Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral inf...Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral infection has been little explored. Here we demonstrated that P2Y13 and its ligand ADP play an important role in protecting hosts from viral infections. First, we demonstrate that P2Y13, as a typical interferon-stimulated gene, is induced together with extracellular ADP during viral infection. Most importantly, extracellular ADP restricts the replication of different kinds of viruses, including vesicular stomatitis virus, Newcastle disease virus, herpes simplex virus 1, and murine leukemia virus. This kind of protection is dependent on P2Y13 but not P2Y1 or P2Y12, which are also considered as receptors for ADP. Furthermore, cyclic adenosine monophosphate and EPAC1 are downregu-lated by extracellular ADP through the P2Y13-coupled Gi alpha subunit. Accordingly, inhibition or deletion of EPAC1 significantly eliminates ADP/P2Y13-mediated antiviral activities. Taken together, our results show that P2Y13 and ADP play pivotal roles in the clearance of invaded virus and have the potential as antiviral targets.展开更多
目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注...目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注射生理盐水)、MRS2211(100 pmol/L)处理组(CCI+鞘内注射MRS2211)。CCI模型组及MRS2211处理组大鼠均于鞘内置管7 d之后行慢性坐骨神经结扎,连续14 d鞘内注射生理盐水、MRS2211(100 pmol/L),2次/d。分别在术前1 d、术后第1,3,5,7,10,14 d测定给药1h后热缩足潜伏期(TWL);分别在第7,14 d处死大鼠,取脊髓背角做Western Blot检测,观察背角P2X4受体和P38MAPK的表达变化。结果:与假手术组相比,CCI组大鼠第1,3,5,7,10,14 d TWL明显缩短(P<0.01);与CCI组相比,MRS2211处理组大鼠术后第1,3,5,7,10,14 d TWL明显延长(P<0.05)。Western Blot结果观察到,与假手术组相比,CCI组第7 d P2X4受体表达上调(P<0.05),在第14 d P2X4受体表达上调更为明显(P<0.05);与假手术组相比,CCI组第7 d P38MAPK表达明显上调(P<0.05),在第14 d P38MAPK表达有所下降,但与假手术组相比仍具有统计学意义(P<0.05);与CCI组相比,MRS2211处理组大鼠第7 d后背角P38MAPK表达上调明显减弱(P<0.05),但在第14 d P38MAPK表达有所上升,但与CCI组相比仍具有统计学意义(P<0.05);此外,鞘内注射MRS2211并不影响CCI大鼠背角P2X4受体表达变化。结论:鞘内注射P2Y13受体拮抗剂MRS2211可以明显抑制CCI大鼠热痛敏症状和脊髓背角P38MAPK表达的上调,但并不影响CCI大鼠P2X4受体表达变化。这提示MRS2211可以抑制小胶质细胞P38MAPK活化但不影响小胶质细胞P2X4受体表达,这可能是其在脊髓水平发挥镇痛作用的机制之一。展开更多
Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surfa...Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.展开更多
基金the National Key R&D Program of China (2018YFA0507000 to B.D.)the National Natural Science Foundation of China (31570896 and 31770969 to B.D., 81672811 to M.Q.)+2 种基金Joint Research Institute for Science and Society (JoRISS)(14JORISS01 to B.D.)Science and Technology Commission of Shanghai Municipality (15JC14O15OO to B.D.)Innovation Program of Shanghai Municipal Educati on Commissi on (2017-01- 07-00-05-E00011 to A/LL.).
文摘Among the most important sensors of extracellular danger signals, purinergic receptors have been demonstrated to play crucial roles in host defense against infection. However, the function of P2 receptors in viral infection has been little explored. Here we demonstrated that P2Y13 and its ligand ADP play an important role in protecting hosts from viral infections. First, we demonstrate that P2Y13, as a typical interferon-stimulated gene, is induced together with extracellular ADP during viral infection. Most importantly, extracellular ADP restricts the replication of different kinds of viruses, including vesicular stomatitis virus, Newcastle disease virus, herpes simplex virus 1, and murine leukemia virus. This kind of protection is dependent on P2Y13 but not P2Y1 or P2Y12, which are also considered as receptors for ADP. Furthermore, cyclic adenosine monophosphate and EPAC1 are downregu-lated by extracellular ADP through the P2Y13-coupled Gi alpha subunit. Accordingly, inhibition or deletion of EPAC1 significantly eliminates ADP/P2Y13-mediated antiviral activities. Taken together, our results show that P2Y13 and ADP play pivotal roles in the clearance of invaded virus and have the potential as antiviral targets.
文摘目的:观察鞘内注射P2Y13受体阻断剂MRS2211对慢性坐骨神经结扎(CCI)大鼠热痛阈及脊髓背角P2X4受体、P38MAPK表达变化的影响,探讨脊髓P2Y13受体在神经病理性疼痛中的作用。方法:成年SD大鼠随机分为3组(n=8):假手术组、CCI模型组(鞘内注射生理盐水)、MRS2211(100 pmol/L)处理组(CCI+鞘内注射MRS2211)。CCI模型组及MRS2211处理组大鼠均于鞘内置管7 d之后行慢性坐骨神经结扎,连续14 d鞘内注射生理盐水、MRS2211(100 pmol/L),2次/d。分别在术前1 d、术后第1,3,5,7,10,14 d测定给药1h后热缩足潜伏期(TWL);分别在第7,14 d处死大鼠,取脊髓背角做Western Blot检测,观察背角P2X4受体和P38MAPK的表达变化。结果:与假手术组相比,CCI组大鼠第1,3,5,7,10,14 d TWL明显缩短(P<0.01);与CCI组相比,MRS2211处理组大鼠术后第1,3,5,7,10,14 d TWL明显延长(P<0.05)。Western Blot结果观察到,与假手术组相比,CCI组第7 d P2X4受体表达上调(P<0.05),在第14 d P2X4受体表达上调更为明显(P<0.05);与假手术组相比,CCI组第7 d P38MAPK表达明显上调(P<0.05),在第14 d P38MAPK表达有所下降,但与假手术组相比仍具有统计学意义(P<0.05);与CCI组相比,MRS2211处理组大鼠第7 d后背角P38MAPK表达上调明显减弱(P<0.05),但在第14 d P38MAPK表达有所上升,但与CCI组相比仍具有统计学意义(P<0.05);此外,鞘内注射MRS2211并不影响CCI大鼠背角P2X4受体表达变化。结论:鞘内注射P2Y13受体拮抗剂MRS2211可以明显抑制CCI大鼠热痛敏症状和脊髓背角P38MAPK表达的上调,但并不影响CCI大鼠P2X4受体表达变化。这提示MRS2211可以抑制小胶质细胞P38MAPK活化但不影响小胶质细胞P2X4受体表达,这可能是其在脊髓水平发挥镇痛作用的机制之一。
基金Supported by An INSERM Avenir Grant (Martinez LO)ANR (Martinez LO and Lichtenstein L, #GENO 102 01)+1 种基金the French Association pour la Recherche sur le Cancer (Vantourout P and Champagne E, #3711-3913-4847)An INSERM young scientist fellowship (Pons V)
文摘Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.
