OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously...OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice,while the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes have not been understood.METHODS Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography(HPLC) after morphine treatment.Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins.Morphine-induced neurobehavioral changes were assessed by locomotor activity,behavioral sensitization and conditioned place preference(CPP)test.The expression of NT5E,an extracellular enzyme involved in formation of nucleosides,including uridine,was specifically knocked down in the dorsal striatum of mice using adeno-associated virus(AAV)-mediated short hairpin RNA(shRNA).RESULTS Both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum,and this was associated with upregulation of NT5E but not other uridine-related proteins.Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes,including hyperlocomotor activity,behavioral sensitization and CPP.CONCLUSION The present study increases our understanding of the contribution of NT5E in regulating morphine-induced neurobehavioral changes,at least as related to uridine,and suggests that NT5E may be a novel therapeutic target to manage morphine abuse.展开更多
Objective: To verify possible relations between 5'-nucleotidase, xanthine oxidase to E3 small ubiquitin-like modifier-protein ligase non structural maintenance of chromosomes elements 2 in sera patients with kidne...Objective: To verify possible relations between 5'-nucleotidase, xanthine oxidase to E3 small ubiquitin-like modifier-protein ligase non structural maintenance of chromosomes elements 2 in sera patients with kidney stones and to evaluate the possibility of a new biomarker for the evaluation of kidney damage. Methods: A sixty patients with known kidney stones who appeared the government health clinics in Kuantan–Pahang and fifty apparently healthy were taken as control group. The 5'-nucleotidase,xanthine oxidase and other biochemical parameters were measured by colorimetric tests. The serum NSMCE2 were measured by enzyme linked immunosorbent assay.Results: The mean serum xanthine oxidase [(39.98±19.70) IU/L] and ecto-5'-nucleotidase activity(40.03±9.53 IU/L) were significantly higher than the controls' levels of(18.04 ±6.26) and(16.06 ±4.61) IU/L respectively. There were 85.00% and 83.33%, of patients with kidney stones who had abnormal ecto-5'-nucleotidase activity and uric acid respectively while xanthine oxidase activity was less sensitive 58.33%.Conclusions: The present study suggests that the increase in serum of xanthine oxidase,ecto-5'-nucleotidase activities E3 small ubiquitin-like modifier-protein ligase NSE2 concentration can be used as biomarkers for diagnosis of kidney damage in patients with kidney stone,also in developments of change DNA damage and inflammation disorders in these patients.展开更多
The toxic effect of fertilizer Diammonium phosphate resulted in alterations of 5'-Nucleotidase activity of tissues liver, kidney and muscles offish C. batrachus at varying intervals and exposures. Alterations in 5...The toxic effect of fertilizer Diammonium phosphate resulted in alterations of 5'-Nucleotidase activity of tissues liver, kidney and muscles offish C. batrachus at varying intervals and exposures. Alterations in 5'-Nuclcotidase activity of body organs gave an idea of the toxicity caused by the fertilizer. Thus the enzyme 5'-Nucleotidase can be used to monitor the pollution in aquatic ecosystem.展开更多
An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease prog...An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.展开更多
Background: Adenosine deaminase (ADA) and 5'-nucleotidase (5'-NT) play a crucial role in adenosine metabolism in healthy individuals. Adenosine is an inflammatory mediator of asthma. Changes in adenosine metab...Background: Adenosine deaminase (ADA) and 5'-nucleotidase (5'-NT) play a crucial role in adenosine metabolism in healthy individuals. Adenosine is an inflammatory mediator of asthma. Changes in adenosine metabolism and role of ADA and 5'-NT in regulating adenosine level in asthmatics and correlation of these changes with severity of asthma are not clearly understood. Methods: In this study, we screened 5217 patients, of which 2416 were diagnosed with asthma. Further, of 2416 asthmatics, only 45 patients who strictly fulfilled the selection criteria were enrolled in the study. The patients were classified into mild, moderate and severe persistent groups;each group consisted of fifteen patients. Fifteen healthy subjects served as controls. Adenosine levels and activities of 5'-NT, total ADA, ADA1 and ADA2 in serum, lymphocytes and erythrocytes were determined. The data were analysed statistically and p vice versa.展开更多
Endogenous adenosine can enter the extracellular space either by direct release or via formation from adenine nucleotides. We have compared the effects of substances blocking the ecto-5'-nucleotidase with a, b-met...Endogenous adenosine can enter the extracellular space either by direct release or via formation from adenine nucleotides. We have compared the effects of substances blocking the ecto-5'-nucleotidase with a, b-methylene adenosine 5'-diphosphate (AOPCP) or adenosine kinase with iodotubercidin (Itu) on field potentials in the hippocampus and the neostriatum in vitro evoked by stimulation of the stratum radiatum or the cortico-striatal pathway respectively. AOPCP enhanced the amplitude of the population spikes by 34% in the hippocampus and by 26.5% in the neostriatum. DPCPX, a selective A1-receptor antagonist, increased the amplitude of the population spikes by 68% in the hippocampus and by 53.5% in the neostriatum. Thus both, release of adenosine from the intracellular space and, extracellular dephosphorylation of adenine nucleotides to a lesser extent, contribute to the effective levels of adenosine in the extracellular space in hippocampus and neostriatum.展开更多
5′-nucleotidase (EC 3.1.3.5) can catalyze the hydrolysis of most ribonucleoside 5′-monophosphates and deoxynucleoside 5′-monophosphates to the corresponding nucleosides and orthophosphates. It is localized predomin...5′-nucleotidase (EC 3.1.3.5) can catalyze the hydrolysis of most ribonucleoside 5′-monophosphates and deoxynucleoside 5′-monophosphates to the corresponding nucleosides and orthophosphates. It is localized predominantly in the plasma membranes of human and animal tissues,and often used as a marker enzyme for plasma membranes展开更多
Background:The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus(HBV)infection remain largely undefined.The present study assessed the clinical characteristics of the CD39/CD73/ad...Background:The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus(HBV)infection remain largely undefined.The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B(CHB).Methods:We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients.B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.Results:CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA,HBeAg positivity,high HBsAg levels,and active liver inflammation,and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction.However,CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments.Furthermore,CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers.In vitro,B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade.Contrastingly,metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.Conclusions:The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden,liver inflammation,and antiviral efficacy in CHB patients,and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation.Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBVinduced immune pathogenesis.展开更多
基金National Natural Science Foundation of China(81373383).
文摘OBJECTIVE There is growing evidence that uridine may act as an endogenous neuromodulator with a potential signaling role in the central nervous system in addition to its function in pyrimidine metabolism.We previously found that acute morphine treatment significantly increased uridine release in the dorsal striatum of mice,while the mechanism involved in morphine-induced uridine release and the role of uridine in morphine-induced neurobehavioral changes have not been understood.METHODS Uridine release in the dorsal striatum of mice was assessed by in vivo microdialysis coupled with high performance liquid chromatography(HPLC) after morphine treatment.Western blotting and immunofluorescence were used to evaluate the expression of uridine-related proteins.Morphine-induced neurobehavioral changes were assessed by locomotor activity,behavioral sensitization and conditioned place preference(CPP)test.The expression of NT5E,an extracellular enzyme involved in formation of nucleosides,including uridine,was specifically knocked down in the dorsal striatum of mice using adeno-associated virus(AAV)-mediated short hairpin RNA(shRNA).RESULTS Both acute and chronic morphine administration significantly increased uridine release in the dorsal striatum,and this was associated with upregulation of NT5E but not other uridine-related proteins.Inhibition of NT5E with APCP or shRNA markedly inhibited morphine-induced uridine release in the dorsal striatum and related neurobehavioral changes,including hyperlocomotor activity,behavioral sensitization and CPP.CONCLUSION The present study increases our understanding of the contribution of NT5E in regulating morphine-induced neurobehavioral changes,at least as related to uridine,and suggests that NT5E may be a novel therapeutic target to manage morphine abuse.
基金Support from the International Islamic University Malaysia,the research management center Grant Scheme project no.IIUM/504/5/29/1
文摘Objective: To verify possible relations between 5'-nucleotidase, xanthine oxidase to E3 small ubiquitin-like modifier-protein ligase non structural maintenance of chromosomes elements 2 in sera patients with kidney stones and to evaluate the possibility of a new biomarker for the evaluation of kidney damage. Methods: A sixty patients with known kidney stones who appeared the government health clinics in Kuantan–Pahang and fifty apparently healthy were taken as control group. The 5'-nucleotidase,xanthine oxidase and other biochemical parameters were measured by colorimetric tests. The serum NSMCE2 were measured by enzyme linked immunosorbent assay.Results: The mean serum xanthine oxidase [(39.98±19.70) IU/L] and ecto-5'-nucleotidase activity(40.03±9.53 IU/L) were significantly higher than the controls' levels of(18.04 ±6.26) and(16.06 ±4.61) IU/L respectively. There were 85.00% and 83.33%, of patients with kidney stones who had abnormal ecto-5'-nucleotidase activity and uric acid respectively while xanthine oxidase activity was less sensitive 58.33%.Conclusions: The present study suggests that the increase in serum of xanthine oxidase,ecto-5'-nucleotidase activities E3 small ubiquitin-like modifier-protein ligase NSE2 concentration can be used as biomarkers for diagnosis of kidney damage in patients with kidney stone,also in developments of change DNA damage and inflammation disorders in these patients.
文摘The toxic effect of fertilizer Diammonium phosphate resulted in alterations of 5'-Nucleotidase activity of tissues liver, kidney and muscles offish C. batrachus at varying intervals and exposures. Alterations in 5'-Nuclcotidase activity of body organs gave an idea of the toxicity caused by the fertilizer. Thus the enzyme 5'-Nucleotidase can be used to monitor the pollution in aquatic ecosystem.
基金supported by a grant from Ministry of Science,Technological Development and Innovation,Serbia,No.451-03-68/2022-14/200178(to NN)University of Defence,No.MFVMA/02/22-24(to MN)。
文摘An imbalance in adenosine-mediated signaling,particularly the increased A_(2A)R-mediated signaling,plays a role in the pathogenesis of Parkinson's disease.Existing therapeutic approaches fail to alter disease progression,demonstrating the need for novel approaches in PD.Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson's disease.However,the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown.The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling.Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test.Immunoblot,quantitative reverse transcription polymerase chain reaction,immunohistochemistry,and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen.Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen.Treatment with intermittent theta burst stimulation began 7 days after the lesion,coinciding with the onset of motor symptoms.After treatment with prolonged intermittent theta burst stimulation,complete motor recovery was observed.This improvement was accompanied by downregulation of the e N/CD73-A_(2A)R pathway and a return to physiological levels of A_(1)R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation.Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A_(1)R and elevated the expression of A_(2A)R.Intermittent theta burst stimulation reversed these effects by restoring the abundances of A_(1)R and A_(2A)R to control levels.The shift in ARs expression likely restored the balance between dopamine-adenosine signaling,ultimately leading to the recovery of motor control.
文摘Background: Adenosine deaminase (ADA) and 5'-nucleotidase (5'-NT) play a crucial role in adenosine metabolism in healthy individuals. Adenosine is an inflammatory mediator of asthma. Changes in adenosine metabolism and role of ADA and 5'-NT in regulating adenosine level in asthmatics and correlation of these changes with severity of asthma are not clearly understood. Methods: In this study, we screened 5217 patients, of which 2416 were diagnosed with asthma. Further, of 2416 asthmatics, only 45 patients who strictly fulfilled the selection criteria were enrolled in the study. The patients were classified into mild, moderate and severe persistent groups;each group consisted of fifteen patients. Fifteen healthy subjects served as controls. Adenosine levels and activities of 5'-NT, total ADA, ADA1 and ADA2 in serum, lymphocytes and erythrocytes were determined. The data were analysed statistically and p vice versa.
文摘Endogenous adenosine can enter the extracellular space either by direct release or via formation from adenine nucleotides. We have compared the effects of substances blocking the ecto-5'-nucleotidase with a, b-methylene adenosine 5'-diphosphate (AOPCP) or adenosine kinase with iodotubercidin (Itu) on field potentials in the hippocampus and the neostriatum in vitro evoked by stimulation of the stratum radiatum or the cortico-striatal pathway respectively. AOPCP enhanced the amplitude of the population spikes by 34% in the hippocampus and by 26.5% in the neostriatum. DPCPX, a selective A1-receptor antagonist, increased the amplitude of the population spikes by 68% in the hippocampus and by 53.5% in the neostriatum. Thus both, release of adenosine from the intracellular space and, extracellular dephosphorylation of adenine nucleotides to a lesser extent, contribute to the effective levels of adenosine in the extracellular space in hippocampus and neostriatum.
基金Project supported by the National Natural Science Foundation of China.
文摘5′-nucleotidase (EC 3.1.3.5) can catalyze the hydrolysis of most ribonucleoside 5′-monophosphates and deoxynucleoside 5′-monophosphates to the corresponding nucleosides and orthophosphates. It is localized predominantly in the plasma membranes of human and animal tissues,and often used as a marker enzyme for plasma membranes
基金supported by grants from the Innovative Research Team in the National Natural Science Foundation of China[81721002]the National Science and Technology Major Project[2018ZX10301202].
文摘Background:The mechanisms underlying B-cell hyperactivation in patients with chronic hepatitis B virus(HBV)infection remain largely undefined.The present study assessed the clinical characteristics of the CD39/CD73/adenosine pathway in patients with chronic hepatitis B(CHB).Methods:We examined CD39 and CD73 expression and adenosine production by B-cells from 202 HBV-infected patients.B-cell-activation phenotypes were assessed by flow cytometry after CpG+CD40 ligand stimulation with or without blockade and activation of the adenosine pathway.Results:CD39 and CD73 expression on circulating B-cells was decreased in CHB patients with high HBV DNA,HBeAg positivity,high HBsAg levels,and active liver inflammation,and was hierarchically restored in complete responders according to HBeAg seroconversion or HBsAg reduction.However,CD39 and CD73 expression on activated memory and tissue-like memory B-cell subsets in complete responders was not increased despite effective antiviral treatments.Furthermore,CD39 and CD73 expression on intra-hepatic B-cells was decreased in inflammatory livers.In vitro,B-cells from CHB patients showed a markedly reduced capacity to generate CD39/CD73-dependent extracellular adenosine and expressed increased levels of activation markers after adenosine-production blockade.Contrastingly,metformin significantly reduced activation-marker expression via regulating AMP-activated protein kinase.Conclusions:The skewed CD39 and CD73 expression on B-cells was associated with a high viral burden,liver inflammation,and antiviral efficacy in CHB patients,and the skewed CD39/CD73/adenosine pathway contributed to B-cell hyperactivation.Regulation of the CD39/CD73/adenosine pathway using metformin may represent a therapeutic option to reverse HBVinduced immune pathogenesis.
