Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has b...Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.展开更多
Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under isch...Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under ischemic insult and the related signaling pathways. Methods Using transient right middle cerebral artery occlusion （tMCAO） and oxygen-glucose-serum deprivation for 2 h as the model of ischemic injury in vivo and in vitro, immunofluorescence, quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, enzyme linked immunosorbent assay （ELISA） were used to investigate location of P2Y1 receptor and GDNF, the expression of GFAP and GDNF, and the changes of signaling molecules. Results Blockage of P2Y1 receptor with the selective antagonist N^6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate diammonium （MRS2179） reduced GFAP production and increased GDNF production in the antagonist group as compared with simple ischemic group both in vivo and in vitro. Oxygen-glucose-serum deprivation and blockage of P2Y1 receptor caused elevation of phosphorylated Akt and cAMP response element binding protein （CREB）, and reduction of phosphorylated Janus kinase2 （JAK2） and signal transducer and activator of transcription3 （STAT3, Ser727）. After blockage of P2Y1 receptor and deprivation of oxygen-glucose-serum, AG490 （inhibitor of JAK2） reduced phosphorylation of STAT3 （Ser727） as well as expression of GFAP; LY294002, an inhibitor of phosphatidylinositol 3-kinase （PI3-K）, decreased phosphorylation of Akt and CREB; the inhibitor of mitogen-activated protein kinase kinase 1/2 （MEK 1/2） U0126, an important molecule of Ras/extracellular signal- regulated kinase （ERK） signaling pathway, decreased the phosphorylation of JAK2, STAT3 （Ser727）, Akt and CREB. Conclusion These results suggest that P2Y1 receptor plays a role in the production of GFAP and GDNF in astrocytes under transient ischemic condition and the related signaling pathways may be JAK2/STAT3 and PI3-K/Akt/CREB, respectively, and that crosstalk probably exists between them.展开更多
目的探讨遗传性癫痫大鼠(TRM)海马和颞叶皮质中神经肽Y(NPY)及其Y1受体(Y1R)的表达和分布。方法逆转录聚合酶链反应(RT-PCR)检测NPY和Y1R m RNA表达。ELISA试剂盒法检测TRM和Wistar大鼠海马和颞叶皮质中NPY浓度。Western blot检测Y1R蛋...目的探讨遗传性癫痫大鼠(TRM)海马和颞叶皮质中神经肽Y(NPY)及其Y1受体(Y1R)的表达和分布。方法逆转录聚合酶链反应(RT-PCR)检测NPY和Y1R m RNA表达。ELISA试剂盒法检测TRM和Wistar大鼠海马和颞叶皮质中NPY浓度。Western blot检测Y1R蛋白表达。免疫荧光双标记法分析TRM及Wistar大鼠海马CA1、CA3和DG区以及颞叶皮质中NPY与Y1R的分布和共定位。结果 ELISA和RT-PCR结果均显示,TRM海马和颞叶皮质中NPY表达明显上调,与Wistar大鼠比较差异有统计学意义(P<0.01)。Western blot结果证实,TRM海马中Y1R蛋白表达明显低于Wistar大鼠,而在颞叶皮质中显著高于Wistar大鼠。免疫荧光分析发现NPY与Y1R在TRM海马CA1、CA3区神经元细胞和DG区颗粒细胞以及颞叶皮质神经元细胞中分布广泛,并存在共定位且主要定位在细胞膜上。结论在TRM海马和颞叶皮质中,NPY及其Y1R表达出现异常变化,而这种异常表达可能与TRM癫痫发生机制有关。展开更多
AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of aceti...AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of acetic acid(AA) and assessed by histology and myeloperoxidase(m PO) activity assay. Then P2Y1 R expression in the colonic tissue was detected by Western blot. In order to explore the regulatory role of P2Y1 R in visceral hypersensitivity, an agonist(m RS2365) and an antagonist(m RS2179) of P2Y1 R were intra-colonically administered and effects were tested through a colorectal distension test. The abdominal withdrawal reflex and abdominal electromyography were tested during the course. RESULTS model assessment tests showed an obvious inflammatoryreaction that appeared on the 2^(nd) d after the AA injection, and the inflammatory reaction gradually recovered and almost disappeared on the 7^(th) d. The model finished on day 8 and showed a clear feature of IBS that had no organic lesion. The average expression of P2Y1 R was significantly higher in the AA group than in the na?ve group(0.319 ± 0.02 vs 0.094 ± 0.016, P < 0.001). m RS2365 could effectively raise the colonic hypersensitivity status at intervention doses of 10(AUC value from 0.30 ± 0.089 to 1.973 ± 0.127 mv?s, P < 0.01) and 100 μmol/L(AUC value from 0.290 ± 0.079 to 1.983 ± 0.195 mv?s, P < 0.01); m RS2179 could effectively reduce the hypersensitivity status at intervention dose of 100 μmol/L(from a mean baseline AUC value of 1.587 ± 0.099 mv?s to 0.140 ± 0.089 mv?s, P < 0.0001). Differences between the m RS2179 group(1.88 ± 1.45) and either the m RS2365 group(3.96 ± 0.19) or the combined treatment(m RS2179 and m RS2365) group(3.28 ± 0.11) were significant(P < 0.01).CONCLUSION P2Y1 R plays a regulatory role in visceral hypersensitivity in rats with experimental IBS. Specific antagonists of P2Y1 R may have potential therapeutic value in treating abdominal pain in IBS.展开更多
目的:观察泽泻汤对代谢综合征(MS)大鼠血浆NPY,胰岛NPY及其Y1R表达的影响,探讨其可能的治疗机制。方法:用高糖高脂饲料喂饲建立MS大鼠,将23只MS大鼠分为三组,分别给盐水、泽泻汤、西布曲明。4周后测体重、血糖、TG,用放免法检测血清胰...目的:观察泽泻汤对代谢综合征(MS)大鼠血浆NPY,胰岛NPY及其Y1R表达的影响,探讨其可能的治疗机制。方法:用高糖高脂饲料喂饲建立MS大鼠,将23只MS大鼠分为三组,分别给盐水、泽泻汤、西布曲明。4周后测体重、血糖、TG,用放免法检测血清胰岛素、血浆NPY;免疫组化法检测胰岛NPY及其Y1R表达,用im age-pro p lus 6.0进行平均光密度分析。结果:与盐水组相比,泽泻汤组大鼠体重、血糖、TG、血清胰岛素、血浆NPY水平、胰岛NPY及其Y1R表达的平均光密度均显著降低(P<0.05)。结论:泽泻汤对MS大鼠有良好的治疗作用,其作用机制可能与抑制胰岛NPY及其Y1R表达有关。展开更多
目的:探讨NPY-Y1受体调控Wnt/β-catenin信号通路对骨质疏松症(OP)成骨细胞作用及影响.方法:选择C518、MC3T3-E1成骨细胞株,NPY-Y1基因敲减和过表达.Wnt通路抑制剂DKK1处理.Real time PCR和Western blot、双荧光素酶报告基因实验、Rescu...目的:探讨NPY-Y1受体调控Wnt/β-catenin信号通路对骨质疏松症(OP)成骨细胞作用及影响.方法:选择C518、MC3T3-E1成骨细胞株,NPY-Y1基因敲减和过表达.Wnt通路抑制剂DKK1处理.Real time PCR和Western blot、双荧光素酶报告基因实验、Rescue实验、RNA-seq分析.结果:DKK1处理后sh NPY-Y1组和NPY-Y1^(OE)组Wnt、NPY-Y1、Runx-2和Osterix mRNA及蛋白差异显著,有统计学意义(P<0.05).双荧光素酶报告基因验证NPY-Y1调控Runx-2活性.敲减Runx-2能挽救NPY-Y1对Runx-2表达.RNA-seq为NPY-Y1、Runx-2和Osterix显著差异基因.结论:NPY-Y1受体可为治疗骨质疏松症靶点,DKK1可成为介导Wnt/β-catenin通路治疗骨质疏松症的潜在药物.展开更多
Zeolitic imidazolate frameworks(ZIFs)as smart drug delivery systems with microenvironment-triggered release have attracted much attention for tumor therapy.However,the exploration of ZIFs in biomedicine still encounte...Zeolitic imidazolate frameworks(ZIFs)as smart drug delivery systems with microenvironment-triggered release have attracted much attention for tumor therapy.However,the exploration of ZIFs in biomedicine still encounters many issues,such as inconvenient surface modification,fast drug release during blood circulation,undesired damage to major organs,and severe in vivo toxicity.To address the above issues,we developed an Mn-ZIF-90 nanosystem functionalized with an originally designed active-targeting and pH-responsive magnetic resonance imaging(MRI)Y1 receptor ligand[Asn28,Pro30,Trp32]-NPY(25-36)for imaging-guided tumor therapy.After Y1 receptor ligand modification,the Mn-ZIF-90 nanosystem exhibited high drug loading,better blood circulation stability,and dual breast cancer cell membrane and mitochondria targetability,further favoring specific microenvironment-triggered tumor therapy.Meanwhile,this nanosystem showed promising T1-weighted magnetic resonance imaging contrast in vivo in the tumor sites.Especially,this nanosystem with fast clean-up had almost no obvious toxicity and no damage occurred to the major organs in mice.Therefore,this nanosystem shows potential for use in imaging-guided tumor therapy.展开更多
BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of no...BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators,such as C-reactive protein and the erythrocyte sedimentation rate,but these indicators have an unsatisfactory specificity.In this study,we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus(NCBI-GEO)databases and verified the selected core genes in a mouse model of dextran sulfate sodium(DSS)-induced colitis.AIM To identify UC-related differentially expressed genes(DEGs)using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC.METHODS Two microarray datasets from the NCBI-GEO database were used,and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams.We annotated these genes based on their functions and signaling pathways,and then protein-protein interactions(PPIs)were identified using the Search Tool for the Retrieval of Interacting Genes.The data were further analyzed with Cytoscape software and the Molecular Complex Detection(MCODE)app.The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed.Finally,colitis model mice were established by administering DSS,and the top three core genes were verified in colitis mice using real-time polymerase chain reaction(PCR).RESULTS One hundred and seventy-seven DEGs,118 upregulated and 59 downregulated,were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways.Seven clusters with close interactions in UC formed:Seventeen core genes were upregulated[C-X-C motif chemokine ligand 13(CXCL13),C-X-C motif chemokine receptor 2(CXCR2),CXCL9,CXCL5,C-C motif chemokine ligand 18,interleukin 1 beta,matrix metallopeptidase 9,CXCL3,formyl peptide receptor 1,complement component 3,CXCL8,CXCL1,CXCL10,CXCL2,CXCL6,CXCL11 and hydroxycarboxylic acid receptor 3]and one was downregulated[neuropeptide Y receptor Y1(NYP1R)]in the top cluster according to the PPI and MCODE analyses.These genes were substantially enriched in the cytokinecytokine receptor interaction and chemokine signaling pathways.The top three core genes(CXCL13,NYP1R,and CXCR2)were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice,but only CXCR2 expression was significantly different.CONCLUSION Core DEGs identified in UC are related to inflammation and immunity inflammation,indicating that these reactions are core features of the pathogenesis of UC.CXCR2 may reflect the degree of inflammation in patients with UC.展开更多
文摘Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.
基金the National Natural Science Foundation of China (No. 30500189)
文摘Objective The present study aimed to explore the role of P2Y1 receptor in glial fibrillary acidic protein （GFAP） production and glial cell line-derived neurotrophic factor （GDNF） secretion of astrocytes under ischemic insult and the related signaling pathways. Methods Using transient right middle cerebral artery occlusion （tMCAO） and oxygen-glucose-serum deprivation for 2 h as the model of ischemic injury in vivo and in vitro, immunofluorescence, quantitative real-time reverse transcription-polymerase chain reaction （RT-PCR）, Western blotting, enzyme linked immunosorbent assay （ELISA） were used to investigate location of P2Y1 receptor and GDNF, the expression of GFAP and GDNF, and the changes of signaling molecules. Results Blockage of P2Y1 receptor with the selective antagonist N^6-methyl-2′-deoxyadenosine 3′,5′-bisphosphate diammonium （MRS2179） reduced GFAP production and increased GDNF production in the antagonist group as compared with simple ischemic group both in vivo and in vitro. Oxygen-glucose-serum deprivation and blockage of P2Y1 receptor caused elevation of phosphorylated Akt and cAMP response element binding protein （CREB）, and reduction of phosphorylated Janus kinase2 （JAK2） and signal transducer and activator of transcription3 （STAT3, Ser727）. After blockage of P2Y1 receptor and deprivation of oxygen-glucose-serum, AG490 （inhibitor of JAK2） reduced phosphorylation of STAT3 （Ser727） as well as expression of GFAP; LY294002, an inhibitor of phosphatidylinositol 3-kinase （PI3-K）, decreased phosphorylation of Akt and CREB; the inhibitor of mitogen-activated protein kinase kinase 1/2 （MEK 1/2） U0126, an important molecule of Ras/extracellular signal- regulated kinase （ERK） signaling pathway, decreased the phosphorylation of JAK2, STAT3 （Ser727）, Akt and CREB. Conclusion These results suggest that P2Y1 receptor plays a role in the production of GFAP and GDNF in astrocytes under transient ischemic condition and the related signaling pathways may be JAK2/STAT3 and PI3-K/Akt/CREB, respectively, and that crosstalk probably exists between them.
基金Supported by MIMS(Shanghai)Ltd.of China,No.IDF-2013-07
文摘AIM To evaluate the role of P2Y1 R in visceral hypersensitivity in rats with experimental irritable bowel syndrome.METHODS A rat model of irritable bowel syndrome was generated by intra-colonic administration of acetic acid(AA) and assessed by histology and myeloperoxidase(m PO) activity assay. Then P2Y1 R expression in the colonic tissue was detected by Western blot. In order to explore the regulatory role of P2Y1 R in visceral hypersensitivity, an agonist(m RS2365) and an antagonist(m RS2179) of P2Y1 R were intra-colonically administered and effects were tested through a colorectal distension test. The abdominal withdrawal reflex and abdominal electromyography were tested during the course. RESULTS model assessment tests showed an obvious inflammatoryreaction that appeared on the 2^(nd) d after the AA injection, and the inflammatory reaction gradually recovered and almost disappeared on the 7^(th) d. The model finished on day 8 and showed a clear feature of IBS that had no organic lesion. The average expression of P2Y1 R was significantly higher in the AA group than in the na?ve group(0.319 ± 0.02 vs 0.094 ± 0.016, P < 0.001). m RS2365 could effectively raise the colonic hypersensitivity status at intervention doses of 10(AUC value from 0.30 ± 0.089 to 1.973 ± 0.127 mv?s, P < 0.01) and 100 μmol/L(AUC value from 0.290 ± 0.079 to 1.983 ± 0.195 mv?s, P < 0.01); m RS2179 could effectively reduce the hypersensitivity status at intervention dose of 100 μmol/L(from a mean baseline AUC value of 1.587 ± 0.099 mv?s to 0.140 ± 0.089 mv?s, P < 0.0001). Differences between the m RS2179 group(1.88 ± 1.45) and either the m RS2365 group(3.96 ± 0.19) or the combined treatment(m RS2179 and m RS2365) group(3.28 ± 0.11) were significant(P < 0.01).CONCLUSION P2Y1 R plays a regulatory role in visceral hypersensitivity in rats with experimental IBS. Specific antagonists of P2Y1 R may have potential therapeutic value in treating abdominal pain in IBS.
文摘目的:观察泽泻汤对代谢综合征(MS)大鼠血浆NPY,胰岛NPY及其Y1R表达的影响,探讨其可能的治疗机制。方法:用高糖高脂饲料喂饲建立MS大鼠,将23只MS大鼠分为三组,分别给盐水、泽泻汤、西布曲明。4周后测体重、血糖、TG,用放免法检测血清胰岛素、血浆NPY;免疫组化法检测胰岛NPY及其Y1R表达,用im age-pro p lus 6.0进行平均光密度分析。结果:与盐水组相比,泽泻汤组大鼠体重、血糖、TG、血清胰岛素、血浆NPY水平、胰岛NPY及其Y1R表达的平均光密度均显著降低(P<0.05)。结论:泽泻汤对MS大鼠有良好的治疗作用,其作用机制可能与抑制胰岛NPY及其Y1R表达有关。
基金financially supported by Natural Science Foundation of China(No.81871411)National Key R&D Program of China(2018YFC0910601)+1 种基金Youth Innovation Promotion Association Foundation of CAS(2017340)The Science&Technology Bureau of Ningbo City(2015B11002).
文摘Zeolitic imidazolate frameworks(ZIFs)as smart drug delivery systems with microenvironment-triggered release have attracted much attention for tumor therapy.However,the exploration of ZIFs in biomedicine still encounters many issues,such as inconvenient surface modification,fast drug release during blood circulation,undesired damage to major organs,and severe in vivo toxicity.To address the above issues,we developed an Mn-ZIF-90 nanosystem functionalized with an originally designed active-targeting and pH-responsive magnetic resonance imaging(MRI)Y1 receptor ligand[Asn28,Pro30,Trp32]-NPY(25-36)for imaging-guided tumor therapy.After Y1 receptor ligand modification,the Mn-ZIF-90 nanosystem exhibited high drug loading,better blood circulation stability,and dual breast cancer cell membrane and mitochondria targetability,further favoring specific microenvironment-triggered tumor therapy.Meanwhile,this nanosystem showed promising T1-weighted magnetic resonance imaging contrast in vivo in the tumor sites.Especially,this nanosystem with fast clean-up had almost no obvious toxicity and no damage occurred to the major organs in mice.Therefore,this nanosystem shows potential for use in imaging-guided tumor therapy.
基金Chinese Medicine Inheritance and Innovation“One Hundred Million”Talent Project Qihuang Scholar(to Li JX)The National Key R&D Program of China during the 13th Five-Year Plan Period,No.2018YFC1705405and The 66th China Postdoctoral Science Foundation,No.2019M660575.
文摘BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators,such as C-reactive protein and the erythrocyte sedimentation rate,but these indicators have an unsatisfactory specificity.In this study,we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus(NCBI-GEO)databases and verified the selected core genes in a mouse model of dextran sulfate sodium(DSS)-induced colitis.AIM To identify UC-related differentially expressed genes(DEGs)using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC.METHODS Two microarray datasets from the NCBI-GEO database were used,and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams.We annotated these genes based on their functions and signaling pathways,and then protein-protein interactions(PPIs)were identified using the Search Tool for the Retrieval of Interacting Genes.The data were further analyzed with Cytoscape software and the Molecular Complex Detection(MCODE)app.The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed.Finally,colitis model mice were established by administering DSS,and the top three core genes were verified in colitis mice using real-time polymerase chain reaction(PCR).RESULTS One hundred and seventy-seven DEGs,118 upregulated and 59 downregulated,were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways.Seven clusters with close interactions in UC formed:Seventeen core genes were upregulated[C-X-C motif chemokine ligand 13(CXCL13),C-X-C motif chemokine receptor 2(CXCR2),CXCL9,CXCL5,C-C motif chemokine ligand 18,interleukin 1 beta,matrix metallopeptidase 9,CXCL3,formyl peptide receptor 1,complement component 3,CXCL8,CXCL1,CXCL10,CXCL2,CXCL6,CXCL11 and hydroxycarboxylic acid receptor 3]and one was downregulated[neuropeptide Y receptor Y1(NYP1R)]in the top cluster according to the PPI and MCODE analyses.These genes were substantially enriched in the cytokinecytokine receptor interaction and chemokine signaling pathways.The top three core genes(CXCL13,NYP1R,and CXCR2)were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice,but only CXCR2 expression was significantly different.CONCLUSION Core DEGs identified in UC are related to inflammation and immunity inflammation,indicating that these reactions are core features of the pathogenesis of UC.CXCR2 may reflect the degree of inflammation in patients with UC.
