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腺苷A_(2B)受体激活减轻脓毒症诱导的急性肺损伤及肺微血管内皮炎症损伤
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作者 王慧霞 安友仲 《中国临床新医学》 2024年第2期138-144,共7页
目的分析腺苷A_(2B)受体(A_(2B) R)激活对脓毒症诱导的急性肺损伤(ALI)的影响并探讨其在肺微血管内皮炎症损伤中的调控作用。方法(1)将24只SD大鼠随机分为假手术组(sham组)、ALI模型组(ALI组)、A_(2B) R激动剂BAY60-6583干预组(ALI+BAY... 目的分析腺苷A_(2B)受体(A_(2B) R)激活对脓毒症诱导的急性肺损伤(ALI)的影响并探讨其在肺微血管内皮炎症损伤中的调控作用。方法(1)将24只SD大鼠随机分为假手术组(sham组)、ALI模型组(ALI组)、A_(2B) R激动剂BAY60-6583干预组(ALI+BAY组)和A_(2B) R抑制剂PSB1115干预组(ALI+PSB组),每组6只。制模后24 h处死大鼠取肺组织,光镜下行肺损伤评分(Smith评分),计算肺湿/干质量比值(W/D)。Evans Blue染色法测定肺水清除率(AFC)。酶联免疫吸附试验(ELISA)测定肺组织炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)的水平。(2)采用TNF-α诱导人肺微血管内皮细胞(HPMECs)损伤模型,设立对照组、TNF-α组、BAY组、PSB组、BAY+TNF-α组和PSB+TNF-α组,各组细胞培养24 h后采用异硫氰酸荧光素(FITC)-白蛋白(albumin)法检测HPMECs单层通透性,Werstern blot法检测IL-1β、细胞间黏附分子-1(ICAM-1)、血管内皮钙黏连蛋白(VE-cadherin)、促血管生成素(ANGPT)的表达水平。结果与sham组比较,ALI组的Smith评分、肺W/D及肺组织TNF-α、IL-6、IL-1β水平均显著升高,AFC显著降低;与ALI组比较,ALI+BAY组的Smith评分、肺W/D及肺组织TNF-α、IL-6、IL-1β水平显著降低,AFC显著升高;而ALI+PSB组结果相反。TNF-α诱导HPMECs损伤模型中,与对照组比较,TNF-α组IL-1β、ICAM-1表达水平及HPMECs单层通透性升高,VE-cadherin、ANGPT表达水平降低。与TNF-α组比较,BAY+TNF-α组IL-1β、ICAM-1表达水平及HPMECs单层通透性降低,VE-cadherin、ANGPT表达水平升高,而PSB1115预处理可逆转上述现象。上述各组之间差异有统计学意义(均P<0.05)。结论腺苷A_(2B) R激活可减轻脓毒症诱导的ALI,并通过减轻肺微血管内皮炎症、降低通透性、促进血管生成等途径起保护作用。 展开更多
关键词 腺苷a_(2b)受体 脓毒症 急性肺损伤 人肺微血管内皮细胞 炎症
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Prolonged intermittent theta burst stimulation restores the balance between A_(2A)R-and A_(1)R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson's disease
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作者 Milica Zeljkovic Jovanovic Jelena Stanojevic +4 位作者 Ivana Stevanovic Milica Ninkovic Tihomir V.Ilic Nadezda Nedeljkovic Milorad Dragic 《Neural Regeneration Research》 SCIE CAS 2025年第7期2053-2067,共15页
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
关键词 a_(1)R a_(2a)R adenosine receptors adenosine ecto-5′-nucleotidase intermittent theta burst stimulation non-invasive brain stimulation Parkinson's disease purinergic signalling
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Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult
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作者 Elisabetta Coppi Federica Cherchi Alasdair J.Gibb 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第2期255-257,共3页
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
关键词 adenosine a_(2a)receptors anoxic depolarization brain ischemia glutamate excitotoxicity medium spiny neurons oxygen and glucose deprivation
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新型含吡啶酮(吡唑)结构的A_(2a)/A_(2b)双靶点腺苷受体拮抗剂的合成及生物活性研究
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作者 李志 胡代强 +2 位作者 付信珍 张淑敏 刘明 《合成化学》 CAS 2022年第9期688-696,共9页
设计并合成了具有吡啶酮或吡唑结构的6个新型双靶点(A_(2a)和A_(2b))腺苷受体拮抗剂。其结构经^(1)H NMR、^(13)C NMR和HR-MS(ESI)表征。采用cAMP法评价了目标化合物(11a~11f)对A_(2a)和A_(2b)受体的抑制活性。活性测试结果表明:该系列... 设计并合成了具有吡啶酮或吡唑结构的6个新型双靶点(A_(2a)和A_(2b))腺苷受体拮抗剂。其结构经^(1)H NMR、^(13)C NMR和HR-MS(ESI)表征。采用cAMP法评价了目标化合物(11a~11f)对A_(2a)和A_(2b)受体的抑制活性。活性测试结果表明:该系列化合物对A_(2a)和A_(2b)受体均有较好的抑制活性。其中化合物11e抑制活性最强,抑制A_(2a)和A_(2b)受体的IC_(50)值分别为8.188 nM和15.22 nM,11e对A_(2b) R受体的抑制活性优于阳性对照药AB928(IC_(50)=36.48 nM)。此外,利用分子对接研究了化合物11e与A_(2a)和A_(2b)靶点的结合情况,结果表明:化合物11e与A_(2a)和A_(2b)靶点具有较好的亲和作用。 展开更多
关键词 吡啶酮 吡唑 a_(2a)/a_(2b)双靶点 腺苷受体拮抗剂 合成 caMP法 分子对接 生物活性
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高良姜素减轻乙型病毒性肝炎模型大鼠的炎性反应
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作者 王维 穆宝龙 +3 位作者 张文双 吴清雷 张慧慧 曹智丽 《基础医学与临床》 CAS 2024年第11期1551-1556,共6页
目的探讨高良姜素(Gal)对乙型病毒性肝炎(乙肝)大鼠炎性反应的影响。方法大鼠随机分为对照组、乙肝组[尾静脉注射乙型肝炎病毒(HBV)]、Gal低(Gal-L)和高剂量(Gal-H)组、阳性药拉米夫定组、Gal-H+AMPK抑制剂(compound C)组,每组12只。造... 目的探讨高良姜素(Gal)对乙型病毒性肝炎(乙肝)大鼠炎性反应的影响。方法大鼠随机分为对照组、乙肝组[尾静脉注射乙型肝炎病毒(HBV)]、Gal低(Gal-L)和高剂量(Gal-H)组、阳性药拉米夫定组、Gal-H+AMPK抑制剂(compound C)组,每组12只。造模后进行药物处理,给药1次/d,持续8周。检测血清中谷丙转氨酶(ALT)、总胆红素(TBIL)、谷草转氨酶(AST)水平;HE染色检测肝组织病理变化;TUNEL染色检测细胞凋亡;染色质免疫共沉淀检测HBV病毒载量;ELISA检测肝组织中单核细胞趋化蛋白-1(MCP-1)、白细胞介素(IL-12)、肿瘤坏死因子-α(TNF-α)水平;Western blot检测天冬氨酸特异性半胱氨酸蛋白酶-3(caspase-3)、Bcl-2相关X蛋白(Bax)、p-AMPK、SIRT1蛋白表达。结果与乙肝组比较,Gal-L组、Gal-H组、拉米夫定组肝脏损伤减轻,血清中AST、TBIL、ALT水平降低,肝组织中细胞凋亡率、HBV病毒载量、MCP-1、IL-12、TNF-α水平及caspase-3、Bax蛋白降低,p-AMPK、SIRT1蛋白升高(P<0.05);Compound C减弱了高剂量Gal对乙肝大鼠肝组织中炎性反应、细胞凋亡及HBV病毒载量的抑制作用。结论Gal抑制乙肝大鼠炎性反应的机制可能与上调AMPK/SIRT1通路有关。 展开更多
关键词 高良姜素 腺苷酸活化蛋白激酶/沉默信息调节因子1(aMPK/SIRT1)通路 乙肝 肝损伤 炎性反应
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Bone-derived MSCs encapsulated in alginate hydrogel prevent collagen-induced arthritis in mice through the activation of adenosine A_(2A/2B)receptors in tolerogenic dendritic cells 被引量:1
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作者 Gaona Shi Yu Zhou +7 位作者 Wenshuai Liu Chengjuan Chen Yazi Wei Xinlong Yan Lei Wu Weiwei Wang Lan Sun Tiantai Zhang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第6期2778-2794,共17页
Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,s... Tolerogenic dendritic cells(tol DCs)facilitate the suppression of autoimmune responses by differentiating regulatory T cells(Treg).The dysfunction of immunotolerance results in the development of autoimmune diseases,such as rheumatoid arthritis(RA).As multipotent progenitor cells,mesenchymal stem cells(MSCs),can regulate dendritic cells(DCs)to restore their immunosuppressive function and prevent disease development.However,the underlying mechanisms of MSCs in regulating DCs still need to be better defined.Simultaneously,the delivery system for MSCs also influences their function.Herein,MSCs are encapsulated in alginate hydrogel to improve cell survival and retention in situ,maximizing efficacy in vivo.The three-dimensional co-culture of encapsulated MSCs with DCs demonstrates that MSCs can inhibit the maturation of DCs and the secretion of pro-inflammatory cytokines.In the collagen-induced arthritis(CIA)mice model,alginate hydrogel encapsulated MSCs induce a significantly higher expression of CD39^(+)CD73^(+)on MSCs.These enzymes hydrolyze ATP to adenosine and activate A_(2A/2B)receptors on immature DCs,further promoting the phenotypic transformation of DCs to tol DCs and regulating naive T cells to Tregs.Therefore,encapsulated MSCs obviously alleviate the inflammatory response and prevent CIA progression.This finding clarifies the mechanism of MSCs-DCs crosstalk in eliciting the immunosuppression effect and provides insights into hydrogel-promoted stem cell therapy for autoimmune diseases. 展开更多
关键词 Mesenchymal stem cells alginate hydrogel Tolerogenic dendritic cells IMMUNOTOLERaNCE adenosine a_(2a/2b)receptor CD39/CD73 Treg Rheumatoid arthritis
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Synthesis and Electronic Structure of A2B Type Halogen Atoms Substituted H3-Triarylcorroles 被引量:1
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作者 李敏智 朱卫华 +3 位作者 MACK John MKHIZE Scebi NYOKONG Tebello 梁旭 《Chinese Journal of Structural Chemistry》 SCIE CAS CSCD 2017年第3期367-380,共14页
Seven electron-deficient A_2 B type H_3-triarylcorroles have been synthesized and characterized. The solvent dependence of the electronic absorption and magnetic circular dichroism(MCD) spectra and a series of TD-DF... Seven electron-deficient A_2 B type H_3-triarylcorroles have been synthesized and characterized. The solvent dependence of the electronic absorption and magnetic circular dichroism(MCD) spectra and a series of TD-DFT calculations have been used to analyze trends in the electronic structures. Significant differences are observed in the optical spectra when solvents of differing polarity are used,which can be assigned to the effect of NH-tautomerism. 展开更多
关键词 a_2b type corrole solvatochromism electronic structure spectroscopy TD-DFT
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Effects of procainamide on adenosine diphosphate-induced platelet aggregation and thromboxane B_2 production in rabbits in vitro
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作者 单春文 林继红 金云海 《Journal of Medical Colleges of PLA(China)》 CAS 1998年第3期202-204,共3页
Turbidimetry and radioimmunoassay were used to study the effects of procainamide (PA ) onadenosine diphosphate (ADP)-induced rabbit platelet aggregation and thromboxane B2 (TXB2) production invitro. PA 8. 5--544. 0 μ... Turbidimetry and radioimmunoassay were used to study the effects of procainamide (PA ) onadenosine diphosphate (ADP)-induced rabbit platelet aggregation and thromboxane B2 (TXB2) production invitro. PA 8. 5--544. 0 μmol L-1 inhibited ADP-induced platelet aggregation and TXB2 production, and theinhibition rates were 26. 7% -- 66. 7 % and 21. 4 % -- 70. 1 %, respectively. There was positive correlation between PA concentration and its efficiency in inhibiting the platelet aggregation and TXB2 production, and alsobetween the inhibition rates of platelet aggregation and that of TXB2 production. The three linear equationsand main parameters were The results indicate that PA could significantly inhibit ADP--induced platelet aggregation and TXB2 production in rabbits. 展开更多
关键词 PROCaINaMIDE adenosine diphosphate (aDP) platelet aggregation thromboxane B_2 (TXB_2 )
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氯-IB-MECA合成的研究进展
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作者 史楚奇 王刚 +2 位作者 傅晶 邓惠文 尹传奇 《武汉工程大学学报》 CAS 2023年第3期237-242,共6页
2-氯-N6-(3-碘苄基)腺苷-5'-N-甲基尿嘧啶(氯-IB-MECA)是由Can-Fite公司开发的具有选择性的A_(3)腺苷受体激动剂,可同时治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎和肝细胞癌,具有广阔的市场前景。根据起始原料的不同对氯-IB-MEC... 2-氯-N6-(3-碘苄基)腺苷-5'-N-甲基尿嘧啶(氯-IB-MECA)是由Can-Fite公司开发的具有选择性的A_(3)腺苷受体激动剂,可同时治疗非酒精性脂肪性肝病、非酒精性脂肪性肝炎和肝细胞癌,具有广阔的市场前景。根据起始原料的不同对氯-IB-MECA合成方法进行了系统讨论。方法1以1-O-甲基-β-D-呋喃核糖苷为起始原料,经选择性羟基保护、氧化反应、酯化反应、酰胺化、酸化及脱保护得到氯-IB-MECA。方法2以2-乙酰氧基-5-((苯甲酰氧基)甲基)四氢呋喃-3,4-二基二苯甲酸酯为原料,经Vorbruggen糖苷化反应、亲核取代反应、保护基交换、氧化反应、羧酸酰胺化得到氯-IB-MECA。方法3以四乙酰核糖为原料,经亲核取代反应、脱乙酰基、邻二羟基保护、伯醇氧化、羧酸酰胺化和水解反应得到氯-IB-MECA。方法4以β-D-呋喃呋喃糖醛酸甲酯三乙酸酯为原料,经亲核取代、酯基酰胺化和脱乙酰基后得到氯-IB-MECA。经过比较认为,方法4原料易得,合成步骤少,反应和分离条件温和,收率高,更适合氯-IB-MECA的工业化生产。 展开更多
关键词 2-氯-N6-(3-碘苄基)腺苷-5'-N-甲基尿嘧啶 a_(3)腺苷受体激动剂 酰胺化 亲核取代 Vorbruggen糖苷化反应
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Role of adenosine in tumor progression: focus on A_(2B) receptor as potential therapeutic target
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作者 Claudia Sorrentino Silvana Morello 《Journal of Cancer Metastasis and Treatment》 CAS 2017年第1期127-138,共12页
Adenosine receptors are a family of G-coupled receptors which mediate the anti-inflammatory and immune-suppressive effects of adenosine in a damaged tissue.A large number of evidence indicate that the accumulation of ... Adenosine receptors are a family of G-coupled receptors which mediate the anti-inflammatory and immune-suppressive effects of adenosine in a damaged tissue.A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression,helping cancer cells to evade immune responses.Tumor cells and/or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A2A receptor,which in turn strongly suppresses an effective T-cell-mediated response,while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells.CD73 inhibitors and A2A antagonists,either as single agents,or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies,are currently in Phase I clinical trial in cancer patients.Recent studies show that A2B receptor plays an important role in mediating the pro-tumor effects of adenosine,since its selective blockade can inhibit tumor growth in some murine tumor models.Targeting A2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment,limiting tumor angiogenesis and metastatic processes.Here,the authors review the current data on involvement of A2B receptor in regulating tumor progression and discuss the development of A2B receptor inhibitors as potential therapeutic agents in cancer treatment. 展开更多
关键词 CD73/a_(2)adenosine receptors axis a_(2b)adenosine receptor tumor immunity tumor metastasis tumor angiogenesis cancer treatment
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银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶和细胞内钙水平的影响 被引量:29
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作者 周龙恩 王文杰 +1 位作者 白金叶 程桂芳 《药学学报》 CAS CSCD 北大核心 2001年第2期92-95,共4页
目的 观察银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶及细胞内钙水平的影响。方法 反相高效液相色谱及Fura 2 /AM荧光指示剂法。结果 银杏内酯B在 0 1- 10 μmol·L-1范围内 ,使花生四烯酸释放量降低10 9% - 2 2 2 % ;0 1- ... 目的 观察银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶及细胞内钙水平的影响。方法 反相高效液相色谱及Fura 2 /AM荧光指示剂法。结果 银杏内酯B在 0 1- 10 μmol·L-1范围内 ,使花生四烯酸释放量降低10 9% - 2 2 2 % ;0 1- 5 0 μmol·L-1时 ,LTB4 和 5 HETE生成量分别降低 2 9 4% - 88 6 %和 2 6 2 % - 89 3 % ;在0 1- 10 0 μmol·L-1使PAF和fMLP刺激引起的细胞内游离钙浓度分别降低 13 9% - 5 1 4%和 2 2 % - 36 6 %。 展开更多
关键词 银杏内酯B 血小板活化因子 磷脂酶a_(2) 5-脂氧酶 细胞内游离钙
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PARP调节癫痫大鼠海马核转录因子κB及相关炎症因子的表达 被引量:10
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作者 王胜军 迟兆富 +2 位作者 王树华 迟令懿 赵秀鹤 《中国病理生理杂志》 CAS CSCD 北大核心 2010年第1期86-90,共5页
目的:探讨癫痫大鼠海马组织核转录因子κB(NF-κB)随时间的变化规律及聚腺苷二磷酸核糖聚合酶(PARP)抑制剂3-氨基苯甲酰胺(3-AB)对NF-κB及白细胞介素1β(IL-1β)、环氧化酶-2(COX-2)的调节作用。方法:应用Western blotting检测海藻氨... 目的:探讨癫痫大鼠海马组织核转录因子κB(NF-κB)随时间的变化规律及聚腺苷二磷酸核糖聚合酶(PARP)抑制剂3-氨基苯甲酰胺(3-AB)对NF-κB及白细胞介素1β(IL-1β)、环氧化酶-2(COX-2)的调节作用。方法:应用Western blotting检测海藻氨酸致痫大鼠海马核蛋白中NF-κBp65在不同时点及3-AB干预癫痫大鼠后的表达;应用RT-PCR及Western blotting检测IL-1β、COX-2 mRNA和蛋白水平在3-AB干预前后的变化。结果:大鼠海马核蛋白内NF-κBp65在癫痫后2h开始增高(P<0.05),持续12h(P<0.05),24h后恢复至对照组水平;应用3-AB后,NF-κBp65在核蛋白中含量明显下降(P<0.05);癫痫发作6h海马组织内IL-1β、COX-2 mRNA和蛋白水平表达增高(P<0.05),3-AB干预显著降低IL-1β、COX-2 mRNA及蛋白的表达(P<0.05)。结论:癫痫发作可诱发海马组织NF-κB的核转位及IL-1β、COX-2的表达,3-AB能明显抑制癫痫诱发的NF-κB核转位及IL-1β、COX-2的表达。 展开更多
关键词 癫痫 聚腺苷二磷酸核糖聚合酶 NF-κB 白细胞介素1 环氧化酶-2
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川芎嗪通过AMPK-NFκB信号通路抑制BV-2小胶质细胞促炎性细胞因子基因表达 被引量:7
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作者 刘长安 朱洁 +2 位作者 蔡标 汪天明 黄金玲 《安徽中医药大学学报》 CAS 2014年第3期76-80,共5页
目的观察川芎嗪(tetramethylpyrazine,TMP)对Aβ25-35诱导的BV-2小鼠小胶质细胞促炎性细胞因子基因表达及对一磷酸腺苷激活的蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)-核因子κB(nuclear factor kappa B,NFκB... 目的观察川芎嗪(tetramethylpyrazine,TMP)对Aβ25-35诱导的BV-2小鼠小胶质细胞促炎性细胞因子基因表达及对一磷酸腺苷激活的蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)-核因子κB(nuclear factor kappa B,NFκB)信号通路的影响。方法采用Aβ25-35激活BV-2细胞的炎性反应,测定TMP高、中、低剂量(终浓度分别为100、30、10μmol/L)对Aβ25-35诱导的BV-2细胞白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factorα,TNF-α)及诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)mRNA表达水平的影响。在AMPK激活剂(AICAR)及抑制剂(化合物C)存在下,检测TMP对AMPK及p65(NFκB亚基)磷酸化的影响。结果 TMP高、中剂量可明显抑制BV-2细胞中IL-1β、IL-6、TNF-α和iNOS基因mRNA表达水平(P<0.01),高剂量TMP可激活BV-2细胞中AMPK(P<0.01),并抑制p65磷酸化(P<0.01)。结论 TMP通过激活BV-2细胞中AMPK活性,抑制NFκB活化,进而抑制促炎性细胞因子基因的表达。 展开更多
关键词 川芎嗪 BV-2细胞 淀粉样蛋白β 促炎性细胞因子 基因表达 aMPK 核因子κB
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Unlocking antitumor immunity with adenosine receptorblockers 被引量:1
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作者 Victoria A.Remley Joel Linden +1 位作者 Todd W.Bauer Julien Dimastromatteo 《Cancer Drug Resistance》 CAS 2023年第4期748-767,共20页
Tumors survive by creating a tumor microenvironment(TME)that suppresses antitumor immunity.The TME suppresses the immune system by limiting antigen presentation,inhibiting lymphocyte and natural killer(NK)cell activat... Tumors survive by creating a tumor microenvironment(TME)that suppresses antitumor immunity.The TME suppresses the immune system by limiting antigen presentation,inhibiting lymphocyte and natural killer(NK)cell activation,and facilitating T cell exhaustion.Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies,and their blockade extends the survival of some but not all cancer patients.Extracellular adenosine triphosphate(ATP)is abundant in inflamed tumors,and its metabolite,adenosine(ADO),is a driver of immunosuppression mediated by adenosine A2A receptors(A2AR)and adenosine A2B receptors(A2BR)found on tumor-associated lymphoid and myeloid cells.This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity. 展开更多
关键词 IMMUNOTHERaPY adenosine adenosine receptors adenosine a2a receptors(a2aR) adenosine a2b receptors(a2bR) tumor cells immune cells tumor microenvironment
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乙型肝炎病毒X蛋白促进磷脂酶A_(2)受体表达加重足细胞焦亡的机制
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作者 冯墨宣 安茜 +4 位作者 余亚妮 陈月琪 杨小倩 李保爽 蒋伟 《中华医学杂志》 CAS CSCD 北大核心 2023年第22期1714-1723,共10页
目的探讨乙型肝炎病毒X蛋白(HBx)诱导足细胞膜上M型磷脂酶A_(2)受体(PLA_(2)R)表达增加对乙型肝炎病毒相关性肾炎(HBV-GN)中足细胞焦亡的影响及其作用机制。方法采用转染HBx基因至人肾脏足细胞内的方法模拟HBV-GN发病过程,并将足细胞分... 目的探讨乙型肝炎病毒X蛋白(HBx)诱导足细胞膜上M型磷脂酶A_(2)受体(PLA_(2)R)表达增加对乙型肝炎病毒相关性肾炎(HBV-GN)中足细胞焦亡的影响及其作用机制。方法采用转染HBx基因至人肾脏足细胞内的方法模拟HBV-GN发病过程,并将足细胞分为以下8组:正常对照+分泌型磷脂酶A_(2)-ⅠB(sPLA_(2)-ⅠB)组、空白质粒+sPLA_(2)-ⅠB组、HBx组、HBx+sPLA_(2)-ⅠB组、HBx+sPLA_(2)-ⅠB+PLA_(2)R对照siRNA组、HBx+sPLA_(2)-ⅠB+PLA_(2)R-siRNA组、HBx+sPLA_(2)-ⅠB+ROS对照siRNA组及HBx+sPLA_(2)-ⅠB+ROS-siRNA组。电镜下观察足细胞形态,荧光显微镜下利用免疫荧光染色观察足细胞膜上PLA_(2)R的表达,流式细胞术分析足细胞焦亡率及活性氧(ROS)表达,实时荧光定量PCR及Western印迹测定PLA_(2)R、核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)、凋亡相关斑点样蛋白(ASC)、胱天蛋白酶1(caspase-1)、白细胞介素(IL)-1β及IL-18 mRNA及蛋白的表达情况。结果与正常对照组相比,体外转染HBx质粒后足细胞膜上M型PLA_(2)R表达增加(4.07±0.41比1.01±0.17,P<0.001),电镜及胱天蛋白酶荧光染料抑制物/碘化丙啶(FLICA/PI)双染细胞焦亡检测提示过表达的PLA_(2)R与其配体sPLA_(2)-ⅠB结合后足细胞损伤加重,焦亡程度增加(20.22%±0.36%比7.86%±0.28%,P<0.001),且PLA_(2)R过表达时ROS(4324515±222764比12920±46,P<0.001)、NLRP3(48.30±2.73比1.00±0.11,P<0.001)、ASC(4.02±0.84比1.01±0.15,P<0.001)、caspase-1(3.99±0.42比1.00±0.11,P<0.001)、IL-1β(9.08±0.75比1.00±0.09,P<0.001)及IL-18(19.20±0.70比1.00±0.02,P<0.001)表达水平增加。相反,加入PLA_(2)R-siRNA或ROS-siRNA敲低相关物质表达后,足细胞损伤减轻,焦亡程度下降,下游信号通路相关基因NLRP3、ASC、caspase-1、IL-1β及IL-18基因表达均减少(均P<0.01)。结论HBx可能通过上调PLA_(2)R靶向ROS-NLRP3信号通路促进HBV-GN中足细胞焦亡。 展开更多
关键词 肾炎 肝炎病毒 乙型 乙型肝炎病毒相关性肾炎 磷脂酶a_(2)受体 焦亡
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上调A1腺苷受体减轻继发性脑损伤
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作者 陈东栋 黄擎擎 +3 位作者 陆华 蒋云召 葛风 王泳 《重庆医科大学学报》 CAS CSCD 北大核心 2021年第5期564-568,共5页
目的:探讨A1腺苷受体(A1 adenosine receptor,A1AR)在脑出血(intracranial hemorrhage,ICH)诱导的继发性脑损伤(secondary brain injury,SBI)中的作用。方法:将30只成年雄性SD大鼠随机分为假手术组、脑出血组、激动剂组[A1腺苷受体激动... 目的:探讨A1腺苷受体(A1 adenosine receptor,A1AR)在脑出血(intracranial hemorrhage,ICH)诱导的继发性脑损伤(secondary brain injury,SBI)中的作用。方法:将30只成年雄性SD大鼠随机分为假手术组、脑出血组、激动剂组[A1腺苷受体激动剂N(6)-环己基黄素,R-PIA]和拮抗剂组(A1腺苷受体拮抗剂8-苯基-1,3-二丙基黄嘌呤,8-PT),最终每组6只。以胶原酶注射法建立ICH模型。造模前30 min给予激动剂和拮抗剂,48 h后进行检查。分别予免疫蛋白印迹检测A1AR、活性Caspase-3、白蛋白、B淋巴细胞瘤-2基因(B cell lymphoma 2,Bcl-2)、Bax的表达;脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TdT-mediated dUTP nick-end labeling,TUNEL)观察神经元凋亡;湿/干比法评估脑水肿程度。结果:激动剂组A1AR的表达明显上调(P=0.000),拮抗剂组A1AR的表达下调。激动剂组细胞凋亡减少(P=0.003),活性Caspase-3、白蛋白的水平下调(t=4.649,P=0.043;t=24.89,P=0.001)。拮抗剂组细胞凋亡增多,活性Caspase-3、白蛋白水平上调(t=12.49,P=0.006;t=8.501,P=0.013)。激动剂组Bcl-2表达增加(t=14.13,P=0.005)、Bax表达下调,脑水肿程度减轻(P=0.007)。结论:激活A1AR可增加Bcl-2表达,减轻脑水肿,减少神经细胞凋亡,抑制继发性脑损伤。 展开更多
关键词 脑出血 继发性脑损伤 a1腺苷受体 B淋巴细胞瘤-2基因
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Clean-DM1, a Korean Polyherbal Formula, Improves High Fat Diet-Induced Diabetic Symptoms in Mice by Regulating IRS/PI3K/AKT and AMPK Expressionsin Pancreas and Liver Tissues
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作者 Piao Wang Yi Liu +7 位作者 Seok Yong Kang Chenzi Lyu Xiang Han Tianjun Ho Kyung Jae Lee Xianglong Meng Yong-Ki Park Hyo Won Jung 《Chinese Journal of Integrative Medicine》 SCIE CAS CSCD 2024年第2期125-134,共10页
Objective:To investigate the effects of Clean-DM1(C-DM1),a polyherbal formulation of Radix Scrophulariae,Radix Astragali,Rhizoma Atractylodis,and Radix Salviae Miltiorrhizae,on high-fat diet(HFD)-induced diabetes mice... Objective:To investigate the effects of Clean-DM1(C-DM1),a polyherbal formulation of Radix Scrophulariae,Radix Astragali,Rhizoma Atractylodis,and Radix Salviae Miltiorrhizae,on high-fat diet(HFD)-induced diabetes mice.Methods:The information about active components of C-DM1 extract and molecular mechanism was obtained from network pharmacology analysis.Main compounds of C-DM1 extract by high performance liquid chromatography-mass spectrometry(HPLC-MS)analysis were conducted for quality control.For in vivo study,mice were induced diabetes by HFD for 12 weeks.The mice in the normal group(Nor)were maintained with a regular diet and treated with saline by gavage.The HFD model mice were randomly divided into 3 groups,including a HFD diabetic model group,a C-DM1 extract-administered group(C-DM1,500 mg/kg),and metformin-administered groups(Met,500 mg/kg),8 mice in each group.Food intake,body weight(BW),and fasting blood glucose(FBG)levels were recorded weekly for 4 weeks.After 4 weeks of treatment,alanine aminotransferase(ALT),aspartate aminotransferase(AST),blood glucose,low-density lipoprotein cholesterol(LDL-C)were determined using an automated clinical chemistry analyzer,and homeostatic model for assessing insulin resistance(HOMA-IR)levels and oral glucose tolerance test(OGTT)were detected.The histopathological changes of liver and pancreatic tissues were observed by hematoxylin-eosin staining.Insulin receptor substrate(IRS)/phosphatidylinositol 3 kinase(PI3K)/protein kinase B(AKT)and adenosine 5'-monophosphate-activated protein kinase(AMPK)expressions in liver and pancreas tissues were detected by Western blot analysis.Results:HPLC-MS identified dihydroisotanshinone,dihydroisotanshinone I,cryptotanshinone,harpagoside,and atractyloside A in C-DM1 extract.The administration of C-DM1 extract significantly decreased body weight,calorie intake,and the levels of blood glucose and insulin in the diabetic mice(P<0.05 or P<0.01).The C-DM1 extract administration improved the impaired glucose tolerance and insulin resistance in the diabetic mice and significantly decreased the levels of LDL-C,ALT and AST(P<0.01).The C-DM1 extract inhibited the histopathological changes of fatty liver and hyperplasia of pancreatic islets in the diabetic mice.The C-DM1 extract significantly increased the phosphorylation of IRS,AKT,and AMPK and the expression of PI3K in pancreas and liver tissues(P<0.05 or P<0.01),which was consistent with the analysis results of network pharmacology.Conclusion:C-DM1 extract improved diabetes symptoms in longterm HFD-induced mice by regulation of IRS/PI3K/AKT and AMPK expressions in pancreas and liver tissues,suggesting that C-DM1 formulation may help prevent the progression of T2DM. 展开更多
关键词 high-fat diet type 2 diabetes mellitus herbal formulation insulin receptor substrate/phosphatidylinositol 3 kinase/protein kinase B adenosine 5'-monophosphate-activated protein kinase network pharmacology high performance liquid chromatography-mass spectrometry analysis
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甘遂的化学成分及其活性研究 被引量:3
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作者 邵霞 林家红 张丽 《中草药》 CAS CSCD 北大核心 2014年第23期3383-3386,共4页
目的对甘遂Euphorbia kansui毒性部位的化学成分进行提取分离和鉴定;并对化合物进行细胞毒活性筛选。方法通过硅胶柱色谱、制备型高效液相色谱等方法进行分离纯化,根据波谱数据分析(MS、1H-NMR、13C-NMR)鉴定化合物结构;通过MTT法对... 目的对甘遂Euphorbia kansui毒性部位的化学成分进行提取分离和鉴定;并对化合物进行细胞毒活性筛选。方法通过硅胶柱色谱、制备型高效液相色谱等方法进行分离纯化,根据波谱数据分析(MS、1H-NMR、13C-NMR)鉴定化合物结构;通过MTT法对单体化合物进行细胞毒活性测试。结果从甘遂乙醇提取物的醋酸乙酯部位分离得到9个化合物,分别鉴定为甘遂萜脂B(1)、3-O-(2,3-二甲基丁酰基)-13-O-十二烷酰基-巨大戟二萜醇(2)、5-O-苯甲酰-20-去氧巨大戟二萜醇(3)、大戟醇(4)、异东莨菪素(5)、腺苷(6)、羟基酪醇(7)、2′,4′,7-三羟基异黄酮(8)、大黄素(9)。其中化合物1为假白榄烷型二萜类化合物,2、3为巨大戟烷型二萜类化合物,4为三萜类化合物。结论化合物6~8为首次从该植物中分离得到的化合物,3和9对肠上皮细胞ICE-6具有较好的抑制作用。 展开更多
关键词 甘遂 甘遂萜脂B 5-O-苯甲酰-20-去氧巨大戟二萜醇 大戟醇 腺苷 2′ 4′ 7-三羟基异黄酮
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丹酚酸B对慢性酒精性肝损伤大鼠肝脏的保护作用 被引量:3
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作者 邱璐璐 蔡钊萌 张宁 《中国临床药理学杂志》 CAS CSCD 北大核心 2020年第16期2419-2421,共3页
目的探讨丹酚酸B通过调控丝氨酸/苏氨酸蛋白激酶组成的异源三聚体依赖的蛋白激酶α1(AMPKα1)激活沉默信息调节因子2相关酶I(SIRT1)减轻酒精性肝损伤(ALD)的作用机制。方法用酒精液体饲料喂养建立ALD大鼠模型;另选大鼠普通饲料喂养作为... 目的探讨丹酚酸B通过调控丝氨酸/苏氨酸蛋白激酶组成的异源三聚体依赖的蛋白激酶α1(AMPKα1)激活沉默信息调节因子2相关酶I(SIRT1)减轻酒精性肝损伤(ALD)的作用机制。方法用酒精液体饲料喂养建立ALD大鼠模型;另选大鼠普通饲料喂养作为空白组和对照组,将造模成功大鼠随机分为3组:模型组、低、高剂量实验组;每组均为8只。对照组、低、高剂量实验组灌胃给予丹酚酸B溶液30,15,30 mg·kg-1;空白组和模型组灌胃给予等量的0.9%NaCl,连续给药8周。用试剂盒检测丙氨酸氨基转移酶(ALT)水平。用蛋白免疫印迹法(Western Blot)检测大鼠肝脏组织SIRT1、AMPKα1及p-AMPKα1的蛋白表达情况。结果空白组、对照组、模型组、低、高剂量实验组的血清ALT水平分别为(24.37±2.08),(23.09±1.02),(59.97±3.68),(43.39±2.91)和(39.08±2.17)U·L-1;SIRT1蛋白表达相对水平分别为0.60±0.02,0.75±0.03,0.13±0.02,0.20±0.01,0.27±0.01;p-AMPKα1蛋白表达相对水平分别为1.01±0.01,1.52±0.10,0.45±0.02,0.62±0.04,0.71±0.05。模型组与空白组比较,低、高剂量组与模型组比较,上述指标的差异均有统计学意义(均P<0.01)。结论丹酚酸B通过调控AMPKα1磷酸化水平激活SIRT1蛋白表达,进而发挥其抗慢性酒精性肝病的保护作用。 展开更多
关键词 酒精性肝损伤 丹酚酸B 沉默信息调节因子2相关酶Ⅰ 丝氨酸/苏氨酸蛋白激酶组成的异源三聚体依赖的蛋白激酶α1
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丹酚酸B对乙醇诱导的HepG2细胞损伤的保护作用 被引量:2
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作者 邱璐璐 初君怡 张宁 《中国临床药理学杂志》 CAS CSCD 北大核心 2020年第22期3643-3646,共4页
目的通过HepG2细胞体外实验探讨丹酚酸B通过调控AMPKα1/SIRT1通路减轻乙醇损伤的分子机制。方法实验1:HepG2细胞分为空白组、模型组、模型给药组、模型转染组、模型转染给药组。模型转染组和模型转染给药组转染AMPKα1 siRNA,模型给药... 目的通过HepG2细胞体外实验探讨丹酚酸B通过调控AMPKα1/SIRT1通路减轻乙醇损伤的分子机制。方法实验1:HepG2细胞分为空白组、模型组、模型给药组、模型转染组、模型转染给药组。模型转染组和模型转染给药组转染AMPKα1 siRNA,模型给药组和转染后的模型转染给药组加入8μmol·L^-1丹酚酸B,其他组加入等体积0.9%NaCl,3 h后,除空白组,其余4组加入100 mmol·L^-1乙醇诱导48 h造模。实验2:HepG2细胞分为空白组、空白给药组、模型组、模型给药组。给药组加入8μmol·L^-1丹酚酸B,空白组和模型组加入等体积0.9%NaCl,3 h后模型组和模型给药组加入100 mmol·L^-1乙醇后孵育48h造模。实验3:HepG2细胞分为空白组、空白给药组、转染组和转染给药组。转染组和转染给药组转染AMPKα1 siRNA,空白给药组和转染给药组加入8μmol·L^-1丹酚酸B,空白组和转染组加等体积0.9%NaCl。以MTT实验测定细胞存活率,以蛋白质印迹法检测AMPKα1、p-AMPKα1、SIRT1蛋白表达水平。结果实验1:空白组、模型组、模型给药组、模型转染组、模型转染给药组的细胞存活率分别为(100.00±1.58)%,(62.21±2.25)%,(81.65±4.16)%,(58.34±3.11)%,(61.64±3.24)%。模型组和空白组相比,模型给药组和模型组相比,模型转染组和模型组相比,差异均有统计学意义(均P<0.01)。实验2:空白组、空白给药组、模型组、模型给药组细胞中p-AMPKα1/AMPKα1的蛋白表达相对量分别为1.00±0.02,1.35±0.13,0.26±0.08,0.71±0.01,空白给药组与空白组相比,模型组与空白组相比,模型给药组与模型组相比,差异均有统计学意义(P<0.01)。实验3:空白组、空白给药组、转染组、转染给药组细胞中p-AMPKα1/AMPKα1的蛋白表达相对量分别为1.00±0.01,2.31±0.15,0.56±0.05,0.60±0.04,SIRT1的蛋白表达相对量分别为1.00±0.02,2.14±0.20,0.43±0.06,0.46±0.04。空白给药组和空白组相比,转染组和空白组相比,差异均有统计学意义(均P<0.01)。结论丹酚酸B通过调控AMPKα1/SIRT1通路发挥抗慢性酒精性肝病的保护作用。 展开更多
关键词 HEPG2细胞 丹酚酸B 沉默信息调节因子2相关酶Ⅰ 丝氨酸/苏氨酸蛋白激酶组成的异源三聚体依赖的蛋白激酶α1
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