Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets.

Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.

Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer.

Diabetes mellitus (DM), is the most common metabolic disease and is characterized by sustained hyperglycemia. Accumulating evidences supports a strong association between DM and numerous lung diseases including chronic obstructive pulmonary disease (COPD), fibrosis, and lung cancer (LC). The global incidence of DM-associated lung disorders is rising and several ongoing studies, including clinical trials, aim to elucidate the molecular mechanisms linking DM with lung disorders, in particular LC. Several potential mechanisms, including hyperglycemia, hyperinsulinemia, glycation, inflammation, and hypoxia, are cited as plausible links between DM and LC. In addition, studies also propose a connection between the use of anti-diabetic medications and reduction in the incidence of LC. However, the exact cause for DM associated lung diseases especially LC is not clear and is an area under intense investigation. Herein, we review the biological links reported between DM and lung disorders with an emphasis on LC. Furthermore, we report common signaling pathways (eg: TGF-ß, IL-6, HIF-1, PDGF) and miRNAs that are dysregulated in DM and LC and serve as molecular targets for therapy. Finally, we propose a nanomedicine based approach for delivering therapeutics (eg: IL-24 plasmid DNA, HuR siRNA) to disrupt signaling pathways common to DM and LC and thus potentially treat DM-associated LC. Finally, we conclude that the effective modulation of commonly regulated signaling pathways would help design novel therapeutic protocols for treating DM patients diagnosed with LC.

Apoptotic profiling of chronic myeloid leukaemia patients' platelets ex vivo before and after treatment with Imatinib.

Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first-generation tyrosine kinase inhibitor, Imatinib. Patients with CML are frequently diagnosed with platelet abnormalities. However, the specific mechanism of platelet abnormalities in CML remains unclear and poorly understood. The aim of this study was therefore to determine the apoptotic profiles of CML patients ex vivo on platelets before and after treatment with Imatinib. Blood samples of healthy volunteers and CML patients at diagnosis and after 6 months treatment with Imatinib were collected. Platelet counts, viability and activation were determined. Results showed that CML patients' platelet counts were elevated upon diagnosis and these levels statistically significantly decreased after 6 months of treatment. Platelet activation was significantly increased after 6 months of treatment compared to levels at diagnosis (P-value < .05). Similarly, platelet apoptosis was also increased after 6 months of treatment. Abnormalities in platelet functioning found in this study may partly be due to clonal proliferation of haematopoietic cells in CML patients, specifically of megakaryocyte precursors as well as the inhibition of platelet tyrosine kinase's and the inhibition of platelet-derived growth factor.

Inhibition of platelet-derived growth factor C and their receptors additionally increases doxorubicin effects in triple-negative breast cancer cells.

Complex of platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of various cell types. Herein, it was found that aberrant PDGFC expression is closely associated with survival rates in triple-negative breast cancer (TNBC) patients. In addition, PDGFC expression was identified to be significantly increased in TNBC cells unlike other subtypes such as PDGFA, PDGFB, and PDGFD. Apparently, the effects of specific PDGF receptor (PDGFR) inhibitors such as sunitinib and ponatinib on HCC1806 and Hs578T TNBC cells were investigated. Both inhibitors decreased cell viability in a dose-dependent manner. In addition, the inhibitors completely inhibited cell growth in both the cell lines and decreased the expression of matrix metalloproteinase-1 (MMP-1), one of the metastasis-related genes. Cell migration was also decreased by the inhibitors. Finally, the combined effects of the inhibitors with doxorubicin (DOX) were investigated. The results showed that the combination of two PDGFR inhibitors with DOX inhibited the growth of cells and enhanced the apoptotic cell death more uniformly than DOX. Consequently, it is demonstrated that PDGFR inhibitors, sunitinib and ponatinib hold the potential for effective treatment of TNBC.

Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling.

Neovascular age-related macular degeneration (neoAMD) is the leading cause of blindness in AMD and manifests as choroidal neovascularization (CNV). Anti-vascular endothelial growth factor (VEGF) therapies are the mainstay treatments but with limited efficacy and cause detrimental effects on the retina after long-term application. These disadvantages warrant alternative strategy. Herein, we examined the effect on CNV by intravitreal injection of bortezomib, a reversible proteasome inhibitor, and further dissected the mechanism. Krypton red Laser was used to create CNV model in mice. The angiogenesis volume was assessed in choroidal flat-mount with isolectin GS-IB4 labeling and the leakage was examined with fluorescein fundus angiography. Injection of Borsub inhibited angiogenesis in the CNV model which was dose-dependent; the injection significantly inhibited leakage as well. Furthermore, Borsub injection reduced the contents of VEGF-A, macrophage chemotactic factor 1 (MCP-1), and platelet-derived growth factor (PDGF)-D but not PDGF-B, examined by enzyme-linked immunosorbent assay, in choroid/retinal pigment epithelium (RPE) tissue. These injections also reduced phospho-VEGFR-2 and phospho-PDGFRß in choroid/RPE tissue examined by immunoblotting. Moreover, Borsub inhibited the recruitment of mural cells or macrophages to laser-injured spots. Injection of Borsub indicated negative effect on scotopic and photopic responses recorded by electroretinogram. Altogether, intravitreal injection of Borsub significantly reduced CNV by antagonizing VEGF-A/Flk-1 and PDGF-D/PDGFRß pathways without impacting electroretinography parameters. Thus, Borsub may offer an invaluable therapy for the prevention and treatment of neoAMD.

Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood-brain barrier.

Disruption of blood-brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.

Ulinastatin Inhibits the Proliferation, Invasion and Phenotypic Switching of PDGF-BB-Induced VSMCs via Akt/eNOS/NO/cGMP Signaling Pathway.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease responsible for thrombosis, blood supply disorders, myocardial infarction and strokes, eventually leading to increased deaths and reduced quality of life. As inflammation plays a vital role in the development of this disease, the present study aims to investigate whether urinary trypsin inhibitor (UTI) with anti-inflammatory property can inhibit the proliferation, invasion and phenotypic switching of PDGF-BB-induced vascular smooth muscle cells (VSMCs) and probe its potential mechanism. METHODS: Western blot was used to detect the expressions of the proteins related to the Akt/eNOS/NO/cGMP signaling pathway, phenotypic switching and proliferation. CCK-8 assay and EdU staining were used to detect cell proliferation of VSMCs. Transwell and wound healing assays were respectively conducted to measure the invasion and migration of VSMCs. The concentration of NO was evaluated by NO detection kit. ELISA assay analyzed the expression of cyclic GMP (cGMP). RESULTS: The expressions of p-Akt and p-eNOS were elevated by UTI treatment. Furthermore, UTI inhibited the proliferation, migration and invasion of VSMCs. UTI also increased the expressions of proteins related to phenotypic switching. The amount of NO and expression of cGMP were both elevated under UTI treatment. CONCLUSION: UTI inhibits the proliferation, invasion and phenotypic switching of PDGF-BB-induced VSMCs via Akt/eNOS/NO/cGMP signaling pathway, which might provide a theoretical basis for the UTI treatment of atherosclerosis.

Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property.

BACKGROUND: Numerous studies suggest that non-steroidal anti-inflammatory drugs reduce cancer cell proliferation, progression, angiogenesis, apoptosis, and invasiveness. OBJECTIVE: The current study focuses on the evaluation of novel mefenamic acid derivatives for the treatment of hepatocellular carcinoma. METHODS: Derivatives were subjected to molecular modeling for prediction of pharmacological activity using software, followed by synthesis and in vitro assay. In in vivo study, disease was induced with N-Nitrosodiethylamine followed by 2-acetylaminofluorene orally for 2 weeks. After 12 weeks of induction, treatment was given for a period of one week. At the end of the treatment, determination of liver weight, a number of nodules, biochemical parameters, immunohistochemistry, histopathology, and gene expression studies, were carried out. RESULTS: Based on molecular docking score for PDGF-α (Platelet-Derived Growth Factor) and IC50 values in HepG2 cell line study, JS-PFA was selected for the in vivo study where JS-PFA showed a statistically significant reduction in a number of nodules and liver weight. Protective role of JS-PFA has been observed in tumorspecific markers like α-fetoprotein, carcinoembryonic antigen, and lactate dehydrogenase levels. The JS-PFA has shown a significant reduction in PDGF-α levels as well as liver markers and total bilirubin levels. Histopathological analysis also showed a protective effect. The results of immunohistochemical analysis of P53 and down-regulation of vascular endothelial growth factor and matrix metalloproteinases-9 genes suggest that derivative inhibits PDGF mediated tumor growth and leads to apoptosis, inhibition of angiogenesis, and metastasis. CONCLUSION: The effectiveness of JS-PFA in our studies suggests targeting PDGF by COX 2 inhibitor can serve as a novel treatment strategy for the treatment of HCC.

Upregulation of PDGF Mediates Robust Liver Regeneration after Nanosecond Pulsed Electric Field Ablation by Promoting the HGF/c-Met Pathway.

Nanosecond pulsed electric field (nsPEF) has emerged as a promising tool for hepatocellular carcinoma ablation recently. However, little is known about how nsPEF affects liver regeneration while being applied to eliminate liver lesions. Besides, the impact of nsPEF ablation on liver function should also be taken into consideration in the process. In this paper, we study the impact of nsPEF ablation on liver function by the measurement of serum levels of AST and ALT as well as liver regeneration and relevant molecular mechanisms in vivo. We found that mouse liver function exhibited a temporary injury without weight loss after ablation. In addition, local hepatic nsPEF ablation promoted significant proliferation of hepatocytes of the whole liver with an increase in HGF level. Moreover, the proliferation of hepatocytes was dramatically inhibited by the inhibitor of c-Met. Of interest, the periablational area is characterized by high level of PDGF and a large amount of activated hepatic stellate cells. Furthermore, neutralizing PDGF was able to significantly inhibit liver regeneration, the increased HGF level, and the accumulation of activated HSCs. Our findings demonstrated that nsPEF not only was a safe ablation approach but also could stimulate the regeneration of the whole liver through the activation of the HGF/c-Met pathway by upregulation of PDGF within the periablational zone.

New therapeutic targets in the treatment of age-related macular degeneration. / Nuevas dianas terapéuticas en el tratamiento de la degeneración macular asociada a la edad.

Age-related macular degeneration and especially neovascular age-related macular degeneration is the leading cause of low vision in developed countries. Even though the introduction of anti-VEGF drugs in recent years completely changed the management of this condition, its cost, the need for repeated intravitreal injections, and loss of efficacy in the long term are still issues to deal with. Currently, a new generation of novel therapies under development is attempting to address some of these limitations. Some of the most prominent among them are new anti-VEGFs such as brolucizumab or abicipar, drugs against angiopoietin-2 receptor such as faricimab, sustained-release systems, or tyrosine kinase inhibitors. As regards dry age-related macular degeneration, neuroprotection, the complement pathway, and stem cell therapy are the most promising targets currently under investigation.

Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth.

Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma.

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-ß sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer.

Development of monoclonal anti-PDGF-CC antibodies as tools for investigating human tissue expression and for blocking PDGF-CC induced PDGFRα signalling in vivo.

PDGF-CC is a member of the platelet-derived growth factor (PDGF) family that stimulates PDGFRα phosphorylation and thereby activates intracellular signalling events essential for development but also in cancer, fibrosis and neuropathologies involving blood-brain barrier (BBB) disruption. In order to elucidate the biological and pathological role(s) of PDGF-CC signalling, we have generated high affinity neutralizing monoclonal antibodies (mAbs) recognizing human PDGF-CC. We determined the complementarity determining regions (CDRs) of the selected clones, and mapped the binding epitope for clone 6B3. Using the monoclonal 6B3, we determined the expression pattern for PDGF-CC in different human primary tumours and control tissues, and explored its ability to neutralize PDGF-CC-induced phosphorylation of PDGFRα. In addition, we showed that PDGF-CC induced disruption of the blood-retinal barrier (BRB) was significantly reduced upon intraperitoneal administration of a chimeric anti-PDGF-CC antibody. In summary, we report on high affinity monoclonal antibodies against PDGF-CC that have therapeutic efficacy in vivo.

Preclinical toxicological assessment of a novel monoclonal antibody targeting human platelet-derived growth factor CC (PDGF-CC) in PDGF-CChum mice.

Platelet-derived growth factor CC (PDGF-CC) is important during foetal development but also in pathogenesis of neurologic diseases, cancer and fibrosis. We have previously demonstrated that blocking the PDGF-CC/PDGF receptor alpha (PDGFRα) axis resulted in reduction of stroke volume and cerebrovascular permeability after experimentally induced stroke. Recently, we could translate these findings into the clinic showing that imatinib, a small tyrosine kinase inhibitor targeting PDGF receptors, can significantly improve neurological outcome after ischemic stroke in human. Herein we report preclinical toxicological analyses of our newly generated monoclonal anti-human PDGF-CC antibody 6B3 (mAb 6B3) in PDGF-CC humanized mice. Beside histological organ assessment, we also analysed serum, urine, haematological parameters and the general health status of the treated mice. We could not find any indications that mAb 6B3 is toxic or has other significant side effects neither in short, nor in long treatment regimens. Our results indicate that mAb 6B3 can be further developed for clinical use. This opens up the possibility to assess the therapeutic potential of blocking PDGF-CC in diverse pathological conditions such as neurologic diseases, cancer and fibrosis.

Combined VEGF/PDGF inhibition using axitinib induces αSMA expression and a pro-fibrotic phenotype in human pericytes.

PURPOSE: Large trials on anti-VEGF/PDGF (vascular endothelial/platelet-derived growth factor) combination therapy have been established to improve management of neovascular activity in age-related macular degeneration. Targeting pericytes, PDGF is thought to induce vessel regression and reduce fibrovascular scarring. The fate of pericytes exposed to anti-VEGF/PDGF combination therapy is not clear. Therefore, this study was designed to study the influence of anti-VEGF/PDGF on pericyte phenotype and cellular behavior. METHODS: Human pericytes from placenta (hPC-PL) were treated with axitinib, a tyrosine kinase inhibitor targeting VEGFR1-3 and PDGFR. Toxic effects were excluded using live/dead staining. Phenotypic changes were evaluated using phalloidin staining for actin cytoskeleton and the expression of stress fibers. MRNA and protein expression levels of α-smooth muscle actin (αSMA) as a marker of proto-myofibroblastic transition were evaluated with real-time PCR and Western blotting. Influences of fibrotic cellular mechanisms were evaluated with a scratch wound migration and a collagen gel contraction assay. RESULTS: Treatment with 0.5, 1, and 2.5 µg/ml axitinib strongly induced a proto-myofibroblast-like actin cytoskeleton with a marked increase in stress fibers. Quantitative real-time PCR and Western blotting revealed these changes to be linked to dose-dependent increases in αSMA mRNA and protein expression. However, fibrotic cellular mechanisms were significantly reduced in the presence of axitinib (scratch wound closure: up to - 78.4%, collagen gel contraction: up to - 37.4%). CONCLUSIONS: Combined anti-VEGF/PDGF inhibition seems to induce a proto-myofibroblast-like phenotype in human pericytes in vitro, but reduce profibrotic cellular mechanisms due to prolonged anti-PDGF inhibition.

Methotrexate inhibits effects of platelet-derived growth factor and interleukin-1ß on rheumatoid arthritis fibroblast-like synoviocytes.

BACKGROUND: A key feature of joints in rheumatoid arthritis (RA) is the formation of hyperplastic destructive pannus tissue, which is orchestrated by activated fibroblast-like synoviocytes (FLS). We have demonstrated that the RA risk gene and tumor suppressor Limb bud and heart development (LBH) regulates cell cycle progression in FLS. Methotrexate (MTX) is the first-line treatment for RA, but its mechanisms of action remain incompletely understood. Here, we studied the effects of MTX on mitogen-induced FLS proliferation and expression of cell cycle regulators in vitro. METHODS: Primary FLS from patients with RA or osteoarthritis were stimulated with the mitogen platelet-derived growth factor (PDGF) and the cytokine interleukin-1ß (IL-1ß) in the presence or absence of MTX. Cells were then subjected to qPCR for gene expression and cell cycle analysis by flow cytometry. RESULTS: Stimulation with PDGF and IL-1ß increased the percentage of FLS in the G2/M phase and shifted the cell morphology to a dendritic shape. These effects were inhibited by MTX. Furthermore, PDGF + IL-1ß reduced LBH mRNA expression. However, MTX treatment yielded significantly higher transcript levels of LBH, and of CDKN1A (p21) and TP53 (p53), compared to untreated samples upon mitogen stimulation. The expression of DNA methyltransferase-1 (DNMT1) was also higher in the presence of MTX and there was strong correlation between DNMT1 and LBH expression. CONCLUSIONS: Therapeutic concentrations of MTX abolish the effects of PDGF and IL-1ß on tumor suppressor expression and inhibit mitogen-promoted FLS proliferation. These data demonstrate novel and important effects of MTX on pathogenic effector cells in the joint, which might involve epigenetic mechanisms.

Mast cells and angiogenesis in pancreatic ductal adenocarcinoma.

Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.

N-oleoylethanolamide suppresses intimal hyperplasia after balloon injury in rats through AMPK/PPARα pathway.

Vascular smooth muscle cell (VSMC) proliferation and migration are crucial events in the pathological course of restenosis after percutaneous coronary intervention (PCI). N-oleoylethanolamide (OEA) is a bioactive lipid amide released upon dietary fat digestion with many reported actions. However, the effect of OEA on restenosis after vascular injury remains unknown. Here, we investigated the effects of OEA on intimal hyperplasia after balloon injury in vivo, its effect on VSMC proliferation and migration induced by platelet-derived growth factor (PDGF) stimulation in vitro, and the underlying mechanism underlying these effects. The results showed that OEA-treated rats displayed a significant reduction in neointima formation after balloon injury. In cultured VSMCs, treatment with OEA decreased cell proliferation and migration induced by PDGF. OEA treatment both in vivo and in vitro led to an increase in adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and peroxisome proliferator-activated receptor alpha (PPARα), and a decrease in proliferating cell nuclear antigen (PCNA) and cyclinD1 expression. Pharmacological inhibition of AMPK and PPARα reversed the suppressive effects of OEA on VSMC proliferation and migration, suggesting that the suppressive effect of OEA on VSMC proliferation and migration is mediated through the activation of AMPK and PPARα. In conclusion, our present study demonstrated that OEA attenuated neointima formation in response to balloon injury by suppressing SMC proliferation and migration through an AMPK and PPARα-dependent mechanism. Our data suggests that OEA may be a potential therapeutic agent for restenosis after PCI.

Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis.

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins of the receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.