General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有...General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。展开更多
在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋...在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋白激酶(Doublestranded RNA-dependent protein kinase,PKR)和血红素调节抑制剂激酶(Heme-regulated inhibitor,HRI)[1],这4个激酶会在不同胁迫条件下磷酸化eIF2α亚基第51位的丝氨酸/苏氨酸,从而削弱了eIF2在翻译过程中结合GTP的能力,进一步抑制细胞总体蛋白翻译以缓解细胞应激,恢复细胞蛋白稳态,这种细胞反应被称为整合应激反应(Integrated stress response,ISR)[2]。展开更多
Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that...Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.展开更多
Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthes...Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels,transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets(Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for28 d. L-Gln administration markedly(linear, P < 0.05) increased Ala, Arg, Asn, Asp, Glu, Gln, His, Ile, Lys,Met, Orn, Phe, Ser, Thr, Tyr, and Val levels and promoted trypsin activity in the jejunal content of piglets.Moreover, L-Gln treatment significantly enhanced concentrations of colonic Gln and Trp, and serum Thr(linear, P < 0.01), and quadratically increased serum Lys and Phe levels(P < 0.05), and decreased plasma Glu, Ile, and Leu levels(linear, P < 0.05). Further investigation revealed that L-Gln administration significantly upregulated Atp1a1, Slc1a5, Slc3a2, Slc6a14, Slc7a5, Slc7a7, and Slc38a1 relative expressions in the jejunum(linear, P < 0.05). Additionally, dietary supplementation with L-Gln enhanced protein abundance of general control nonderepressible 2(GCN2, P = 0.010), phosphorylated eukaryotic initiation factor 2 subunit alpha(eIF2α, P < 0.001), and activating transcription factor 4(ATF4) in the jejunum of piglets(P = 0.008). These results demonstrated for the first time that a low crude protein diet with highlevel L-Gln inclusion exhibited side effects on piglets. Specifically, 2% and 3% L-Gln administration exceeded the intestinal utilization capacity and compromised the jejunal AA utilization efficiency, which is independent of digestive enzyme activities. A high level of L-Gln supplementation would inhibit protein synthesis by GCN2/eIF2α/ATF4 signaling in piglets fed low-protein diets, which, in turn, upregulates certain AA transporters to maintain AA homeostasis.展开更多
Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component pho...Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component photocatalyst.Herein,we synthesized a novel typeⅡNb_(2)O_(5)/GCN heterojunction to investigate its efficiency in the photocatalytic upcycling of polybutylene adipate/terephthalate(PBAT)microplastics(MPs)into acids and alcohols under visible light irradiation(100mW/cm^(2)).The findings indicate that the charge transfer within the typeⅡNb_(2)O_(5)/GCN occurs from the conduction band of GCN to the conduction band of Nb_(2)O_(5),thereby enhancing the separation efficiency of carriers Notably,the rates of ethanol and acetic acid generation from 1.5mg/mL PBAT MPs treated with the 60%Nb_(2)O_(5)/GCN photocatalyst were 21.8-fold and 1.8-fold higher,respectively,compared to those by Nb_(2)O_(5) alone.Density functional theory calculations demonstrate that the hydroxyl radicals(·OH)produced by the Nb_(2)O_(5)/GCN heterojunction cleaves the ester bond(O-C=O)of PBAT MP into the monomer.These monomers are subsequently converted into acids and alcohols through various reactions,including C-C bond cleavage,hydrodeoxygenation,and C-C bond coupling.This study highlights the effectiveness of heterojunction photocatalyst in converting PBAT MPs into valuable chemicals,thus significantly promoting advancements in bioplastics recycling.展开更多
氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接...氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接各种组织代谢的枢纽。氨基酸感应在肝脏糖脂代谢的调控中起到十分重要的作用。因此准确地感应细胞内和细胞外氨基酸的水平,成为维持细胞内稳态的关键。真核细胞中存在一些众所周知的氨基酸感应因子,即一般性调控阻遏蛋白激酶2 (general control non-derepressible-2, GCN2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)以及味觉受体等,在维持机体代谢稳态中发挥重要作用。本文对氨基酸调控肝脏糖脂代谢的作用与机制做了详细介绍,为进一步探究氨基酸感应机制以及治疗肝脏糖脂代谢紊乱疾病奠定了基础。展开更多
色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉...色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、酪氨酸蛋白激酶2/信号转导与转录激活因子3(Janus kinase 2/signal transducer and activator of transcription 3,JAK2/STAT3)信号通路和一般性调控阻遏蛋白激酶2(general control non-derepressible 2,GCN2)经典应激反应促进细胞增殖;5-羟色胺经其受体(5-hydroxytryptamine receptor,5-HTR)和转运体(serotonin transporter,SETR)内化后激活下游信号分子,促进细胞增殖。然而高表达的吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)大量消耗色氨酸,导致色氨酸耗竭和代谢物大量累积,从而抑制细胞增殖;同时犬尿氨酸激活芳烃受体(aryl hydrocarbon receptor,AhR),阻滞细胞周期进程,抑制细胞增殖。该文综述了色氨酸代谢途径及其代谢物诱导的多种信号通路对细胞增殖的调控机理,旨在临床靶向治疗时,可通过精准地调控色氨酸代谢的限速酶来治疗由细胞异常增殖而引起的代谢性疾病。展开更多
文摘General control non-derepressible 2(GCN2)属于一种压力应答丝氨酸/苏氨酸激酶,在整合应激反应(ISR)中负责感受氨基酸缺乏应激后产生一系列反应。GCN2的激活对于细胞的氧化应激、增殖、自噬、凋亡、免疫、蛋白质毒性和血管生成等均有关键的调节作用,与肿瘤、心肌损伤、肺纤维化等的发生发展有一定的相关性。综述GCN2的生物学功能、结构特征、作用机制和疾病关联性,并总结分析GCN2抑制剂或激动剂的研发现状,重点阐述GCN2抑制剂或激动剂在抗肿瘤方向的临床应用潜力,为靶向GCN2激酶的新药开发提供参考。
文摘在哺乳动物中有4个真核翻译起始因子2α(Eu⁃karyotic initiation factor 2α,eIF2α)激酶,即一般性调控阻遏蛋白激酶2(General control nonderepressible 2,GCN2)、蛋白激酶R样内质网激酶(PKR-like ER ki⁃nase,PERK)、双链RNA依赖性蛋白激酶(Doublestranded RNA-dependent protein kinase,PKR)和血红素调节抑制剂激酶(Heme-regulated inhibitor,HRI)[1],这4个激酶会在不同胁迫条件下磷酸化eIF2α亚基第51位的丝氨酸/苏氨酸,从而削弱了eIF2在翻译过程中结合GTP的能力,进一步抑制细胞总体蛋白翻译以缓解细胞应激,恢复细胞蛋白稳态,这种细胞反应被称为整合应激反应(Integrated stress response,ISR)[2]。
基金This work was supported by the National Natural Science Foundation of China(31830044,91957207,81870592,82270905,81970742,82000764,82170868,and 81970731)The National Key R&D Program of China(grant 2018YFA0800600).
文摘Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.
基金supported by grants from the National Key R&D Program of China(2022YFF1100102,2022YFF1100104,2022YFC2105005)the National Natural Science Foundation of China(No.32172749,31625025).
文摘Gln, one of the most abundant amino acids(AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters,protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels,transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets(Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for28 d. L-Gln administration markedly(linear, P < 0.05) increased Ala, Arg, Asn, Asp, Glu, Gln, His, Ile, Lys,Met, Orn, Phe, Ser, Thr, Tyr, and Val levels and promoted trypsin activity in the jejunal content of piglets.Moreover, L-Gln treatment significantly enhanced concentrations of colonic Gln and Trp, and serum Thr(linear, P < 0.01), and quadratically increased serum Lys and Phe levels(P < 0.05), and decreased plasma Glu, Ile, and Leu levels(linear, P < 0.05). Further investigation revealed that L-Gln administration significantly upregulated Atp1a1, Slc1a5, Slc3a2, Slc6a14, Slc7a5, Slc7a7, and Slc38a1 relative expressions in the jejunum(linear, P < 0.05). Additionally, dietary supplementation with L-Gln enhanced protein abundance of general control nonderepressible 2(GCN2, P = 0.010), phosphorylated eukaryotic initiation factor 2 subunit alpha(eIF2α, P < 0.001), and activating transcription factor 4(ATF4) in the jejunum of piglets(P = 0.008). These results demonstrated for the first time that a low crude protein diet with highlevel L-Gln inclusion exhibited side effects on piglets. Specifically, 2% and 3% L-Gln administration exceeded the intestinal utilization capacity and compromised the jejunal AA utilization efficiency, which is independent of digestive enzyme activities. A high level of L-Gln supplementation would inhibit protein synthesis by GCN2/eIF2α/ATF4 signaling in piglets fed low-protein diets, which, in turn, upregulates certain AA transporters to maintain AA homeostasis.
基金financially supported by the National Natural Science Foundation of China(Nos.52170024,T2421005,and 22006031).
文摘Photocatalysis holds great promise for the conversion of plastic waste into valuable chemicals.However,the conversion efficiency is constrained by the poor carriers’separation efficiency over the single component photocatalyst.Herein,we synthesized a novel typeⅡNb_(2)O_(5)/GCN heterojunction to investigate its efficiency in the photocatalytic upcycling of polybutylene adipate/terephthalate(PBAT)microplastics(MPs)into acids and alcohols under visible light irradiation(100mW/cm^(2)).The findings indicate that the charge transfer within the typeⅡNb_(2)O_(5)/GCN occurs from the conduction band of GCN to the conduction band of Nb_(2)O_(5),thereby enhancing the separation efficiency of carriers Notably,the rates of ethanol and acetic acid generation from 1.5mg/mL PBAT MPs treated with the 60%Nb_(2)O_(5)/GCN photocatalyst were 21.8-fold and 1.8-fold higher,respectively,compared to those by Nb_(2)O_(5) alone.Density functional theory calculations demonstrate that the hydroxyl radicals(·OH)produced by the Nb_(2)O_(5)/GCN heterojunction cleaves the ester bond(O-C=O)of PBAT MP into the monomer.These monomers are subsequently converted into acids and alcohols through various reactions,including C-C bond cleavage,hydrodeoxygenation,and C-C bond coupling.This study highlights the effectiveness of heterojunction photocatalyst in converting PBAT MPs into valuable chemicals,thus significantly promoting advancements in bioplastics recycling.
基金Research from the corresponding author’s laboratory was supported by grants from the National Key Research and Development Program of China(No.2018YFA0800600)the National Natural Science Foundation of China(No.91957207,31830044,81870592,81770852,81700761,81700750,81970742,81970731,81570777 and 81600623)+1 种基金Basic Research Project of Shanghai Science and Technology Commission(No.16JC1404900,17XD1404200)CAS Interdisciplinary Innovation Team,Novo Nordisk-Chinese Academy of Sciences Research Fund(No.NNCAS-2008-10)。
文摘氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接各种组织代谢的枢纽。氨基酸感应在肝脏糖脂代谢的调控中起到十分重要的作用。因此准确地感应细胞内和细胞外氨基酸的水平,成为维持细胞内稳态的关键。真核细胞中存在一些众所周知的氨基酸感应因子,即一般性调控阻遏蛋白激酶2 (general control non-derepressible-2, GCN2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)以及味觉受体等,在维持机体代谢稳态中发挥重要作用。本文对氨基酸调控肝脏糖脂代谢的作用与机制做了详细介绍,为进一步探究氨基酸感应机制以及治疗肝脏糖脂代谢紊乱疾病奠定了基础。
文摘色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、酪氨酸蛋白激酶2/信号转导与转录激活因子3(Janus kinase 2/signal transducer and activator of transcription 3,JAK2/STAT3)信号通路和一般性调控阻遏蛋白激酶2(general control non-derepressible 2,GCN2)经典应激反应促进细胞增殖;5-羟色胺经其受体(5-hydroxytryptamine receptor,5-HTR)和转运体(serotonin transporter,SETR)内化后激活下游信号分子,促进细胞增殖。然而高表达的吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)大量消耗色氨酸,导致色氨酸耗竭和代谢物大量累积,从而抑制细胞增殖;同时犬尿氨酸激活芳烃受体(aryl hydrocarbon receptor,AhR),阻滞细胞周期进程,抑制细胞增殖。该文综述了色氨酸代谢途径及其代谢物诱导的多种信号通路对细胞增殖的调控机理,旨在临床靶向治疗时,可通过精准地调控色氨酸代谢的限速酶来治疗由细胞异常增殖而引起的代谢性疾病。
