The Experts below are selected from a list of 2313 Experts worldwide ranked by ideXlab platform
Akio Ohta - One of the best experts on this subject based on the ideXlab platform.
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hostile hypoxia a2 Adenosinergic tumor biology as the next barrier to overcome for tumor immunologists
Cancer immunology research, 2014Co-Authors: Michail V Sitkovsky, Dmitriy Lukashev, Stephen Hatfield, Bryan Belikoff, Robert Abbott, Akio OhtaAbstract:Hypoxia-driven, A2A adenosine receptor (A2AR)–mediated (hypoxia–A2-Adenosinergic), T-cell–autonomous immunosuppression was first recognized as critical and nonredundant in protecting normal tissues from inflammatory damage and autoimmunity. However, this immunosuppressive mechanism can be highjacked by bacteria and tumors to provide misguided protection for pathogens and cancerous tissues. Inhibitors of the hypoxia–A2-Adenosinergic pathway represent a conceptually novel type of immunologic coadjuvants that could be combined with cancer vaccines, adoptive cell transfer, and/or blockade of negative immunologic regulators to further prolong patient survival and to minimize treatment-related side effects. In support of this approach are preclinical studies and findings that some human cancers are resistant to chemotherapies and immunotherapies due to the tumor-generated extracellular adenosine and A2AR on antitumor T and natural killer (NK) cells. Among the coadjuvants are (i) antagonists of A2AR, (ii) extracellular adenosine-degrading drugs, (iii) inhibitors of adenosine generation by CD39/CD73 ectoenzymes, and (iv) inhibitors of hypoxia–HIF-1α signaling. Combining these coadjuvants with CTLA-4 and/or PD-1 blockade is expected to have additive or even synergistic effects of targeting two different antitumor protective mechanisms. It is expected that even after multicombinatorial blockade of negative immunologic regulators, the antitumor T and NK cells would still be vulnerable to inhibition by hypoxia and A2AR. Yet to be tested is the potential capacity of coadjuvants to minimize the side effects of CTLA-4 and/or PD-1 blockade by decreasing the dose of blocking antibodies or by eliminating the need for dual blockade. Cancer Immunol Res; 2(7); 598–605. ©2014 AACR .
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the antihypoxia Adenosinergic pathogenesis as a result of collateral damage by overactive immune cells
Journal of Leukocyte Biology, 2009Co-Authors: Stephen Hatfield, Michail V Sitkovsky, Dmitriy Lukashev, Bryan Belikoff, Akio OhtaAbstract:Here, we attract attention to the possibility of iatrogenic exacerbation of immune-mediated tissue damage as a result of the unintended weakening of the tissue-protecting, hypoxia-Adenosinergic pathway. These immunosuppressive, anti-inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF-1 .W e show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia-Adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage. J. Leukoc. Biol. 86: 545–548; 2009.
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the Adenosinergic immunomodulatory drugs
Current Opinion in Pharmacology, 2009Co-Authors: Akio Ohta, Michail V SitkovskyAbstract:Hypoxia-driven increase of extracellular adenosine in local tissue microenvironments of inflamed and cancerous tissues plays a critical role in the regulation of tissue destruction by activated immune cells. Accumulated data suggest that injection or consumption of A2A adenosine receptor (A2AR) antagonists may represent a drug treatment that diminishes adenosine-mediated immunosuppression. Since this, in turn, enhances the immune response, inhibition of adenosine-A2AR signaling may be a promising approach to enhance anti-tumor or anti-pathogen immune response. Patients with disorders characterized by excessive inflammation may be at risk to A2AR antagonists (e.g. caffeine) because of the effect to increase inflammatory damage secondary to enhanced immunity. On the other hand, enhancement of hypoxia-Adenosinergic immunomodulatory pathways may be beneficial to prevent inflammatory tissue destruction.
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The antihypoxia–Adenosinergic pathogenesis as a result of collateral damage by overactive immune cells
Journal of Leukocyte Biology, 2009Co-Authors: Stephen Hatfield, Michail V Sitkovsky, Dmitriy Lukashev, Bryan Belikoff, Akio OhtaAbstract:Here, we attract attention to the possibility of iatrogenic exacerbation of immune-mediated tissue damage as a result of the unintended weakening of the tissue-protecting, hypoxia-Adenosinergic pathway. These immunosuppressive, anti-inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF-1 .W e show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia-Adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage. J. Leukoc. Biol. 86: 545–548; 2009.
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hypoxia Adenosinergic immunosuppression tumor protection by t regulatory cells and cancerous tissue hypoxia
Clinical Cancer Research, 2008Co-Authors: Michail V Sitkovsky, Jorgen Kjaergaard, Dmitriy Lukashev, Akio OhtaAbstract:Cancerous tissue protection from tumor-recognizing CD8 + and CD4 + T cells (antitumor T cells) limits the therapeutic potential of immunotherapies. We propose that tumor protection is to a large extent due to ( a ) inhibition of antitumor T cells by hypoxia-driven accumulation of extracellular adenosine in local tumor microenvironment and due to ( b ) T regulatory cell-produced extracellular adenosine. The adenosine triggers the immunosuppressive signaling via intracellular cyclic AMP–elevating A2A adenosine receptors (A2AR) on antitumor T cells. In addition, the activated antitumor T cells in hypoxic tumor microenvironment could be inhibited by elevated levels of immunosuppressive hypoxia-inducible factor-1α. Complete rejection or tumor growth retardation was observed when A2AR has been genetically eliminated or antagonized with synthetic drug or with natural A2AR antagonist 1,3,7-trimethylxanthine (caffeine). The promising strategy may be in combining the anti-hypoxia-Adenosinergic treatment that prevents inhibition of antitumor T cells by tumor-produced and T regulatory cell-produced adenosine with targeting of other negative regulators, such as CTL antigen-4 blockade. Observations of tumor rejection in mice and massive prospective epidemiologic studies support the feasibility of anti-hypoxia-Adenosinergic combined immunotherapy.
Michail V Sitkovsky - One of the best experts on this subject based on the ideXlab platform.
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hostile hypoxia a2 Adenosinergic tumor biology as the next barrier to overcome for tumor immunologists
Cancer immunology research, 2014Co-Authors: Michail V Sitkovsky, Dmitriy Lukashev, Stephen Hatfield, Bryan Belikoff, Robert Abbott, Akio OhtaAbstract:Hypoxia-driven, A2A adenosine receptor (A2AR)–mediated (hypoxia–A2-Adenosinergic), T-cell–autonomous immunosuppression was first recognized as critical and nonredundant in protecting normal tissues from inflammatory damage and autoimmunity. However, this immunosuppressive mechanism can be highjacked by bacteria and tumors to provide misguided protection for pathogens and cancerous tissues. Inhibitors of the hypoxia–A2-Adenosinergic pathway represent a conceptually novel type of immunologic coadjuvants that could be combined with cancer vaccines, adoptive cell transfer, and/or blockade of negative immunologic regulators to further prolong patient survival and to minimize treatment-related side effects. In support of this approach are preclinical studies and findings that some human cancers are resistant to chemotherapies and immunotherapies due to the tumor-generated extracellular adenosine and A2AR on antitumor T and natural killer (NK) cells. Among the coadjuvants are (i) antagonists of A2AR, (ii) extracellular adenosine-degrading drugs, (iii) inhibitors of adenosine generation by CD39/CD73 ectoenzymes, and (iv) inhibitors of hypoxia–HIF-1α signaling. Combining these coadjuvants with CTLA-4 and/or PD-1 blockade is expected to have additive or even synergistic effects of targeting two different antitumor protective mechanisms. It is expected that even after multicombinatorial blockade of negative immunologic regulators, the antitumor T and NK cells would still be vulnerable to inhibition by hypoxia and A2AR. Yet to be tested is the potential capacity of coadjuvants to minimize the side effects of CTLA-4 and/or PD-1 blockade by decreasing the dose of blocking antibodies or by eliminating the need for dual blockade. Cancer Immunol Res; 2(7); 598–605. ©2014 AACR .
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the antihypoxia Adenosinergic pathogenesis as a result of collateral damage by overactive immune cells
Journal of Leukocyte Biology, 2009Co-Authors: Stephen Hatfield, Michail V Sitkovsky, Dmitriy Lukashev, Bryan Belikoff, Akio OhtaAbstract:Here, we attract attention to the possibility of iatrogenic exacerbation of immune-mediated tissue damage as a result of the unintended weakening of the tissue-protecting, hypoxia-Adenosinergic pathway. These immunosuppressive, anti-inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF-1 .W e show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia-Adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage. J. Leukoc. Biol. 86: 545–548; 2009.
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the Adenosinergic immunomodulatory drugs
Current Opinion in Pharmacology, 2009Co-Authors: Akio Ohta, Michail V SitkovskyAbstract:Hypoxia-driven increase of extracellular adenosine in local tissue microenvironments of inflamed and cancerous tissues plays a critical role in the regulation of tissue destruction by activated immune cells. Accumulated data suggest that injection or consumption of A2A adenosine receptor (A2AR) antagonists may represent a drug treatment that diminishes adenosine-mediated immunosuppression. Since this, in turn, enhances the immune response, inhibition of adenosine-A2AR signaling may be a promising approach to enhance anti-tumor or anti-pathogen immune response. Patients with disorders characterized by excessive inflammation may be at risk to A2AR antagonists (e.g. caffeine) because of the effect to increase inflammatory damage secondary to enhanced immunity. On the other hand, enhancement of hypoxia-Adenosinergic immunomodulatory pathways may be beneficial to prevent inflammatory tissue destruction.
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The antihypoxia–Adenosinergic pathogenesis as a result of collateral damage by overactive immune cells
Journal of Leukocyte Biology, 2009Co-Authors: Stephen Hatfield, Michail V Sitkovsky, Dmitriy Lukashev, Bryan Belikoff, Akio OhtaAbstract:Here, we attract attention to the possibility of iatrogenic exacerbation of immune-mediated tissue damage as a result of the unintended weakening of the tissue-protecting, hypoxia-Adenosinergic pathway. These immunosuppressive, anti-inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF-1 .W e show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia-Adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage. J. Leukoc. Biol. 86: 545–548; 2009.
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adenosine a2a receptor antagonists blockade of Adenosinergic effects and t regulatory cells
British Journal of Pharmacology, 2009Co-Authors: Michail V Sitkovsky, Dmitry Lukashev, Silvia Deaglio, Karen M Dwyer, Simon C Robson, Akiko OhtaAbstract:The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e.g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these Adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, Adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-Adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel ‘anti-Adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block Adenosinergic pathways and speculates on their future application together with impacts on human disease.
Maria Jose Da Silva Fernandes - One of the best experts on this subject based on the ideXlab platform.
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Modulation of Seizures and Synaptic Plasticity by Adenosinergic Receptors in an Experimental Model of Temporal Lobe Epilepsy Induced by Pilocarpine in Rats
Epilepsia, 2020Co-Authors: Eduardo Paulo Morowsky Vianna, Alice T Ferreira, Flavia Dona, Esper A Cavalheiro, Maria Jose Da Silva FernandesAbstract:Purpose: Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5'-nucleotidase. the purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5'-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats.Methods: Adult rats were pretreated with different Adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. the neuroprotective effect also was evaluated.Results: A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas Pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5'-nucleotidase staining was detected in the hippocampus during silent and chronic phases.Conclusions: the present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 Adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5'-nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.UNIFESP, Dept Neurol & Neurocirurg, BR-04023900 São Paulo, BrazilUNIFESP, Disc Neurol Expt, BR-04023900 São Paulo, BrazilUNIFESP, Dept Biofis, BR-04023900 São Paulo, BrazilUNIFESP, Dept Neurol & Neurocirurg, BR-04023900 São Paulo, BrazilUNIFESP, Disc Neurol Expt, BR-04023900 São Paulo, BrazilUNIFESP, Dept Biofis, BR-04023900 São Paulo, BrazilWeb of Scienc
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Modulation of seizures and synaptic plasticity by Adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats.
Epilepsia, 2020Co-Authors: Eduardo Paulo Morowsky Vianna, Alice T Ferreira, Flavia Dona, Esper A Cavalheiro, Maria Jose Da Silva FernandesAbstract:Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5'-nucleotidase. The purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5'-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats. Adult rats were pretreated with different Adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. The neuroprotective effect also was evaluated. A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5 -nucleotidase staining was detected in the hippocampus during silent and chronic phases. The present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 Adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5 -nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.
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modulation of seizures and synaptic plasticity by Adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats
Epilepsia, 2005Co-Authors: Eduardo Paulo Morowsky Vianna, Alice T Ferreira, Flavia Dona, Esper A Cavalheiro, Maria Jose Da Silva FernandesAbstract:Summary: Purpose: Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5′-nucleotidase. The purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5′-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats. Methods: Adult rats were pretreated with different Adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. The neuroprotective effect also was evaluated. Results: A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5´-nucleotidase staining was detected in the hippocampus during silent and chronic phases. Conclusions: The present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 Adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5´-nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.
Paulo Santos - One of the best experts on this subject based on the ideXlab platform.
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the Adenosinergic system in diabetic retinopathy
Experimental Diabetes Research, 2016Co-Authors: Joana Vindeirinho, Ana Raquel Santiago, Claudia Cavadas, Antonio F Ambrosio, Paulo SantosAbstract:The neurodegenerative and inflammatory environment that is prevalent in the diabetic eye is a key player in the development and progression of diabetic retinopathy. The Adenosinergic system is widely regarded as a significant modulator of neurotransmission and the inflammatory response, through the actions of the four types of adenosine receptors (A1R, A2AR, A2BR, and A3R), and thus could be revealed as a potential player in the events unfolding in the early stages of diabetic retinopathy. Herein, we review the studies that explore the impact of diabetic conditions on the retinal Adenosinergic system, as well as the role of the said system in ameliorating or exacerbating those conditions. The experimental results described suggest that this system is heavily affected by diabetic conditions and that the modulation of its components could reveal potential therapeutic targets for the treatment of diabetic retinopathy, particularly in the early stages of the disease.
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effect of diabetes hyperglycemia on the rat retinal Adenosinergic system
PLOS ONE, 2013Co-Authors: Joana Vindeirinho, Claudia Cavadas, Gabriel Nascimento Costa, Mariana Correia, Paulo SantosAbstract:The early stages of diabetic retinopathy (DR) are characterized by alterations similar to neurodegenerative and inflammatory conditions such as increased neural apoptosis, microglial cell activation and amplified production of pro-inflammatory cytokines. Adenosine regulates several physiological functions by stimulating four subtypes of receptors, A1AR, A2AAR, A2BAR, and A3AR. Although the Adenosinergic signaling system is affected by diabetes in several tissues, it is unknown whether diabetic conditions in the retina can also affect it. Adenosine delivers potent suppressive effects on virtually all cells of the immune system, but its potential role in the context of DR has yet to be studied in full. In this study, we used primary mixed cultures of rat retinal cells exposed to high glucose conditions, to mimic hyperglycemia, and a streptozotocin rat model of type 1 diabetes to determine the effect diabetes/hyperglycemia have on the expression and protein levels of adenosine receptors and of the enzymes adenosine deaminase and adenosine kinase. We found elevated mRNA and protein levels of A1AR and A2AAR, in retinal cell cultures under high glucose conditions and a transient increase in the levels of the same receptors in diabetic retinas. Adenosine deaminase and adenosine kinase expression and protein levels showed a significant decrease in diabetic retinas 30 days after diabetes induction. An enzymatic assay performed in retinal cell cultures revealed a marked decrease in the activity of adenosine deaminase under high glucose conditions. We also found an increase in extracellular adenosine levels accompanied by a decrease in intracellular levels when retinal cells were subjected to high glucose conditions. In conclusion, this study shows that several components of the retinal Adenosinergic system are affected by diabetes and high glucose conditions, and the modulation observed may uncover a possible mechanism for the alleviation of the inflammatory and excitotoxic conditions observed in diabetic retinas.
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Effect of diabetes/hyperglycemia on the rat retinal Adenosinergic system.
PLOS ONE, 2013Co-Authors: Joana Vindeirinho, Claudia Cavadas, Gabriel Nascimento Costa, Mariana B. Correia, Paulo SantosAbstract:The early stages of diabetic retinopathy (DR) are characterized by alterations similar to neurodegenerative and inflammatory conditions such as increased neural apoptosis, microglial cell activation and amplified production of pro-inflammatory cytokines. Adenosine regulates several physiological functions by stimulating four subtypes of receptors, A1AR, A2AAR, A2BAR, and A3AR. Although the Adenosinergic signaling system is affected by diabetes in several tissues, it is unknown whether diabetic conditions in the retina can also affect it. Adenosine delivers potent suppressive effects on virtually all cells of the immune system, but its potential role in the context of DR has yet to be studied in full. In this study, we used primary mixed cultures of rat retinal cells exposed to high glucose conditions, to mimic hyperglycemia, and a streptozotocin rat model of type 1 diabetes to determine the effect diabetes/hyperglycemia have on the expression and protein levels of adenosine receptors and of the enzymes adenosine deaminase and adenosine kinase. We found elevated mRNA and protein levels of A1AR and A2AAR, in retinal cell cultures under high glucose conditions and a transient increase in the levels of the same receptors in diabetic retinas. Adenosine deaminase and adenosine kinase expression and protein levels showed a significant decrease in diabetic retinas 30 days after diabetes induction. An enzymatic assay performed in retinal cell cultures revealed a marked decrease in the activity of adenosine deaminase under high glucose conditions. We also found an increase in extracellular adenosine levels accompanied by a decrease in intracellular levels when retinal cells were subjected to high glucose conditions. In conclusion, this study shows that several components of the retinal Adenosinergic system are affected by diabetes and high glucose conditions, and the modulation observed may uncover a possible mechanism for the alleviation of the inflammatory and excitotoxic conditions observed in diabetic retinas.
Bernardo Baldisserotto - One of the best experts on this subject based on the ideXlab platform.
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involvement of cholinergic and Adenosinergic systems on the branchial immune response of experimentally infected silver catfish with streptococcus agalactiae
Journal of Fish Diseases, 2018Co-Authors: Matheus D Baldissera, Carine F Souza, Pedro H Doleski, Karen L S Moreira, M L Da Veiga, M I U M Da Rocha, Roberto Christ Vianna Santos, Bernardo BaldisserottoAbstract:It has been recognized that the cholinergic and Adenosinergic systems have an essential role in immune and inflammatory responses during bacterial fish pathogens, such as the enzymes acetylcholinesterase (AChE) and adenosine deaminase (ADA), which are responsible for catalysis of the anti-inflammatory molecules acetylcholine (ACh) and adenosine (Ado) respectively. Thus, the aim of this study was to investigate the involvement of the cholinergic and Adenosinergic systems on the immune response and inflammatory process in gills of experimentally infected Rhamdia quelen with Streptococcus agalactiae. Acetylcholinesterase activity decreased, while ACh levels increased in gills of infected animals compared to uninfected animals. On the other hand, a significant increase in ADA activity with a concomitant decrease in Ado levels was observed in infected animals compared to uninfected animals. Based on this evidence, we concluded that infection by S. agalactiae in silver catfish alters the cholinergic and Adenosinergic systems, suggesting the involvement of AChE and ADA activities on immune and inflammatory responses, regulating the ACh and Ado levels. In summary, the downregulation of AChE activity exerts an anti-inflammatory profile in an attempt to reduce or prevent the tissue damage, while the upregulation of ADA activity exerts a pro-inflammatory profile, contributing to disease pathophysiology.
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cholinergic and Adenosinergic systems exert a pro inflammatory profile in peripheric and splenic lymphocytes of rhamdia quelen experimentally infected by aeromonas caviae
Aquaculture, 2018Co-Authors: Matheus D Baldissera, Carine F Souza, Pedro H Doleski, Karen L S Moreira, M L Da Veiga, M I U M Da Rocha, Roberto Christ Vianna Santos, Camila M Verdi, Bruno Stefanello Vizzotto, Bernardo BaldisserottoAbstract:Abstract It has been recognized that the cholinergic and Adenosinergic systems, through the enzymes acetylcholinesterase (AChE) and adenosine deaminase (ADA), exert an important role in the immune and inflammatory responses during bacterial fish diseases. The immune response against Aeromonas caviae remains poorly understood, and the involvement of these systems, through the anti-inflammatory molecules acetylcholine (ACh) and adenosine (Ado), has not been studied. Thus, the aim of this study was to evaluate the involvement of cholinergic and Adenosinergic systems on the inflammatory and immune responses in peripheric and splenic lymphocytes of fish experimentally infected with A . caviae . AChE and ADA activities in peripheric and splenic lymphocytes increased in infected animals on day 4 post-infection compared to uninfected animals, while the ACh and Ado levels decreased. Moreover, spleen histopathology revealed an increase in the number of melano-macrophage centers, as well as lipid inclusions and cellular debris in the ellipsoids. This evidence indicates that infection by A . caviae alters the cholinergic and Adenosinergic systems, suggesting the involvement of AChE and ADA activities in the impairment of the immune system, since infection leads to a reduction in ACh and Ado levels, respectively. In summary, the upregulation of AChE and ADA activities in peripheric and splenic lymphocytes exerts a pro-inflammatory profile, contributing to systemic and tissue inflammatory damage, and consequently to disease pathogenesis.
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the Adenosinergic system not the cholinergic system exerts an anti inflammatory profile in lymphatic immune organs of fish naturally infected with ichthyophthirius multifiliis
Aquaculture, 2017Co-Authors: Matheus D Baldissera, Carine F Souza, Pedro H Doleski, Karen L S Moreira, M L Da Veiga, M I U M Da Rocha, Ana Paula Gottlieb Almeida, Bernardo BaldisserottoAbstract:Abstract Studies have demonstrated that fish are able to mount protective immune responses against various parasites, including Ichthyophthirius multifiliis, an economically important protozoosis in freshwater aquaculture. Although the immune response against this parasite have been partly elucidated in the literature, the involvement of the cholinergic and Adenosinergic systems, through the anti-inflammatory molecules acetylcholine (ACh) and adenosine (Ado), has not been studied. Thus, the aim of this study was to evaluate the involvement of the cholinergic and Adenosinergic systems in the immune and inflammatory responses in the immune lymphatic organs of silver catfish, Rhamdia quelen, naturally infected with I. multifiliis. Acetylcholinesterase (AChE) activity increased, while adenosine deaminase (ADA) activity decreased in the head kidney and spleen of silver catfish naturally infected with I. multifiliis compared to the uninfected control group. Moreover, the levels of ACh in the head kidney and spleen decreased in infected animals, while the Ado levels increased compared to the uninfected control group. A negative and significant Pearson correlation was observed between AChE activity and ACh levels, as well as between ADA activity and Ado levels. Therefore, the cholinergic system exerts a pro-inflammatory profile due to upregulation of AChE activity and a consequent reduction in ACh levels, which contributes to inflammatory damage. Conversely, the Adenosinergic system plays an anti-inflammatory profile via downregulation of ADA activity and consequent augmentation of Ado levels, which may contribute to restricting the inflammatory process and improving the immune response during ichthyophthiriasis.
