Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete ...Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a ＂microvascular network-- transport across microvascular network--flow in interstitium＂ model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.展开更多
Background:Sweat glands(SGs)have low regenerative potential after severe burns or trauma and their regeneration or functional recovery still faces many obstacles.In practice,restoring SG function requires not only the...Background:Sweat glands(SGs)have low regenerative potential after severe burns or trauma and their regeneration or functional recovery still faces many obstacles.In practice,restoring SG function requires not only the structural integrity of the gland itself,but also its neighboring tissues,especially blood vessels.Collagen triple helix repeat containing-1(CTHRC1)was first identified in vascular repair,and increasing reports showed a close correlation between cutaneous appendage specification,patterning and regeneration.The purpose of the present study was to clarify the role of CTHRC1 in SGs and their adjacent microvessels and find therapeutic strategies to restore SG function.Methods:The SGs and their adjacent microvascular network of Cthrc^(1−/−)mice were first inves-tigated using sweat test,laser Doppler imaging,tissue clearing technique and transcriptome analysis.The effects of CTHRC1 on dermal microvascular endothelial cells(DMECs)were further explored with cell proliferation,DiI-labeled acetylated low-density lipoprotein uptake,tube for-mation and intercellular junction establishment assays.The effects of CTHRC1 on SG function restoration were finally confirmed by replenishing the protein into the paws of Cthrc(1−/−)mice.Results:CTHRC1 is a key regulator of SG function in mice.At the tissue level,Cthrc1 deletion resulted in the disorder and reduction of the microvascular network around SGs.At the molecular level,the knockout of Cthrc1 reduced the expression of vascular development genes and functional proteins in the dermal tissues.Furthermore,CTHRC1 administration considerably enhanced SG function by inducing adjacent vascular network reconstruction.Conclusions:CTHRC1 promotes the development,morphogenesis and function execution of SGs and their neighboring vasculature.Our study provides a novel target for the restoration or regeneration of SG function in vivo.展开更多
There is a pressing need for effective therapeutics for coronavirus disease 2019(COVID-19),the respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus.The process of drug develop...There is a pressing need for effective therapeutics for coronavirus disease 2019(COVID-19),the respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus.The process of drug development is a costly and meticulously paced process,where progress is often hindered by the failure of initially promising leads.To aid this chal-lenge,in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening,thereby saving valuable time and resources during a pandemic crisis.The SARS-CoV-2 virus attacks the lung,an organ where the unique three-dimensional(3D)structure of its functional units is critical for proper respiratory function.The in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell types.Current model systems include Transwell,organoid and organ-on-a-chip or microphysiological systems(MPSs).We review models that have direct relevance toward modeling the pathology of COVID-19,including the processes of inflammation,edema,coagulation,as well as lung immune function.We also consider the practical issues that may influence the design and fabrication of MPS.The role of lung MPS is addressed in the context of multi-organ models,and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung MPS to accelerate drug development for COVID-19 and other infectious diseases.展开更多
通过中医药系统药理学平台(Traditional Chinese Medicine Database and Analysis Platform, TCMSP)和文献获取五指毛桃和贯叶金丝桃的主要成分,用本草组鉴(HERB)平台预测药物相关靶点,并以"microvascular angina""cardi...通过中医药系统药理学平台(Traditional Chinese Medicine Database and Analysis Platform, TCMSP)和文献获取五指毛桃和贯叶金丝桃的主要成分,用本草组鉴(HERB)平台预测药物相关靶点,并以"microvascular angina""cardiac syndrome X"为关键词,通过GeneCards、OMIM(Online Mendelian Inheritance in Man)、TTD(Therapeutic Target Database)及HERB数据库搜集微血管性心绞痛疾病相关靶点。以STRING平台数据为基础,利用Cytoscape软件构建五指毛桃-贯叶金丝桃药对与微血管性心绞痛共同靶点的蛋白-蛋白相互作用网络。通过Metascape平台分析"药物-成分-靶点"网络及其参与的生物过程及通路。采用AutoDock Vina软件对活性成分与关键靶点进行分子对接。最终通过筛选得到五指毛桃-贯叶金丝桃药对治疗微血管性心绞痛的19个潜在有效成分和71个潜在作用靶点。生物信息学分析发现磷脂酰肌醇3激酶(phosphatidylinositol-3-kinase, PI3K)-蛋白激酶B(protein kinase B,AKT)、白细胞介素17(interleukin-17,IL17)、缺氧诱导因子1(hypoxia-inducible factor 1,HIF-1)等信号通路与五指毛桃-贯叶金丝桃治疗微血管性心绞痛的分子机制相关。分子对接结果显示,五指毛桃-贯叶金丝桃中的β-谷甾醇、木犀草素等成分与丝裂原活化蛋白激酶1(mitogen-associated protein kinase 1,MAPK1)、表皮生长因子受体(epidermal growth factor receptor, EGFR)等靶点的亲和力强。结果表明五指毛桃-贯叶金丝桃可能通过作用于多个靶点,调节PI3K-AKT信号通路、IL17信号通路、HIF-1信号通路等多条信号通路,发挥抗氧化应激、抑制炎症反应、调节血管生成、改善血管内皮功能等作用,为其治疗微血管性心绞痛体内外研究提供参考。展开更多
基金Project supported by the National Natural Science Foundation of China (Grant No:10372026)
文摘Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a ＂microvascular network-- transport across microvascular network--flow in interstitium＂ model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.
基金supported by grants from the National Natural Science Foundation of China(81830064,81721092,32000969,82002056)Key Support Program for Growth Factor Research(SZYZ-TR-03)+3 种基金Chinese PLA General Hospital for Military Medical Innovation Research Project(CX-19026)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)the Military Medical Research and Development Projects(AWS17J005)Beijing Natural Science Foundation(7204306).
文摘Background:Sweat glands(SGs)have low regenerative potential after severe burns or trauma and their regeneration or functional recovery still faces many obstacles.In practice,restoring SG function requires not only the structural integrity of the gland itself,but also its neighboring tissues,especially blood vessels.Collagen triple helix repeat containing-1(CTHRC1)was first identified in vascular repair,and increasing reports showed a close correlation between cutaneous appendage specification,patterning and regeneration.The purpose of the present study was to clarify the role of CTHRC1 in SGs and their adjacent microvessels and find therapeutic strategies to restore SG function.Methods:The SGs and their adjacent microvascular network of Cthrc^(1−/−)mice were first inves-tigated using sweat test,laser Doppler imaging,tissue clearing technique and transcriptome analysis.The effects of CTHRC1 on dermal microvascular endothelial cells(DMECs)were further explored with cell proliferation,DiI-labeled acetylated low-density lipoprotein uptake,tube for-mation and intercellular junction establishment assays.The effects of CTHRC1 on SG function restoration were finally confirmed by replenishing the protein into the paws of Cthrc(1−/−)mice.Results:CTHRC1 is a key regulator of SG function in mice.At the tissue level,Cthrc1 deletion resulted in the disorder and reduction of the microvascular network around SGs.At the molecular level,the knockout of Cthrc1 reduced the expression of vascular development genes and functional proteins in the dermal tissues.Furthermore,CTHRC1 administration considerably enhanced SG function by inducing adjacent vascular network reconstruction.Conclusions:CTHRC1 promotes the development,morphogenesis and function execution of SGs and their neighboring vasculature.Our study provides a novel target for the restoration or regeneration of SG function in vivo.
基金funding from National Institutes of Health(No.1UG3TR003148-01)the American Heart Association(No.442611-NU-80922)+1 种基金California Institute for Regenerative Medicine(No.DISC2COVID19-11838)COVID-19 research funding from David Geffen School of Medicine at UCLA.
文摘There is a pressing need for effective therapeutics for coronavirus disease 2019(COVID-19),the respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus.The process of drug development is a costly and meticulously paced process,where progress is often hindered by the failure of initially promising leads.To aid this chal-lenge,in vitro human microphysiological systems need to be refined and adapted for mechanistic studies and drug screening,thereby saving valuable time and resources during a pandemic crisis.The SARS-CoV-2 virus attacks the lung,an organ where the unique three-dimensional(3D)structure of its functional units is critical for proper respiratory function.The in vitro lung models essentially recapitulate the distinct tissue structure and the dynamic mechanical and biological interactions between different cell types.Current model systems include Transwell,organoid and organ-on-a-chip or microphysiological systems(MPSs).We review models that have direct relevance toward modeling the pathology of COVID-19,including the processes of inflammation,edema,coagulation,as well as lung immune function.We also consider the practical issues that may influence the design and fabrication of MPS.The role of lung MPS is addressed in the context of multi-organ models,and it is discussed how high-throughput screening and artificial intelligence can be integrated with lung MPS to accelerate drug development for COVID-19 and other infectious diseases.
