The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and af...Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.展开更多
Tor网络作为最受欢迎的匿名网络之一,使用TCP协议作为传输层协议,这一选择导致了行首阻塞、带宽分配不公平以及低效的拥塞控制等问题,严重影响了Tor网络的性能和扩展性。目前有研究使用QUIC协议的Tor Over QUIC模式来解决这些问题。然而...Tor网络作为最受欢迎的匿名网络之一,使用TCP协议作为传输层协议,这一选择导致了行首阻塞、带宽分配不公平以及低效的拥塞控制等问题,严重影响了Tor网络的性能和扩展性。目前有研究使用QUIC协议的Tor Over QUIC模式来解决这些问题。然而,Tor Over QUIC模式下性能评估指标单一,仅聚焦在时延和安全性评估,难以全面反映协议升级对匿名网络核心特性的综合影响,导致协议优化方向不明确且部署决策缺乏数据支撑。这种评估维度缺失不仅制约了QUIC协议优势的充分发挥,更可能因性能短板影响用户采用意愿,容易影响Tor Over QUIC的推广与使用。因此,提出了一种基于Tor Over QUIC的多维度性能评估方法,从时延、匿名性、安全性、鲁棒性和可用性等多个维度对Tor Over QUIC模式下的性能进行综合评估,以指导Tor Over QUIC的部署与使用。对Tor网络和Tor Over QUIC网络进行的对比实验表明,所提评估方法是有效且实用的。展开更多
为深入了解雷帕霉素靶蛋白(Target of rapamycin,TOR)信号调控网络以及在植物生长发育和胁迫响应中的生物学功能,以“TOR”“葡萄糖”“生长发育”“SnRK1”“信号网络”为关键词,在Web of Science和National Center for Biotechnology ...为深入了解雷帕霉素靶蛋白(Target of rapamycin,TOR)信号调控网络以及在植物生长发育和胁迫响应中的生物学功能,以“TOR”“葡萄糖”“生长发育”“SnRK1”“信号网络”为关键词,在Web of Science和National Center for Biotechnology Information等数据库检索,共获取78篇相关文献,并归纳总结了植物TOR激酶的基本结构信息、TOR信号网络、Glc-TOR信号通路以及TOR和SnRK1的调控机制,分析了TOR信号通路在调控植物生长发育及应对逆境胁迫等多个方面的功能。结果表明:绝大多数植物中只含有1个TOR激酶,且TOR、RAPTOR亚基以及LST 8亚基组成TORC1发挥作用;TOR激酶包含HEAT、FAT、FRB、Kinase和FATC 5个结构域;TOR激酶通过响应光、氨基酸、激素等信号,调控细胞生长发育过程中的蛋白质合成;TOR激酶在调控植物根的分支、逆境胁迫响应、ABA信号和矿质元素吸收方面发挥作用;TOR与Glc、SnRK1等其他营养信号网络协同作用,实现基因表达、代谢、生长和生存的整合与协调。展开更多
放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白...放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白翻译等均有重要调节作用。mTOR异常表达与肿瘤发生及治疗反应密切相关。肿瘤的放疗敏感性与"4R"效应有关。mTOR抑制剂可通过影响细胞周期进展、DNA损伤修复及抗血管形成等多种途径发挥放疗增敏作用。初期研究证实依维莫司具有放疗增敏作用并且毒性可耐受。应用mTOR抑制剂后不同细胞及个体反应不同,可能与基因表达状态有关,需进一步研究证实。展开更多
Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton h...Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton has further exacerbated its pest status and amplified the need for more sustainable methods of control.RNA interference(RNAi)-based pest management strategies,such as root soaking and transgenic plants that express dsRNAs,have proven to be reliable,eco-friendly pest control strategies.To identify new RNAi targets for potential A.suturalis population control,we investigated the target of rapamycin(TOR)signaling pathway.A critical role for this pathway in A.suturalis reproductive regulation was suggested by pharmacological analyses.Subsequent RNAi-mediated knockdown of the A.suturalis TOR pathway genes TOR,Ras homolog enriched in the brain(Rheb),and ribosomal S6 kinase(S6K)reduced fertility.Moreover,a spray-induced and nanocarrier-delivered gene silencing(SI-NDGS)system targeting TOR successfully suppressed ovarian development,which demonstrates its effectiveness as a pest control target.These results provide a critical foundation for understanding reproductive regulation in A.suturalis and introduce new candidates for RNAi-based A.suturalis management.展开更多
Objective:To explore the protective mechanisms of nerve growth factor (NGF) on spinal cord injury (SCI) and provide theoretical basis for its clinical application. Methods: The SCI of Wistar rats was done by Allens w...Objective:To explore the protective mechanisms of nerve growth factor (NGF) on spinal cord injury (SCI) and provide theoretical basis for its clinical application. Methods: The SCI of Wistar rats was done by Allens weight dropping way by a 10 g×2.5 cm impact on the posterior of spinal cord T 8. NGF (3 g/L, 20 μl) or normal saline was injected through catheter into subarachnoid space 2, 4, 8, 12 and 24 h after SCI. The expression of N-methyl-D-asparate receptor 1 (NMDAR 1) and neuronal constitutive nitric oxide synthase (ncNOS) mRNA in rat spinal cord was detected by in situ hybridization. Results: Abnormal expression of NMDAR 1 and ncNOS mRNA appeared in spinal ventral horn motorneuron in injured rats, as compared with that in control group. The expression of NMDAR 1 and ncNOS mRNA in NGF group was significantly lower than that in saline group (P<0.01). Conclusion: NGF can protect spinal cord against injury in vivo. One of the mechanisms is that NGF can prohibit NMDAR 1 and nitric oxide (NO) production after spinal cord injury.展开更多
AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were inject...AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear transloca-tion of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.展开更多
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
基金supported by American Diabetes Association,American Heart Association,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
文摘Tor网络作为最受欢迎的匿名网络之一,使用TCP协议作为传输层协议,这一选择导致了行首阻塞、带宽分配不公平以及低效的拥塞控制等问题,严重影响了Tor网络的性能和扩展性。目前有研究使用QUIC协议的Tor Over QUIC模式来解决这些问题。然而,Tor Over QUIC模式下性能评估指标单一,仅聚焦在时延和安全性评估,难以全面反映协议升级对匿名网络核心特性的综合影响,导致协议优化方向不明确且部署决策缺乏数据支撑。这种评估维度缺失不仅制约了QUIC协议优势的充分发挥,更可能因性能短板影响用户采用意愿,容易影响Tor Over QUIC的推广与使用。因此,提出了一种基于Tor Over QUIC的多维度性能评估方法,从时延、匿名性、安全性、鲁棒性和可用性等多个维度对Tor Over QUIC模式下的性能进行综合评估,以指导Tor Over QUIC的部署与使用。对Tor网络和Tor Over QUIC网络进行的对比实验表明,所提评估方法是有效且实用的。
文摘为深入了解雷帕霉素靶蛋白(Target of rapamycin,TOR)信号调控网络以及在植物生长发育和胁迫响应中的生物学功能,以“TOR”“葡萄糖”“生长发育”“SnRK1”“信号网络”为关键词,在Web of Science和National Center for Biotechnology Information等数据库检索,共获取78篇相关文献,并归纳总结了植物TOR激酶的基本结构信息、TOR信号网络、Glc-TOR信号通路以及TOR和SnRK1的调控机制,分析了TOR信号通路在调控植物生长发育及应对逆境胁迫等多个方面的功能。结果表明:绝大多数植物中只含有1个TOR激酶,且TOR、RAPTOR亚基以及LST 8亚基组成TORC1发挥作用;TOR激酶包含HEAT、FAT、FRB、Kinase和FATC 5个结构域;TOR激酶通过响应光、氨基酸、激素等信号,调控细胞生长发育过程中的蛋白质合成;TOR激酶在调控植物根的分支、逆境胁迫响应、ABA信号和矿质元素吸收方面发挥作用;TOR与Glc、SnRK1等其他营养信号网络协同作用,实现基因表达、代谢、生长和生存的整合与协调。
文摘放疗是肿瘤的重要治疗手段之一,仍有部分患者在接受放疗后存在复发或抗拒。哺乳动物雷帕霉素靶蛋白(mamma-lian target of rapamycin,mTOR)是PI3K/AKT信号通路的主要效应分子,分为mTORC1和mTORC2,对细胞生长及增殖、细胞周期进展及蛋白翻译等均有重要调节作用。mTOR异常表达与肿瘤发生及治疗反应密切相关。肿瘤的放疗敏感性与"4R"效应有关。mTOR抑制剂可通过影响细胞周期进展、DNA损伤修复及抗血管形成等多种途径发挥放疗增敏作用。初期研究证实依维莫司具有放疗增敏作用并且毒性可耐受。应用mTOR抑制剂后不同细胞及个体反应不同,可能与基因表达状态有关,需进一步研究证实。
基金supported by the National Natural Science Foundation of China(32072428)。
文摘Adelphocoris suturalis is a polyphagous pest that is increasingly causing severe economic damage due to more frequent outbreaks.The development of non-target resistance to commercial Bacillus thuringiensis(Bt)cotton has further exacerbated its pest status and amplified the need for more sustainable methods of control.RNA interference(RNAi)-based pest management strategies,such as root soaking and transgenic plants that express dsRNAs,have proven to be reliable,eco-friendly pest control strategies.To identify new RNAi targets for potential A.suturalis population control,we investigated the target of rapamycin(TOR)signaling pathway.A critical role for this pathway in A.suturalis reproductive regulation was suggested by pharmacological analyses.Subsequent RNAi-mediated knockdown of the A.suturalis TOR pathway genes TOR,Ras homolog enriched in the brain(Rheb),and ribosomal S6 kinase(S6K)reduced fertility.Moreover,a spray-induced and nanocarrier-delivered gene silencing(SI-NDGS)system targeting TOR successfully suppressed ovarian development,which demonstrates its effectiveness as a pest control target.These results provide a critical foundation for understanding reproductive regulation in A.suturalis and introduce new candidates for RNAi-based A.suturalis management.
文摘Objective:To explore the protective mechanisms of nerve growth factor (NGF) on spinal cord injury (SCI) and provide theoretical basis for its clinical application. Methods: The SCI of Wistar rats was done by Allens weight dropping way by a 10 g×2.5 cm impact on the posterior of spinal cord T 8. NGF (3 g/L, 20 μl) or normal saline was injected through catheter into subarachnoid space 2, 4, 8, 12 and 24 h after SCI. The expression of N-methyl-D-asparate receptor 1 (NMDAR 1) and neuronal constitutive nitric oxide synthase (ncNOS) mRNA in rat spinal cord was detected by in situ hybridization. Results: Abnormal expression of NMDAR 1 and ncNOS mRNA appeared in spinal ventral horn motorneuron in injured rats, as compared with that in control group. The expression of NMDAR 1 and ncNOS mRNA in NGF group was significantly lower than that in saline group (P<0.01). Conclusion: NGF can protect spinal cord against injury in vivo. One of the mechanisms is that NGF can prohibit NMDAR 1 and nitric oxide (NO) production after spinal cord injury.
基金Supported by Shanghai Municipal Health Bureau Youth Grant, No. 2008Y032
文摘AIM: To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis. METHODS: Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeⅠand type Ⅲ collagen proteins and mRNA. RESULTS: A mouse model of liver injury was successfully established, and IMD decreased nuclear transloca-tion of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeⅠcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type Ⅲ collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05). CONCLUSION: IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.
