The title compound 9S,9aS-neotuberostemonine （1） was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction an...The title compound 9S,9aS-neotuberostemonine （1） was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombicsystem, space group P212121, with a-9.0115（11）, b = 10.612（4）, c = 22.074（3） A, V= 2110.9（8）S^3, Z= 4, Mr= 375.49, Dc= 1.182 g/cm3, λ= 0.71079 A,μ= 0.080 cm^-1, F（000） = 816, S = 1.019,R = 0.0579 and wR = 0.1358. A total of 3109 unique reflections were collected, of which 2902were observed （I〉 2σ（I））. The absolute configuration of 1 could be assigned by referring to theconserved configuration of the methyl groups at C（13） and C（20）. In the solid state, the moleculeswere linked into a chain along the a-axis through weak hydrogen bond C（ll）-H（11A）…O（2）.Compound 1 shows significant inhibition of cough by 24%, 44% and 65% at doses of 50, 100 and150 mg/kg, respectively.展开更多
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.展开更多
背景:传统观察性研究难以揭露烧伤与生物标志物间的潜在因果关系,孟德尔随机化凭借遗传变异作为工具变量模拟随机对照试验的优势,成为解析复杂疾病因果关联的重要工具。目的:基于孟德尔随机化方法探讨烧伤与41种炎症因子和35种血液和尿...背景:传统观察性研究难以揭露烧伤与生物标志物间的潜在因果关系,孟德尔随机化凭借遗传变异作为工具变量模拟随机对照试验的优势,成为解析复杂疾病因果关联的重要工具。目的:基于孟德尔随机化方法探讨烧伤与41种炎症因子和35种血液和尿液标志物的关系。方法:①烧伤的完整全基因组关联研究数据在IEU open gwas project数据库(由英国The University of Bristol构建)中获取,该数据包括了218131例样本,16380465个单核苷酸多态性;②41种炎症因子数据来源于芬兰青年心血管风险研究数据库(由图尔库大学应用和预防心血管医学研究中心构建)一项8293人的研究数据;③35种血液和尿液生物标志物数据来源于英国生物样本库(由英国政府、惠康基金会和英国医学研究理事会共同发起的大型生物医学数据库项目)(n=363228人)。以单核苷酸多态性作为工具变量,利用逆方差加权、MR Egger、加权中位数和加权模式的方法进行分析。采用Cochrane’s Q检验来识别结果的异质性,MR Egger截距检验和MR-PRESSO检验及“留一法”检验等评估暴露-结局关联的可靠性。结果与结论:烧伤降低了白细胞介素9(OR=0.97;95%CI,0.949 to 0.997;P=0.030)和睾酮(OR=0.997;95%CI,0.995 to 0.999;P=0.025)水平,且不存在异质性和水平多效性,证明了结果的稳健性。研究通过孟德尔随机化分析表明,烧伤后白细胞介素9和睾酮水平降低,提示提高白细胞介素9和睾酮水平可能有助于烧伤后组织修复和改善蛋白质分解速率。展开更多
基金supported by Guangdong Key Scientific Project(2013A022100029)Zhongshan Scientific Scheme(2017B1134)
文摘The title compound 9S,9aS-neotuberostemonine （1） was isolated from the 95%ethanol extract of the roots of Stemona tuberosa. The crystal structure of 1, C22H33NO4, wasdetermined by single-crystal X-ray diffraction analysis. The crystal belongs to orthorhombicsystem, space group P212121, with a-9.0115（11）, b = 10.612（4）, c = 22.074（3） A, V= 2110.9（8）S^3, Z= 4, Mr= 375.49, Dc= 1.182 g/cm3, λ= 0.71079 A,μ= 0.080 cm^-1, F（000） = 816, S = 1.019,R = 0.0579 and wR = 0.1358. A total of 3109 unique reflections were collected, of which 2902were observed （I〉 2σ（I））. The absolute configuration of 1 could be assigned by referring to theconserved configuration of the methyl groups at C（13） and C（20）. In the solid state, the moleculeswere linked into a chain along the a-axis through weak hydrogen bond C（ll）-H（11A）…O（2）.Compound 1 shows significant inhibition of cough by 24%, 44% and 65% at doses of 50, 100 and150 mg/kg, respectively.
基金supported by the National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
文摘背景:传统观察性研究难以揭露烧伤与生物标志物间的潜在因果关系,孟德尔随机化凭借遗传变异作为工具变量模拟随机对照试验的优势,成为解析复杂疾病因果关联的重要工具。目的:基于孟德尔随机化方法探讨烧伤与41种炎症因子和35种血液和尿液标志物的关系。方法:①烧伤的完整全基因组关联研究数据在IEU open gwas project数据库(由英国The University of Bristol构建)中获取,该数据包括了218131例样本,16380465个单核苷酸多态性;②41种炎症因子数据来源于芬兰青年心血管风险研究数据库(由图尔库大学应用和预防心血管医学研究中心构建)一项8293人的研究数据;③35种血液和尿液生物标志物数据来源于英国生物样本库(由英国政府、惠康基金会和英国医学研究理事会共同发起的大型生物医学数据库项目)(n=363228人)。以单核苷酸多态性作为工具变量,利用逆方差加权、MR Egger、加权中位数和加权模式的方法进行分析。采用Cochrane’s Q检验来识别结果的异质性,MR Egger截距检验和MR-PRESSO检验及“留一法”检验等评估暴露-结局关联的可靠性。结果与结论:烧伤降低了白细胞介素9(OR=0.97;95%CI,0.949 to 0.997;P=0.030)和睾酮(OR=0.997;95%CI,0.995 to 0.999;P=0.025)水平,且不存在异质性和水平多效性,证明了结果的稳健性。研究通过孟德尔随机化分析表明,烧伤后白细胞介素9和睾酮水平降低,提示提高白细胞介素9和睾酮水平可能有助于烧伤后组织修复和改善蛋白质分解速率。
