Objective:Osteoarthritis(OA)is a degenerative joint disease characterized by extracellular matrix(ECM)degradation,chondrocyte apoptosis,and chronic inflammation.Cartilage destruction and ECM degeneration contribute to...Objective:Osteoarthritis(OA)is a degenerative joint disease characterized by extracellular matrix(ECM)degradation,chondrocyte apoptosis,and chronic inflammation.Cartilage destruction and ECM degeneration contribute to joint function loss and disability.Signal transducer and activator of transcription 3(STAT3)up-regulates the expression of MMP-13,which degrades collagen Ⅱ.Our previous study found that 5,7,3',4'-tetramethoxyflavone(TMF)exhibited protective effects on OA chondrocytes.This study aims to investigate the protective role of TMF in inhibiting ECM degradation by mediating the Sirt1/STAT3 signaling pathway.Methods:Rat OA models were established by the injection of monosodium iodoacetate(MIA).Hematoxylin&eosin(HE)staining and immunohistochemistry(IHC)analysis were performed.IL-1β stimulated C28/I2 cells were used as OA-like chondrocyte cell model.Western blotting assays were used to determine the protein expression.Results:The expression of MMP-13 was upregulated while type Ⅱ collagen expression is downregulated,and the phosphorylation level of STAT3 is increased in rat OA models.TMF reverses the STAT3-mediated expression of MMP-13 and type v collagen.Activation of STAT3 or inhibition of Sirt1 function attenuates the inhibitory effect of TMF on ECM degradation.Conclusion:TMF can inhibit ECM degradation mediated by the STAT3 signal pathway by activating Sirt1 expression in OA cell and animal models.展开更多
Background：Protein arginine methyltransferases 1 （PRMT1） is over-expressed in a variety of cancers,including lung cancer,and is correlated with a poor prognosis of tumor development.This study aimed to investigate ...Background：Protein arginine methyltransferases 1 （PRMT1） is over-expressed in a variety of cancers,including lung cancer,and is correlated with a poor prognosis of tumor development.This study aimed to investigate the role of PRMT1 in nonsmall cell lung cancer （NSCLC） migration in vitro.Methods：In this study,PRMT1 expression in the NSCLC cell line A549 was silenced using lentiviral vector-mediated short hairpin RNAs.Cell migration was measured using both scratch wound healing and transwell cell migration assays.The mRNA expression levels of matrix metalloproteinase 2 （MMP-2） and tissue inhibitor ofmetalloproteinase 1,2 （TIMP l,2） were measured using quantitative real-time reverse transcription-polymerase chain reaction.The expression levels of protein markers for epithelial-mesenchymal transition （EMT） （E-cadherin,N-cadherin）,focal adhesion kinase （FAK）,Src,AKT,and their corresponding phosphorylated states were detected by Western blot.Results：Cell migration was significantly inhibited in the PRMT1 silenced group compared to the control group.The mRNA expression of MMP-2 decreased while TIMP 1 and TIMP2 increased significantly.E-cadherin mRNA expression also increased while N-cadherin decreased.Only phosphorylated Src levels decreased in the silenced group while FAK or AKT remained unchanged.Conclusions：PRMT1-small hairpin RNA inhibits the migration abilities of NSCLC A549 cells by inhibiting EMT,extracellular matrix degradation,and Src phosphorylation in vitro.展开更多
By integrating laboratory physical modeling experiments with machine learning-based analysis of dominant factors,this study explored the feasibility of pulse hydraulic fracturing(PHF)in deep coal rocks and revealed th...By integrating laboratory physical modeling experiments with machine learning-based analysis of dominant factors,this study explored the feasibility of pulse hydraulic fracturing(PHF)in deep coal rocks and revealed the fracture propagation patterns and the mechanisms of pulsating loading in the process.The results show that PHF induces fatigue damage in coal matrix,significantly reducing breakdown pressure and increasing fracture network volume.Lower vertical stress differential coefficient(less than 0.31),lower peak pressure ratio(less than 0.9),higher horizontal stress differential coefficient(greater than 0.13),higher pulse amplitude ratio(greater than or equal to 0.5)and higher pulse frequency(greater than or equal to 3 Hz)effectively decrease the breakdown pressure.Conversely,higher vertical stress differential coefficient(greater than or equal to 0.31),higher pulse amplitude ratio(greater than or equal to 0.5),lower horizontal stress differential coefficient(less than or equal to 0.13),lower peak pressure ratio(less than 0.9),and lower pulse frequency(less than 3 Hz)promote the formation of a complex fracture network.Vertical stress and peak pressure are the most critical geological and engineering parameters affecting the stimulation effectiveness of PHF.The dominant mechanism varies with coal rank due to differences in geomechanical characteristics and natural fracture development.Low-rank coal primarily exhibits matrix strength degradation.High-rank coal mainly involves the activation of natural fractures and bedding planes.Medium-rank coal shows a coexistence of matrix strength degradation and micro-fracture connectivity.The PHF forms complex fracture networks through the dual mechanism of matrix strength degradation and fracture network connectivity enhancement.展开更多
OBJECTIVE:The aim of this study was to investigate the protective effects of Tuina(a traditional Chinese massage therapy)on intervertebral disc(IVD)degeneration and the regulatory mechanisms of the transforming growth...OBJECTIVE:The aim of this study was to investigate the protective effects of Tuina(a traditional Chinese massage therapy)on intervertebral disc(IVD)degeneration and the regulatory mechanisms of the transforming growth factor-β1(TGF-β1)/small mothers against decapentaplegic(Smad)signaling pathway.METHODS:Thirty New Zealand white rabbits were randomized into five groups:the control group,model group,model+Tuina group(Tuina group),model+TGF-β1 group(TGF-β1 group),and model+TGF-β1 inhibitor SB431542 group(SB431542 group).The model was established by posterolateral annulus fibrosus puncturing(AFP).Recombinant TGF-β1 and inhibitor SB431542 was injected into the TGF-β1 group and SB431542 group with a microsyringe,respectively.The rabbits in the Tuina group received Tuina treatment along the bladder meridian for 4 weeks.Magnetic resonance imaging(MRI)was performed on rabbits before AFP and after 4 weeks of intervention.Lumbar IVDs(L2-L3 to L4-L5)were harvested after intervention.Histopathological changes in the IVDs were measured by hematoxylin and eosin(HE)staining.Type I collagen was analyzed by immunohistochemistry detection.The expression level of matrix metalloproteinase-3(MMP3)was determined by enzyme-linked immunosorbent assay.Cell apoptosis was evaluated by terminal deoxynucleotidyl transferasemediated nick end labeling and Western blotting.Realtime polymerase chain reaction and Western blotting were used to analyze the expression of TGF-β1 and Smad2/3/4 and a disintegrin and metalloproteinase with thrombospondin motifs 5.RESULTS:Posterolateral AFP induced IVD degeneration in rabbits with histopathological damage and noticeable changes in MRI images.Tuina alleviated histopathological changes and reversed the expression of extracellular matrix degeneration-related molecules and apoptosis-related proteins.Furthermore,AFP induced the activation of TGF-β1 and Smad2/3/4,whereas Tuina therapy markedly reduced the protein expression of Smad2/3 and the gene expression of TGF-β1 and Smad2/3/4.Additionally,the TGF-β1/Smad signaling pathway was activated in the TGF-β1 group,while the TGF-β1/Smad signaling pathway was inhibited in the SB431542 group.CONCLUSION:Posterolateral AFP induced disc degeneration as determined by MRI assessment and histological analysis.Tuina alleviated disc degeneration,possibly by inhibiting the fibrotic response mediated by the TGF-β1/Smad pathway,thus alleviating extracellular matrix degeneration and reducing cell apoptosis.展开更多
This study investigated the role of the nuclear factor of activated T cells c3(NFATc3)in vascular smooth muscle cells(VSMCs)during aortic aneurysm and dissection(AAD)progression and the underlying molecular mechanisms...This study investigated the role of the nuclear factor of activated T cells c3(NFATc3)in vascular smooth muscle cells(VSMCs)during aortic aneurysm and dissection(AAD)progression and the underlying molecular mechanisms.Cytoplasmic and nuclear NFATc3 levels were elevated in human and mouse AAD.VSMC–NFATc3 deletion reduced thoracic AAD(TAAD)and abdominal aortic aneurysm(AAA)progression in mice,contrary to VSMC–NFATc3 overexpression.VSMC–NFATc3 deletion reduced extracellular matrix(ECM)degradation and maintained the VSMC contractile phenotype.Nuclear NFATc3 targeted and transcriptionally upregulated matrix metalloproteinase 9(MMP9)and MMP2,promoting ECM degradation and AAD development.NFATc3 promoted VSMC phenotypic switching by binding to eukaryotic elongation factor 2(eEF2)and inhibiting its phosphorylation in the VSMC cytoplasm.Restoring eEF2 reversed the beneficial effects in VSMC-specific NFATc3-knockout mice.Cabamiquine—targets eEF2 and inhibits protein synthesis—inhibited AAD development and progression in VSMC-NFATc3-overexpressing mice.VSMC–NFATc3 promoted VSMC switch and ECM degradation while exacerbating AAD development,making it a novel potential therapeutic target for preventing and treating AAD.展开更多
An abdominal aortic aneurysm(AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we...An abdominal aortic aneurysm(AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein(BAI), the main component of the Chinese traditional drug "Huang Qin", attenuates the incidence and severity of AAA in Apoe儃/儃 mice infused with angiotensin II(AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species(ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2(MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor(AT1R) and inhibiting mitogen-activated protein kinases(MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention.展开更多
基金Project Supported by Jiangxi Provincial Natural Science Foundation(20212ACB206002)。
文摘Objective:Osteoarthritis(OA)is a degenerative joint disease characterized by extracellular matrix(ECM)degradation,chondrocyte apoptosis,and chronic inflammation.Cartilage destruction and ECM degeneration contribute to joint function loss and disability.Signal transducer and activator of transcription 3(STAT3)up-regulates the expression of MMP-13,which degrades collagen Ⅱ.Our previous study found that 5,7,3',4'-tetramethoxyflavone(TMF)exhibited protective effects on OA chondrocytes.This study aims to investigate the protective role of TMF in inhibiting ECM degradation by mediating the Sirt1/STAT3 signaling pathway.Methods:Rat OA models were established by the injection of monosodium iodoacetate(MIA).Hematoxylin&eosin(HE)staining and immunohistochemistry(IHC)analysis were performed.IL-1β stimulated C28/I2 cells were used as OA-like chondrocyte cell model.Western blotting assays were used to determine the protein expression.Results:The expression of MMP-13 was upregulated while type Ⅱ collagen expression is downregulated,and the phosphorylation level of STAT3 is increased in rat OA models.TMF reverses the STAT3-mediated expression of MMP-13 and type v collagen.Activation of STAT3 or inhibition of Sirt1 function attenuates the inhibitory effect of TMF on ECM degradation.Conclusion:TMF can inhibit ECM degradation mediated by the STAT3 signal pathway by activating Sirt1 expression in OA cell and animal models.
基金This study was supported by grants from the Natural Science Foundation of Huzhou City，the Public Welfare Technical Applied Research Project of Huzhou City （No.2013GY 19 No.2013（3Z14）.Conflict of Interest：None declared
文摘Background：Protein arginine methyltransferases 1 （PRMT1） is over-expressed in a variety of cancers,including lung cancer,and is correlated with a poor prognosis of tumor development.This study aimed to investigate the role of PRMT1 in nonsmall cell lung cancer （NSCLC） migration in vitro.Methods：In this study,PRMT1 expression in the NSCLC cell line A549 was silenced using lentiviral vector-mediated short hairpin RNAs.Cell migration was measured using both scratch wound healing and transwell cell migration assays.The mRNA expression levels of matrix metalloproteinase 2 （MMP-2） and tissue inhibitor ofmetalloproteinase 1,2 （TIMP l,2） were measured using quantitative real-time reverse transcription-polymerase chain reaction.The expression levels of protein markers for epithelial-mesenchymal transition （EMT） （E-cadherin,N-cadherin）,focal adhesion kinase （FAK）,Src,AKT,and their corresponding phosphorylated states were detected by Western blot.Results：Cell migration was significantly inhibited in the PRMT1 silenced group compared to the control group.The mRNA expression of MMP-2 decreased while TIMP 1 and TIMP2 increased significantly.E-cadherin mRNA expression also increased while N-cadherin decreased.Only phosphorylated Src levels decreased in the silenced group while FAK or AKT remained unchanged.Conclusions：PRMT1-small hairpin RNA inhibits the migration abilities of NSCLC A549 cells by inhibiting EMT,extracellular matrix degradation,and Src phosphorylation in vitro.
基金Supported by the National Natural Science Foundation of China(52274014,52421002).
文摘By integrating laboratory physical modeling experiments with machine learning-based analysis of dominant factors,this study explored the feasibility of pulse hydraulic fracturing(PHF)in deep coal rocks and revealed the fracture propagation patterns and the mechanisms of pulsating loading in the process.The results show that PHF induces fatigue damage in coal matrix,significantly reducing breakdown pressure and increasing fracture network volume.Lower vertical stress differential coefficient(less than 0.31),lower peak pressure ratio(less than 0.9),higher horizontal stress differential coefficient(greater than 0.13),higher pulse amplitude ratio(greater than or equal to 0.5)and higher pulse frequency(greater than or equal to 3 Hz)effectively decrease the breakdown pressure.Conversely,higher vertical stress differential coefficient(greater than or equal to 0.31),higher pulse amplitude ratio(greater than or equal to 0.5),lower horizontal stress differential coefficient(less than or equal to 0.13),lower peak pressure ratio(less than 0.9),and lower pulse frequency(less than 3 Hz)promote the formation of a complex fracture network.Vertical stress and peak pressure are the most critical geological and engineering parameters affecting the stimulation effectiveness of PHF.The dominant mechanism varies with coal rank due to differences in geomechanical characteristics and natural fracture development.Low-rank coal primarily exhibits matrix strength degradation.High-rank coal mainly involves the activation of natural fractures and bedding planes.Medium-rank coal shows a coexistence of matrix strength degradation and micro-fracture connectivity.The PHF forms complex fracture networks through the dual mechanism of matrix strength degradation and fracture network connectivity enhancement.
基金National Natural Science Foundation of China:Based on TGF-β1/Smads Signaling Pathway to Study the Effect Mechanism of Tuina along the Bladder Meridian on Intervertebral Disc Degeneration(82004497)China Postdoctoral Science Foundation:Based on TGF-β1/RhoA/JNK Signaling Pathway to Study the Effect Mechanism of Tuina along the Bladder Meridian on Intervertebral Disc Degeneration(No.2021M693788)。
文摘OBJECTIVE:The aim of this study was to investigate the protective effects of Tuina(a traditional Chinese massage therapy)on intervertebral disc(IVD)degeneration and the regulatory mechanisms of the transforming growth factor-β1(TGF-β1)/small mothers against decapentaplegic(Smad)signaling pathway.METHODS:Thirty New Zealand white rabbits were randomized into five groups:the control group,model group,model+Tuina group(Tuina group),model+TGF-β1 group(TGF-β1 group),and model+TGF-β1 inhibitor SB431542 group(SB431542 group).The model was established by posterolateral annulus fibrosus puncturing(AFP).Recombinant TGF-β1 and inhibitor SB431542 was injected into the TGF-β1 group and SB431542 group with a microsyringe,respectively.The rabbits in the Tuina group received Tuina treatment along the bladder meridian for 4 weeks.Magnetic resonance imaging(MRI)was performed on rabbits before AFP and after 4 weeks of intervention.Lumbar IVDs(L2-L3 to L4-L5)were harvested after intervention.Histopathological changes in the IVDs were measured by hematoxylin and eosin(HE)staining.Type I collagen was analyzed by immunohistochemistry detection.The expression level of matrix metalloproteinase-3(MMP3)was determined by enzyme-linked immunosorbent assay.Cell apoptosis was evaluated by terminal deoxynucleotidyl transferasemediated nick end labeling and Western blotting.Realtime polymerase chain reaction and Western blotting were used to analyze the expression of TGF-β1 and Smad2/3/4 and a disintegrin and metalloproteinase with thrombospondin motifs 5.RESULTS:Posterolateral AFP induced IVD degeneration in rabbits with histopathological damage and noticeable changes in MRI images.Tuina alleviated histopathological changes and reversed the expression of extracellular matrix degeneration-related molecules and apoptosis-related proteins.Furthermore,AFP induced the activation of TGF-β1 and Smad2/3/4,whereas Tuina therapy markedly reduced the protein expression of Smad2/3 and the gene expression of TGF-β1 and Smad2/3/4.Additionally,the TGF-β1/Smad signaling pathway was activated in the TGF-β1 group,while the TGF-β1/Smad signaling pathway was inhibited in the SB431542 group.CONCLUSION:Posterolateral AFP induced disc degeneration as determined by MRI assessment and histological analysis.Tuina alleviated disc degeneration,possibly by inhibiting the fibrotic response mediated by the TGF-β1/Smad pathway,thus alleviating extracellular matrix degeneration and reducing cell apoptosis.
基金supported by grants from the National Natural Science Foundation of China(82470476,82200447)to Xiu Liu(82470418,82170274)to Shaoyi Zheng+8 种基金(82001230)to Yonghua Tuo(82070312)to Sijia LiangGuangdong Provincial International Science and Technology Cooperation Project(2022A0505050036,China)to Shaoyi ZhengGuangzhou Science and Technology Projects&Key Research Development Program(202206010065,China)to Shaoyi ZhengGuangdong Basic and Applied Basic Research Foundation(2022A1515011747,China)to Shaoyi Zheng(2024A1515013074)to Xiu LiuScience and Technology Projects in Guangzhou(2024A04J5091,China)to Xiu Liu(2024A03J0196)to Yonghua TuoOutstanding Youths Development Scheme of Nanfang Hospital of Southern Medical University(2023J004,China)to Xiu Liu.
文摘This study investigated the role of the nuclear factor of activated T cells c3(NFATc3)in vascular smooth muscle cells(VSMCs)during aortic aneurysm and dissection(AAD)progression and the underlying molecular mechanisms.Cytoplasmic and nuclear NFATc3 levels were elevated in human and mouse AAD.VSMC–NFATc3 deletion reduced thoracic AAD(TAAD)and abdominal aortic aneurysm(AAA)progression in mice,contrary to VSMC–NFATc3 overexpression.VSMC–NFATc3 deletion reduced extracellular matrix(ECM)degradation and maintained the VSMC contractile phenotype.Nuclear NFATc3 targeted and transcriptionally upregulated matrix metalloproteinase 9(MMP9)and MMP2,promoting ECM degradation and AAD development.NFATc3 promoted VSMC phenotypic switching by binding to eukaryotic elongation factor 2(eEF2)and inhibiting its phosphorylation in the VSMC cytoplasm.Restoring eEF2 reversed the beneficial effects in VSMC-specific NFATc3-knockout mice.Cabamiquine—targets eEF2 and inhibits protein synthesis—inhibited AAD development and progression in VSMC-NFATc3-overexpressing mice.VSMC–NFATc3 promoted VSMC switch and ECM degradation while exacerbating AAD development,making it a novel potential therapeutic target for preventing and treating AAD.
基金supported by the National Natural Science Foundation of China(31571193,81422002,91339201)
文摘An abdominal aortic aneurysm(AAA) is a permanent, localized dilatation of the abdominal aorta. In western countries, the morbidity of AAA is approximately 8%. Currently, pharmacotherapies for AAA are limited. Here, we demonstrate that baicalein(BAI), the main component of the Chinese traditional drug "Huang Qin", attenuates the incidence and severity of AAA in Apoe儃/儃 mice infused with angiotensin II(AngII). Mechanically, BAI treatment decreases AngII-induced reactive oxygen species(ROS) production in the aortic wall. Moreover, BAI inhibits inflammatory cell accumulation in the aortas of mice infused with AngII. It also inhibits AngII-induced activation of matrix metalloproteinase 2(MMP-2) and MMP-9 to maintain elastin content in vivo. In addition, it blocks AngII cascade by downregulating angiotensin type 1 receptor(AT1R) and inhibiting mitogen-activated protein kinases(MAPKs). Taken together, our findings show that BAI is an effective agent for AAA prevention.
