Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminog...Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.展开更多
Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus...Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
Sewage sludge(SS)and SS impregnated with activating agents(ZnCl_(2) and KOH)were pyrolyzed in a fixed-bed reactor to produce gaseous fuel and activated char.The effects of heating rate,pyrolysis temperature and activa...Sewage sludge(SS)and SS impregnated with activating agents(ZnCl_(2) and KOH)were pyrolyzed in a fixed-bed reactor to produce gaseous fuel and activated char.The effects of heating rate,pyrolysis temperature and activator type on gas yields,pore structure and adsorption properties of activated char were systematically studied.The results demonstrated that increasing the pyrolysis temperature from 450℃ to 850℃ propo rtionally enhanced H_(2) and CO yields from the rapid pyrolysis of SS,while CH_(4) yield showed minimal variation between 650℃ and 850℃.ZnCl_(2) notably increased the CO yield,reaching71.9 ml·g^(-1)at 850℃,but caused a marked reduction in CH_(4) yield under the tested conditions.Similarly,KOH promoted CO yield at 750℃ and 850℃,with minimal impact on CH_(4) production.Both activators facilitated higher H_(2) yields in the range of 450-550℃,while the maximum H_(2) yield(109.8 ml·g^(-1))was observed at 850℃ in the absence of activator.The activated char derived from ZnCl_(2)-assisted pyrolysis exhibited well-developed micro-and mesopore structures,with specific surface areas ranging from 188.2 to 54.1 m^(2)·g^(-1)across pyrolysis temperatures of 450-850℃.When evaluated as adsorbents for methylene blue removal,activated char with greater specific surface area and total pore volume exhibited superior adsorption capacity.The adsorption process was well-described by the pseudo-second-order kinetic model.展开更多
南海中央海盆海底扩张活动结束之后,出现了频繁的岩浆活动。由于海盆被海水覆盖,针对活跃的岩浆活动开展实测调查非常困难。本文利用二维地震剖面资料,结合拖网样品资料及有关钻探资料的研究成果,在建立岩浆活动与沉积作用关系模型的基...南海中央海盆海底扩张活动结束之后,出现了频繁的岩浆活动。由于海盆被海水覆盖,针对活跃的岩浆活动开展实测调查非常困难。本文利用二维地震剖面资料,结合拖网样品资料及有关钻探资料的研究成果,在建立岩浆活动与沉积作用关系模型的基础上,通过解释地震剖面反射特征和地震相特征,较全面地分析了南海中央海盆扩张期后岩浆活动的特征与期次。结果表明,南海中央海盆的岩浆活动具有脉动期,形成大量的海底山和岩浆底辟,即以多期次间隙性喷发和浅层侵入为特征。南海中央海盆后扩张期的岩浆活动主要有4个期次,其中11.6、7.5、5.3 Ma 3个期次的分析结果与岩石样品的测年结果吻合,而且进一步确定1.6 Ma左右的岩浆活动时间较长,一直延续至近代,分布范围广;2.6~1.6 Ma期间曾被认为是南海中央海盆岩浆活动静默期,本研究首次发现岩浆活动的踪迹;这一时期既有一次性活动形成的岩浆底辟和海底火山,也有通过多次火山活动而形成的规模较大的岩浆底辟和海底火山。展开更多
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT)a grant from the Major Program of Hubei Province,No.2023BAA005(to ZT)+1 种基金a grant from the Key Research and Discovery Program of Hubei Province,No.2021BCA109(to ZT)the Research Foundation of Tongji Hospital,No.2022B37(to PZ)。
文摘Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.
基金supported by the Natural Science Foundation of Hubei Province of China(Grant No.2023AFB671)the National Natural Science Foundation of China(Grant Nos.82360177 and 82560182)+1 种基金the Key Project of Jiangxi Provincial Natural Science Foundation(Grant No.20224ACB206011)“Xuncheng Talents”Project in Jiujiang City,Jiangxi Province(Grant No.JJXC2023071).
文摘Objectives The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells(H-BMSCs)represents a promising strategy for preventing and treating osteoporosis.Thus,the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1(lncRNA FOXD2-AS1)regulates early osteogenic differentiation in H-BMSCs,thereby identifying potential therapeutic targets.Methods Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs.The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase(ALP)staining.To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in this process,AG490 inhibitor(a JAK2/STAT3 pathway inhibitor)and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.Results FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression,while its knockdown had the opposite effects.From a mechanistic perspective,FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation,whereas its suppression attenuated their activation.Also,the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing,indicating that the pathway plays a role in this process.Conclusion FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation,revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
基金financially supported by the National Natural Science Foundation of China(U21A2062)National innovative training program for college students of China(202410792014)。
文摘Sewage sludge(SS)and SS impregnated with activating agents(ZnCl_(2) and KOH)were pyrolyzed in a fixed-bed reactor to produce gaseous fuel and activated char.The effects of heating rate,pyrolysis temperature and activator type on gas yields,pore structure and adsorption properties of activated char were systematically studied.The results demonstrated that increasing the pyrolysis temperature from 450℃ to 850℃ propo rtionally enhanced H_(2) and CO yields from the rapid pyrolysis of SS,while CH_(4) yield showed minimal variation between 650℃ and 850℃.ZnCl_(2) notably increased the CO yield,reaching71.9 ml·g^(-1)at 850℃,but caused a marked reduction in CH_(4) yield under the tested conditions.Similarly,KOH promoted CO yield at 750℃ and 850℃,with minimal impact on CH_(4) production.Both activators facilitated higher H_(2) yields in the range of 450-550℃,while the maximum H_(2) yield(109.8 ml·g^(-1))was observed at 850℃ in the absence of activator.The activated char derived from ZnCl_(2)-assisted pyrolysis exhibited well-developed micro-and mesopore structures,with specific surface areas ranging from 188.2 to 54.1 m^(2)·g^(-1)across pyrolysis temperatures of 450-850℃.When evaluated as adsorbents for methylene blue removal,activated char with greater specific surface area and total pore volume exhibited superior adsorption capacity.The adsorption process was well-described by the pseudo-second-order kinetic model.
文摘南海中央海盆海底扩张活动结束之后,出现了频繁的岩浆活动。由于海盆被海水覆盖,针对活跃的岩浆活动开展实测调查非常困难。本文利用二维地震剖面资料,结合拖网样品资料及有关钻探资料的研究成果,在建立岩浆活动与沉积作用关系模型的基础上,通过解释地震剖面反射特征和地震相特征,较全面地分析了南海中央海盆扩张期后岩浆活动的特征与期次。结果表明,南海中央海盆的岩浆活动具有脉动期,形成大量的海底山和岩浆底辟,即以多期次间隙性喷发和浅层侵入为特征。南海中央海盆后扩张期的岩浆活动主要有4个期次,其中11.6、7.5、5.3 Ma 3个期次的分析结果与岩石样品的测年结果吻合,而且进一步确定1.6 Ma左右的岩浆活动时间较长,一直延续至近代,分布范围广;2.6~1.6 Ma期间曾被认为是南海中央海盆岩浆活动静默期,本研究首次发现岩浆活动的踪迹;这一时期既有一次性活动形成的岩浆底辟和海底火山,也有通过多次火山活动而形成的规模较大的岩浆底辟和海底火山。
