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
During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membra...During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.展开更多
Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of a...Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.展开更多
Adenosine triphosphate(ATP)induced cell death(AICD)is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions.This co...Adenosine triphosphate(ATP)induced cell death(AICD)is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions.This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology.This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer.This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis,deciphering the intricate mechanisms governing AICD,elucidating its intricate involvement in cancer signaling pathways,and scrutinizing validated key genes.Moreover,the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.展开更多
Jujube contains abundant cyclic adenosine monophosphate(cAMP)and the ultrasonic-assisted pectinase extraction(UAPE)conditions for obtaining the maximum cAMP yield from jujube were optimized.Orthogonal array design was...Jujube contains abundant cyclic adenosine monophosphate(cAMP)and the ultrasonic-assisted pectinase extraction(UAPE)conditions for obtaining the maximum cAMP yield from jujube were optimized.Orthogonal array design was applied to evaluate the effects of 4 variables by UAPE on cAMP yield.The results showed that the optimal cAMP yield(783.0μg/g)was derived at ratio of liquid to solid 5 mL/g,ratio of pectinase to raw material 1.5%,time 60 min and temperature 40℃.Moreover,the effect of cAMP on the anti-allergic function of action induced by immunoglobulin E(IgE)and its meschanism was investigated through establishing the sensitized cell model in rat basophilic leukemia(RBL-2 H3)cells using dinitrophenylated(DNP)-bovine serum albumin(BSA)-IgE.The results showed that cAMP interfered with sensitized cells,effectively inhibited the occurrence of basophil degranulation in dose dependence,and significantly reduced the activity ofβ-hexosamindase(β-hex),at the optimal concentration of 50μg/mL.The level of anti-inflammatory factor interleukin-10(IL-10)was promoted and the content of pro-inflammatory factor tumor necrosis factor-α(TNF-α)was suppressed by cAMP.In addition,influx of intracellular Ca^(2+) was repressed effectively.Our results demonstrate that jujube cAMP regulated the cytokine balance in the allergy pathway through blocking the influx of extracellular Ca^(2+),with the prevention of allergy symptoms.展开更多
BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in ...BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in innate and adaptive immunity.Adenosine receptors expressed on the surface ofγδT cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role ofγδT cell regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis(T.spiralis)infection.The intestinal A2AR and A2AR inγδT cells were detected by immunohistochemistry,and the inflammatory cytokines were measured by western blot.The role of A2AR on the isolatedγδT cells,including proliferation,apoptosis,and cytokine production,were evaluated in vitro.Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction(RT-PCR).The animals were administered with A2AR agonist,or A2AR antagonist.Besides,γδT cells were also injected back into the animals,and the parameters described above were examined,as well as the clinical features.Furthermore,the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression(P<0.05),and suppression of A2AR enhanced PI-IBS clinical characteristics,indicated by the abdominal withdrawal reflex and colon transportation test.PI-IBS was associated with an increase in intestinal T cells,and cytokine levels of interleukin-1(IL-1),IL-6,IL-17A,and interferon-α(IFN-α).Also,γδT cells expressed A2AR in vitro and generated IL-1,IL-6,IL-17A,and IFN-α,which can be controlled by A2AR agonist and antagonist.Mechanistic studies demonstrated that the A2AR antagonist improved the function ofγδT cells through the PKA/CREB/NF-κB signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function ofγδT cells via the PKA/CREB/NF-κB signaling pathway.展开更多
BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brai...BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain.However,recent studies have shown that DARPP-32 is also expressed in other tissues,including colorectal cancer(CRC),where its function is not well understood.AIM To explore the effect of DARPP-32 on CRC progression.METHODS The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays.The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2’-deoxyuridine assays,while apoptosis was measured by flow cytometry.The migratory and invasive potential of CRC cell lines were deter-mined using wound healing and transwell chamber assays.In vivo studies involved monitoring the growth rate of xenograft tumors.Finally,the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses.RESULTS DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC.Overexpression of DARPP-32 was shown to promote cancer cell proliferation,migration,and invasion and reduce apoptosis.DARPP-32 knockdown resulted in the opposite functional effects.Mechanistically,DARPP-32 may regulate the phosphoinositide 3-kinase(PI3K)/AKT signaling pathway in order to carry out its biological function.CONCLUSION DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.展开更多
Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory p...Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.展开更多
Purpose: Regadenoson (REG) is currently becoming the stress agent of choice in patients undergoing pharmacologic single photon emission computed tomography (SPECT). However, in patients with left bundle branch block (...Purpose: Regadenoson (REG) is currently becoming the stress agent of choice in patients undergoing pharmacologic single photon emission computed tomography (SPECT). However, in patients with left bundle branch block (LBBB) and ventricular paced rhythm (VPR), hesitation exists amongst clinicians to use REG-SPECT due to the concern that the increased heart rate could cause false positive SPECT results. We sought to evaluate the comparability of A-SPECT and REG-SPECT in patients with LBBB and VPR. Methods: Retrospective study of 30 patients who served as their own controls. All 30 patients who underwent REG-SPECT (Grp 1) were compared to their prior A-SPECT (Grp 2) done within two years prior to REG-SPECT. Heart rate (HR) and blood pressure (BP) parameters, ECG, stress perfusion and gated variables, SPECT ischemia, and side-effects were evaluated. Statistical significance was set at P < 0.05. Results: Grp 1 and Grp 2 were comparable in hemodynamic parameters with increase in HR and decrease in systolic and diastolic BP with administration of adenosine and REG stress agents. However, there were no significant differences found in hemodynamic parameters and II degree AV block between the groups. All normal A-SPECT were found to be normal with REG-SPECT. No differences could be found between the two groups among SPECT parameters. Muscle pain was significantly higher in REG (10.0% vs. 0.0%, P = 0.083) and so was the use of aminophylline (16.7% vs. 0.0%, P = 0.025) to relieve the side-effect. Conclusion: REG-SPECT can be administered in patients with LBBB and VPR patients based on favorable and comparable hemodynamic responses and arrhythmia occurrences to A-SPECT. REG-SPECT can also be used for adequate interpretation of presence or absence of SPECT ischemia particularly in the LAD territory without any concern for false positive perfusion defects.展开更多
The activation of adenosine A1 receptors is important for protecting against ischemic brain injury and pretreatment with electroacupuncture has been shown to mitigate ischemic brain insult. The aim of this study was t...The activation of adenosine A1 receptors is important for protecting against ischemic brain injury and pretreatment with electroacupuncture has been shown to mitigate ischemic brain insult. The aim of this study was to test whether the adenosine A1 receptor mediates electroacupuncture pretreatment-induced neuroprotection against ischemic brain injury. We first performed 30 minutes of electroacupuncture pretreatment at the Baihui acupoint(GV20), delivered with a current of 1 mA, a frequency of 2/15 Hz, and a depth of 1 mm. High-performance liquid chromatography found that adenosine triphosphate and adenosine levels peaked in the cerebral cortex at 15 minutes and 120 minutes after electroacupuncture pretreatment, respectively. We further examined the effect of 15 or 120 minutes electroacupuncture treatment on ischemic brain injury in a rat middle cerebral artery-occlusion model. We found that at 24 hours reperfusion,120 minutes after electroacupuncture pretreatment, but not for 15 minutes, significantly reduced behavioral deficits and infarct volumes. Last, we demonstrated that the protective effect gained by 120 minutes after electroacupuncture treatment before ischemic injury was abolished by pretreatment with the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(1 mg/kg, intraperitoneally). Our results suggest that pretreatment with electroacupuncture at the Baihui acupoint elicits protection against transient cerebral ischemia via action at adenosine A1 receptors.展开更多
Aim: To further investigate the relaxation mechanism of neferine (NED, a bis-benzylisoquinoline alkaloid extracted (isolated) from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavern...Aim: To further investigate the relaxation mechanism of neferine (NED, a bis-benzylisoquinoline alkaloid extracted (isolated) from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavernosum tissue in vitro. Methods: The effects of Nef on the concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in isolated and incubated rabbit corpus cavernosum tissue were recorded using ^125I radioimmunoassay. Results: The basal concentration of cAMP in corpus cavernosum tissue was 5.67 ± 0.97 pmol/mg. Nef increased the cAMP concentration in a dose-dependent manner (P 〈 0.05), but this effect was not inhibited by an adenylate cyclase inhibitor (cis-N-[2-phenylcyclopentyl]azacyclotridec-1-en-2-amine, MDL-12, 330A) (P 〉 0.05). The accumulation of cAMP induced by prostaglandin Et (PGEt, a stimulator of cAMP production) was also augmented by Nef in a dose-dependent manner (P 〈 0.05). The basal concentration of cGMP in corpus cavernosum tissue is 0.44 ± 0.09 pmol/mg. Nef did not affect this concentration of cGMP, either in the presence or in the absence of a guanyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) (P 〉 0.05). Also, sodium nitroprusside (SNP, a stimulator of cGMP production)-induced cGMP production was not enhanced by Nef (P 〉 0.05). Conclusion: Nef, with its relaxation mechanism, can enhance the concentration of cAMP in rabbit corpus cavernosum tissue, probably by inhibiting phosphodiesterase activity. (Asian JAndro12008 Mar; 10: 307-312)展开更多
Objective: To verify possible associations between adenosine aminohydrolase(ADA) and AMP-aminohydrolase(AMPDA) to E3 SUMO-protein ligase NSE2(NSMCE2) in patients with renal stones. And to isolate, purify and character...Objective: To verify possible associations between adenosine aminohydrolase(ADA) and AMP-aminohydrolase(AMPDA) to E3 SUMO-protein ligase NSE2(NSMCE2) in patients with renal stones. And to isolate, purify and characterize ADA in patients with renal stones and healthy group.Methods: A total of 60 renal stones patients and 50 control were enrolled in a case-control study. The blood urea, creatinine, uric acid, protein, albumin, ADA and AMPDA were measured by colorimetric tests. The serum NSMCE2 was measured by ELISA.Results: Serum ADA, AMPDA and specii c activity of enzymes showed signii cant decrease(P < 0.05) in patients with renal stones compared to control group, mean levels of sera NSMCE2 and uric acid had a signii cant increase(P < 0.01 and P < 0.05, respectively) in patients compared to control group.Conclusions: The present study suggests that ADA, AMP deaminase and NSMCE2 can be used as a indicator to monitor the DNA damage and inl ammation disorders in the patients with kidney stones.展开更多
Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine ...Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine receptors mediate apoptosis. Extracellular adenosine also inducesapoptosis of gastric cancer cells. Extracellular adenosine is transported into cells through an adenosine transporter and converted to AMP by adenosine kinase. In turn, AMP activates AMP-activated protein kinase(AMPK). AMPK is the factor responsible for caspase-independent apoptosis of GT3-TKB gastric cancer cells. Extracellular adenosine, on the other hand, induces caspase-dependent apoptosis of MKN28 and MKN45 gastric cancer cells by two mechanisms. Firstly, AMP, converted from intracellularly transported adenosine, initiates apoptosis, regardless of AMPK. Secondly, the A3 adenosine receptor, linked to Gi/Gq proteins, mediates apoptosis by activating the Gq protein effector, phospholipase Cγ, to produce inositol 1,4,5-trisphosphate and diacylglycerol, which activate protein kinase C. Consequently, the mechanisms underlying adenosine-induced apoptosis vary, depending upon gastric cancer cell types. Understand the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor-made chemotherapy for gastric cancer.展开更多
Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was app...Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 (P2X3) receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.展开更多
A new adenosine biosensor based on aptamer probe is introduced in this article. An amino-labeled aptamer probe was immobilized on the gold electrode modified with an o-phenylenediamine electropolymerized film. When ad...A new adenosine biosensor based on aptamer probe is introduced in this article. An amino-labeled aptamer probe was immobilized on the gold electrode modified with an o-phenylenediamine electropolymerized film. When adenosine is bound specifically to the aptamer probe, the interface of the biosensor is changed, resulting in the decrement of the peak current. The response current is proportional to the amount of adenosine in sample. The used electrode can be easily regenerated in hot water. The proposed biosensor represents a linear response to adenosine over a concentration range of 1.0x 10^-7-l.0x10^-4 mol/L with a detection limit of 1.0xl0^-8 mol/L. The presented biosensor exhibits a nice specificity towards adenosine. It offers a promising approach for adenosine assay due to its excellent electrochemical properties that are believed to be very attractive for electrochemical studies and electroanalytical applications.展开更多
Retaining or improving periodontal ligament (PDL) function is crucial for restoring periodontal defects. The aim of this study was to evaluate the physiological effects of low-power laser irradiation (LPLI) on the...Retaining or improving periodontal ligament (PDL) function is crucial for restoring periodontal defects. The aim of this study was to evaluate the physiological effects of low-power laser irradiation (LPLI) on the proliferation and osteogenic differentiation of human PDL (hPDL) cells. Cultured hPDL cel Is were irradiated (660 nm) daily with doses of O, 1, 2 or 4 J .cm-2. Cell proliferation was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect of LPLI on osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. Additionally, osteogenic marker gene expression was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Our data showed that LPLI at a dose of 2 J.cm-2 significantly promoted hPDL cell proliferation at days 3 and 5. In addition, LPLI at energy doses of 2 and 4 J.cm-2 showed potential osteogenic capacity, as it stimulated ALP activity, calcium deposition, and osteogenic gene expression. We also showed that cyclic adenosine monophosphate (cAMP) is a critical regulator of the LPLI-mediated effects on hPDL cells. This study shows that LPLI can promote the proliferation and osteogenic differentiation of hPDL cells. These results suggest the potential use of LPLI in clinical applications for periodontal tissue regeneration.展开更多
An efficient protocol for the synthesis of N^6-(2-Hydroxyethyl)adenosine and its analogues through nucleophilic substitution was developed. All the reactions were completed in 10 rain under microwave irradiation. Us...An efficient protocol for the synthesis of N^6-(2-Hydroxyethyl)adenosine and its analogues through nucleophilic substitution was developed. All the reactions were completed in 10 rain under microwave irradiation. Using water as solvent makes our method eco-friendly and easy to handle with.展开更多
At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increa...At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected significantly increased levels of cyclic adenosine monophosphate response element binding protein These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippocampus of the senescence-accelerated mouse.展开更多
AIM To evaluate the relationship between serum adenosine deaminase(ADA) levels and histological features in patients with autoimmune hepatitis(AIH).METHODS A total of 80 subjects(52 AIH cases and 28 healthy controls) ...AIM To evaluate the relationship between serum adenosine deaminase(ADA) levels and histological features in patients with autoimmune hepatitis(AIH).METHODS A total of 80 subjects(52 AIH cases and 28 healthy controls) were included in the study. Patients were diagnosed according to the simplified criteria suggested by the International Autoimmune Hepatitis Group. All of the cases had been diagnosed with AIH between 2010-2015 at Hacettepe University, Department of Gastroenterology. Serum blood samples were collected and stored at-80 ℃ until the biochemical estimation of ADA activity. The diagnosis of patients was confirmed by liver biopsy. Serum ADA > 20 U/L was considered to be high level.RESULTS Mean serum ADA levels were significantly higher in AIH patients than those in healthy controls(25.4 ± 9.6 U/L vs 12.8 ± 2.2 U/L, P < 0.001). Serum ADA levels > 20 U/L were found in 63.5% AIH patients and in 0% healthy controls(P < 0.001). Mean serum ADA levels were significantly increased in each stage of histological activity: 15.2 ± 3.5 U/L for patients with mild interface hepatitis, 23.1 ± 10.0 U/L for patients with moderate interface hepatitis and 30.9 ± 7.0 U/L for patients with severe interface hepatitis(P < 0.001). Correlation analysis showed that there was a positive association between serum ADA levels and histological activity(r = 0.71, P < 0.001). Receiver operating characteristic analysis suggested that 24.5 U/L was the optimum cut-off point of ADA level for severe interface hepatitis(sensitivity 88%, specificity 85.2%, area under thecurve: 0.88).CONCLUSION Because of the positive correlation with inflammatory activity, serum ADA level may be a potential biomarker for predicting or monitoring histological activity in patients with AIH.展开更多
Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases.However,the pathogenesis underlying long-term adenosine A1 receptor...Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases.However,the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear.In this study,rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine(CPA)for five weeks.The mobility of rats was evaluated by forced swimming test,while their cognitive capabilities were evaluated by Y-maze test.Expression of sortilin,α-synuclein,p-JUN,and c-JUN proteins in the substantia nigra were detected by western blot analysis.In addition,immunofluorescence staining of sortilin andα-synuclein was performed to detect expression in the substantia nigra.The results showed that,compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(5 mg/kg)+CPA co-treated rats,motor and memory abilities were reduced,surface expression of sortin andα-synuclein in dopaminergic neurons was reduced,and total sortilin and totalα-synuclein were increased in CPA-treated rats.MN9D cells were incubated with 500 nM CPA alone or in combination with 10μM SP600125(JNK inhibitor)for 48 hours.Quantitative real-time polymerase chain reaction analysis of sortilin andα-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone,but the combination of CPA and SP600125 could inhibit this expression.Predictions made using Jasper,PROMO,and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents.A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction.After sortilin expression was inhibited by sh-SORT1,expression of p-JUN and c-JUN was detected by western blot analysis.Long-term adenosine A1 receptor activation levels upregulatedα-synuclein expression at the post-transcriptional level by affecting sortilin expression.The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind toα-synuclein.Co-immunoprecipitation revealed an interaction between sortilin andα-synuclein in MN9D cells.Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression andα-synuclein accumulation,and dramatically improved host cognition and kineticism.This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan(approval No.AUP#20070090)in March 2007 and the Animals Ethics Committee of University of South China(approval No.LL0387-USC)in June 2017.展开更多
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.
基金supported by University of Florence RICATEN 2023 to EC.Grant/Award Numbers 58514_InternazionalizzazioneUniversity of Florence,to EC.Parkinson’s UK,Grant/Award Number:H-0902 to AJGWellcome Trust,Grant/Award Number:0926/Z/10/Z to AJG。
文摘During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.
基金supported by the Natural Nature Science Foundation of China,Nos.82030071,81874004the Science and Technology Major Project of Changsha,No.kh2103008(all to JZH).
文摘Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.
基金Supported by National Natural Science Foundation of China,No.81960877University Innovation Fund of Gansu Province,No.2021A-076+4 种基金Gansu Province Science and Technology Plan(Innovation Base and Talent Plan),No.21JR7RA561Natural Science Foundation of Gansu Province,No.21JR1RA267 and No.22JR5RA582Education Technology Innovation Project of Gansu Province,No.2022A-067Innovation Fund of Higher Education of Gansu Province,No.2023A-088Gansu Province Science and Technology Plan International Cooperation Field Project,No.23YFWA0005.
文摘Adenosine triphosphate(ATP)induced cell death(AICD)is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions.This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology.This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer.This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis,deciphering the intricate mechanisms governing AICD,elucidating its intricate involvement in cancer signaling pathways,and scrutinizing validated key genes.Moreover,the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.
基金supported by grant from the National Key Research and Development Program of China(2018YFC1602201)the Open Research Fund Program of Beijing Key Lab of Plant Resource Research and Development,Beijing Technology and Business University(PRRD-2021-YB8)+1 种基金the National Natural Science Fund(31601395)the Key Program for Shaanxi Science and Technology(2020NY-146)。
文摘Jujube contains abundant cyclic adenosine monophosphate(cAMP)and the ultrasonic-assisted pectinase extraction(UAPE)conditions for obtaining the maximum cAMP yield from jujube were optimized.Orthogonal array design was applied to evaluate the effects of 4 variables by UAPE on cAMP yield.The results showed that the optimal cAMP yield(783.0μg/g)was derived at ratio of liquid to solid 5 mL/g,ratio of pectinase to raw material 1.5%,time 60 min and temperature 40℃.Moreover,the effect of cAMP on the anti-allergic function of action induced by immunoglobulin E(IgE)and its meschanism was investigated through establishing the sensitized cell model in rat basophilic leukemia(RBL-2 H3)cells using dinitrophenylated(DNP)-bovine serum albumin(BSA)-IgE.The results showed that cAMP interfered with sensitized cells,effectively inhibited the occurrence of basophil degranulation in dose dependence,and significantly reduced the activity ofβ-hexosamindase(β-hex),at the optimal concentration of 50μg/mL.The level of anti-inflammatory factor interleukin-10(IL-10)was promoted and the content of pro-inflammatory factor tumor necrosis factor-α(TNF-α)was suppressed by cAMP.In addition,influx of intracellular Ca^(2+) was repressed effectively.Our results demonstrate that jujube cAMP regulated the cytokine balance in the allergy pathway through blocking the influx of extracellular Ca^(2+),with the prevention of allergy symptoms.
基金Supported by National Natural Science Foundation of China,No.81160057,No.81860102,and No.82060102Natural Science Foundation of Hainan Province,High-level Personnel Program,No.821RC1116+1 种基金Research Project of Health Industry in Hainan Province,No.20A200066Hainan Provincial Clinical Medical Center.
文摘BACKGROUND Immunological dysfunction-induced low-grade inflammation is regarded as one of the predominant pathogenetic mechanisms in post-infectious irritable bowel syndrome(PI-IBS).γδT cells play a crucial role in innate and adaptive immunity.Adenosine receptors expressed on the surface ofγδT cells participate in intestinal inflammation and immunity regulation.AIM To investigate the role ofγδT cell regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS The PI-IBS mouse model has been established with Trichinella spiralis(T.spiralis)infection.The intestinal A2AR and A2AR inγδT cells were detected by immunohistochemistry,and the inflammatory cytokines were measured by western blot.The role of A2AR on the isolatedγδT cells,including proliferation,apoptosis,and cytokine production,were evaluated in vitro.Their A2AR expression was measured by western blot and reverse transcription polymerase chain reaction(RT-PCR).The animals were administered with A2AR agonist,or A2AR antagonist.Besides,γδT cells were also injected back into the animals,and the parameters described above were examined,as well as the clinical features.Furthermore,the A2AR-associated signaling pathway molecules were assessed by western blot and RT-PCR.RESULTS PI-IBS mice exhibited elevated ATP content and A2AR expression(P<0.05),and suppression of A2AR enhanced PI-IBS clinical characteristics,indicated by the abdominal withdrawal reflex and colon transportation test.PI-IBS was associated with an increase in intestinal T cells,and cytokine levels of interleukin-1(IL-1),IL-6,IL-17A,and interferon-α(IFN-α).Also,γδT cells expressed A2AR in vitro and generated IL-1,IL-6,IL-17A,and IFN-α,which can be controlled by A2AR agonist and antagonist.Mechanistic studies demonstrated that the A2AR antagonist improved the function ofγδT cells through the PKA/CREB/NF-κB signaling pathway.CONCLUSION Our results revealed that A2AR contributes to the facilitation of PI-IBS by regulating the function ofγδT cells via the PKA/CREB/NF-κB signaling pathway.
基金Supported by Chongqing Key Diseases Research and Application Demonstration Program,No.2019ZX003General Project of Chongqing Nature Science Foundation,No.cstc2021jcyj-msxmX0283.
文摘BACKGROUND Dopamine and cyclic adenosine monophosphate(cAMP)-regulated phosphop-rotein with an apparent Mr of 32000(DARPP-32)is a protein that is involved in regulating dopamine and cAMP signaling pathways in the brain.However,recent studies have shown that DARPP-32 is also expressed in other tissues,including colorectal cancer(CRC),where its function is not well understood.AIM To explore the effect of DARPP-32 on CRC progression.METHODS The expression levels of DARPP-32 were assessed in CRC tissues using both quantitative polymerase chain reaction and immunohistochemistry assays.The proliferative capacity of CRC cell lines was evaluated with Cell Counting Kit-8 and 5-ethynyl-2’-deoxyuridine assays,while apoptosis was measured by flow cytometry.The migratory and invasive potential of CRC cell lines were deter-mined using wound healing and transwell chamber assays.In vivo studies involved monitoring the growth rate of xenograft tumors.Finally,the underlying molecular mechanism of DARPP-32 was investigated through RNA-sequencing and western blot analyses.RESULTS DARPP-32 was frequently upregulated in CRC and associated with abnormal clinicopathological features in CRC.Overexpression of DARPP-32 was shown to promote cancer cell proliferation,migration,and invasion and reduce apoptosis.DARPP-32 knockdown resulted in the opposite functional effects.Mechanistically,DARPP-32 may regulate the phosphoinositide 3-kinase(PI3K)/AKT signaling pathway in order to carry out its biological function.CONCLUSION DARPP-32 promotes CRC progression via the PI3K/AKT signaling pathway.
基金supported by the National Natural Science Foundation of ChinaNos.81971047 (to WTL) and 82073910 (to XFW)+2 种基金the Natural Science Foundation of Jiangsu Province,No.BK20191253 (to XFW)Key R&D Program (Social Development) Project of Jiangsu Province,No.BE2019 732 (to WTL)Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) Clinical Capacity Enhancement Project,No.JSPH-511B2018-8 (to YBP)。
文摘Opioids,such as morphine,are the most potent drugs used to treat pain.Long-term use results in high tolerance to morphine.High mobility group box-1(HMGB1) has been shown to participate in neuropathic or inflammatory pain,but its role in morphine tolerance is unclear.In this study,we established rat and mouse models of morphine tolerance by intrathecal injection of morphine for 7 consecutive days.We found that morphine induced rat spinal cord neurons to release a large amount of HMGB1.HMGB1 regulated nuclear factor κB p65 phosphorylation and interleukin-1β production by increasing Toll-like receptor 4receptor expression in microglia,thereby inducing morphine tolerance.Glycyrrhizin,an HMGB1 inhibito r,markedly attenuated chronic morphine tole rance in the mouse model.Finally,compound C(adenosine 5’-monophosphate-activated protein kinase inhibitor) and zinc protoporphyrin(heme oxygenase-1 inhibitor)alleviated the morphine-induced release of HMGB1 and reduced nuclear factor κB p65 phosphorylation and interleukin-1β production in a mouse model of morphine tolerance and an SH-SY5Y cell model of morphine tole rance,and alleviated morphine tolerance in the mouse model.These findings suggest that morphine induces HMGB1 release via the adenosine 5’-monophosphate-activated protein kinase/heme oxygenase-1 signaling pathway,and that inhibiting this signaling pathway can effectively reduce morphine tole rance.
文摘Purpose: Regadenoson (REG) is currently becoming the stress agent of choice in patients undergoing pharmacologic single photon emission computed tomography (SPECT). However, in patients with left bundle branch block (LBBB) and ventricular paced rhythm (VPR), hesitation exists amongst clinicians to use REG-SPECT due to the concern that the increased heart rate could cause false positive SPECT results. We sought to evaluate the comparability of A-SPECT and REG-SPECT in patients with LBBB and VPR. Methods: Retrospective study of 30 patients who served as their own controls. All 30 patients who underwent REG-SPECT (Grp 1) were compared to their prior A-SPECT (Grp 2) done within two years prior to REG-SPECT. Heart rate (HR) and blood pressure (BP) parameters, ECG, stress perfusion and gated variables, SPECT ischemia, and side-effects were evaluated. Statistical significance was set at P < 0.05. Results: Grp 1 and Grp 2 were comparable in hemodynamic parameters with increase in HR and decrease in systolic and diastolic BP with administration of adenosine and REG stress agents. However, there were no significant differences found in hemodynamic parameters and II degree AV block between the groups. All normal A-SPECT were found to be normal with REG-SPECT. No differences could be found between the two groups among SPECT parameters. Muscle pain was significantly higher in REG (10.0% vs. 0.0%, P = 0.083) and so was the use of aminophylline (16.7% vs. 0.0%, P = 0.025) to relieve the side-effect. Conclusion: REG-SPECT can be administered in patients with LBBB and VPR patients based on favorable and comparable hemodynamic responses and arrhythmia occurrences to A-SPECT. REG-SPECT can also be used for adequate interpretation of presence or absence of SPECT ischemia particularly in the LAD territory without any concern for false positive perfusion defects.
基金supported by the National Natural Science Foundation of China,No.81273926,81573742the Natural Science Foundation of Zhejiang Province of China,No.LY15H290006
文摘The activation of adenosine A1 receptors is important for protecting against ischemic brain injury and pretreatment with electroacupuncture has been shown to mitigate ischemic brain insult. The aim of this study was to test whether the adenosine A1 receptor mediates electroacupuncture pretreatment-induced neuroprotection against ischemic brain injury. We first performed 30 minutes of electroacupuncture pretreatment at the Baihui acupoint(GV20), delivered with a current of 1 mA, a frequency of 2/15 Hz, and a depth of 1 mm. High-performance liquid chromatography found that adenosine triphosphate and adenosine levels peaked in the cerebral cortex at 15 minutes and 120 minutes after electroacupuncture pretreatment, respectively. We further examined the effect of 15 or 120 minutes electroacupuncture treatment on ischemic brain injury in a rat middle cerebral artery-occlusion model. We found that at 24 hours reperfusion,120 minutes after electroacupuncture pretreatment, but not for 15 minutes, significantly reduced behavioral deficits and infarct volumes. Last, we demonstrated that the protective effect gained by 120 minutes after electroacupuncture treatment before ischemic injury was abolished by pretreatment with the A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(1 mg/kg, intraperitoneally). Our results suggest that pretreatment with electroacupuncture at the Baihui acupoint elicits protection against transient cerebral ischemia via action at adenosine A1 receptors.
基金Acknowledgment The authors thank Prof. Jia-Ling Wang for kindly supplying the neferine. The technical support from Prof. Bo-Hua Shu is also greatly appreciated. This study was sponsored by the National Natural Science Foundation of China (No. 30471736) and China Postdoctoral Science Foundation (No. 20070410176).
文摘Aim: To further investigate the relaxation mechanism of neferine (NED, a bis-benzylisoquinoline alkaloid extracted (isolated) from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavernosum tissue in vitro. Methods: The effects of Nef on the concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in isolated and incubated rabbit corpus cavernosum tissue were recorded using ^125I radioimmunoassay. Results: The basal concentration of cAMP in corpus cavernosum tissue was 5.67 ± 0.97 pmol/mg. Nef increased the cAMP concentration in a dose-dependent manner (P 〈 0.05), but this effect was not inhibited by an adenylate cyclase inhibitor (cis-N-[2-phenylcyclopentyl]azacyclotridec-1-en-2-amine, MDL-12, 330A) (P 〉 0.05). The accumulation of cAMP induced by prostaglandin Et (PGEt, a stimulator of cAMP production) was also augmented by Nef in a dose-dependent manner (P 〈 0.05). The basal concentration of cGMP in corpus cavernosum tissue is 0.44 ± 0.09 pmol/mg. Nef did not affect this concentration of cGMP, either in the presence or in the absence of a guanyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) (P 〉 0.05). Also, sodium nitroprusside (SNP, a stimulator of cGMP production)-induced cGMP production was not enhanced by Nef (P 〉 0.05). Conclusion: Nef, with its relaxation mechanism, can enhance the concentration of cAMP in rabbit corpus cavernosum tissue, probably by inhibiting phosphodiesterase activity. (Asian JAndro12008 Mar; 10: 307-312)
基金Supported by the Research Management Center,International Islamic University Malaysia,Grant Scheme Project No.IIUM/504/5/29/1
文摘Objective: To verify possible associations between adenosine aminohydrolase(ADA) and AMP-aminohydrolase(AMPDA) to E3 SUMO-protein ligase NSE2(NSMCE2) in patients with renal stones. And to isolate, purify and characterize ADA in patients with renal stones and healthy group.Methods: A total of 60 renal stones patients and 50 control were enrolled in a case-control study. The blood urea, creatinine, uric acid, protein, albumin, ADA and AMPDA were measured by colorimetric tests. The serum NSMCE2 was measured by ELISA.Results: Serum ADA, AMPDA and specii c activity of enzymes showed signii cant decrease(P < 0.05) in patients with renal stones compared to control group, mean levels of sera NSMCE2 and uric acid had a signii cant increase(P < 0.01 and P < 0.05, respectively) in patients compared to control group.Conclusions: The present study suggests that ADA, AMP deaminase and NSMCE2 can be used as a indicator to monitor the DNA damage and inl ammation disorders in the patients with kidney stones.
文摘Extracellular adenosine induces apoptosis in a variety of cancer cells via intrinsic and extrinsic pathways. In the former pathway, adenosine uptake into cells triggers apoptosis, and in the latter pathway, adenosine receptors mediate apoptosis. Extracellular adenosine also inducesapoptosis of gastric cancer cells. Extracellular adenosine is transported into cells through an adenosine transporter and converted to AMP by adenosine kinase. In turn, AMP activates AMP-activated protein kinase(AMPK). AMPK is the factor responsible for caspase-independent apoptosis of GT3-TKB gastric cancer cells. Extracellular adenosine, on the other hand, induces caspase-dependent apoptosis of MKN28 and MKN45 gastric cancer cells by two mechanisms. Firstly, AMP, converted from intracellularly transported adenosine, initiates apoptosis, regardless of AMPK. Secondly, the A3 adenosine receptor, linked to Gi/Gq proteins, mediates apoptosis by activating the Gq protein effector, phospholipase Cγ, to produce inositol 1,4,5-trisphosphate and diacylglycerol, which activate protein kinase C. Consequently, the mechanisms underlying adenosine-induced apoptosis vary, depending upon gastric cancer cell types. Understand the contribution of each downstream target molecule of adenosine to apoptosis induction may aid the establishment of tailor-made chemotherapy for gastric cancer.
文摘Applying a stimulating current to acupoints through acupuncture needles–known as electroacupuncture–has the potential to produce analgesic effects in human subjects and experimental animals. When acupuncture was applied in a rat model, adenosine 5-triphosphate disodium in the extracellular space was broken down into adenosine, which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process. Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture. The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves. In neuropathic pain, there is upregulation of P2X purinoceptor 3 (P2X3) receptor expression in dorsal root ganglion neurons. Conversely, the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated. The pathways upon which electroacupuncture appear to act are interwoven with pain pathways, and electroacupuncture stimuli converge with impulses originating from painful areas. Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.
基金Supported by the National Natural Science Foundation of China(Nos20675028, 20435010 and 20375012)the Science Commission of Hunan Province, China
文摘A new adenosine biosensor based on aptamer probe is introduced in this article. An amino-labeled aptamer probe was immobilized on the gold electrode modified with an o-phenylenediamine electropolymerized film. When adenosine is bound specifically to the aptamer probe, the interface of the biosensor is changed, resulting in the decrement of the peak current. The response current is proportional to the amount of adenosine in sample. The used electrode can be easily regenerated in hot water. The proposed biosensor represents a linear response to adenosine over a concentration range of 1.0x 10^-7-l.0x10^-4 mol/L with a detection limit of 1.0xl0^-8 mol/L. The presented biosensor exhibits a nice specificity towards adenosine. It offers a promising approach for adenosine assay due to its excellent electrochemical properties that are believed to be very attractive for electrochemical studies and electroanalytical applications.
基金supported by grants from the Kaohsiung Medical University of Taiwan (KMU-Q099018 and KMU-Q098025)
文摘Retaining or improving periodontal ligament (PDL) function is crucial for restoring periodontal defects. The aim of this study was to evaluate the physiological effects of low-power laser irradiation (LPLI) on the proliferation and osteogenic differentiation of human PDL (hPDL) cells. Cultured hPDL cel Is were irradiated (660 nm) daily with doses of O, 1, 2 or 4 J .cm-2. Cell proliferation was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect of LPLI on osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. Additionally, osteogenic marker gene expression was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Our data showed that LPLI at a dose of 2 J.cm-2 significantly promoted hPDL cell proliferation at days 3 and 5. In addition, LPLI at energy doses of 2 and 4 J.cm-2 showed potential osteogenic capacity, as it stimulated ALP activity, calcium deposition, and osteogenic gene expression. We also showed that cyclic adenosine monophosphate (cAMP) is a critical regulator of the LPLI-mediated effects on hPDL cells. This study shows that LPLI can promote the proliferation and osteogenic differentiation of hPDL cells. These results suggest the potential use of LPLI in clinical applications for periodontal tissue regeneration.
基金the National Natural Science Foundation of China(No.20372018)
文摘An efficient protocol for the synthesis of N^6-(2-Hydroxyethyl)adenosine and its analogues through nucleophilic substitution was developed. All the reactions were completed in 10 rain under microwave irradiation. Using water as solvent makes our method eco-friendly and easy to handle with.
文摘At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected significantly increased levels of cyclic adenosine monophosphate response element binding protein These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippocampus of the senescence-accelerated mouse.
文摘AIM To evaluate the relationship between serum adenosine deaminase(ADA) levels and histological features in patients with autoimmune hepatitis(AIH).METHODS A total of 80 subjects(52 AIH cases and 28 healthy controls) were included in the study. Patients were diagnosed according to the simplified criteria suggested by the International Autoimmune Hepatitis Group. All of the cases had been diagnosed with AIH between 2010-2015 at Hacettepe University, Department of Gastroenterology. Serum blood samples were collected and stored at-80 ℃ until the biochemical estimation of ADA activity. The diagnosis of patients was confirmed by liver biopsy. Serum ADA > 20 U/L was considered to be high level.RESULTS Mean serum ADA levels were significantly higher in AIH patients than those in healthy controls(25.4 ± 9.6 U/L vs 12.8 ± 2.2 U/L, P < 0.001). Serum ADA levels > 20 U/L were found in 63.5% AIH patients and in 0% healthy controls(P < 0.001). Mean serum ADA levels were significantly increased in each stage of histological activity: 15.2 ± 3.5 U/L for patients with mild interface hepatitis, 23.1 ± 10.0 U/L for patients with moderate interface hepatitis and 30.9 ± 7.0 U/L for patients with severe interface hepatitis(P < 0.001). Correlation analysis showed that there was a positive association between serum ADA levels and histological activity(r = 0.71, P < 0.001). Receiver operating characteristic analysis suggested that 24.5 U/L was the optimum cut-off point of ADA level for severe interface hepatitis(sensitivity 88%, specificity 85.2%, area under thecurve: 0.88).CONCLUSION Because of the positive correlation with inflammatory activity, serum ADA level may be a potential biomarker for predicting or monitoring histological activity in patients with AIH.
基金supported by the National Natural Sciences Foundation of China,No.81770460(to YCL)the Postdoctoral Research Fellowship of the Saskatchewan Health Research Foundation,No.SHRF,4144(to YCL)+2 种基金the third level of the Chuanshan Talent project of the University of South China,No.2017CST20(to YCL)the Aid Program,No.2017KJ268 and the Key Lab for Clinical Anatomy&Reproductive Medicine,No.2017KJ182 from the Science and Technology Bureau of Hengyang City,China(to YCL and XC)the Postgraduate Student Research Innovation Projects of Hunan Province,China,No.CX2018B62(to ABG)
文摘Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases.However,the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear.In this study,rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine(CPA)for five weeks.The mobility of rats was evaluated by forced swimming test,while their cognitive capabilities were evaluated by Y-maze test.Expression of sortilin,α-synuclein,p-JUN,and c-JUN proteins in the substantia nigra were detected by western blot analysis.In addition,immunofluorescence staining of sortilin andα-synuclein was performed to detect expression in the substantia nigra.The results showed that,compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine(5 mg/kg)+CPA co-treated rats,motor and memory abilities were reduced,surface expression of sortin andα-synuclein in dopaminergic neurons was reduced,and total sortilin and totalα-synuclein were increased in CPA-treated rats.MN9D cells were incubated with 500 nM CPA alone or in combination with 10μM SP600125(JNK inhibitor)for 48 hours.Quantitative real-time polymerase chain reaction analysis of sortilin andα-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone,but the combination of CPA and SP600125 could inhibit this expression.Predictions made using Jasper,PROMO,and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents.A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction.After sortilin expression was inhibited by sh-SORT1,expression of p-JUN and c-JUN was detected by western blot analysis.Long-term adenosine A1 receptor activation levels upregulatedα-synuclein expression at the post-transcriptional level by affecting sortilin expression.The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind toα-synuclein.Co-immunoprecipitation revealed an interaction between sortilin andα-synuclein in MN9D cells.Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression andα-synuclein accumulation,and dramatically improved host cognition and kineticism.This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan(approval No.AUP#20070090)in March 2007 and the Animals Ethics Committee of University of South China(approval No.LL0387-USC)in June 2017.