor from patients with idiopathic macular holes. Methods: This comparative cross-sectional study included 38 patients in two groups: a cataract control group (n=17) and an idiopathic macular hole group (n=21). The levels of 48 cytokines in aqueous humor were detected by multiplex analysis with antibody-coupled magnetic beads. The Kolmogorov–Smirnov test was used to check whether the data were normally distributed; Student’s t-test and the Mann–Whitney U test were used to assess differences in cytokine levels between the two groups. Spearman correlation analysis was used to assess relationships among cytokine levels in the experimental group. Signaling pathways containing cytokines with significantly different expression in the experimental group were identified. Results: There were significant differences in aqueous humor cytokine levels between patients with idiopathic macular holes and patients in the cataract control group. Notably, hepatocyte growth factor (p=0.0001), GM-CSF (p=0.0111), and IFN-γ (p=0.0120) were significantly upregulated in the experimental group , while TNF-α (p=0.0032), GRO-α (p<0.0001), and MIF (p<0.0001) were significantly downregulated in the experimental group. Furthermore, the GM-CSF level showed significant positive correlations with levels of IL-1 (r=0.67904, p<0.001), IL-4 (r=0.76017, p<0.001), and IFN-γ (r=0.59922, p=0.004097) in the experimental group. Moreover, the levels of nerve growth factor and hepatocyte growth factor showed a significant positive correlation (r=0.64951, p=0.001441) in the experimental group. Conclusions: Patients with idiopathic macular holes showed significant variation in aqueous humor immune response after the onset of hole formation, including the recruitment of immune cells and regulation of cytokine expression. Our findings also suggest that it is not appropriate to use patients with macular holes as the control group in studies of aqueous humor cytokine levels in ophthalmic diseases.

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“…One of the most recent study, demonstrate that AK1 from the human vitreous fluid is responsible for maintaining an inflammatory status in diabetic eyes (Fig. 3a) [37]. Also, the ATP, ADP, and AMP ratio is crucial in ocular diseases like age-related macular degeneration, glaucoma or retinal degeneration [38][39][40].…”

Section: Human Adenylate Kinases and Immunity And Inflammationmentioning

confidence: 97%

Adenylate Kinase: A Ubiquitous Enzyme Correlated with Medical Conditions

Ionescu

2019

Protein J

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Adenylate kinase is a small, usually monomeric, enzyme found in every living thing due to its crucial role in energetic metabolism. This paper outlines the most relevant data about adenylate kinases isoforms, and the connection between dysregulation or mutation of human adenylate kinase and medical conditions. The following datadases were consulted: National Centre for Biotechnology Information, Protein Data Bank, and Mouse Genomic Informatics. The SmartBLAST tool, EMBOSS Needle Program, and Clustal Omega Program were used to analyze the best protein match, and to perform pairwise sequence alignment and multiple sequence alignment. Human adenylate kinase genes are located on different chromosomes, six of them being on the chromosomes 1 and 9. The adenylate kinases' intracellular localization and organ distribution explain their dysregulation in many diseases. The cytosolic isoenzyme 1 and the mitochondrial isoenzyme 2 are the main adenylate kinases that are integrated in the vast network of inflammatory modulators. The cytosolic isoenzyme 5 is correlated with limbic encephalitis and Leu673Pro mutation of the isoenzyme 7 leads to primary male infertility due to impairment of the ciliary function. The impairment of the mitochondrial isoenzymes 2 and 4 is demonstrated in neuroblastoma or glioma. The adenylate kinases are disease modifier that can assess the risk of diseases where oxidative stress plays a crucial role in pathogenesis like metabolic syndrome or neurodegenerative diseases. Because adenylate kinases has ATP as substrate, they are integrated in the global network of energetic process of any organism therefore are valid target for new pharmaceutical compounds. Keywords Adenylate kinase • Nucleotide metabolism • Phosphotransfer enzymes • AMP-activated protein kinase • Adenine nucleotide • Homeostasis Abbreviations ADP Adenosine diphosphate AK Adenylate kinase AMP Adenosine monophosphate AMPK AMP-activated protein kinases Ap5A P1,P5-di(adenosine-5′) pentaphosphate ATP Adenosine triphosphate B4P Bis(adenosine)-5′-tetraphosphate BLAST Basic local alignment search tool BLOSUM BLOcks SUbstitution Matrix CDP Cytidine diphosphate dNTP Deoxy-nucleoside triphosphates DGYP Aspartic acid glycine tyrosine proline GTP

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Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy

Cited by 26 publications

References 50 publications

Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage

Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage

Analysis of multiple cytokines in aqueous humor of patients with idiopathic macular hole

Adenylate Kinase: A Ubiquitous Enzyme Correlated with Medical Conditions

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