BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the stron...BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.展开更多
We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly ...We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.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
Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,an...Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,and its dynamic changes are closely related to the proliferation of endothelial cells,the recruitment of pericytes to blood vessels,and functional differentiation during embryonic vascular development.The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells.Indeed,mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation.Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms,arteriovenous malformations,and cerebral atherosclerosis.In this review,we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis,and we discuss its relationship to functional dysregulation in cerebrovascular diseases.This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis,treatment,and prevention.展开更多
Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic p...Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic pyrophosphate （ePPi）. Mechanical stimulation regulates ENPP-1 expression. This study sought to investigate the changes in ENPP-1 expression after stimulation using cyclic mechanical tension （CMT）.展开更多
OBJECTIVE:To investigate the efficacy of Shenweifang(SWF)-containing serum on transforming growth factor(TGF)-β1–induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells(NRK-49 ...OBJECTIVE:To investigate the efficacy of Shenweifang(SWF)-containing serum on transforming growth factor(TGF)-β1–induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells(NRK-49 F).METHODS:Sprague-Dawley rats were gavaged with one of five solutions:(a)saline;(b)saline plus low-dose SWF;(c)saline plus medium-dose SWF;(d)saline plus highdose SWF;and(e)saline plus valsartan.NRK-49 F cells were treated with TGF-β1 and cultured using serum from the gavaged rats.RESULTS:TGF-β1 treatment increased the expression ofα-smooth muscle actin,proliferating cell nuclear antigen,collagenⅠ,Smad3,mitogen-activated protein kinase(MAPK)10,and c-Jun N-terminal kinase(JNK)3 and induced abnormalities in cell morphology,cell cycle progression,and cell proliferation.CONCLUSIONS:SWF-or valsartan-containing serum corrected(or partially corrected)TGF-β1–induced abnormal changes in this in vitro system.SWF-containing serum reversed abnormalities in morphology,cell cycle progression,and proliferation in TGF-β1–treated NRK-49F cells,probably by blocking the TGF-β1/Smads and TGF-β1/MAPK/JNK pathways.展开更多
Background Insulin-like growth factor binding protein-related protein 1 （IGFBPrP1） can activate hepatic stellate cells and increase extracellular matrix （ECM） in vitro. However, the effects of IGFBPrP1 in mice wit...Background Insulin-like growth factor binding protein-related protein 1 （IGFBPrP1） can activate hepatic stellate cells and increase extracellular matrix （ECM） in vitro. However, the effects of IGFBPrP1 in mice with hepatic fibrosis, and the mechanisms of these effects, are currently unknown. We aim to address these issues in this study. Methods Intraperitoneal injection of thioacetamide （TAA） is a classic method for establishing a mouse model of hepatic fibrosis. Using this model, we administered anti-IGFBPrP1 antibody, again via intraperitoneal injection. The morphological changes of liver fibrosis were observed with both HE and Masson stainning. The immunohistochemical assays and Western blotting were used to measure changes in IGFBPrP1, a-smooth muscle actin （a-SMA） and ECM in liver tissues, and the expression of transforming growth factor-β1 （TGF-β1） and Smad3. Data were statistically analyzed using one-way analysis of variance （ANOVA）, the SNK-q test for inter-group differences. Results The Masson staining analysis showed that compared with normal control group, content of collagen fiber in TAA5w group was significantly increased （P 〈0.01）, and it was significantly decreased in TAA5w/alGFBPrP1 group compared with in TAA5w group （P 〈0.01）. The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin （FN） was significantly up-regulated in the TAA5w group （P 〈0.01）. Anti-IGFBPrP1 treatment reversed these changes （P 〈0.01）. Conclusions IGFBPrP1 plays an important role in the development of hepatic fibrosis. Anti-IGFBPrP1 prevents fibrosis in mice by suppressing the activation of hepatic stellate cells, inhibiting the synthesis of major components of the ECM （namely, collagen I and FN）. The mechanism for this suppression of fibrosis is associated with the TGF-β1/Smad3 signaling pathways.展开更多
基金supported by a grant from the Shanxi Province Foundation for Returness(2012-4)
文摘BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.
基金grants fromthe Chinese Academy of Sciences (No. KJ951-BI608), the National Natural Sciences FOundation ofChina (No. 39625007 and
文摘We reported in this manuscript that TGF-beta1 induces apoptosis in AML12 murine hepatocytes, which is associated with the activation of p38 MAPK signaling pathway. SB202190, a specific inhibitor of p38 MAPK, strongly inhibited the TGF-beta1-induced apoptosis and PAI-1 promoter activity. Treatment of cells with TGF-beta1 activates p38. Furthermore, over-expression of dominant negative mutant p38 also reduced the TGF-beta1-induced apoptosis. The data indicate that the activation of p38 is involved in TGF-beta1-mediated gene expression and apoptosis.
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 the National Natural Science Foundation of China,No.81801175(to CLT)the Fundamental Research Funds for the Central Universities of China,No.WK9110000044(to CLT)+2 种基金China Scholarship Council,No.201706270155(to CLT)the China Postdoctoral Science Foundation,No.2019M662179(to CLT)the Anhui Province Postdoctoral Science Foundation of China,No.2019B324(to CLT)
文摘Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,and its dynamic changes are closely related to the proliferation of endothelial cells,the recruitment of pericytes to blood vessels,and functional differentiation during embryonic vascular development.The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells.Indeed,mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation.Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms,arteriovenous malformations,and cerebral atherosclerosis.In this review,we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis,and we discuss its relationship to functional dysregulation in cerebrovascular diseases.This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis,treatment,and prevention.
文摘Background Ectonucleotide pyrophosphatase/phosphodiesterase （ENPP）-I is a membrane-bound protein that catalyzes the hydrolysis of extracellular nucleoside triphosphates to monophosphate and extracellular inorganic pyrophosphate （ePPi）. Mechanical stimulation regulates ENPP-1 expression. This study sought to investigate the changes in ENPP-1 expression after stimulation using cyclic mechanical tension （CMT）.
基金Supported by the Department of Science and Technology of Southwest Medical University(No.2017-ZRQN-072)the Department of Science and Technology of Affiliated Hospital of Southwest Medical University(No.16231)。
文摘OBJECTIVE:To investigate the efficacy of Shenweifang(SWF)-containing serum on transforming growth factor(TGF)-β1–induced fibroblast-myofibroblast transition in normal rat kidney interstitial fibroblast cells(NRK-49 F).METHODS:Sprague-Dawley rats were gavaged with one of five solutions:(a)saline;(b)saline plus low-dose SWF;(c)saline plus medium-dose SWF;(d)saline plus highdose SWF;and(e)saline plus valsartan.NRK-49 F cells were treated with TGF-β1 and cultured using serum from the gavaged rats.RESULTS:TGF-β1 treatment increased the expression ofα-smooth muscle actin,proliferating cell nuclear antigen,collagenⅠ,Smad3,mitogen-activated protein kinase(MAPK)10,and c-Jun N-terminal kinase(JNK)3 and induced abnormalities in cell morphology,cell cycle progression,and cell proliferation.CONCLUSIONS:SWF-or valsartan-containing serum corrected(or partially corrected)TGF-β1–induced abnormal changes in this in vitro system.SWF-containing serum reversed abnormalities in morphology,cell cycle progression,and proliferation in TGF-β1–treated NRK-49F cells,probably by blocking the TGF-β1/Smads and TGF-β1/MAPK/JNK pathways.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30871146）, and the New Century Excellent Talent of the Ministry of Education of China （No. NCET-06-0264）.
文摘Background Insulin-like growth factor binding protein-related protein 1 （IGFBPrP1） can activate hepatic stellate cells and increase extracellular matrix （ECM） in vitro. However, the effects of IGFBPrP1 in mice with hepatic fibrosis, and the mechanisms of these effects, are currently unknown. We aim to address these issues in this study. Methods Intraperitoneal injection of thioacetamide （TAA） is a classic method for establishing a mouse model of hepatic fibrosis. Using this model, we administered anti-IGFBPrP1 antibody, again via intraperitoneal injection. The morphological changes of liver fibrosis were observed with both HE and Masson stainning. The immunohistochemical assays and Western blotting were used to measure changes in IGFBPrP1, a-smooth muscle actin （a-SMA） and ECM in liver tissues, and the expression of transforming growth factor-β1 （TGF-β1） and Smad3. Data were statistically analyzed using one-way analysis of variance （ANOVA）, the SNK-q test for inter-group differences. Results The Masson staining analysis showed that compared with normal control group, content of collagen fiber in TAA5w group was significantly increased （P 〈0.01）, and it was significantly decreased in TAA5w/alGFBPrP1 group compared with in TAA5w group （P 〈0.01）. The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin （FN） was significantly up-regulated in the TAA5w group （P 〈0.01）. Anti-IGFBPrP1 treatment reversed these changes （P 〈0.01）. Conclusions IGFBPrP1 plays an important role in the development of hepatic fibrosis. Anti-IGFBPrP1 prevents fibrosis in mice by suppressing the activation of hepatic stellate cells, inhibiting the synthesis of major components of the ECM （namely, collagen I and FN）. The mechanism for this suppression of fibrosis is associated with the TGF-β1/Smad3 signaling pathways.
