1.Blocking Adenosine/A2AR Pathway for Cancer Therapy.
Jia LIU ; Yuequan SHI ; Xiaoyan LIU ; Dongming ZHANG ; Yu BAI ; Yan XU ; Mengzhao WANG
Chinese Journal of Lung Cancer 2022;25(7):460-467
Adenosine is a metabolite produced abundantly in the tumor microenvironment, dampening immune response in inflamed tissues via adenosine A2A receptor (A2AR) which is widely expressed on immune cells, inhibiting anti-tumor immune response accordingly. Therefore, blocking adenosine signaling pathway is of potential to promote anti-tumor immunity. This review briefly introduces adenosine signaling pathway, describes its role in regulating tumor immunity and highlights A2AR blockade in cancer therapy. Prospective anti-tumor activity of adenosine/A2AR inhibition has been revealed by preclinical data, and a number of clinical trials of A2AR antagonists are under way. Primary results from clinical trials suggest that A2AR antagonists are well tolerated in cancer patients and are effective both as monotherapy and in combination with other therapies. In the future, finding predictive biomarkers are critical to identify patients most likely to benefit from adenosine pathway blockade, and further researches are needed to rationally combine A2AR antagonists with other anti-tumor therapies.
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Adenosine/therapeutic use*
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Adenosine A2 Receptor Antagonists/therapeutic use*
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Humans
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Lung Neoplasms
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Receptor, Adenosine A2A/metabolism*
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Tumor Microenvironment
2.The significance of TGF-beta expression in scar in adenosine receptor A(2A) knockout mice.
Hu XIAO ; Li RAN ; Ying-ying ZHUO ; De-chang WANG ; Ran HUO ; Yi-bing WANG ; Yong-qiang FENG ; Qiang LI
Chinese Journal of Plastic Surgery 2010;26(2):136-138
OBJECTIVETo discuss the mechanism of scar hypertrophy in adenosine receptor A(2A) (A(2A) R) knockout mice.
METHODSAnimal models of hypertrophic scar were established in 12 A(2A) R knockout mice and 12 wild-type mice as control. The thickness and the size of transverse section of the hypertrophic scar were observed by H-E staining. The hydroxyproline (HYP) in the scar was measured colorimetrically. The TGF-beta expression was tested by Western blotting method.
RESULTSThe hypertrophic scar in wild-type mice was more severe than that in knockout mice. Compared with self-control, the increase of the thickness and the size of transverse section of hypertrophic scar was markedly higher in wild-type group than in the knockout group (P < 0.01). There was significant difference in HYP content between the two groups (P < 0.01). Compared with self-control, the increase of TGF-beta expression in wild-type group was much more than that in knockout group (P < 0.01).
CONCLUSIONSThe TGF-beta expression decreases in the A(2A) R knockout mice. The scar hypertrophy is also much less in the A(2A) R knockout mice.
Animals ; Cicatrix ; metabolism ; pathology ; Disease Models, Animal ; Mice ; Mice, Knockout ; Receptor, Adenosine A2A ; genetics ; Transforming Growth Factor beta ; genetics ; metabolism
3.Expressions of P-JNK in nerve cell apoptosis of A2AR knockout newborn mice after hypoxia/ischemia brain damage.
Hai-Ling FAN ; Shui-Gui YIN ; Pu LOU ; Su-Wei REN ; Sheng HUANG ; Xiang CHEN
Chinese Journal of Applied Physiology 2013;29(2):187-192
OBJECTIVETo investigate the effect of adenosine A2A receptor knockout (A(2A)RKO) on relationship between continuous activation of phospho-c-Jun N-terminal kinase (P-JNK) and expression of nerve cell apoptosis in hippocampus CA1 domain of newborn mice after hypoxia/ischemia brain damage(HIBD) and its potential mechanism.
METHODSA(2A)RKO mice and adenosine A2A receptor wildtype (A(2A)RWT) littermates (n = 80) were divided into Sham operation group (S) and model group (M), 1, 3 and 7 day after HIBD, totally 8 groups. HIBD was developed with 7 day-old neonatal mice according classical Rice-Vannucci method. It was tested the effect of A(2A)RKO on short-term neurofunctional outcomes consisted of three developmental reflexes (righting, geotaxis and cliff aversion), the changes of brain pathology with hematoxylin-eosin (HE) staining and Nissl staining, the expressions of nerve cell apoptosis with terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling(TUNEL) staining and P-JNK were observed by immunohistochemistry.
RESULTSThe neurological behavior injuries and brain histopathological damages and nerve apoptosis cells were aggravated in A(2A)RKO newborn mice after HIBD. The positive expressions of P-JNK were significantly higher in the ischemic hippocampus CA1 domain after HIBD than ones in group S respectively (P < 0.01), reaching to peak at 1 day and then began gradually decreasing. P-JNK expression in model knockout(MKO) at 1, 3 and 7 day increased greatly compared to those in the previous time point of corresponding model wildtype (MWT) (P < 0.01, P < 0.05, P > 0.05); there was a positive correlation between the expressions of P-JNK and nerve cell apoptosis after HIBD in newborn mice(r = 0.837, P < 0.01).
CONCLUSIONEarly continuous activation of P-JNK might be involved in the aggravated nerve apoptosis cells and brain damage induced by A(2A) RKO newborn mice after HIBD.
Animals ; Animals, Newborn ; Apoptosis ; Hypoxia-Ischemia, Brain ; metabolism ; pathology ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Mice ; Mice, Knockout ; Neurons ; drug effects ; metabolism ; pathology ; Receptor, Adenosine A2A ; genetics
4.Sleep disturbance induced by cocaine abstinence involving in A2A receptor over-expression in rat hypothalamus.
Fenfang HONG ; Xiaojun LIU ; Changsheng HE ; Shulong YANG
Journal of Biomedical Engineering 2012;29(6):1068-1072
Adult rats were implanted with sleep-wake recording electrodes in our experiments. Polygraphic signs of undisturbed sleep-wake activities were recorded for 24 h before cocaine administration, cocaine withdrawal day 1 (acute), day 8 (subacute), and day 14 (subchronic). Western blot method was performed to examine the expression levels of adenosine receptor subtypes in hypothalamus and cerebellum. Non rapid eye movement (NREM) sleep was significantly increased during nighttime (P < 0.01) and daytime (P < 0.05) on withdrawal day 8. The increase of NREM sleep was significant during nighttime (P < 0.01) and slight during daytime on withdrawal day 14, whereas both daytime and nighttime rapid eye movement (REM) sleeps were reduced markedly (P < 0.01) on withdrawal day 8 and 14. In addition, A2A receptor level was significantly enhanced on cocaine withdrawal day 8 and day 14 (P < 0.05), whereas A1 receptor level reduced markedly on withdrawal day 14 (P < 0.05). However, compared with that in the control group, no significant changes existed among adenosine A1, A2A and A2B receptors in rat cerebellum on cocaine withdrawal day 1, day 8 and day 14. Our findings suggest that sleep disorder caused by subacute and subchronic cocaine abstinence may be associated with over-expression of adenosine A2A receptor in rat hypothalamus to some extent.
Animals
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Cocaine
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adverse effects
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Dyssomnias
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chemically induced
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Electroencephalography
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Hypothalamus
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metabolism
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Male
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Rats
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Rats, Sprague-Dawley
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Receptor, Adenosine A2A
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metabolism
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Substance Withdrawal Syndrome
5.Effects of caffeine citrate on myelin basic protein in neonatal rats with hypoxic-ischemic brain damage.
Fa-Lin XU ; Hui-Qing CHENG ; Cai-Hong WANG ; Yan-Hua ZHANG ; Jia-Jia GUO
Chinese Journal of Contemporary Pediatrics 2015;17(9):984-988
OBJECTIVETo study the effects of caffeine citrate on myelin basic protein (MBP) expression in the cerebral white matter of neonatal rats with hypoxic-ischemic brain damage (HIBD) and the related mechanism.
METHODSForty-eight seven-day-old Sprague-Dawley neonatal rats were randomly assigned to 3 groups: sham operation (n=16), HIBD (n=16) and HIBD+caffeine citrate (n=16). The rats in the HIBD and HIBD+caffeine citrate groups were subjected to left common carotid artery ligation, and then were exposed to 80 mL/L oxygen and 920 mL/L nitrogen for 2 hours to induce HIBD. The rats in the sham operation group were only subjected to a sham operation, without the left common carotid artery ligation or hypoxia exposure. Caffeine citrate (20 mg/kg) was injected intraperitoneally before hypoxia ischemia (HI) and immediately, 24 hours, 48 hours and 72 hours after HI. The other two groups were injected intraperitoneally with an equal volume of normal saline at the corresponding time points. On postnatal day 12, the expression of MBP in the left subcortical white matter was detected by immunohistochemistry, and the levels of adenosine A1 receptor mRNA and A2a receptor mRNA in the left brain were detected by real-time PCR.
RESULTSThe expression of MBP in the left subcortical white matter in the HIBD group was lower than in the sham operation group (P<0.05). The MBP expression in the HIBD+caffeine citrate group was significantly higher than in the HIBD group, but was still lower than the sham operation group (P<0.05). Real-time PCR showed that the adenosine A1 receptor mRNA expression was significantly higher in the HIBD group than in the sham operation group, and it was significantly lower in the HIBD+caffeine citrate group than in the HIBD group (P<0.05).
CONCLUSIONSCaffeine citrate can improve brain white matter damage following HIBD in neonatal rats and the protection mechanism might be related with the down-regulation of adenosine A1 receptor expression.
Animals ; Animals, Newborn ; Caffeine ; pharmacology ; Citrates ; pharmacology ; Female ; Hypoxia-Ischemia, Brain ; drug therapy ; metabolism ; pathology ; Male ; Myelin Basic Protein ; analysis ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptor, Adenosine A1 ; genetics ; Receptor, Adenosine A2A ; genetics ; White Matter ; chemistry
6.In Silico System Pharmacology for the Potential Bioactive Ingredients Contained in Xingnaojing Injection () and Its Material Basis for Sepsis Treatment.
Shi-Tang MA ; Cheng-Tao FENG ; You-Xi XIONG ; Xiao-Lin ZHANG ; Cheng-Gui MIAO ; Hao YU
Chinese journal of integrative medicine 2018;24(12):944-949
OBJECTIVE:
To elucidate the action mechanism of Xingnaojing Injection (, XNJI) for sepsis, and to target screen the potential bioactive ingredients.
METHODS:
An integrated protocol that combines in silico target screen (molecular docking) and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound-target (C-T) interaction network. The XNJI's bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-lipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction.
RESULTS:
Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment.
CONCLUSIONS
The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.
Arachidonate 5-Lipoxygenase
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metabolism
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Computer Simulation
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Drug Evaluation, Preclinical
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Drugs, Chinese Herbal
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chemistry
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pharmacology
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therapeutic use
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Humans
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Injections
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Phytochemicals
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therapeutic use
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Receptor, Adenosine A2A
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metabolism
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Reproducibility of Results
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Sepsis
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drug therapy
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metabolism
7.Protective effect of new adenosine analog B2 against serum deprivation-induced PC12 cell injury.
Jing SUN ; Min LI ; Rui-xia KANG ; Jian-gong SHI ; Jian-jun ZHANG
Acta Pharmaceutica Sinica 2011;46(10):1199-1203
This study is to investigate the effect of compound B2 on the damage of PC12 cells induced by serum deprivation and to explore its related mechanisms. The binding characteristics of B2 to rat striatum adenosine A2A receptor was studied by radioligand 3H-MSX-2 binding assay. Cell viability was detected by MTT assay. ROS formation was measured after DCFDA fluorescent staining. B2 has affinity to rat adenosine A2A receptor (K1 = 0.37 micromol x L(-1)). B2 remarkably increased PC12 cell survival rate in serum deprivation-induced PC12 cells. The percentage of serum deprivation-induced death of PC12 was 49.6%, and the treatment of B2 (0.1-100 micromol x L(-1)) increased the cell viability to 63.3%, 74.9%, 86.3% and 88.1%, respectively. Adenosine A2A receptor antagonist SCH 58261 could significantly block the protective effect of B2. The cell viability with 0.1 micromol x L(-1) SCH 58261 decreased by 16.1%, 24.0% and 19.8%, in the presence of B2 (0.1-10 micromol x L(-1)). Serum deprivation-induced ROS formation was 3.5 times more than that of control group, and treatment with B2 significantly and dose-dependently inhibited ROS over-formation. The protective effect of B2 may be related with adenosine A2A receptor. Decrease of serum-deprivation induced ROS formation may also be one of the mechanisms.
Adenosine
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analogs & derivatives
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metabolism
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pharmacology
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Adenosine A2 Receptor Antagonists
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pharmacology
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Animals
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Cell Survival
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drug effects
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Corpus Striatum
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metabolism
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Culture Media, Serum-Free
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Female
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Male
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PC12 Cells
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Pyrimidines
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pharmacology
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Rats
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Rats, Wistar
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Reactive Oxygen Species
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metabolism
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Receptor, Adenosine A2A
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metabolism
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Triazoles
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pharmacology
8.Activation of the adenosine A2A receptor at the acute stage of moderate traumatic brain injury enhances the neuroprotective effects of oxaloacetate.
Nan YANG ; Zhi-Zhong HUANG ; Si-Wei TAN ; Xing CHEN ; Yan PENG ; Yuan-Guo ZHOU ; Ya-Lei NING
Acta Physiologica Sinica 2022;74(4):505-512
The purpose of the present study was to investigate the effect of glutamate scavenger oxaloacetate (OA) combined with CGS21680, an adenosine A2A receptor (A2AR) agonist, on acute traumatic brain injury (TBI), and to elucidate the underlying mechanisms. C57BL/6J mice were subjected to moderate-level TBI by controlled cortical impact, and then were treated with OA, CGS21680, or OA combined with CGS21680 at acute stage of TBI. At 24 h post TBI, neurological severity score, brain water content, glutamate concentration in cerebrospinal fluid (CSF), mRNA and protein levels of IL-1β and TNF-α, mRNA level and activity of glutamate oxaloacetate aminotransferase (GOT), and ATP level of brain tissue were detected. The results showed that neurological deficit, brain water content, glutamate concentration in CSF, and the inflammatory cytokine IL-1β and TNF-α production were exacerbated in CGS21680 treated mice. Administrating OA suppressed the rise of both glutamate concentration in CSF and brain water content, and elevated the ATP level of cerebral tissue. More interestingly, neurological deficit, brain edema, glutamate concentration, IL-1β and TNF-α levels were ameliorated significantly in mice treated with OA combined with CGS21680. The combined treatment exhibited better therapeutic effects than single OA treatment. We also observed that GOT activity was enhanced in single CGS21680 treatment group, and both the GOT mRNA level and GOT activity were up-regulated in early-stage combined treatment group. These results suggest that A2AR can improve the efficiency of GOT and potentiate the ability of OA to metabolize glutamate. This may be the mechanism that A2AR activation in combination group augmented the neuroprotective effect of OA rather than aggravated the brain damages. Taken together, the present study provides a new insight for the clinical treatment of TBI with A2AR agonists and OA.
Adenosine A2 Receptor Agonists/therapeutic use*
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Adenosine Triphosphate
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Animals
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Brain Injuries/metabolism*
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Brain Injuries, Traumatic/metabolism*
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Glutamic Acid
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Mice
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Mice, Inbred C57BL
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Neuroprotective Agents/therapeutic use*
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Oxaloacetic Acid/therapeutic use*
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RNA, Messenger
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Receptor, Adenosine A2A/metabolism*
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Tumor Necrosis Factor-alpha/genetics*
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Water