Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Becaplermin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources
PubMed2003

Latent transforming growth factor-beta binding protein-1, a component of latent transforming growth factor-beta complex, accelerates the migration of aortic smooth muscle cells in diabetic rats through integrin-beta3.

Aortic smooth muscle cells (SMCs) of diabetic animals have unique properties, including the overexpression of transforming growth factor-beta (TGF-beta) type II receptor, fibronectin, and platelet-derived growth factor beta-receptor. TGF-beta1 is produced and secreted as latent high-molecular weight complex consisting of mature TGF-beta1, latency-associated peptide (LAP), and a latent TGF-beta1 binding protein (LTBP-1). LAP has an important function in the latency of TGF-beta complex, but the role of LTBP-1 is not known in diabetic angiopathy. SMC migration from the medial layer to the intimal layer of an artery is an initial major process of the formation of intimal thickening of an artery. Migration activities of SMCs from diabetic rat with 1-500 pg/ml of LTBP-1 increased significantly compared with that without LTBP-1. LTBP-1 at 10-500 pg/ml stimulated the migration of diabetic SMCs more than SMCs from control rat. An anti-integrin-beta(3) antibody reduced LTBP-1-stimulated migration of diabetic SMCs to 51% compared with no antibody, but it did not reduce that of control SMCs. Furthermore, cross-linking experiments show that LTBP-1 binds integrin-beta(3) in diabetic SMCs much more than in control SMCs in coincidence with the increase of integrin-beta(3) in diabetic aorta by immunohistochemistry. Taken together, these observations suggest that LTBP-1 plays a critical role in intimal thickening of diabetic artery through the acceleration of SMC migration via integrin-beta(3).

Animals↗
PubMed2003

Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes.

Increased expression of endothelin-1 (ET-1) is associated with diabetic retinopathy and vasculopathy, although the molecular explanation has not been defined. The effects of high glucose and protein kinase C (PKC) activation on platelet-derived growth factor (PDGF)-BB and of ET-1 expression in the retina of streptozotocin (STZ)-induced diabetic rats and bovine retinal pericytes (BRPC) were examined. In 4-week diabetic rats, PDGF-B and prepro-ET-1 (ppET-1) mRNA levels increased significantly by 2.8- and 1.9-fold, respectively, as quantified by RT-PCR. Treatment with PKC-beta isoform-specific inhibitor (LY333531) or insulin normalized retinal ET-1 and PDGF-B expression. In BRPC, high glucose levels increased ppET-1 and PDGF-B mRNA expression by 1.7- and 1.9-fold, respectively. The addition of PDGF-BB but not PDGF-AA increased expression of ppET-1 and vascular endothelial growth factor mRNA by 1.6- and 2.1-fold, respectively, with both inhibited by AG1296, a selective PDGF receptor kinase inhibitor. A general PKC inhibitor, GF109203X, suppressed PDGF-BB's induction of ET-1 mRNA. Thus, increased ET-1 expression in diabetic retina could be due to increased expression of PDGF-BB, mediated via PDGF-beta receptors in part by PKC activation. The novel demonstration of elevated expression of PDGF-B and its induction by PKC activation identifies a potential new molecular step in the pathogenesis of diabetic retinopathy.

Animals↗
PubMed2006

Platelet-derived growth factor-BB controls epithelial tumor phenotype by differential growth factor regulation in stromal cells.

Platelet-derived growth factor (PDGF) stimulates tumor growth and progression by affecting tumor and stromal cells. In the HaCaT skin carcinogenesis model, transfection of immortal nontumorigenic and PDGF-receptor-negative HaCaT keratinocytes with PDGF-B induced formation of benign tumors. Here, we present potential mechanisms underlying this tumorigenic conversion. In vivo, persistent PDGF-B expression induced enhanced tumor cell proliferation but only transiently stimulated stromal cell proliferation and angiogenesis. In vitro and in vivo studies identified fibroblasts as PDGF target cells essential for mediating transient angiogenesis and persistent epithelial hyperproliferation. In fibroblast cultures, long-term PDGF-BB treatment caused an initial up-regulation of vascular endothelial growth factor (VEGF)-A, followed by a drastic VEGF down-regulation and myofibroblast differentiation. Accordingly, in HaCaT/PDGF-B transplants, initially enhanced VEGF expression by stromal fibroblasts was subsequently reduced, followed by down-regulation of angiogenesis, myofibroblast accumulation, and vessel maturation. The PDGF-induced, persistently increased expression of the hepatocyte growth factor by fibroblasts in vitro and in vivo was most probably responsible for enhanced epithelial cell proliferation and benign tumor formation. Thus, by paracrine stimulation of the stroma, PDGF-BB induced epithelial hyperproliferation, thereby promoting tumorigenicity, whereas the time-limited activation of the stroma followed by stromal maturation provides a possible explanation for the benign tumor phenotype.

Actins↗
PubMed2006

Effects of platelet-derived growth factor-BB on the metabolic function and morphologic features of equine tendon in explant culture.

OBJECTIVE: To evaluate the effects of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) on the metabolic function and morphologic features of equine superficial digital flexor tendon (SDFT) in explant culture. Animals-6 euthanized horses (2 to 5 years old). METHODS: Forelimb SDFT explants were cultured for 6 days as untreated control specimens or treated with rhPDGF-BB (1, 10, 50, or 100 ng/mL of medium). Treatment effects on explant gene expression were evaluated via real-time PCR analysis of collagen type I, collagen type III, PDGF-A, and PDGF-B mRNA. Explants were assayed for total collagen, glycosaminoglycan, and DNA content; histologic changes were assessed via H and E staining and immunohistochemical localization of collagen types I and III. RESULTS: No morphologic or proliferative changes were detected in tendon explant sections. After high-dose rhPDGF-BB treatment, gene expression of collagen types I and III was increased and decreased, respectively. Expression of PDGF-A and PDGF-B mRNA was significantly increased at 24 hours, but later decreased to have few or negative autoinductive effects. Although PDGF gene expression waned after 48 hours of culture, collagen type I gene expression was significantly increased at 48 hours and reached peak value on day 6. Glycosaminoglycan and DNA content of explants were unchanged with rhPDGF-BB treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that rhPDGF-BB use may be of benefit in the repair of equine tendon, particularly through induction of collagen type I mRNA. Positive autoinductive effects of PDGF-BB in equine SDFT explants were detected early following culture medium supplementation, but these diminished with time.

Animals↗
PubMed1997

The effect of diclofenac (Voltaren) on the contraction of collagen lattices.

The inhibition of prostaglandin synthesis by diclofenac was studied with regard to effects on connective-tissue contraction and on the chemotaxis of fibroblasts stimulated by platelet-derived growth factor type BB (PDGF-BB). Collagen lattices populated with human fibroblasts responded to diclofenac with significantly increased contraction; the peak effect occurred at a dose of 5 micrograms/ml. Using a two-chamber system, PDGF-BB significantly increased the chemotactic activity of fibroblasts, and addition of diclofenac further increased this activity. Higher doses of diclofenac resulted in cell death, which was also reflected in lessened contraction of lattices with 50 micrograms/ml diclofenac, half of the cells were dead. The study showed that inhibition of prostaglandin synthesis by diclofenac increases the contraction of collagen lattices populated with human fibroblasts and increases the chemotactic activity of fibroblasts stimulated with PDGF-BB.

Becaplermin↗
PubMed1995

TGF-beta and PDGF act synergistically in affecting the growth of human osteoblast-enriched cultures.

Transforming growth factor beta (TGF-beta) is a polypeptide found in high concentrations in bone and is produced by and acts on primary adult human derived osteoblast-enriched cultures (PHO cells). Receptors for TGF-beta are present on PHO cells and TGF-beta is mitogenic for these cells. Results of these studies in conjunction with those of others suggest that TGF-beta may have an important therapeutic role in orthopaedic surgery; however, with respect to its mitogenic actions, further studies were needed to establish whether TGF-beta was acting directly to stimulate the growth of PHO cells. TGF-beta has been found in other systems to act as an indirect mitogen, stimulating growth via secretion of another growth factor, platelet-derived growth factor (PDGF). In an effort to determine whether the TGF-beta growth stimulation was mediated directly or indirectly, we have examined the growth stimulation of PHO cells by PDGF alone and in combination with TGF-beta. These studies revealed that TGF-beta in combination with either PDGF-AA or BB led to stimulation greater than that observed with either growth factor alone. TGF-beta in combination with PDGF-BB led to a synergistic stimulatory response while that observed with the AA isoform was more nearly additive. Further studies demonstrated that TGF-beta was capable of up-regulating the protein levels of the PDGF alpha (alpha) receptor within thirty minutes of TGF-beta pretreatment. Thus, TGF-beta appears to have both direct and indirect mechanisms of action as a mitogen in the PHO system. Finally, we showed that both the positive and negative alkaline phosphatase staining PHO cells were responsive to the mitogenic effects of both growth factor singly and in combination.

Alkaline Phosphatase↗
PubMed1997

Effect of growth factors on the proliferation of ligament fibroblasts from skeletally mature rabbits.

Growth factors have been shown to stimulate fibroblast proliferation during wound and ligament healing. In this study, we analyzed individual effects of eight growth factors in vitro on the proliferation of fibroblasts from the medial collateral (MCL) and anterior cruciate (ACL) ligaments of skeletally mature rabbits. We compared the proliferative response of growth factor-treated and nontreated fibroblasts of both ligaments. The growth-factor treated fibroblasts of the MCL and ACL were also compared. We found that the fibroblasts exposed to epidermal growth factor, basic fibroblast growth factor and platelet-derived growth factor-BB proliferated significantly more than untreated fibroblasts. Acidic fibroblast growth factor at a dose of 1.0 ng/ml caused significant increases in fibroblast proliferation only in the MCL. Transforming growth factor-beta 1, insulin-like growth factor-1, platelet-derived growth factor-AA, and interleukin-1 alpha did not significantly stimulate fibroblast proliferation. MCL fibroblasts generally did not proliferate significantly more than ACL fibroblasts with the exception of MCL fibroblasts exposed to the highest doses of basic fibroblast growth factor, acidic fibroblast growth factor and platelet-derived growth factor-BB. The data were also compared with those obtained earlier using fibroblasts from skeletally immature rabbits (Schmidt et al., JOR 1995). The proliferative response of both the MCL and the ACL fibroblasts was found to decrease with skeletal maturation. Thus, our findings suggest that animal age and fibroblast origin are important factors in determining the proliferative response to growth factors.

Animals↗
PubMed1994

The role of PDGF-BB on the development of the collateral circulation after acute arterial occlusion.

The survival of tissues in the presence of arterial occlusion is critically dependent on the development of collateral blood vessels. Identification of the biochemical mediators and their mechanism of action is fundamental to an understanding of the evolution of the collateral circulation. The ability of PDGF-BB to promote this was evaluated in an animal model of hind limb ischaemia. In order to obtain significant quantities of this mitogen for use in our animal model, human recombinant PDGF-BB was expressed in a Chinese Hamster Ovary (CHO) cell line. The transfected CHO cells produced 544 micrograms/l of PDGF-BB in serum free medium (SFM). The 30 kDa form of PDGF-BB was purified to homogeneity as judged by silver staining and amino-acid sequencing. Purified PDGF-BB was shown to be bioactive by a cell proliferation assay. The exogenous administration of PDGF-BB enhanced the recovery of blood flow after acute arterial occlusion. The results suggest that PDGF-BB may have therapeutic value in promoting collateral development following arterial occlusion.

Acute Disease↗
PubMed1994

Platelet-derived growth factor induces phosphatidylinositol 3-kinase release from the middle T-pp60c-src complex and association with the platelet-derived growth factor receptor.

Both platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) induce mitogenesis in normal rat kidney (NRK) fibroblasts transformed by the polyoma virus middle T (pmt) oncogene. In unstimulated pmt-NRK cells phosphatidylinositol 3-kinase forms a complex with the middle T protein and pp60c-src. PDGF treatment causes a release of phosphatidylinositol 3-kinase activity from the complex and a simultaneous increase in activity associated with the PDGF receptor. In contrast after treatment with EGF the majority of phosphatidylinositol 3-kinase activity remains associated with the middle T-pp60c-src complex. Proliferation of NRK fibroblasts transformed by the v-src oncogene is already maximal, and no further stimulation is observed with either PDGF or EGF. Neither growth factor induces dissociation of the complex between phosphatidylinositol 3-kinase and pp60v-src. These observations suggest that the complex between phosphatidylinositol 3-kinase, the middle T protein and pp60c-src is dissociable, and that phosphatidylinositol 3-kinase plays different roles in mitogenic signal transduction by the PDGF and EGF receptors.

Animals↗
PubMed1995

PDGF-BB triggered cytoplasmic calcium responses in cells with endogenous or stably transfected PDGF beta-receptors.

Platelet-derived growth factor-BB (PDGF-BB) triggered signal transduction was investigated in human foreskin fibroblasts with endogenous PDGF beta-receptors, and porcine aortic endothelial (PAE) cells with stably transfected PDGF beta-receptors. Immunoprecipitation and immunoblotting showed that PDGF induced dose-dependent autophosphorylation of PDGF beta-receptor, and the PLC-gamma associates with autophosphorylated PDGF beta-receptors and becomes phosphorylated. Activation of PLC-gamma is known to induce fluctuations of the concentration of cytoplasmic calcium ([Ca2+]i). Microfluorometry and digital imaging were employed for measurements of the concentration of [Ca2+]i. In both cell types the growth factor induced four types of [Ca2+]i responses; no rise, a small and sluggish monophasic rise, a biphasic rise with an initial transient peak followed by a sustain elevation, and finally regular oscillations. The frequencies and amplitudes of the oscillatory responses were independent of agonist concentration after stimulation with PDGF-BB. Latency, the period from application of stimulus to the first [Ca2+]i peak, was reduced at higher concentrations of agonist. Also, the proportion of responding cells increased with higher concentrations of ligand. Oscillations of [Ca2+]i were elicited at submaximal concentrations of agonist. In PAE cells PDGF-BB triggered a single [Ca2+]i peak in absence of external Ca2+. Ligand-induced oscillations and sustained increases of [Ca2+]i were counteracted by the inorganic Ca2+ channel blocker Ce3+. These results show that similar types of [Ca2+]i responses occur in different cell types independently of whether the PDGF beta-receptors are expressed endogeneously or after transfection. Potentially, the different [Ca2+]i responses have distinct physiological consequences.

Animals↗
PubMed1997

Influence of PDGF-BB on proliferation and transition through the MyoD-myogenin-MEF2A expression program during myogenesis in mouse C2 myoblasts.

We have previously demonstrated that PDGF-BB enhances proliferation of C2 myoblasts. This has led us to examine whether the mitogenic influence of PDGF-BB in the C2 model correlates with modulation of specific steps associated with myogenic differentiation. C2 myoblasts transiting through these differentiation specific steps were monitored via immunocytochemistry. We show that the influence of PDGF on enhancing cell proliferation correlates with a delay in the emergence of cells positive for sarcomeric myosin. We further monitored the influence of PDGF-BB on differentiation steps preceding the emergence of myosin+ cells. We demonstrate that mononucleated C2 cells first express MyoD (MyoD+/myogenin- cells) and subsequently, myogenin. Cells negative for both MyoD and myogenin (the phenotype preceding the MyoD+ state) were present at all times in culture and comprised the majority, if not all, of the cells which responded mitogenically to PDGF. Additionally, the frequency of the MyoD+/myogenin+ cell phenotype was reduced in cultures receiving PDGF, suggesting that PDGF can modulate the transition of the cells into the myogenin+ state. We determined that many of the myogenin+ cells subsequently become MEF2A+ and this phenomenon is not influenced by PDGF-BB. FGF-2 also enhanced the proliferation of C2 myoblasts and suppressed the appearance of the myogenin+ cells, but did not influence the subsequent transition into the MEF2A+ state. The study raises the possibility that PDGF-BB and FGF-2 might delay the transition of the C2 cells into the MyoD+/myogenin+ state by depressing a paracrine signal that enhances differentiation.

Animals↗
PubMed1998

The international standard for platelet-derived growth factor-BB: comparison of candidate preparations by in vitro bioassays and immunoassays.

In an international collaborative study, four preparations of recombinant, human sequence, platelet-derived growth factor-BB (PDGF-BB), two glycosylated and two nonglycosylated, were evaluated, using in vitro bioassays and immunoassays, by seven laboratories in three countries, for their suitability to serve as the international standard (IS) for PDGF-BB. The study shows that interlaboratory variation in estimates of PDGF-BB potency is reduced by use of a common standard. The bioassays, using various types of fibroblast, detected PDGF-BB and PDGF-AB as equally potent, while immunoassays discriminated between the two isoforms. On the basis of the results reported here, the World Health Organization (WHO) established the preparation coded 94/728 as the first IS for PDGF-BB, with an assigned unitage of 3000 International Units per ampoule. The IS may be obtained by writing to NIBSC, PO Box 1193, Potters Bar, EN6 3QH, UK, or through web site http:¿¿www.nibsc.ac.uk.

Becaplermin↗
PubMed2001

Vascular endothelial growth factor in porcine-derived extracellular matrix.

An extracellular matrix (ECM) derived from the submucosa of the porcine small intestine (SIS) has been shown to induce angiogenesis and host tissue remodeling when used as a xenogeneic bioscaffold in animal models of wound repair. In the present study, we compared the in vitro effects of SIS ECM extracts to several purified angiogenic growth factors on human dermal microvascular endothelial cell (HMEC) growth patterns. The SIS ECM was shown to induce tube formation from HMEC in a three-dimensional fibrin-based angiogenesis assay in a manner similar to that caused by the addition of vascular endothelial growth factor (VEGF). This tube formation was blocked in the presence of anti-VEGF neutralizing antibody. Western blots and ELISA procedures showed that the SIS ECM contains as much as 0.77 ng VEGF/g SIS. The closely related endothelial cell mitogen, platelet-derived growth factor (PDGF), was not detectable in the SIS extracts. We conclude that VEGF is present in the SIS extracellular matrix. The role of VEGF in SIS-induced wound repair remains unknown, but its presence in the ECM makes it a possible contributor to the angiogenic effect of SIS when this ECM is used as a tissue repair scaffold in animal models of wound repair.

Animals↗
PubMed1998

Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium.

We have investigated the role of phosphatidylinositol 3-kinase (PI3-kinase) in cellular interactions with collagenous matrices. Platelet-derived growth factor-BB (PDGF-BB) elicited a mobilization of intracellular Ca2+ in pig aortic endothelial (PAE) cells transfected with wild type PDGF beta-receptor. This response was greatly reduced in PAE cells transfected with PDGF beta-receptors mutated at positions Y740 and Y751 to prevent PI3-kinase binding. The experimental drug 1D-myo-inositol 1,2,6-trisphosphate (alpha-trinositol) induced a rapid increase and subsequent oscillations of the cytoplasmic Ca2+ concentration in cultured fibroblasts. This response was not due to an effect of alpha-trinositol on inositol 1,4,5-trisphosphate (IP3) receptors. alpha-Trinositol did not influence PDGF-BB elicited chemotaxis through collagen-coated membranes of PAE cells transfected with the wild-type PDGF beta-receptor, but restored PDGF-BB elicited chemotaxis of PAE cells transfected with the PI3-kinase binding-site mutated PDGF beta-receptor. Collagen gel contraction has been suggested to serve as a model for cellular control of interstitial fluid pressure (PIF) in dermis. The PI3-kinase inhibitors wortmannin (50 nM) and LY294002 (5 microM) inhibited the stimulation of fibroblast-mediated collagen gel contraction by 0.4 nM PDGF-BB. Injection of wortmannin in rat paw skin induced a lowering of PIF, and this effect was abolished in animals pre-treated with alpha-trinositol. Pretreatment of rats with alpha-trinositol abolished the decrease in PIF induced by injecting monoclonal anti-rat alpha 2 beta 1 integrin IgG in rat paw skin. Taken together our data indicate that cell-collagen interactions in vivo and in vitro depend on PI3-kinase, and that this dependence can be bypassed by a drug eliciting intracellular Ca2+ mobilization.

Androstadienes↗
PubMed1994

Platelet-derived growth factor expression and stimulation in human meningiomas.

The platelet-derived growth factor (PDGF) family consists of subunits A and B and receptors alpha and beta. This paper evaluates the potential role of the homodimer PDGF-BB as a growth factor in meningiomas. It analyzes the expression of messenger RNA in members of the PDGF family in these tumors, measures the growth response of meningiomas to exogenous PDGF-BB in culture, and examines the induction of the c-fos proto-oncogene by PDGF-BB. Northern blot analysis was carried out on tissue from 20 meningiomas to measure the expression of PDGF-A, PDGF-B, PDGF-alpha receptor (PDGF-alpha-R) and PDGF-beta receptor (PDGF-beta-R). All tumors expressed PDGF-A and PDGF-B subunits. Nineteen of the 20 tumors expressed PDGF-beta-R and none expressed PDGF-alpha-R as measured by this technique. Because the beta receptor is selectively sensitive to stimulation by the PDGF-B subunit, these data suggest that meningiomas might be susceptible to stimulation by PDGF-BB. To test this hypothesis, the effect of exogenous PDGF-BB on meningioma growth was evaluated by incubating cells from 10 human meningiomas. Tritiated thymidine incorporation was used to evaluate stimulation of growth over a 48-hour period using PDGF-BB concentrations of 1, 3, or 6 ng/ml. Linear regression analysis and multiple-factor analysis of variance were used to measure PDGF-BB effects. Three of the 10 tumor specimens responded significantly to PDGF-BB, with a three- to sixfold increase in thymidine incorporation over 72 hours of exposure, and there was a significant overall growth-stimulating effect of PDGF-BB in the 10 tumor specimens tested. In the last set of experiments, the functionality of the PDGF-beta-R was determined by examining the induction of the proto-oncogene c-fos by PDGF-BB in meningioma cell cultures. A significant increase in c-fos protein was observed 3 hours after PDGF-BB addition. These findings demonstrate that PDGF-A, PDGF-B, and PDGF-beta-R are expressed in meningiomas and suggest that the beta receptor is functional: when it is activated, c-fos levels are increased, and an increase in meningioma cell division is observed after the addition of PDGF-BB. These studies support the hypothesis that PDGF acts as a growth factor in meningiomas.

Adult↗
PubMed2002

Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells.

OBJECT: The intracellular events transducing mitogenic signals from platelet-derived growth factor-beta (PDGFbeta) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)-Akt-p70S6K pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB. METHODS: Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70S6K. Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K. The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of P13-K, on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated. Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K. Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation. CONCLUSIONS: These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K-Akt-p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1-MEK-1-MAPK/ERK cascade.

Adult↗
PubMed2006

Heavy water inhibiting the expression of transforming growth factor-beta1 and the development of kaolin-induced hydrocephalus in mice.

OBJECT: The authors investigated the effects of heavy water (D2O) on intrameningeal fibrosis and on the expression of cytokine production in mice with kaolin-induced hydrocephalus. METHODS: Mice in which kaolin was injected into the cisterna magna were divided into two groups: 1) Group H, which had free access to H2O as tap water; and 2) Group D, which had free access to 30% D2O as tap water before and after kaolin injection. A distilled water-injected group, which had free access to H2O as tap water was designated the sham-operated group. The authors examined the effects of D2O within 28 days after injection on the development of hydrocephalus and intrameningeal fibrosis, as well as on the expression levels of several inflammatory and fibrogenic cytokines: transforming growth factor-beta1 (TGFbeta1), fibroblast growth factor-2 (FGF2), platelet-derived growth factor (PDGF)-BB, and interleukin (IL)-6. The cerebral ventricles were less expanded, and intrameningeal fibrosis was milder in Group D than in Group H. The proliferation of fibroblasts was assessed by applying the bromodeoxyuridine labeling index, which was lower in Group D than in Group H. Expression of TGFbeta1 in the macrophages, choroid plexus, and meninges was inhibited in Group D but not in Group H. The serum level of total TGFbeta1 was significantly lower in Group D than in Group H on Day 14, whereas the levels of FGF2, PDGF-BB, and IL-6 did not differ significantly among the groups. CONCLUSIONS: Administration of D2O prevented the development of kaolin-induced hydrocephalus in mice and inhibited intrameningeal fibrosis and upregulation of TGFbeta1.

Animals↗
PubMed2003

Suppressive effect of taurine on platelet-derived growth factor (PDGF) BB-induced c-fos and c-jun mRNA expressions through extracellular signal-regulated kinase (ERK) in mesenchymal cell lines.

Platelet-derived growth factor (PDGF) plays an important role in the pathogenic course of atherosclerosis, pulmonary fibrosis, and glomerulonephritis, and increased activity of the PDGF signaling pathway has been implicated as a contributing factor in the progression of the diseases. Taurine may be a prophylactic amino acid for atherosclerosis not only by decreasing plasma cholesterol level, but also by inhibiting the cell proliferation-signaling pathway. To elucidate how taurine affects the signaling pathway, we investigated the effect of taurine on the expression of immediate-early genes and activation of mitogen-activated protein kinases (MAPKs) in NIH/3T3 cells as standard mesenchymal cells. Taurine inhibited PDGF-BB-induced c-fos and c-jun mRNA expressions dose-dependently, although structural analogues of taurine did not. Taurine decreased the PDGF-induced p44/p42 ERK (extracellular signal-regulated kinase) phosphorylation state dose-dependently, although no phosphorylation was observed on JNK/SAPK (c-Jun N-terminal kinase/stress-activated protein kinase) and p38 MAPK. Further, PDGF-BB-induced tyrosine phosphorylation of the PDGF-beta receptor was not influenced by treatment with taurine, indicating that taurine never affects ligand-receptor interaction, and may act downstream of the PDGF receptor. Thus, the inhibitory mechanism of taurine on PDGF-induced c-fos and c-jun mRNA expressions may depend on the p44/p42 ERK pathway, but not on PDGF-beta receptor tyrosine phosphorylation, JNK/SAPK or p38 MAPK pathway. These results suggest that taurine may suppress the cell proliferation-signaling pathway through the inhibition of ERK activity and immediate-early gene expression.

Animals↗