The human immunodeficiency virus type 1 （HIV-1） can interact with and exploit the host cellular machinery to replicate and propagate itself. Numerous studies have shown that the Mitogen-activated protein kinase （M...The human immunodeficiency virus type 1 （HIV-1） can interact with and exploit the host cellular machinery to replicate and propagate itself. Numerous studies have shown that the Mitogen-activated protein kinase （MAPK） signal pathway can positively regulate the replication of HIV-1, but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood. In this study, we used the Extracellular signal-regulated kinase （ERK） pathway inhibitor, PD98059, the Jun N-terminal kinase （JNK） pathway inhibitor, SP600125, and the p38 pathway inhibitor, SB203580, to investigate the roles of these pathways in HIV-1 replication. We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity. In addition, SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-INL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity. We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059 when cells were treated with all three MAPK pathway inhibitors in combination. Finally, we show that HIV-1 virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.展开更多
Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CS...Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions;by which mechanisms it promotes neurite outgrowth;and how it protects the brain from Alzheimer disease (AD).展开更多
细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标...细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用,尤其是1-(4-氟苄基)-3-(5-(4-吗啉代苯基)吡啶-2-基)脲(18f)的IC50分别达到0.36和0.55µmol/L,对正常细胞L02毒性较低(>10µmol/L).同时,18f能抑制ERK的激酶活力(IC50=0.051µmol/L)和磷酸化水平,但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶(MEK)的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.展开更多
基金supported by the Key Projects in the National Science and Technology Pillar Program during the Eleventh Five-Year Plan Period of China (2008ZX10001-002)Major Science and Technology Innovation Cross Project of the Chinese Academy of Sciences (KSCX1-YW-10)
文摘The human immunodeficiency virus type 1 （HIV-1） can interact with and exploit the host cellular machinery to replicate and propagate itself. Numerous studies have shown that the Mitogen-activated protein kinase （MAPK） signal pathway can positively regulate the replication of HIV-1, but exactly how each MAPK pathway affects HIV-1 infection and replication is not understood. In this study, we used the Extracellular signal-regulated kinase （ERK） pathway inhibitor, PD98059, the Jun N-terminal kinase （JNK） pathway inhibitor, SP600125, and the p38 pathway inhibitor, SB203580, to investigate the roles of these pathways in HIV-1 replication. We found that application of PD98059 results in a strong VSV-G pseudotyped HIV-1NL4-3 luciferase reporter virus and HIV-1NL4-3 virus inhibition activity. In addition, SB203580 and SP600125 also elicited marked VSV-G pseudotyped HIV-INL4-3 luciferase reporter virus inhibition activity but no HIV-1NL4-3 virus inhibition activity. We also found that SB203580 and SP600125 can enhance the HIV-1 inhibition activity of PD98059 when cells were treated with all three MAPK pathway inhibitors in combination. Finally, we show that HIV-1 virus inhibition activity of the MAPK pathway inhibitors was the result of the negative regulation of HIV-1 LTR promoter activity.
文摘Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions;by which mechanisms it promotes neurite outgrowth;and how it protects the brain from Alzheimer disease (AD).
文摘细胞外信号相关激酶(ERK)是恶性肿瘤发生发展中的关键激酶,为了寻找新型结构的ERK抑制剂,采用拼合原理设计合成了两类共12个含有吗啉环的脲类化合物,其结构经1 H NMR、13C NMR和HRMS确证.ERK激酶活力和细胞增殖测试结果表明,大部分目标化合物对人结直肠癌细胞SW480和HCT-116具有中等强度的抑制作用,尤其是1-(4-氟苄基)-3-(5-(4-吗啉代苯基)吡啶-2-基)脲(18f)的IC50分别达到0.36和0.55µmol/L,对正常细胞L02毒性较低(>10µmol/L).同时,18f能抑制ERK的激酶活力(IC50=0.051µmol/L)和磷酸化水平,但不影响总ERK表达和上游丝裂原活化的细胞外信号调节激酶(MEK)的激活.上述结果为新型苄基吡啶基脲类ERK抑制剂的深入研究提供了重要参考信息.
