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Molecular Medicine Reports Apr 2018The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on...
The Hippo signaling pathway is involved in the formation and development of the cardiovascular system. In the present study, the effects of WWC family member 3 (WWC3) on vascular smooth muscle cells (VSMCs) following injury were investigated, in addition to the associated mechanisms underlying this process. Platelet‑derived growth factor BB (PDGF‑BB) was used as a cell injury factor, and rats with balloon injuries were used as a model of carotid intimal injury. Furthermore, the expression levels of WWC3 in VSMCs and arteries post‑injury were investigated, in addition to the effect of WWC3 on the proliferation and migration of VSMCs. The results demonstrated that following injury, WWC3 expression was suppressed in VSMCs and the rat carotid artery, and the activity of the Hippo signaling pathway was significantly downregulated. In addition, the expression of YY1‑associated protein‑1 (YAP) and a number of its downstream target genes, including connective tissue growth factor (CTGF), were enhanced, thus enhancing the proliferation and migration of VSMCs. Knockdown of WWC3 suppressed the levels of large tumor suppressor kinase 1 (LATS1) expression and YAP phosphorylation, and the expression of YAP, CTGF and cyclin E was subsequently enhanced, thus promoting cell proliferation and migration. Similar results were obtained following overexpression of WWC3. Treatment with PDGF‑BB was revealed to suppress the proliferation and migration of VSMCs transfected with the WWC3 plasmid, compared with VSMCs transfected with an empty vector. The present study demonstrated that WWC3 may interact with LATS1 in order to upregulate the Hippo signaling pathway via co‑immunoprecipitation and enhancement of the phosphorylation of LATS1, in addition to the corresponding suppression of the nuclear import of YAP. However, VSMCs transfected with WWC3 plasmid with a deletion of the WW domain fail to exhibit this effect. These results suggested that WWC3 expression is downregulated in VSMCs during neointimal hyperplasia following injury (PDGF‑BB stimulation or balloon injury). WWC3 upregulates the activity of the Hippo signaling pathway, and weakens the proliferation and migration of VSMCs. Furthermore, the results of the present study suggested that WWC3 may interact with LATS1 to promote the phosphorylation of YAP and reduce its nuclear translocation, upregulate the activity of the Hippo pathway, and suppress the proliferation and migration of VSMCs following injury.
Topics: Animals; Becaplermin; Cell Movement; Cell Proliferation; Gene Expression; Gene Knockdown Techniques; Intracellular Signaling Peptides and Proteins; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Binding; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins c-sis; Rats; Signal Transduction; Vascular System Injuries
PubMed: 29393412
DOI: 10.3892/mmr.2018.8484 -
Scientific Reports Jun 2022The skin has a protective barrier against the external environment, making the transdermal delivery of active macromolecules very difficult. Cell-penetrating peptides...
The skin has a protective barrier against the external environment, making the transdermal delivery of active macromolecules very difficult. Cell-penetrating peptides (CPPs) have been accepted as useful delivery tools owing to their high transduction efficiency and low cytotoxicity. In this study, we evaluated the hydrophobic peptide, macromolecule transduction domain 1067 (MTD 1067) as a CPP for the transdermal delivery of protein cargoes of various sizes, including growth hormone-releasing hexapeptide-6 (GHRP-6), a truncated form of insulin-like growth factor-I (des(1-3)IGF-I), and platelet-derived growth factor BB (PDGF-BB). The MTD 1067-conjugated GHRP-6 (MTD-GHRP-6) was chemically synthesized, whereas the MTD 1067-conjugated des(1-3)IGF-I and PDGF-BB proteins (MTD-des(1-3)IGF-I and MTD-PDGF-BB) were generated as recombinant proteins. All the MTD 1067-conjugated cargoes exhibited biological activities identical or improved when compared to those of the original cargoes. The analysis of confocal microscopy images showed that MTD-GHRP-6, MTD-des(1-3)IGF-I, and MTD-PDGF-BB were detected at 4.4-, 18.8-, and 32.9-times higher levels in the dermis, respectively, compared to the control group without MTD. Furthermore, the MTD 1067-conjugated cargoes did not show cytotoxicity. Altogether, our data demonstrate the potential of MTD 1067 conjugation in developing functional macromolecules for cosmetics and drugs with enhanced transdermal permeability.
Topics: Becaplermin; Cell-Penetrating Peptides; Insulin-Like Growth Factor I; Proto-Oncogene Proteins c-sis; Recombinant Proteins
PubMed: 35760980
DOI: 10.1038/s41598-022-14463-9 -
Cell Reports Apr 2018Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked...
Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked the in vivo dynamics of perivascular mural cells as a function of electroencephalogram (EEG) activity following status epilepticus. We segmented the cortical vascular bed to provide a size- and type-specific analysis of mural cell plasticity topologically. We find that mural cells are added and removed from veins, arterioles, and capillaries after seizure induction. Loss of mural cells is proportional to seizure severity and vascular pathology (e.g., rigidity, perfusion, and permeability). Treatment with platelet-derived growth factor subunits BB (PDGF-BB) reduced mural cell loss, vascular pathology, and epileptiform EEG activity. We propose that perivascular mural cells play a pivotal role in seizures and are potential targets for reducing pathophysiology.
Topics: Animals; Becaplermin; Capillary Permeability; Cerebral Arteries; Cerebral Veins; Electroencephalography; Mice; Mice, Transgenic; Status Epilepticus
PubMed: 29694884
DOI: 10.1016/j.celrep.2018.03.110 -
Scientific Reports Mar 2017The prognosis for successful treatment of periodontal diseases is generally poor. Current therapeutic strategies often fail to regenerate infected periodontium. Recently... (Meta-Analysis)
Meta-Analysis Review
The prognosis for successful treatment of periodontal diseases is generally poor. Current therapeutic strategies often fail to regenerate infected periodontium. Recently an alternative strategy has been developed that combines conventional treatment with the application of recombinant human growth factors (rhGFs). But ambiguities in existed studies on the clinical efficacy of rhGFs do not permit either the identification of the specific growth factors effective for therapeutic interventions or the optimal concentration of them. Neither is it known whether the same rhGF can stimulate regeneration of both soft tissue and bone, or whether different patient populations call for differential use of the growth factors. In order to explore these issues, a meta-analysis was carried out. Particular attention was given to the therapeutic impact of fibroblast growth factor 2(FGF-2) and platelet derived growth factor BB (PDGF-BB). Our findings indicate that 0.3% rhFGF-2 and 0.3 mg/ml rhPDGF-BB show a greater capacity for periodontal regeneration than other concentrations and superiority to control groups with statistical significance. In the case of patients suffering only from gingival recession, however, the application of rhPDGF-BB produces no significant regenerative advantage. The findings of this study can potentially endow clinicians with guidelines for the appropriate application of these two rhGFs.
Topics: Becaplermin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fibroblast Growth Factor 2; Humans; Periodontal Diseases; Periodontium; Proto-Oncogene Proteins c-sis; Randomized Controlled Trials as Topic; Recombinant Proteins; Regeneration; Treatment Outcome
PubMed: 28246406
DOI: 10.1038/s41598-017-00113-y -
Journal of Clinical Periodontology Mar 2015The aim was to evaluate the effects of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and recombinant human fibroblast growth factor-2 (rhFGF-2) on... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
The aim was to evaluate the effects of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and recombinant human fibroblast growth factor-2 (rhFGF-2) on treating periodontal intra-bony defects, compared to the control (carrier alone).
METHODS
Electronic and hand searches were performed to identify eligible studies. The weighed mean differences of linear defect fill (LDF), probing depth (PD) reduction, clinical attachment level (CAL) gain and gingival recession (GR) were calculated using random effect meta-analysis.
RESULTS
The searches yielded 1018 articles, of which seven studies were included. Only one included study was considered at low risk of bias. The outcomes that reached statistical significance in comparison to carriers alone included: LDF (0.95 mm, 95% CI: 0.62-1.28 mm or 20.17%, 95% CI: 11.81-28.54%) and CAL gain (0.34 mm, 95% CI: 0.03-0.65 mm) for PDGF, and LDF (21.22%, 95% CI: 5.82-36.61%) for FGF-2.
CONCLUSIONS
Within the limits of this review, rhPDGF-BB demonstrated significantly more LDF and CAL gain; rhFGF-2 resulted in significantly higher percentage of LDF.
Topics: Alveolar Bone Loss; Becaplermin; Bone Regeneration; Fibroblast Growth Factor 2; Gingival Recession; Guided Tissue Regeneration, Periodontal; Humans; Periodontal Attachment Loss; Periodontal Pocket; Proto-Oncogene Proteins c-sis; Treatment Outcome
PubMed: 25605424
DOI: 10.1111/jcpe.12354 -
Molecular Medicine (Cambridge, Mass.) Apr 2013Bone has a high capacity for self-renewal and repair. Prolonged local secretion of interleukin 1β (IL-1β), however, is known to be associated with severe bone loss and...
Bone has a high capacity for self-renewal and repair. Prolonged local secretion of interleukin 1β (IL-1β), however, is known to be associated with severe bone loss and delayed fracture healing. Since induction of bone resorption by IL-1β may not sufficiently explain these pathologic processes, we investigated, in vitro, if and how IL-1β affects migration of multipotent mesenchymal stromal cells (MSC) or osteoblasts. We found that homogenous exposure to IL-1β significantly diminished both nondirectional migration and site-directed migration toward the chemotactic factors platelet-derived growth factor (PDGF)-BB and insulin like growth factor 1 (IGF-1) in osteoblasts. Exposure to a concentration gradient of IL-1β induced an even stronger inhibition of migration and completely abolished the migratory response of osteoblasts toward PDGF-BB, IGF-1, vascular endothelial growth factor A (VEGF-A) and the complement factor C5a. IL-1β induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases (JNK) activation and inhibition of these signaling pathways suggested an involvement in the IL-1β effects on osteoblast migration. In contrast, basal migration of MSC and their migratory activity toward PDGF-BB was found to be unaffected by IL-1β. These results indicate that the presence of IL-1β leads to impaired recruitment of osteoblasts which might influence early stages of fracture healing and could have pathological relevance for bone remodeling in inflammatory bone disease.
Topics: Becaplermin; Cell Adhesion; Cell Movement; Cells, Cultured; Humans; Insulin-Like Growth Factor I; Interleukin-1beta; Mesenchymal Stem Cells; Mitogen-Activated Protein Kinases; Osteoblasts; Proto-Oncogene Proteins c-sis; Receptors, Interleukin-1 Type I; Recombinant Proteins; Vascular Endothelial Growth Factor A
PubMed: 23508571
DOI: 10.2119/molmed.2012.00058 -
PloS One 2022Primary brain calcification (PBC) is a rare and intractable neurodegenerative disease. SLC20A2 and PDGFB are two major causative genes. As there is no effective...
INTRODUCTION
Primary brain calcification (PBC) is a rare and intractable neurodegenerative disease. SLC20A2 and PDGFB are two major causative genes. As there is no effective treatment to avoid further progression or to prevent the onset of the disease, the patients may experience psychological distress. There is a qualitative study on the experiences of patients with primary brain calcification with SLC20A2 variants. However, the experiences of patients with PDGFB variants of the disease have not been explored. The purpose of this study is to identify the experiences of patients with PDGFB variants after diagnosis.
MATERIALS AND METHODS
Semi-structured interviews were conducted once or twice a year for three years with five patients over the age of 21. The data were analyzed using inductive qualitative methods.
RESULTS
Seven categories, 15 subcategories, and 129 codes were extracted. The seven categories are as follows: [Shock at hearing the term 'brain calcification' for the first time], [Anxiety regarding the risk of heredity], [Anxiety, along with severe headaches, and various other symptoms], [Gratitude for the family members who care], [Accepting the disease as a non-life-threatening illness], [Feeling alienated due to the rare intractable disease], and [Modifying lifestyle due to the illness].
DISCUSSION
The most stressful aspect of the disease was the headache that persisted even with the use of analgesics, which was different from patients with the SLC20A2 variants. In addition, we found unique concepts such as anxiety regarding the risk of heredity and a feeling of alienation due to the rare and intractable disease.
Topics: Becaplermin; Brain; Brain Diseases; Calcinosis; Humans; Mutation; Neurodegenerative Diseases; Proto-Oncogene Proteins c-sis; Sodium-Phosphate Cotransporter Proteins, Type III
PubMed: 36206226
DOI: 10.1371/journal.pone.0275227 -
Journal of Cardiovascular Pharmacology Jun 2022Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the fate of cells. To further understand its function in...
Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the fate of cells. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury. The roles of CFTR in PDGF-BB-stimulated VSMC proliferation and migration were detected by mitochondrial tetrazolium assay, wound healing assay, transwell chamber method, western blot, and qPCR. We found that CFTR expression was declined in injured rat carotid arteries, while adenoviral overexpression of CFTR in vivo attenuated neointimal formation in carotid arteries. CFTR overexpression inhibited PDGF-BB-induced VSMC proliferation and migration, whereas CFTR silencing caused the opposite results. Mechanistically, CFTR suppressed the phosphorylation of PDGF receptor β, serum and glucocorticoid-inducible kinase 1, JNK, p38 and ERK induced by PDGF-BB, and the increased mRNA expression of matrix metalloproteinase-9 and MMP2 induced by PDGF-BB. In conclusion, our results indicated that CFTR may attenuate neointimal formation by suppressing PDGF-BB-induced activation of serum and glucocorticoid-inducible kinase 1 and the JNK/p38/ERK signaling pathway.
Topics: Animals; Becaplermin; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Cells, Cultured; Cystic Fibrosis Transmembrane Conductance Regulator; Glucocorticoids; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley
PubMed: 35266910
DOI: 10.1097/FJC.0000000000001257 -
American Journal of Physiology. Cell... Jan 2007Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in... (Review)
Review
Smooth muscle cell (SMC) differentiation is an essential component of vascular development and these cells perform biosynthetic, proliferative, and contractile roles in the vessel wall. SMCs are not terminally differentiated and possess the ability to modulate their phenotype in response to changing local environmental cues. The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms involved in controlling phenotypic switching of SMC with particular focus on examination of processes that contribute to the repression of SMC marker genes. We discuss the environmental cues which actively regulate SMC phenotypic switching, such as platelet-derived growth factor-BB, as well as several important regulatory mechanisms required for suppressing expression of SMC-specific/selective marker genes in vivo, including those dependent on conserved G/C-repressive elements, and/or highly conserved degenerate CArG elements found in the promoters of many of these marker genes. Finally, we present evidence indicating that SMC phenotypic switching involves multiple active repressor pathways, including Krüppel-like zinc finger type 4, HERP, and ERK-dependent phosphorylation of Elk-1 that act in a complementary fashion.
Topics: Animals; Becaplermin; Cell Differentiation; Gene Expression Regulation; Genetic Markers; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis
PubMed: 16956962
DOI: 10.1152/ajpcell.00394.2006 -
Oncology Reports Jan 2021Platelet‑derived growth factor (PDGF) is a potent mitogen and chemoattractant that serves a role in the development of several types of solid cancer, and abnormal PDGF...
Platelet‑derived growth factor (PDGF) is a potent mitogen and chemoattractant that serves a role in the development of several types of solid cancer, and abnormal PDGF activity has been reported in numerous human tumors. Tumor‑derived PDGF ligands are considered to act in either a paracrine or autocrine manner, serving roles in the phosphorylation of receptors on tumor and stromal cells in the tumor microenvironment. Despite the well‑established association between PDGF and tumor progression, the precise mechanisms of autocrine PDGF signaling in pancreatic tumor cells remain elusive. Therefore, the present study aimed to analyze the influence of PDGF‑BB in pancreatic cancer. Pancreatic adenocarcinoma BxPC‑3 cells were cultured and treated with recombinant human PDGF‑BB in vitro. Cell proliferation was tested using an MTT assay. Cell apoptosis was measured using flow cytometry. Tumor cell migration and invasion were examined via wound‑healing and Transwell assays, respectively. The expression and subcellular localization of Yes‑associated protein (YAP) was determined using western blotting and immunofluorescence. The transcriptional activity of target genes was tested using a luciferase assay and reverse transcription‑quantitative PCR. The present study revealed that PDGF‑BB significantly promoted cell proliferation in pancreatic adenocarcinoma BxPC‑3 cells and enhanced the aggressiveness of this cell line, as demonstrated by Transwell and wound‑healing assays. Anoikis resistance is an important mechanism by which metastatic cells avoid apoptosis when detaching from adjacent cells or the extracellular matrix. PDGF‑BB treatment inhibited anoikis under anchorage‑independent conditions. Mechanistic experiments revealed that PDGF‑BB promoted the upregulation and activation of the transcriptional coactivator YAP, an effector of the Hippo signaling pathway. RhoA or protein phosphatase‑1 (PP‑1) inhibition partially abolished the accumulation and activation of YAP, suggesting PDGF‑BB‑mediated YAP dephosphorylation and transactivation via the RhoA/PP‑1 cascade. Pharmacologic inhibition of the PDGF receptor directly downregulated YAP activity and the expression levels of downstream genes. Furthermore, verteporfin, a small molecular inhibitor of the Hippo/YAP signaling pathway, partially reversed the effects of PDGF‑BB on cell proliferation, anoikis resistance and cell migration. In conclusion, the present study revealed that the Hippo/YAP signaling pathway may be involved in the tumor‑promoting activity of PDGF‑BB in pancreatic cancer.
Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Anoikis; Apoptosis; Becaplermin; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Culture Media; Gene Expression Regulation, Neoplastic; Hippo Signaling Pathway; Humans; Pancreatic Neoplasms; Protein Isoforms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-sis; Signal Transduction; Transcription Factors; Transcriptional Activation; Up-Regulation; Verteporfin; YAP-Signaling Proteins
PubMed: 33416116
DOI: 10.3892/or.2020.7859