首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献,搜索用时 15 毫秒
1.
BACKGROUND: Bryostatin‐1, a highly oxygenated marine macrolide with a unique polyacetate backbone isolated from the marine animal Bugula neritina (Linnaeus), is now being developed as an anti‐cancer drug for treating malignancy. In the present study, developmental toxicity of bryostatin‐1 was evaluated in Sprague–Dawley rats. METHODS: Bryostatin‐1 was intravenously administered to rats on gestation days 6–15 at 4.0, 8.0, and 16.0 µg/kg on a daily basis. Then the reproductive parameters were determined in animals, and fetuses were examined for external, visceral, and skeletal malformations. RESULTS: The total weight gains were significantly different in animals between the control group and 8.0 and 16.0 µg/kg bryostatin‐1 groups during and after treatment. The resorption and death fetus rates were significantly different between the bryostatin‐1 group (16 µg/kg) and the control group. The fetal weight and fetal crown‐rump length in the bryostatin‐1 groups were significantly lower than that in the control group. CONCLUSIONS: Our results indicated that maternal toxicity occurred when the dose of bryostatin‐1 was at 8.0 µg/kg, embryotoxicity at 16.0 µg/kg, and fetotoxicity at 4.0 µg/kg; but bryostatin‐1 showed no teratogenic effect in rats. In light of our findings, bryostatin‐1 should be used with caution in pregnant women with cancer, if they would like to continue the pregnancy. Birth Defects Res (Part B) 89:171–174, 2010. © 2010 Wiley‐Liss, Inc.  相似文献   

2.
3.
4.
Pulmonary fibrosis (PF) is chronic and irreversible damage to the lung characterized by fibroblast activation and matrix deposition. Although recently approved novel anti‐fibrotic agents can improve the lung function and survival of patients with PF, the overall outcomes remain poor. In this study, a novel imidazopurine compound, 3‐(2‐chloro‐6‐fluorobenzyl)‐1,6,7‐trimethyl‐1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione (IM‐1918), markedly inhibited transforming growth factor (TGF)‐β‐stimulated reporter activity and reduced the expression of representative fibrotic markers, such as connective tissue growth factor, fibronectin, collagen and α‐smooth muscle actin, on human lung fibroblasts. However, IM‐1918 neither decreased Smad‐2 and Smad‐3 nor affected p38MAPK and JNK. Instead, IM‐1918 reduced Akt and extracellular signal‐regulated kinase 1/2 phosphorylation increased by TGF‐β. Additionally, IM‐1918 inhibited the phosphorylation of fibroblast growth factor receptors 1 and 3. In a bleomycin‐induced murine lung fibrosis model, IM‐1918 profoundly reduced fibrotic areas and decreased collagen and α‐smooth muscle actin accumulation. These results suggest that IM‐1918 can be applied to treat lung fibrosis.  相似文献   

5.
VEGF (vascular endothelial growth factor) is a potent proangiogenic cytokine, and vascular change is one of the characteristic features of airway remodelling. Since the glucocorticoids have shown antifibrosis properties, we sought to investigate whether budesonide, a widely used glucocorticoid in clinical practice, could attenuate TGF‐β1 (transforming growth factor‐β1)‐induced VEGF production by HFL‐1 (human lung fibroblasts). HFL‐1 fibroblasts were treated with various concentrations of budesonide (10?11 M, 10?9 M and 10?7 M) in the absence or presence of TGF‐β1. Postculture media were collected for ELISA of VEGF at the indicated times. The cell lysates were subjected to Western blotting analysis to test TGF‐β1/Smad and MAP (mitogen‐activated protein) kinase signalling activation, respectively. The results suggested that budesonide pretreatment reduced the significant increase of VEGF release induced by TGF‐β1 in HFL‐1 fibroblasts in a dose‐dependent manner, and suppressed the increase of phospho‐Smad3 and phosphor‐ERK (extracellular signal‐regulated kinase) protein levels. In conclusion, budesonide may reduce TGF‐β1‐induced VEGF production in the lung, probably through the Smad/ERK signalling pathway and, thus, may provide new sight into the molecular mechanism underlying glucocorticoid therapy for airway inflammatory diseases.  相似文献   

6.
7.
In spite of showing high sequence similarity and forming structurally similar ternary complex in vitro, the in vivo role of TGF‐β1 and TGF‐β3 ligands suggests against their functional redundancy and necessitates the importance for the study of the specificity of these ligands. A comparative computational analysis of binary and ternary complexes of these two ligands shows that anchor residues of ligand and receptor at TGF‐β:TβR2 interface are similar in both complexes. However, the potential anchor residues of TGF‐β at TGF‐β:TβR1 interface are different, Tyr50 and Lys51 in TGF‐β3 complex and Lys60 and Tyr6 in TGF‐β1 complex. Pro55 and Asp57 of TβRI may act as anchor residues in complexes of both ligands along with Ile54 for TGF‐β3 complex and Val61 for TGF‐β1 complex. Arg58 of TβR1 acts as a potential hot residue for TGF‐β3 ternary complex but not for TGF‐β1 ternary complex formation whereas Pro55 and Phe60 may act as hot residues for both complexes. The Delphi analysis of the pH dependence of the binding energy indicates that pH has a remarkable effect on the binding energy of TβR2 to the open form of TGF‐β3. Lowering of pH from 7 to 4 favors binding of the open form of TGF‐β3 to TβR2. Now, apart from the residues at pH 7, residues Arg25, Lys31 and Arg94 of TGF‐β3 and Asp118 and Glu119 of TβR2 also contribute significantly to the binding energy. Contrary to the binding energy of TβR2 to TGF‐β3/TGF‐β1, TβR1 shows appreciable pH dependence for its binding in ternary complex of TGF‐β3/TGF‐β1. In TGF‐β3 ternary complex, the TβR1 electrostatic interaction energy disfavors complex formation at pH 7 while it is favored at pH 4. Copyright © 2014 John Wiley & Sons, Ltd.  相似文献   

8.
BACKGROUND: Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d‐MPH and d,l‐MPH as commitments to the FDA. METHODS: Rabbits received 15, 50, 150 mg/kg/day (mkd) d‐MPH or 20, 60, 200, 300 mkd d,l‐MPH on gestation days 7–20. Rats received 2.5, 10, 40 mkd d‐MPH, or 7, 25, 75, 80 mkd d,l‐MPH on gestation days 6–17. RESULTS: d‐MPH—In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥15 mkd in rabbits and ≥10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and ≥10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l‐MPH—In rabbits, mortality occurred at ≥200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at ≥20 mkd in rabbits and ≥25 mkd in rats. Decreased food consumption occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. Decreased body weight parameters occurred at ≥200 mkd in rabbits and ≥25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at ≥75 mkd. CONCLUSIONS: There was no teratogenicity with d‐MPH. There was a low teratogenic risk with d,l‐MPH in only the rabbit. Higher Cmax may explain differences in results from previous studies. Birth Defects Res (Part B) 83:489‐501, 2008. © 2008 Wiley‐Liss, Inc.  相似文献   

9.
10.
11.
Epithelial‐mesenchymal transition (EMT) plays an important role in idiopathic pulmonary fibrosis (IPF). Astragaloside IV (ASV), a natural saponin from astragalus membranaceus, has shown anti‐fibrotic property in bleomycin (BLM)‐induced pulmonary fibrosis. The current study was undertaken to determine whether EMT was involved in the beneficial of ASV against BLM‐induced pulmonary fibrosis and to elucidate its potential mechanism. As expected, in BLM‐induced IPF, ASV exerted protective effects on pulmonary fibrosis and ASV significantly reversed BLM‐induced EMT. Intriguing, transforming growth factor‐β1 (TGF‐β1) was found to be up‐regulated, whereas Forkhead box O3a (FOXO3a) was hyperphosphorylated and less expressed. However, ASV treatment inhibited increased TGF‐β1 and activated FOXO3a in lung tissues. TGF‐β1 was administered to alveolar epithelial cells A549 to induce EMT in vitro. Meanwhile, stimulation with TGF‐β1‐activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway and induced FOXO3a hyperphosphorylated and down‐regulated. It was found that overexpression of FOXO3a leading to the suppression of TGF‐β1‐induced EMT. Moreover, ASV treatment, similar with the TGF‐β1 or PI3K/Akt inhibitor, reverted these cellular changes and inhibited EMT in A549 cells. Collectively, the results suggested that ASV significantly inhibited TGF‐β1/PI3K/Akt‐induced FOXO3a hyperphosphorylation and down‐regulation to reverse EMT during the progression of fibrosis.  相似文献   

12.
Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)‐β and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We previously showed that keratinocytes in vitro downregulate TGF‐β‐induced expression of CTGF in fibroblasts by an interleukin (IL)‐1 α‐dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL‐1α and β. Human dermal fibroblasts and NIH 3T3 cells were treated with IL‐1α or β in presence or absence of TGF‐β1. IL‐1 suppressed basal and TGF‐β‐induced CTGF mRNA and protein expression. IL‐1α and β inhibited TGF‐β‐stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3‐binding CAGA elements. Furthermore, IL‐1α and β inhibited TGF‐β‐stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition, RNA interference suggested that TGF‐β activated kinase1 (TAK1) is necessary for IL‐1 inhibition of TGF‐β‐stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin. J. Cell. Biochem. 110: 1226–1233, 2010. Published 2010 Wiley‐Liss, Inc.  相似文献   

13.
Recent studies have implicated a role of the epidermal growth factor receptor (EGFR) pathway in kidney disease. Skin toxicity associated with therapeutics which completely block the EGFR pathway precludes their use in chronic dosing. Therefore, we developed antibodies which specifically neutralize the EGFR ligands TGFα (transforming growth factor‐alpha) and epiregulin but not EGF (epidermal growth factor), amphiregulin, betacellulin, HB‐EGF (heparin‐binding epidermal growth factor), or epigen. The epitope of one such neutralizing antibody, LY3016859, was characterized in detail to elucidate the structural basis for ligand specificity. Here we report a crystal structure of the LY3016859 Fab fragment in complex with soluble human TGFα. Our data demonstrate a conformational epitope located primarily within the C‐terminal subdomain of the ligand. In addition, point mutagenesis experiments were used to highlight specific amino acids which are critical for both antigen binding and neutralization, most notably Ala41, Glu44, and His45. These results illustrate the structural basis for the ligand specificity/selectivity of LY3016859 and could also provide insight into further engineering to alter specificity and/or affinity of LY3016859.  相似文献   

14.
Lung cancer remains a leading cause to cancer‐related death worldwide. The anti‐cancer ability of microRNA‐144‐3p has been reported in many cancer types. This study focused on the mechanisms underlying miR‐144‐3p in inhibiting lung cancer. The expression levels of miR‐144‐3p and steroid receptor coactivator (Src) in different lung cancer cell lines and those in bronchial epithelial cells (16HBE) were compared. miR‐144‐3p mimic and siSrc were transfected into A549 cells. Under the conditions of transforming growth factor‐β1 (TGF‐β1). Small interfering transfection or TGF‐β1 treatment, cell invasive and adhesive abilities were analyzed by Transwell and cell adhesion assays. miR‐144‐3p inhibitor and siSrc were co‐transfected into A549 cells and the changes in cell invasion and adhesion were detected. The activation of Src–protein kinase B–extracellular‐regulated protein kinases (Src–Akt–Erk) pathway was determined using Western blot. The downregulated miR‐144‐3p and upregulated Src were generally detected in lung cancer cell lines and were the most significant genes in A549 cells. Both miR‐144‐3p overexpression and Src inhibition could obviously inhibit the invasion and adhesion abilities of A549 cells in the presence or absence of the effects of TGF‐β1. The inhibition of Src could block the promotive effects of miR‐144‐3p inhibitor and TGF‐β1 on cell invasion and adhesion. Furthermore, we found that miR‐144‐3p could negatively regulate the phosphorylation levels of Akt and Erk. Our data indicated the essential role of Src in the mechanisms underlying TGF‐β1‐induced cell invasion and adhesion of lung cancer, and that miR‐144‐3p could effectively suppress TGF‐β1‐induced aggressive lung cancer cells by regulating Src expression.  相似文献   

15.
BACKGROUND: Intetumumab is a human IgG1 anti‐αv‐integrin monoclonal antibody that inhibits angiogenesis. Integrin binding and angiogenesis are important in reproduction including fertilization, implantation, and embryofetal development. These studies were designed to determine the pharmacological relevance of the rabbit for the evaluation of potential effects on embryofetal development and to evaluate the placental transfer of intetumumab in rabbits. METHODS: In vitro pharmacology studies evaluated the binding of intetumumab to rabbit cells and the inhibition of vessel sprouting from rabbit aorta. For the evaluation of placental transfer, pregnant rabbits (8/group) were injected intravenously with intetumumab 50 or 100 mg/kg every 2 days from Gestation Day (GD)7 to GD19. Maternal sera, fetal homogenates/sera, and amniotic fluid were collected at necropsy on GD19 or GD28 for evaluation of intetumumab concentrations. Clinical condition of the dams was monitored and fetuses were screened for abnormalities. RESULTS: Intetumumab (5–40 µg/mL) inhibited aortic cell adhesion to vitronectin and vessel sprouting from rabbit aortic rings. Immunohistochemical staining of rabbit tissues demonstrated binding of intetumumab to placenta. Administration of intetumumab to pregnant rabbits was well tolerated by the dams and the fetuses did not show major abnormalities. Fetal exposure to intetumumab relative to maternal exposure was <0.1% on GD19 and 100–130% on GD29. CONCLUSIONS: The rabbit is a pharmacologically relevant species for evaluation of potential developmental effects of intetumumab. Intetumumab crosses the rabbit placenta during the fetal period (GD 19–28). Birth Defects Res (Part B) 89:116–123, 2010. © 2010 Wiley‐Liss, Inc.  相似文献   

16.
17.
Chronic allograft dysfunction (CAD) induced by kidney interstitial fibrosis is the main cause of allograft failure in kidney transplantation. Endothelial‐to‐mesenchymal transition (EndMT) may play an important role in kidney fibrosis. We, therefore, undertook this study to characterize the functions and potential mechanism of EndMT in transplant kidney interstitial fibrosis. Proteins and mRNAs associated with EndMT were examined in human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor‐beta1 (TGF‐β1) at different doses or at different intervals with western blotting, qRT‐PCR and ELISA assays. Cell motility and migration were evaluated with motility and migration assays. The mechanism of EndMT induced by TGF‐β1 was determined by western blotting analysis of factors involved in various canonical and non‐canonical pathways. In addition, human kidney tissues from control and CAD group were also examined for these proteins by HE, Masson's trichrome, immunohistochemical, indirect immunofluorescence double staining and western blotting assays. TGF‐β1 significantly promoted the development of EndMT in a time‐dependent and dose‐dependent manner and promoted the motility and migration ability of HUVECs. The TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways were found to be associated with the pathogenesis of EndMT induced by TGF‐β1, which was also proven in vivo by the analysis of specimens from the control and CAD groups. EndMT may promote transplant kidney interstitial fibrosis by targetting the TGF‐β/Smad and Akt/mTOR/p70S6K signalling pathways, and hence, result in the development of CAD in kidney transplant recipients.  相似文献   

18.
19.
Colon carcinoma invasiveness is a process involving cell–cell and cell–matrix alterations, local proteolysis of the ECM (extracellular matrix) or changes in cytokine and growth factor levels. In order to evaluate the role of TGF‐β1 (transforming growth factor‐β1) and small G protein RhoA in tumour progression, the influence of TGF‐β1 treatment or RhoA‐associated kinase inhibitor on the production of NO (nitric oxide) and MMP‐2 and MMP‐9 (metalloproteinases‐2 and ‐9) was analysed in three human colon adenocarcinoma cell lines (HT29, LS180, SW948) representing different stages of tumour development. All the tested cell lines produced low amounts of MMP‐2 and MMP‐9. rhTGF‐β1 and the synthetic Rho kinase inhibitor (Y‐27632) decreased MMP‐2 secretion by colon cancer cells, especially in the most advanced stage of colon cancer. rhTGF‐β1 decreased NO secretion by cells, while Y‐27632 had no effect on it. Immunoblotting with anti‐RhoA antibodies followed by densitometry revealed that RhoA levels were slightly increased after incubation of colon carcinoma cells (SW948) with rhTGF‐β1. rhTGF‐β1 induced α‐smooth muscle actin (α‐SMA) expression, especially in high Duke's grade of colon cancer, while Y‐27632 blocked it. Summing up, in colon carcinoma cells, TGF‐β1 and RhoA protein may regulate tumour invasiveness measured as MMP, NO and α‐SMA expression or assayed using motility data and may be a good target for cancer therapy.  相似文献   

20.
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号