白藜芦醇是天然存在的沉默信息调节因子2相关酶1(sirtuin1,SIRT1)小分子激动剂,其肾的保护作用已在多种肾疾病动物模型中得到了验证。然而,白藜芦醇是否能够改善力竭训练导致的大鼠肾损伤,以及是否通过SIRT1/NF-κB信号通路调节运动性...白藜芦醇是天然存在的沉默信息调节因子2相关酶1(sirtuin1,SIRT1)小分子激动剂,其肾的保护作用已在多种肾疾病动物模型中得到了验证。然而,白藜芦醇是否能够改善力竭训练导致的大鼠肾损伤,以及是否通过SIRT1/NF-κB信号通路调节运动性肾损伤大鼠肾炎症反应,尚缺乏系统研究。本研究将32只SD大鼠随机分为安静对照组(Con组),白藜芦醇组(Rsv组),力竭运动组(Ex组),力竭运动+白藜芦醇组(Ex+Rsv组)。Rsv和Ex+Rsv组每天灌胃50 mg/kg体重剂量的白藜芦醇, Ex和Ex+Rsv组进行4周力竭训练,最后1次训练后24 h取材。本研究结果显示,与Con组相比,Ex组大鼠Scr(175.66±16.08 vs.153.34±8.67,P<0.01)、BUN(6.67±0.53 vs.5.37±0.19,P<0.01)和尿NGAL(9.01±0.18 vs.7.48±0.31,P<0.01)水平均显著升高,Ex组大鼠肾组织NF-κB P65在蛋白质水平表达显著升高(0.77±0.10 vs. 0.27±0.03,P<0.01);各组大鼠肾组织SIRT1在蛋白质水平表达上,Rsv组显著高于Con组(0.90±0.14 vs. 0.43±0.15,P<0.05),Ex+Rsv组显著高于Ex组(1.0±0.28 vs. 0.38±0.12,P<0.01);与Ex组相比,Ex+Rsv组大鼠肾组织NF-κB P65(0.57±0.13 vs. 0.77±0.10,P<0.05)和Ac-NF-κB P65(0.52±0.13 vs. 0.78±0.11,P<0.05)在蛋白质水平表达显著降低。以上结果表明,4周大强度力竭运动导致大鼠出现运动性肾损伤,并激活大鼠肾NF-κB的表达。白藜芦醇可显著提高大鼠肾组织SIRT1在蛋白质水平的表达,并增加脱乙酰化作用,降低NF-κB P65蛋白质乙酰化修饰水平,进一步降低NF-κB的表达。白藜芦醇减轻力竭训练致大鼠肾的炎症反应的机制可能与SIRT1/NF-κB通路有关。展开更多
Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of res...Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.展开更多
Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR3...Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.展开更多
Background Sirtuin 1 （SIRT1） has been reported to have diverse roles in various biological processes through deacetylation of histone and nonhistone proteins.However,the correlations among SIRT1 protein expression,c...Background Sirtuin 1 （SIRT1） has been reported to have diverse roles in various biological processes through deacetylation of histone and nonhistone proteins.However,the correlations among SIRT1 protein expression,clinicopathological parameters,and survival of colorectal cancer patients remain unclear.Methods SIRT1 protein expression was measured by immunohistochemistry in a paraffin-embedded tissue microarray,including 120 paired colorectal cancer and normal mucosa tissues.The correlations among SIRT1 protein expression,clinicopathological features,and prognosis were analyzed.Results All samples （100%） were positive for SIRT1,with variable staining in the cytoplasm rather than in the nucleus.There was significant difference in SIRT1 overexpression between adenocarcinomas and normal mucosal tissue （P〈0.01,x2 test）.SIRT1 overexpression was more frequently observed in advanced-stage tumors （P=0.046,0.002,x2test）.SIRT1 overexpression was significantly correlated with poor overall survival （P=0.013,log-rank test） and diseasefree survival （P=0.012,log-rank test）.Conclusions SIRT1 overexpression correlated with advanced stage and poor prognosis.SIRT1 may play an important role in the progression of colorectal cancer.展开更多
Sirtuin 1(SIRT1)is a protein deacetylase,which regulates various physiological activities by deacetylating different protein substrates.An increasing number of studies have revealed critical roles of SIRT1 in differen...Sirtuin 1(SIRT1)is a protein deacetylase,which regulates various physiological activities by deacetylating different protein substrates.An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism,proliferation,genomic instability,and chemotherapy resistance.Depending on the protein targets in a certain oncogenic context,SIRT1 may play a unique role in each individual blood cancer subtype.Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia(AML)and chronic myelogenous leukemia(CML)promotes disease maintenance.On the other hand,an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome(MDS)stem cells and holds promise as a potential therapeutic approach.Herein,we present a concise summary of the different functions of SIRT1 in hematologic malignancies.展开更多
类端粒沉默干扰体1(disruptor of telomeric silencing 1-like,DOT1L)是一种组蛋白H3第79位赖氨酸(H3K79)甲基转移酶,参与基因转录的表观遗传调控。近来研究发现,类端粒沉默干扰体1基因在生长板(growth plate)和关节软骨中广泛表达,并...类端粒沉默干扰体1(disruptor of telomeric silencing 1-like,DOT1L)是一种组蛋白H3第79位赖氨酸(H3K79)甲基转移酶,参与基因转录的表观遗传调控。近来研究发现,类端粒沉默干扰体1基因在生长板(growth plate)和关节软骨中广泛表达,并参与维持关节软骨稳态。全基因组关联研究(genome-wide association studies,GWAS)结果显示,类端粒沉默干扰体1基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)可增加欧洲人和中国汉族髋、膝关节骨关节炎(osteoarthritis,OA)患病风险。功能学实验证实,类端粒沉默干扰体1可下调去乙酰化酶沉默信息调节蛋白1(sirtuin-1,SIRT1)在关节软骨的表达,进而控制关节软骨内Wnt信号通路过度活化从而对关节产生保护作用;类端粒沉默干扰体1缺失可诱发小鼠和体外培养软骨细胞发生膝关节骨关节炎样改变。由此推断,调控类端粒沉默干扰体1-沉默信息调节蛋白1-Wnt信号通路网络可能是保护关节软骨、阻滞膝关节骨关节炎发生发展的有效措施。本文将在简述类端粒沉默干扰体1结构特点与活性的基础上,重点综述类端粒沉默干扰体1与膝关节骨关节炎发生发展之间的关系,以期为膝关节骨关节炎的诊治提供新靶点。展开更多
Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functio...Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functions as an activator of proteins adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)and sirtuin 1(SIRT1).We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues,such as orirenierine A(2)and orirenierine B(3)isolated from the medicinal plant Oricia renieri.Methods We investigated the binding to human SIRT1(hSIRT1)of 25 natural products including theβ-indoloquinazoline alkaloids 1−3 and analogues,in comparison with the reference product sirtinol(R and S isomers).A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1(PDB structures 4KXQ and 4IG9).For each compound bound to SIRT1,the empirical energy of interaction(ΔE)was calculated and compared to that of sirtinol.Results In our model,compound 1 was found to bind modestly to the sirtinol site of SIRT1.In contrast,the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity.Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol.The replacement of the hydroxy substituent(2)with a methoxy group(3)reduced the SIRT1 binding capacity.Other SIRT1-binding natural products were identified,such as the alkaloids orisuaveolines A and B.Structure-binding relationships were discussed.Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1.This deacetylase enzyme could represent a molecular target for the alkaloid 2.This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.展开更多
Calorie restriction(CR)is a dietary regime based on low calorie intake.CR without malnutrition extends lifespan in a wide range of organisms from yeast to rodents,and CR can prevent and delay the onset of age-related ...Calorie restriction(CR)is a dietary regime based on low calorie intake.CR without malnutrition extends lifespan in a wide range of organisms from yeast to rodents,and CR can prevent and delay the onset of age-related functional decline and diseases in human and non-human primates.CR is a safe and effective intervention to reduce vascular risk factors in humans.In recent years,studies in rodents have provided mechanistic insights into the beneficial effects of CR on vascular homeostasis,including reduced oxidative stress,enhanced nitric oxide(NO)bioactivity,and decreased inflammation.A number of important molecules,including sirtuins,AMP-activated protein kinase,mammalian targets of rapamycin,endothelial nitric oxidase and their regulatory pathways are involved in the maintenance of vascular homeostasis.Evidence has shown that these pathways are responsible for many aspects of CR’s effects,and that they may also mediate the effects of CR on vasculature.展开更多
文摘白藜芦醇是天然存在的沉默信息调节因子2相关酶1(sirtuin1,SIRT1)小分子激动剂,其肾的保护作用已在多种肾疾病动物模型中得到了验证。然而,白藜芦醇是否能够改善力竭训练导致的大鼠肾损伤,以及是否通过SIRT1/NF-κB信号通路调节运动性肾损伤大鼠肾炎症反应,尚缺乏系统研究。本研究将32只SD大鼠随机分为安静对照组(Con组),白藜芦醇组(Rsv组),力竭运动组(Ex组),力竭运动+白藜芦醇组(Ex+Rsv组)。Rsv和Ex+Rsv组每天灌胃50 mg/kg体重剂量的白藜芦醇, Ex和Ex+Rsv组进行4周力竭训练,最后1次训练后24 h取材。本研究结果显示,与Con组相比,Ex组大鼠Scr(175.66±16.08 vs.153.34±8.67,P<0.01)、BUN(6.67±0.53 vs.5.37±0.19,P<0.01)和尿NGAL(9.01±0.18 vs.7.48±0.31,P<0.01)水平均显著升高,Ex组大鼠肾组织NF-κB P65在蛋白质水平表达显著升高(0.77±0.10 vs. 0.27±0.03,P<0.01);各组大鼠肾组织SIRT1在蛋白质水平表达上,Rsv组显著高于Con组(0.90±0.14 vs. 0.43±0.15,P<0.05),Ex+Rsv组显著高于Ex组(1.0±0.28 vs. 0.38±0.12,P<0.01);与Ex组相比,Ex+Rsv组大鼠肾组织NF-κB P65(0.57±0.13 vs. 0.77±0.10,P<0.05)和Ac-NF-κB P65(0.52±0.13 vs. 0.78±0.11,P<0.05)在蛋白质水平表达显著降低。以上结果表明,4周大强度力竭运动导致大鼠出现运动性肾损伤,并激活大鼠肾NF-κB的表达。白藜芦醇可显著提高大鼠肾组织SIRT1在蛋白质水平的表达,并增加脱乙酰化作用,降低NF-κB P65蛋白质乙酰化修饰水平,进一步降低NF-κB的表达。白藜芦醇减轻力竭训练致大鼠肾的炎症反应的机制可能与SIRT1/NF-κB通路有关。
基金supported by grants from the National Natural Science Foundation of China(Nos.81370660,81170524)
文摘Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.
基金supported by the National Notural Science Foundation of China,Nos.82071556 and 82271291 (both to WM)
文摘Activated G-protein-coupled receptor 39(GPR39)has been shown to attenuate inflammation by interacting with sirtuin 1(SIRT1)and peroxisome proliferator-activated receptor-γcoactivator 1α(PGC-1α).However,whether GPR39 attenuates neuropathic pain remains unclear.In this study,we established a Sprague-Dawley rat model of spared nerve injury-induced neuropathic pain and found that GPR39 expression was significantly decreased in neurons and microglia in the spinal dorsal horn compared with sham-operated rats.Intrathecal injection of TC-G 1008,a specific agonist of GPR39,significantly alleviated mechanical allodynia in the rats with spared nerve injury,improved spinal cord mitochondrial biogenesis,and alleviated neuroinflammation.These changes were abolished by GPR39 small interfering RNA(siRNA),Ex-527(SIRT1 inhibitor),and PGC-1αsiRNA.Taken together,these findings show that GPR39 activation ameliorates mechanical allodynia by activating the SIRT1/PGC-1αpathway in rats with spared nerve injury.
基金This study was supported by grants from the National Natural Science Foundation of China （No.81372290 and 81372291） and Peking University People＇s Hospital Research and Development Funds （No.RDB 2012-18 and RDB 2013-15）.
文摘Background Sirtuin 1 （SIRT1） has been reported to have diverse roles in various biological processes through deacetylation of histone and nonhistone proteins.However,the correlations among SIRT1 protein expression,clinicopathological parameters,and survival of colorectal cancer patients remain unclear.Methods SIRT1 protein expression was measured by immunohistochemistry in a paraffin-embedded tissue microarray,including 120 paired colorectal cancer and normal mucosa tissues.The correlations among SIRT1 protein expression,clinicopathological features,and prognosis were analyzed.Results All samples （100%） were positive for SIRT1,with variable staining in the cytoplasm rather than in the nucleus.There was significant difference in SIRT1 overexpression between adenocarcinomas and normal mucosal tissue （P〈0.01,x2 test）.SIRT1 overexpression was more frequently observed in advanced-stage tumors （P=0.046,0.002,x2test）.SIRT1 overexpression was significantly correlated with poor overall survival （P=0.013,log-rank test） and diseasefree survival （P=0.012,log-rank test）.Conclusions SIRT1 overexpression correlated with advanced stage and poor prognosis.SIRT1 may play an important role in the progression of colorectal cancer.
基金supported by the National Institutes of Health(No.R01HL141336),the Margaret E.Early Medical Research Trust Award,the Stop Cancer Research Career Development Award,V Scholar Award of Cancer Research,and the Gehr Family Center for Leukemia Research,USA
文摘Sirtuin 1(SIRT1)is a protein deacetylase,which regulates various physiological activities by deacetylating different protein substrates.An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism,proliferation,genomic instability,and chemotherapy resistance.Depending on the protein targets in a certain oncogenic context,SIRT1 may play a unique role in each individual blood cancer subtype.Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia(AML)and chronic myelogenous leukemia(CML)promotes disease maintenance.On the other hand,an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome(MDS)stem cells and holds promise as a potential therapeutic approach.Herein,we present a concise summary of the different functions of SIRT1 in hematologic malignancies.
文摘类端粒沉默干扰体1(disruptor of telomeric silencing 1-like,DOT1L)是一种组蛋白H3第79位赖氨酸(H3K79)甲基转移酶,参与基因转录的表观遗传调控。近来研究发现,类端粒沉默干扰体1基因在生长板(growth plate)和关节软骨中广泛表达,并参与维持关节软骨稳态。全基因组关联研究(genome-wide association studies,GWAS)结果显示,类端粒沉默干扰体1基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)可增加欧洲人和中国汉族髋、膝关节骨关节炎(osteoarthritis,OA)患病风险。功能学实验证实,类端粒沉默干扰体1可下调去乙酰化酶沉默信息调节蛋白1(sirtuin-1,SIRT1)在关节软骨的表达,进而控制关节软骨内Wnt信号通路过度活化从而对关节产生保护作用;类端粒沉默干扰体1缺失可诱发小鼠和体外培养软骨细胞发生膝关节骨关节炎样改变。由此推断,调控类端粒沉默干扰体1-沉默信息调节蛋白1-Wnt信号通路网络可能是保护关节软骨、阻滞膝关节骨关节炎发生发展的有效措施。本文将在简述类端粒沉默干扰体1结构特点与活性的基础上,重点综述类端粒沉默干扰体1与膝关节骨关节炎发生发展之间的关系,以期为膝关节骨关节炎的诊治提供新靶点。
文摘Objective Bouchardatine(1)is a β-indoloquinazoline alkaloid isolated from the plant Bouchardatia neurococca,acting as a modulator of adipogenesis and lipogenesis,and as an anticancer agent.The natural product functions as an activator of proteins adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK)and sirtuin 1(SIRT1).We used molecular modeling to investigate the SIRT1-binding capacity of compound 1 and various structural analogues,such as orirenierine A(2)and orirenierine B(3)isolated from the medicinal plant Oricia renieri.Methods We investigated the binding to human SIRT1(hSIRT1)of 25 natural products including theβ-indoloquinazoline alkaloids 1−3 and analogues,in comparison with the reference product sirtinol(R and S isomers).A sirtinol binding model was elaborated starting from the closed and open state conformations of the catalytic domain of hSIRT1(PDB structures 4KXQ and 4IG9).For each compound bound to SIRT1,the empirical energy of interaction(ΔE)was calculated and compared to that of sirtinol.Results In our model,compound 1 was found to bind modestly to the sirtinol site of SIRT1.In contrast,the presence of a phenolic OH group at position 7 on the quinazolinone moiety conferred a much higher binding capacity.Compound 2 provided SIRT1 protein complexes as stable as those observed with sirtinol.The replacement of the hydroxy substituent(2)with a methoxy group(3)reduced the SIRT1 binding capacity.Other SIRT1-binding natural products were identified,such as the alkaloids orisuaveolines A and B.Structure-binding relationships were discussed.Conclusion The study underlines the capacity of β-indoloquinazoline alkaloids to interact with SIRT1.This deacetylase enzyme could represent a molecular target for the alkaloid 2.This compound merits further attention for the design of drugs active against SIRT1-dependent pathologies.
基金supported by the National Natural Science Foundation of China (31271227,91339201)the Beijing Nova Program (XX2013064)the National Basic Research Program of China (2011CB503902)
文摘Calorie restriction(CR)is a dietary regime based on low calorie intake.CR without malnutrition extends lifespan in a wide range of organisms from yeast to rodents,and CR can prevent and delay the onset of age-related functional decline and diseases in human and non-human primates.CR is a safe and effective intervention to reduce vascular risk factors in humans.In recent years,studies in rodents have provided mechanistic insights into the beneficial effects of CR on vascular homeostasis,including reduced oxidative stress,enhanced nitric oxide(NO)bioactivity,and decreased inflammation.A number of important molecules,including sirtuins,AMP-activated protein kinase,mammalian targets of rapamycin,endothelial nitric oxidase and their regulatory pathways are involved in the maintenance of vascular homeostasis.Evidence has shown that these pathways are responsible for many aspects of CR’s effects,and that they may also mediate the effects of CR on vasculature.
