OBJECTIVE Pulmonary arterial hypertension(PAH)is a malignant pulmonary vascular disease lacking efficacy therapeutics.Therefore,it urgently needs to develop safe and effective drugs for PAH treatment.Osthole derived f...OBJECTIVE Pulmonary arterial hypertension(PAH)is a malignant pulmonary vascular disease lacking efficacy therapeutics.Therefore,it urgently needs to develop safe and effective drugs for PAH treatment.Osthole derived from Cnidium monnieri(L.)Cusson(Shechuangzi)or Angelica pubescens Maxim(Duhuo)has the capacity to alleviate PAH by decreasing pulmonary arterial pressure and alleviating pulmonary vascular remodeling in rats,which is a candidate drug for the prevention of PAH,but the underlying modulatory mechanism is still unclear.Our study aims at investigating the metabolic modulatory mechanism of osthole against PAH employing functional metabolomics strategy.METHODS PAH model rats were successfully established with MCT,following osthole administration,then functional metabolomics based on untargeted metabolomics assay,targeted lipidomics analysis,qRT-PCR,Western blotting and ELISA were performed to investigate the modulatory mechanism of osthole against pulmonary arterial pressure and pulmonary vascular remodeling in PAH.RESULTS Untargeted metabolomics results found that sphingosine 1-phosphate(S1P)was the differential metabolites characterized PAH and reversed by osthole treatment.S1P is a crucial sphingolipid metabolite catalyzed by sphingosine kinases1(Sphk1)and functions as promoting PASMCs proliferation contributing to pulmonary vascular remodeling and pulmonary arterial pressure increase.We revealed that osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 via inactivating microRNA-21-PI3K/Akt/mTOR signal pathway to decrease pulmonary arterial pressure in rats with PAH.Then,targeted phospholipid metabolomics results uncovered that decadienyl-L-carnitine(C10:2)was the differential metabolite characterized PAH and corrected by osthole treatment in rat with PAH.C10:2 is the intermediate metabolite of fatty acid oxidation(FAO),and C10:2 accumulation indicated mitochondrial dysfunction and FAO increase.CONCLUSION Osthole could block lipid metabolic reprogramming through functional modulating the expression of fatty acid translocase,fatty acid synthase,phospholipase A2,carnitine palmitoyltransferase 1A to inhibit C10:2,thus to improve mitochondrial dysfunction and inhibit utilizing lipid to biosynthesize necessary essence for pulmonary artery smooth muscle cells(PASMCs)proliferation.Moreover,we delineated that C10:2 and metabolic reprogramming enzymes were modulated by miRNA-22-3p which was involved in PASMCs proliferation and pulmonary vascular remodeling.Therefore,osthole inhibited miRNA-22-3p mediated lipid metabolic reprogramming to ameliorate pulmonary vascular remodeling.展开更多
目的比较无创通气间歇期氧气驱动雾化、无创通气间歇期空气驱动雾化、无创通气同时空气驱动雾化对慢性阻塞性肺疾病急性加重(AECOPD)患者雾化过程中二氧化碳分压、氧饱和度(SpO_(2))及心率的动态变化及治疗效果的影响。方法根据随机对...目的比较无创通气间歇期氧气驱动雾化、无创通气间歇期空气驱动雾化、无创通气同时空气驱动雾化对慢性阻塞性肺疾病急性加重(AECOPD)患者雾化过程中二氧化碳分压、氧饱和度(SpO_(2))及心率的动态变化及治疗效果的影响。方法根据随机对照研究的方法将99例需使用无创通气及雾化吸入治疗的慢性阻塞性肺疾病急性加重患者根据计算机产生的随机数字表随机分为对照组、观察一组、观察二组各33例,对照组给予无创通气间歇期氧气驱动雾化吸入,观察一组给予无创通气间歇空气驱动雾化,观察二组给予无创通气同时空气驱动雾化,记录雾化0、5、10、15 min和雾化结束5、10、15 min的经皮二氧化碳分压(PtCO_(2))、SpO_(2)及心率变化。记录治疗前至治疗第7天每天早晨动脉血气PaCO_(2)、PaO_(2)数值,记录三组住院时间。结果三组雾化过程中PtCO_(2)对比结果显示,时间主效应和时间组别交互效应差异均有统计学意义(P<0.001),且对照组PtCO_(2)数值与时间呈线性关系(F=10.166,P=0.003),随时间变化呈上升状态;观察一组各时间点PtCO_(2)数值与时间呈线性关系(F=10.544,P=0.003),随时间变化呈下降状态;观察二组各时间点PtCO_(2)数值与时间呈线性关系(F=20.003,P<0.001),随时间呈下降状态。再分别对三组每个时间点PtCO_(2)数值进行多样本方差分析,对照组雾化15 min PtCO_(2)高于观察一组、观察二组;观察一组、观察二组均与对照组雾化前后PtCO_(2)差值(dPtCO_(2))差异有统计学意义(P<0.05);对三组雾化结束观察期每个时间点PtCO_(2)数值进行多样本方差分析,结果显示三组雾化结束0 min PtCO_(2)、雾化结束5 min PtCO_(2)差异有统计学意义(P<0.05),雾化结束10 min PtCO_(2)、雾化结束15 min PtCO_(2)三组差异无统计学意义(P>0.05);三组雾化过程中SpO_(2)对比显示三组时间组别交互效应差异均有统计学意义(P<0.05)。且观察一组各时间点SpO_(2)数值随时间呈下降趋势。对照组雾化10 min SpO_(2)、雾化15 min SpO_(2)高于观察一组和观察二组;三组均能使动脉血气中PaCO_(2)随治疗时间的增加而好转(P<0.05)。结论三种雾化治疗方式均能取得良好的治疗效果,但无创通气间歇期氧气驱动雾化会使雾化过程中PtCO_(2)及SpO_(2)上升;无创通气间歇期空气驱动雾化会使雾化过程中PtCO_(2)及SpO_(2)下降;无创通气同时空气驱动雾化使雾化过程中PtCO_(2)下降及保持SpO_(2)平稳,因此无创通气同时空气驱动雾化是相对更加安全的雾化吸入方式,值得临床推广。展开更多
航空发动机和燃气轮机涡轮盘榫槽具有外形复杂、加工困难的特点,通常采用专用成套榫槽拉刀加工。传统的榫槽拉刀设计周期长,对不同工步的刀具需要重新设计计算切削用量,效率低下。针对这一问题以涡轮盘榫槽粗拉刀设计阶段为研究对象,分...航空发动机和燃气轮机涡轮盘榫槽具有外形复杂、加工困难的特点,通常采用专用成套榫槽拉刀加工。传统的榫槽拉刀设计周期长,对不同工步的刀具需要重新设计计算切削用量,效率低下。针对这一问题以涡轮盘榫槽粗拉刀设计阶段为研究对象,分析多约束条件下的拉刀切削参数和拉削宽度关系,在Matlab AppDesigner软件环境下搭建参数快速计算平台。同时对某型号涡轮盘榫槽型面进行参数化建模,根据榫槽拉刀设计流程以及榫槽加工方式分配建立成套榫槽拉刀通用模板,通过UG NX12.0的表达式功能串联刀具设计参数和约束条件,结合NX Open C/C++API和Visual Studio 2019编译环境,实现成套涡轮盘榫槽拉刀的快速设计,提高设计效率。展开更多
文摘OBJECTIVE Pulmonary arterial hypertension(PAH)is a malignant pulmonary vascular disease lacking efficacy therapeutics.Therefore,it urgently needs to develop safe and effective drugs for PAH treatment.Osthole derived from Cnidium monnieri(L.)Cusson(Shechuangzi)or Angelica pubescens Maxim(Duhuo)has the capacity to alleviate PAH by decreasing pulmonary arterial pressure and alleviating pulmonary vascular remodeling in rats,which is a candidate drug for the prevention of PAH,but the underlying modulatory mechanism is still unclear.Our study aims at investigating the metabolic modulatory mechanism of osthole against PAH employing functional metabolomics strategy.METHODS PAH model rats were successfully established with MCT,following osthole administration,then functional metabolomics based on untargeted metabolomics assay,targeted lipidomics analysis,qRT-PCR,Western blotting and ELISA were performed to investigate the modulatory mechanism of osthole against pulmonary arterial pressure and pulmonary vascular remodeling in PAH.RESULTS Untargeted metabolomics results found that sphingosine 1-phosphate(S1P)was the differential metabolites characterized PAH and reversed by osthole treatment.S1P is a crucial sphingolipid metabolite catalyzed by sphingosine kinases1(Sphk1)and functions as promoting PASMCs proliferation contributing to pulmonary vascular remodeling and pulmonary arterial pressure increase.We revealed that osthole reversed high level of S1P by modulating metabolic enzyme Sphk1 via inactivating microRNA-21-PI3K/Akt/mTOR signal pathway to decrease pulmonary arterial pressure in rats with PAH.Then,targeted phospholipid metabolomics results uncovered that decadienyl-L-carnitine(C10:2)was the differential metabolite characterized PAH and corrected by osthole treatment in rat with PAH.C10:2 is the intermediate metabolite of fatty acid oxidation(FAO),and C10:2 accumulation indicated mitochondrial dysfunction and FAO increase.CONCLUSION Osthole could block lipid metabolic reprogramming through functional modulating the expression of fatty acid translocase,fatty acid synthase,phospholipase A2,carnitine palmitoyltransferase 1A to inhibit C10:2,thus to improve mitochondrial dysfunction and inhibit utilizing lipid to biosynthesize necessary essence for pulmonary artery smooth muscle cells(PASMCs)proliferation.Moreover,we delineated that C10:2 and metabolic reprogramming enzymes were modulated by miRNA-22-3p which was involved in PASMCs proliferation and pulmonary vascular remodeling.Therefore,osthole inhibited miRNA-22-3p mediated lipid metabolic reprogramming to ameliorate pulmonary vascular remodeling.
文摘目的比较无创通气间歇期氧气驱动雾化、无创通气间歇期空气驱动雾化、无创通气同时空气驱动雾化对慢性阻塞性肺疾病急性加重(AECOPD)患者雾化过程中二氧化碳分压、氧饱和度(SpO_(2))及心率的动态变化及治疗效果的影响。方法根据随机对照研究的方法将99例需使用无创通气及雾化吸入治疗的慢性阻塞性肺疾病急性加重患者根据计算机产生的随机数字表随机分为对照组、观察一组、观察二组各33例,对照组给予无创通气间歇期氧气驱动雾化吸入,观察一组给予无创通气间歇空气驱动雾化,观察二组给予无创通气同时空气驱动雾化,记录雾化0、5、10、15 min和雾化结束5、10、15 min的经皮二氧化碳分压(PtCO_(2))、SpO_(2)及心率变化。记录治疗前至治疗第7天每天早晨动脉血气PaCO_(2)、PaO_(2)数值,记录三组住院时间。结果三组雾化过程中PtCO_(2)对比结果显示,时间主效应和时间组别交互效应差异均有统计学意义(P<0.001),且对照组PtCO_(2)数值与时间呈线性关系(F=10.166,P=0.003),随时间变化呈上升状态;观察一组各时间点PtCO_(2)数值与时间呈线性关系(F=10.544,P=0.003),随时间变化呈下降状态;观察二组各时间点PtCO_(2)数值与时间呈线性关系(F=20.003,P<0.001),随时间呈下降状态。再分别对三组每个时间点PtCO_(2)数值进行多样本方差分析,对照组雾化15 min PtCO_(2)高于观察一组、观察二组;观察一组、观察二组均与对照组雾化前后PtCO_(2)差值(dPtCO_(2))差异有统计学意义(P<0.05);对三组雾化结束观察期每个时间点PtCO_(2)数值进行多样本方差分析,结果显示三组雾化结束0 min PtCO_(2)、雾化结束5 min PtCO_(2)差异有统计学意义(P<0.05),雾化结束10 min PtCO_(2)、雾化结束15 min PtCO_(2)三组差异无统计学意义(P>0.05);三组雾化过程中SpO_(2)对比显示三组时间组别交互效应差异均有统计学意义(P<0.05)。且观察一组各时间点SpO_(2)数值随时间呈下降趋势。对照组雾化10 min SpO_(2)、雾化15 min SpO_(2)高于观察一组和观察二组;三组均能使动脉血气中PaCO_(2)随治疗时间的增加而好转(P<0.05)。结论三种雾化治疗方式均能取得良好的治疗效果,但无创通气间歇期氧气驱动雾化会使雾化过程中PtCO_(2)及SpO_(2)上升;无创通气间歇期空气驱动雾化会使雾化过程中PtCO_(2)及SpO_(2)下降;无创通气同时空气驱动雾化使雾化过程中PtCO_(2)下降及保持SpO_(2)平稳,因此无创通气同时空气驱动雾化是相对更加安全的雾化吸入方式,值得临床推广。
文摘航空发动机和燃气轮机涡轮盘榫槽具有外形复杂、加工困难的特点,通常采用专用成套榫槽拉刀加工。传统的榫槽拉刀设计周期长,对不同工步的刀具需要重新设计计算切削用量,效率低下。针对这一问题以涡轮盘榫槽粗拉刀设计阶段为研究对象,分析多约束条件下的拉刀切削参数和拉削宽度关系,在Matlab AppDesigner软件环境下搭建参数快速计算平台。同时对某型号涡轮盘榫槽型面进行参数化建模,根据榫槽拉刀设计流程以及榫槽加工方式分配建立成套榫槽拉刀通用模板,通过UG NX12.0的表达式功能串联刀具设计参数和约束条件,结合NX Open C/C++API和Visual Studio 2019编译环境,实现成套涡轮盘榫槽拉刀的快速设计,提高设计效率。
