Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after...Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.展开更多
Sonic Hedgehog(SHH)信号转导途径,作为调控胚胎发育和组织稳态的重要途径,近年来被发现通过多种机制参与心肌梗死后血管的再生过程。本文系统性地回顾了SHH通路的核心分子机制及其在血管再生中的作用。这些发现为未来针对心肌梗死后血...Sonic Hedgehog(SHH)信号转导途径,作为调控胚胎发育和组织稳态的重要途径,近年来被发现通过多种机制参与心肌梗死后血管的再生过程。本文系统性地回顾了SHH通路的核心分子机制及其在血管再生中的作用。这些发现为未来针对心肌梗死后血管再生的精准干预提供了潜在的靶点。展开更多
Graphene nanoplatelets(GNPs)have attracted tremendous interest due to their unique properties and bonding capabilities.This study focuses on the effect of GNP dispersion on the mechanical,thermal,and morphological beh...Graphene nanoplatelets(GNPs)have attracted tremendous interest due to their unique properties and bonding capabilities.This study focuses on the effect of GNP dispersion on the mechanical,thermal,and morphological behavior of GNP/epoxy nanocomposites.This study aims to understand how the dispersion of GNPs affects the properties of epoxy nanocomposite and to identify the best dispersion approach for improving mechanical performance.A solvent mixing technique that includes mechanical stirring and ultrasonication was used for producing the nanocomposites.Fourier transform infrared spectroscopy was used to investigate the interaction between GNPs and the epoxy matrix.The measurements of density and moisture content were used to confirm that GNPs were successfully incorporated into the nanocomposite.The findings showed that GNPs are successfully dispersed in the epoxy matrix by combining mechanical stirring and ultrasonication in a single step,producing well-dispersed nanocomposites with improved mechanical properties.Particularly,the nanocomposites at a low GNP loading of 0.1 wt%,demonstrate superior mechanical strength,as shown by increased tensile properties,including improved Young's modulus(1.86 GPa),strength(57.31 MPa),and elongation at break(4.98).The nanocomposite with 0.25 wt%GNP loading performs better,according to the viscoelastic analysis and flexural properties(113.18 MPa).Except for the nanocomposite with a 0.5 wt%GNP loading,which has a higher thermal breakdown temperature,the thermal characteristics do not significantly alter.The effective dispersion of GNPs in the epoxy matrix and low agglomeration is confirmed by the morphological characterization.The findings help with filler selection and identifying the best dispersion approach,which improves mechanical performance.The effective integration of GNPs and their interaction with the epoxy matrix provides the doorway for additional investigation and the development of sophisticated nanocomposites.In fields like aerospace,automotive,and electronics where higher mechanical performance and functionality are required,GNPs'improved mechanical properties and successful dispersion present exciting potential.展开更多
Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication ...Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication method achieved high drug encapsulation in commercial milk-derived EVs(S-CM EVs),but impaired EV structure,compromising transcytosis.Incubation method(I-CM EVs)preserved EVs delivery ability,but had low drug loading.Further proteomic and transmembrane studies showed that sonication greatly damaged membrane proteins involved in trans-epithelial transportation,especially endoplasmic reticulum-Golgi pathway.To overcome this dilemma,we generated a hybrid CM EVs(H-CM EVs)by fusing I-CM EVs and S-CM EVs.H-CM EVs demonstrated comparable drug encapsulation to S-CM EVs(56.14%),significantly higher than I-CM EVs(11.92%).Importantly,H-CM EVs could maintain efficient drug delivery capability by restoring membrane fluidity,repairing damaged proteins,and enhancing enzyme resistance of SCM EVs.H-CM EVs exhibited excellent absorption characteristics with 1.85-fold higher of area under the curve and 2.50-fold higher of max plasma concentration than those of SCM EVs.On typeⅠdiabetic mice,orally delivery of insulin loaded H-CM EVs and I-CM EVs showed improved hypoglycemic effects with pharmacological availabilities of 5.15%and 5.31%,which was 1.7-fold higher than that of S-CM EVs(3.00%).This H-CM EVs platform not only achieved high drug loading and maintained functionality for effective oral delivery but also highlighted the significant translational potential for improved clinical outcomes.展开更多
Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology i...Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.展开更多
To quantitatively study the location errors induced by deviation of sonic speed, the line and plane location tests were carried out. A broken pencil was simulated as acoustic emission source in the rocks. The line and...To quantitatively study the location errors induced by deviation of sonic speed, the line and plane location tests were carried out. A broken pencil was simulated as acoustic emission source in the rocks. The line and plane location tests were carried out in the granite rod using two sensors and the cube of marble using four sensors, respectively. To compare the position accuracy between line and plane positions, the line poison test was also carried out on the marble surface. The results show that for line positioning, the maximum error of absolute distance is about 0.8 cm. With the speed difference of 200 m/s, the average value of absolute difference from the position error is about 0.4 cm. For the plane positioning, in the case of the sensor array of 30 cm, the absolute positioning distance is up to 8.7 cm. It can be seen that the sonic speed seriously impacts on the plane positioning accuracy. The plane positioning error is lager than the line positioning error, which means that when the line position can satisfy the need in practical engineering, it is better to use the line position instead of the plane location. The plane positioning error with the diagonal speed is the minimum one.展开更多
目的:研究大鼠胃癌前病变形成过程中胃黏膜Sonic Hedgehog(Shh)信号通路的变化。方法:72只乳鼠随机分为正常组36只,造模组36只,雌雄各半。造模组灌服800 mg/L的1-甲基-3-硝基-1-亚硝基胍(MNNG)0.1 m L/d,正常组灌服生理盐水0.1 m L/d,共...目的:研究大鼠胃癌前病变形成过程中胃黏膜Sonic Hedgehog(Shh)信号通路的变化。方法:72只乳鼠随机分为正常组36只,造模组36只,雌雄各半。造模组灌服800 mg/L的1-甲基-3-硝基-1-亚硝基胍(MNNG)0.1 m L/d,正常组灌服生理盐水0.1 m L/d,共10 d。随后在实验观察第10周、22周、34周末每组分别雌雄各处死6只。HE染色检测胃黏膜组织病理学变化,q RTPCR法检测胃黏膜组织Shh、Ptch1、Smo、Gli1、Gli2、Gli3、Su Fu、Cyclin D1、Cyclin E1、c-Myc、β-actin m RNA的表达。Western blot检测胃黏膜组织Shh、Ptch1、Smo、Gli1、Su Fu、Cyclin D1、Cyclin E1、cMyc、p-c-Myc蛋白表达。结果:随造模时间的延长,模型组大鼠胃黏膜萎缩及异型增生逐渐加重,其胃黏膜内Shh、Smo、Gli1、Cyclin D1、Cyclin E1及c-Myc m RNA表达较正常组不同程度升高,而Ptch1和Su Fu m RNA不同程度降低。模型组胃黏膜内Shh、Smo、Gli1、Cyclin D1、Cyclin E1、p-c-Myc蛋白水平较正常组增加,Ptch1和Su Fu则降低,但差异无统计学意义。结论:大鼠胃癌前病变的形成过程中存在Shh信号通路的激活,提示Shh信号通路可能参与胃癌前病变的发生与发展。展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171456(to QY)and 81971229(to QY)the Natural Science Foundation of Chongqing,Nos.CSTC2021JCYJ-MSXMX0263(to QY)and CSTB2023NSCQ-MSX1015(to XL)Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).
文摘Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.
基金the Puncak RM for the project under the grant 6733204-13069 to carry out the experiments。
文摘Graphene nanoplatelets(GNPs)have attracted tremendous interest due to their unique properties and bonding capabilities.This study focuses on the effect of GNP dispersion on the mechanical,thermal,and morphological behavior of GNP/epoxy nanocomposites.This study aims to understand how the dispersion of GNPs affects the properties of epoxy nanocomposite and to identify the best dispersion approach for improving mechanical performance.A solvent mixing technique that includes mechanical stirring and ultrasonication was used for producing the nanocomposites.Fourier transform infrared spectroscopy was used to investigate the interaction between GNPs and the epoxy matrix.The measurements of density and moisture content were used to confirm that GNPs were successfully incorporated into the nanocomposite.The findings showed that GNPs are successfully dispersed in the epoxy matrix by combining mechanical stirring and ultrasonication in a single step,producing well-dispersed nanocomposites with improved mechanical properties.Particularly,the nanocomposites at a low GNP loading of 0.1 wt%,demonstrate superior mechanical strength,as shown by increased tensile properties,including improved Young's modulus(1.86 GPa),strength(57.31 MPa),and elongation at break(4.98).The nanocomposite with 0.25 wt%GNP loading performs better,according to the viscoelastic analysis and flexural properties(113.18 MPa).Except for the nanocomposite with a 0.5 wt%GNP loading,which has a higher thermal breakdown temperature,the thermal characteristics do not significantly alter.The effective dispersion of GNPs in the epoxy matrix and low agglomeration is confirmed by the morphological characterization.The findings help with filler selection and identifying the best dispersion approach,which improves mechanical performance.The effective integration of GNPs and their interaction with the epoxy matrix provides the doorway for additional investigation and the development of sophisticated nanocomposites.In fields like aerospace,automotive,and electronics where higher mechanical performance and functionality are required,GNPs'improved mechanical properties and successful dispersion present exciting potential.
基金financial support from the the Regional Innovation and Development Joint Fund of National Natural Science Foundation of China(grant numbers:U22A20356)the National Key R&D Program of China(No.2021YFE0115200)the National Natural Science Foundation of China(No.81872818).
文摘Milk-derived extracellular vesicles(EVs)are promising for oral drug delivery,yet different loading methods exhibit distinct impacts on drug encapsulation and membrane integrity.This study demonstrated that sonication method achieved high drug encapsulation in commercial milk-derived EVs(S-CM EVs),but impaired EV structure,compromising transcytosis.Incubation method(I-CM EVs)preserved EVs delivery ability,but had low drug loading.Further proteomic and transmembrane studies showed that sonication greatly damaged membrane proteins involved in trans-epithelial transportation,especially endoplasmic reticulum-Golgi pathway.To overcome this dilemma,we generated a hybrid CM EVs(H-CM EVs)by fusing I-CM EVs and S-CM EVs.H-CM EVs demonstrated comparable drug encapsulation to S-CM EVs(56.14%),significantly higher than I-CM EVs(11.92%).Importantly,H-CM EVs could maintain efficient drug delivery capability by restoring membrane fluidity,repairing damaged proteins,and enhancing enzyme resistance of SCM EVs.H-CM EVs exhibited excellent absorption characteristics with 1.85-fold higher of area under the curve and 2.50-fold higher of max plasma concentration than those of SCM EVs.On typeⅠdiabetic mice,orally delivery of insulin loaded H-CM EVs and I-CM EVs showed improved hypoglycemic effects with pharmacological availabilities of 5.15%and 5.31%,which was 1.7-fold higher than that of S-CM EVs(3.00%).This H-CM EVs platform not only achieved high drug loading and maintained functionality for effective oral delivery but also highlighted the significant translational potential for improved clinical outcomes.
基金funded by grants from the National Natural Science Foundation of China(grant numbers 82170912 and 82370910)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202404).
文摘Periodontal disease is a risk factor for many systemic diseases such as Alzheimer’s disease and adverse pregnancy outcomes.Cleft palate(CP),the most common congenital craniofacial defect,has a multifaceted etiology influenced by complex genetic and environmental risk factors such as maternal bacterial or virus infection.A prior case-control study revealed a surprisingly strong association between maternal periodontal disease and CP in offspring.However,the precise relationship remains unclear.In this study,the relationship between maternal oral pathogen and CP in offspring was studied by sonicated P.gingivalis injected intravenously and orally into pregnant mice.We investigated an obvious increasing CP(12.5%)in sonicated P.gingivalis group which had inhibited osteogenesis in mesenchyme and blocked efferocytosis in epithelium.Then glycolysis and H4K12 lactylation(H4K12la)were detected to elevate in both mouse embryonic palatal mesenchyme(MEPM)cells and macrophages under P.gingivalis exposure which further promoted the transcription of metallopeptidase domain17(ADAM17),subsequently mediated the shedding of transforming growth factor-beta receptor 1(TGFBR1)in MEPM cells and mer tyrosine kinase(MerTK)in macrophages and resulted in the suppression of efferocytosis and osteogenesis in palate,eventually caused abnormalities in palate fusion and ossification.The abnormal efferocytosis also led to a predominance of M1 macrophages,which indirectly inhibited palatal osteogenesis via extracellular vesicles.Furthermore,pharmacological ADAM17 inhibition could ameliorate the abnormality of P.gingivalis-induced abnormal palate development.Therefore,our study extends the knowledge of how maternal oral pathogen affects fetal palate development and provides a novel perspective to understand the pathogenesis of CP.
基金Projects (50934006, 10872218) supported by the National Natural Science Foundation of ChinaProject (2010CB732004) supported by the National Basic Research Program of ChinaProject (kjdb2010-6) supported by Doctoral Candidate Innovation Research Support Program of Science & Technology Review, China
文摘To quantitatively study the location errors induced by deviation of sonic speed, the line and plane location tests were carried out. A broken pencil was simulated as acoustic emission source in the rocks. The line and plane location tests were carried out in the granite rod using two sensors and the cube of marble using four sensors, respectively. To compare the position accuracy between line and plane positions, the line poison test was also carried out on the marble surface. The results show that for line positioning, the maximum error of absolute distance is about 0.8 cm. With the speed difference of 200 m/s, the average value of absolute difference from the position error is about 0.4 cm. For the plane positioning, in the case of the sensor array of 30 cm, the absolute positioning distance is up to 8.7 cm. It can be seen that the sonic speed seriously impacts on the plane positioning accuracy. The plane positioning error is lager than the line positioning error, which means that when the line position can satisfy the need in practical engineering, it is better to use the line position instead of the plane location. The plane positioning error with the diagonal speed is the minimum one.
文摘目的:研究大鼠胃癌前病变形成过程中胃黏膜Sonic Hedgehog(Shh)信号通路的变化。方法:72只乳鼠随机分为正常组36只,造模组36只,雌雄各半。造模组灌服800 mg/L的1-甲基-3-硝基-1-亚硝基胍(MNNG)0.1 m L/d,正常组灌服生理盐水0.1 m L/d,共10 d。随后在实验观察第10周、22周、34周末每组分别雌雄各处死6只。HE染色检测胃黏膜组织病理学变化,q RTPCR法检测胃黏膜组织Shh、Ptch1、Smo、Gli1、Gli2、Gli3、Su Fu、Cyclin D1、Cyclin E1、c-Myc、β-actin m RNA的表达。Western blot检测胃黏膜组织Shh、Ptch1、Smo、Gli1、Su Fu、Cyclin D1、Cyclin E1、cMyc、p-c-Myc蛋白表达。结果:随造模时间的延长,模型组大鼠胃黏膜萎缩及异型增生逐渐加重,其胃黏膜内Shh、Smo、Gli1、Cyclin D1、Cyclin E1及c-Myc m RNA表达较正常组不同程度升高,而Ptch1和Su Fu m RNA不同程度降低。模型组胃黏膜内Shh、Smo、Gli1、Cyclin D1、Cyclin E1、p-c-Myc蛋白水平较正常组增加,Ptch1和Su Fu则降低,但差异无统计学意义。结论:大鼠胃癌前病变的形成过程中存在Shh信号通路的激活,提示Shh信号通路可能参与胃癌前病变的发生与发展。
