Background Transforming growth factor beta （TGF-beta） plays an essential role in the regulation of normal physiologic processes of cells. TGF-beta has been shown to regulate several mitogen-activated protein kinases...Background Transforming growth factor beta （TGF-beta） plays an essential role in the regulation of normal physiologic processes of cells. TGF-beta has been shown to regulate several mitogen-activated protein kinases （MAPK） pathways in several epithelial cells. However, the effects of TGF-beta on soft tissue sarcoma are seldom reported. Our previous studies suggested that there should be some other signal transduction pathways besides Smads, which are important to regulate the growth of human embryonal rhabdomyosarcoma （RMS） cells. In the present study, we examined the expression and functional relations of extracellular signal-regulated kinase 2 （ERK2） and Smad4 in human RMS tissue and a RMS cell line, RD. Methods RD cells and normal human primary skeletal myoblasts （Mb） were treated with TGF-betal to establish the expression profile of ERK2 at the mRNA and protein levels detected by RT-PCR and immunofluorescence. Immunohistochemistry was used to detect the expression of ERK2 and Smad4 in 50 tissue specimens of human RMS and 23 specimens of normal skeletal muscles. Follow-up of specimens was performed 6 months to 70 months later. Results RD cells and human RMS tissues showed the higher expression of ERK2 and Smad4 than the normal control, either the protein level or the mRNA level. And, exogenous TGF-betal stimulation can lead to higher expression of ERK2 and its nuclear translocation, so TGF-betal can also activatedMAPK （ERK2） pathway, resulting in a sustained activation of ERK2 for at least 2 hours. Immunohistochemistry analysis, however, showed that there was no correlation between ERK2 and Smad4 protein. The overexpression of ERK2 and Smad4 had no indicative effects on histological subtypes, histological grading, gender, age, and prognosis. Conclusions In RMS, signaling of TGF-betal from cell surface to nucleus can also be directed through the MAPK （ERK2） pathway besides the TGF-betal/Smads pathway. The activation of ERK2 by TGF-betal may be Smad4 independent. Moreover, there may be some other tanglesome relationships between the TGF-betal/Smads pathway and the MAPK pathway which takes part in the development, invasion and metastasis of tumor cells.展开更多
OBJECTIVE:To investigate the mechanism by which Sini decoction(四逆汤,SND)improves renal fibrosis(Rf)in rats based on transforming growth factor β1/Smad(TGF-β1/Smad)signaling pathway.METHODS:Network pharmacology was...OBJECTIVE:To investigate the mechanism by which Sini decoction(四逆汤,SND)improves renal fibrosis(Rf)in rats based on transforming growth factor β1/Smad(TGF-β1/Smad)signaling pathway.METHODS:Network pharmacology was applied to obtain potentially involved signaling pathways in SND's improving effects on Rf.The targets of SND drug components and the targets of Rf were obtained by searching databases,such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCSMP)and GeenCard.The intersection targets of two searches were obtained and underwent signaling pathway analysis using a Venn diagram.Then experimental pharmacology was utilized to prove and investigate the effects of SND on target proteins in the TGF-β1/Smad signaling pathway.The Rf rat model was established by unilateral ureteral occlusion(UUO).The expression levels of transforming growth factor,matrix metalloproteinase-9(MMP-9),matrix metal protease-2(MMP-2),connective tissue growth factor(CTGF),and tissue inhibitor of metalloproteinase-1(TIMP-1)were determined by Masson staining of rat renal tissue,and immunohistochemical methods.The expression levels of Smad3,Smad2,and Smad7 in renal tissue were determined by Western blotting(WB).The mechanism of the improving effects of SND on Rf was investigated based on TGF-β1/Smad signaling pathway.RESULTS:A total of 12 drug components of Fuzi(Radix Aconiti Lateralis Preparata),5 drug components of Ganjiang(Rhizoma Zingiber),and 9 drug components of Gancao(Radix Glycy et Rhizoma)were obtained from the database search,and 207 shared targets were found.A total of 1063 Rf targets were found in the database search.According to the Venn diagram,in total,96 intersection targets were found in two database searches.The metabolic pathways involved included TGF-β signaling pathway,phosphatidylinositol-3-kinase/serine-threonine protein kinase signaling(PI3K/Akt)pathway,and hypoxia-inducible factor-1(HIF-1)signaling pathway.Masson staining analysis showed that compared with the model group,the renal interstitial collagen deposition levels in the SSN and SND groups were significantly lower(P<0.05).Immunohistochemical analysis,compared with the control group,the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the model group were significantly decreased(P<0.05,P<0.01),and the positive cell area expression levels of CTGF and TGF-β1 were significantly increased(P<0.01).Compared with the model group,the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the SSN and SND groups were significantly increased(P<0.05,P<0.01),and the positive cell area expression levels of CTGF and TGF-β1 in the kidney tissue were significantly decreased(P<0.05,P<0.01).WB results showed that the SSN group and the SND group could reduce the expression of Smad2 and Smad3(P<0.05)and increase the expression of Smad7(P<0.05).展开更多
Background： Transforming growth factor-beta 1 （TGF-β 1） and gene variants have been extensively studied in various human diseases. For example, TGF-β1 polymorphisms were associated with fibrosis and pneumoconiosi...Background： Transforming growth factor-beta 1 （TGF-β 1） and gene variants have been extensively studied in various human diseases. For example, TGF-β1 polymorphisms were associated with fibrosis and pneumoconiosis, but the data remained controversial. The aim of this meta-analysis was to assess the association between TGF-β1-509 C〉T [rs 1800469], ＋869 T〉C [rs 1800470], and ＋915 G〉C [rs 1800471 ] polymorphisms and pneumoconiosis, Methods： A comprehensive literature search was conducted through searching in PubMed, Embase, the Chinese Biomedical Database, and the Wei Pu （Chinese） Database by the end of April 2016. Eleven publications with 21 studies were included in this recta-analysis, covering a total of 4333 patients with pneumoconiosis and 3478 controls. Study quality was assessed, and heterogeneity and publication bias were measured. All statistical analyses were performed using STATA version 12.0 （StataCorp, College Station, TX, USA） software. Results： The data showed significant associations between TGF-β1-509 C〉T polymorphism and the risk ofpneumoconiosis development （T vs. C, odds ratio [OR] = 1.35, 95% confidence interval [CI]： 1.00-1.81, P = 0.046）; between TGF-fll ＋915 G〉C polymorphism and the pneumoconiosis risk （C vs. G, OR = 1.69, 95% CI： 1.19-2.40, P = 0.004; CG vs. GG, OR = 1.79, 95% CI： 1.23-2.60, P = 0.002; CC＋CG vs. GG, OR = 1.80, 95% CI： 1.24-2.61, P = 0.002）. In addition, the subgroup analysis of ethnicity versus pneumoconiosis types indicated a significant association of silicosis among Asian populations but not that of coal workers＇ pneumoconiosis in Caucasian populations. In contrast, no significant association was exhibited between TGF-β1 ＋869 T〉C polymorphism and risk ofpneumoconiosis. Conclusion： The polymorphisms of both TGF-β1 -509 C〉T and ＋915 G〉C are associated with increased risk of pneumoconiosis. Key words： Meta analysis; Pneumoconiosis; Polymorphism; Transforming Growth Factor-betal展开更多
基金This work was supported by a grant from China Medical Board of New York(No.CMB 00-722)
文摘Background Transforming growth factor beta （TGF-beta） plays an essential role in the regulation of normal physiologic processes of cells. TGF-beta has been shown to regulate several mitogen-activated protein kinases （MAPK） pathways in several epithelial cells. However, the effects of TGF-beta on soft tissue sarcoma are seldom reported. Our previous studies suggested that there should be some other signal transduction pathways besides Smads, which are important to regulate the growth of human embryonal rhabdomyosarcoma （RMS） cells. In the present study, we examined the expression and functional relations of extracellular signal-regulated kinase 2 （ERK2） and Smad4 in human RMS tissue and a RMS cell line, RD. Methods RD cells and normal human primary skeletal myoblasts （Mb） were treated with TGF-betal to establish the expression profile of ERK2 at the mRNA and protein levels detected by RT-PCR and immunofluorescence. Immunohistochemistry was used to detect the expression of ERK2 and Smad4 in 50 tissue specimens of human RMS and 23 specimens of normal skeletal muscles. Follow-up of specimens was performed 6 months to 70 months later. Results RD cells and human RMS tissues showed the higher expression of ERK2 and Smad4 than the normal control, either the protein level or the mRNA level. And, exogenous TGF-betal stimulation can lead to higher expression of ERK2 and its nuclear translocation, so TGF-betal can also activatedMAPK （ERK2） pathway, resulting in a sustained activation of ERK2 for at least 2 hours. Immunohistochemistry analysis, however, showed that there was no correlation between ERK2 and Smad4 protein. The overexpression of ERK2 and Smad4 had no indicative effects on histological subtypes, histological grading, gender, age, and prognosis. Conclusions In RMS, signaling of TGF-betal from cell surface to nucleus can also be directed through the MAPK （ERK2） pathway besides the TGF-betal/Smads pathway. The activation of ERK2 by TGF-betal may be Smad4 independent. Moreover, there may be some other tanglesome relationships between the TGF-betal/Smads pathway and the MAPK pathway which takes part in the development, invasion and metastasis of tumor cells.
基金National Natural Science Foundation of China:General Program:Research on the Protective Effect of Component Wu Sini Decoction on Hypothyroidism and Kidney Injury and Its Mechanism of Action(No.81373546)Study on the Protective Effect and Mechanism of Wu Sini decoction on Renal Fibrosis(No.2016021165)+1 种基金Shanxi University of Chinese Medicine Pharmacology Discipline Construction Project(No.2023XKJS-25)Shanxi University of Chinese Medicine Pharmacy Discipline Construction Project(No.2023XKJS-26)。
文摘OBJECTIVE:To investigate the mechanism by which Sini decoction(四逆汤,SND)improves renal fibrosis(Rf)in rats based on transforming growth factor β1/Smad(TGF-β1/Smad)signaling pathway.METHODS:Network pharmacology was applied to obtain potentially involved signaling pathways in SND's improving effects on Rf.The targets of SND drug components and the targets of Rf were obtained by searching databases,such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCSMP)and GeenCard.The intersection targets of two searches were obtained and underwent signaling pathway analysis using a Venn diagram.Then experimental pharmacology was utilized to prove and investigate the effects of SND on target proteins in the TGF-β1/Smad signaling pathway.The Rf rat model was established by unilateral ureteral occlusion(UUO).The expression levels of transforming growth factor,matrix metalloproteinase-9(MMP-9),matrix metal protease-2(MMP-2),connective tissue growth factor(CTGF),and tissue inhibitor of metalloproteinase-1(TIMP-1)were determined by Masson staining of rat renal tissue,and immunohistochemical methods.The expression levels of Smad3,Smad2,and Smad7 in renal tissue were determined by Western blotting(WB).The mechanism of the improving effects of SND on Rf was investigated based on TGF-β1/Smad signaling pathway.RESULTS:A total of 12 drug components of Fuzi(Radix Aconiti Lateralis Preparata),5 drug components of Ganjiang(Rhizoma Zingiber),and 9 drug components of Gancao(Radix Glycy et Rhizoma)were obtained from the database search,and 207 shared targets were found.A total of 1063 Rf targets were found in the database search.According to the Venn diagram,in total,96 intersection targets were found in two database searches.The metabolic pathways involved included TGF-β signaling pathway,phosphatidylinositol-3-kinase/serine-threonine protein kinase signaling(PI3K/Akt)pathway,and hypoxia-inducible factor-1(HIF-1)signaling pathway.Masson staining analysis showed that compared with the model group,the renal interstitial collagen deposition levels in the SSN and SND groups were significantly lower(P<0.05).Immunohistochemical analysis,compared with the control group,the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the model group were significantly decreased(P<0.05,P<0.01),and the positive cell area expression levels of CTGF and TGF-β1 were significantly increased(P<0.01).Compared with the model group,the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the SSN and SND groups were significantly increased(P<0.05,P<0.01),and the positive cell area expression levels of CTGF and TGF-β1 in the kidney tissue were significantly decreased(P<0.05,P<0.01).WB results showed that the SSN group and the SND group could reduce the expression of Smad2 and Smad3(P<0.05)and increase the expression of Smad7(P<0.05).
文摘Background： Transforming growth factor-beta 1 （TGF-β 1） and gene variants have been extensively studied in various human diseases. For example, TGF-β1 polymorphisms were associated with fibrosis and pneumoconiosis, but the data remained controversial. The aim of this meta-analysis was to assess the association between TGF-β1-509 C〉T [rs 1800469], ＋869 T〉C [rs 1800470], and ＋915 G〉C [rs 1800471 ] polymorphisms and pneumoconiosis, Methods： A comprehensive literature search was conducted through searching in PubMed, Embase, the Chinese Biomedical Database, and the Wei Pu （Chinese） Database by the end of April 2016. Eleven publications with 21 studies were included in this recta-analysis, covering a total of 4333 patients with pneumoconiosis and 3478 controls. Study quality was assessed, and heterogeneity and publication bias were measured. All statistical analyses were performed using STATA version 12.0 （StataCorp, College Station, TX, USA） software. Results： The data showed significant associations between TGF-β1-509 C〉T polymorphism and the risk ofpneumoconiosis development （T vs. C, odds ratio [OR] = 1.35, 95% confidence interval [CI]： 1.00-1.81, P = 0.046）; between TGF-fll ＋915 G〉C polymorphism and the pneumoconiosis risk （C vs. G, OR = 1.69, 95% CI： 1.19-2.40, P = 0.004; CG vs. GG, OR = 1.79, 95% CI： 1.23-2.60, P = 0.002; CC＋CG vs. GG, OR = 1.80, 95% CI： 1.24-2.61, P = 0.002）. In addition, the subgroup analysis of ethnicity versus pneumoconiosis types indicated a significant association of silicosis among Asian populations but not that of coal workers＇ pneumoconiosis in Caucasian populations. In contrast, no significant association was exhibited between TGF-β1 ＋869 T〉C polymorphism and risk ofpneumoconiosis. Conclusion： The polymorphisms of both TGF-β1 -509 C〉T and ＋915 G〉C are associated with increased risk of pneumoconiosis. Key words： Meta analysis; Pneumoconiosis; Polymorphism; Transforming Growth Factor-betal
