Role Of Pigment Epithelium-derived Factor Research Articles

Suppressive Role of Pigment Epithelium-derived Factor in a Rat Model of Corneal Allograft Rejection.

Immunological rejection is the most common reason for corneal transplantation failure. The importance of T cells in corneal allograft rejection is well demonstrated. Recent studies highlight that pigment epithelium-derived factor (PEDF) plays an immunoregulatory role in ocular diseases by enhancing the suppressive phenotype of regulatory T cells besides its other functions in neurotrophy and antiangiogenesis. The effects of PEDF on immune rejection were examined in rat models of corneal transplantation using slit-lamp microscope observation, immunohistochemistry, flow cytometry, and Western blot. In vitro, we demonstrated PEDF reduced alloreactive T-cell activation using real-time polymerase chain reaction, flow cytometry, and Western blot. Topical administration of PEDF provided corneal transplantation rats with an improved graft survival rate of corneal allografts, reduced hemangiogenesis, and infiltration of immune cells in corneas, in particular, type 17 T helper cells while increased regulatory T cells. Moreover, nerve reinnervation within grafts was promoted in PEDF-treated recipient rats. In vitro, PEDF inhibited alloreactive T-cell activation via the c-Jun N-terminal kinase/c-Jun signaling pathway and upregulated the expressions of interleukin-10 and transforming growth factor-β, emphasizing the suppressive role of PEDF on immune responses. Our results underscore the feasibility of PEDF in alleviating corneal allograft rejection and further illustrate its potential in managing immune-related diseases.

Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia

BackgroundPulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. MethodsFor PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. ResultsPEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. ConclusionsOur findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/β-catenin pathway.

PEDF protects retinal pigment epithelium from ferroptosis and ameliorates dry AMD-like pathology in a murine model.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision damage among elderly individuals. There is still no efficient treatment for dry AMD. Retinal pigment epithelial (RPE) degeneration has been confirmed to play an important role in dry AMD. Recent studies have reported that ferroptosis caused by iron overload and lipidperoxidation may be the primary causes of RPE degeneration. However, the upstream regulatory molecules of RPE ferroptosis remain largely unknown. Pigment epithelium-derived factor (PEDF) is an important endogenic protective factor for the RPE. Our results showed that in the murine dry AMD model induced by sodium iodate (SI), PEDF expression was downregulated. Moreover, dry AMD-like pathology was observed in PEDF-knockout mice. Therefore, the aim of this study was to reveal the effects and mechanism of PEDF on RPE ferroptosis and investigate potential therapeutic targets for dry AMD. The results of lipid peroxidation and transmission electron microscope showed that retinal ferroptosiswas significantly activated in SI-treated mice and PEDF-knockout mice. Restoration of PEDF expression ameliorated SI-induced retinal dysfunction in mice, as assessed by electroretinography and optical coherence tomography. Mechanistically, western blotting and immunofluorescence analysis demonstrated that the overexpression of PEDF could upregulate the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain-1 (FTH1), which proved to inhibit lipidperoxidation and RPE ferroptosis induced by SI. This study revealed the novel role of PEDF in ferroptosis inhibition and indicated that PEDF might be a potential therapeutic target for dry AMD.

The role of PEDF, VEGF, and Ki-67 in tissue invasion and tumor angiogenesis of medullary thyroid carcinoma

Objective: This study investigated the role of pigment epithelium-derived factor (PEDF), vascular endothelial growth factor (VEGF), nuclear factor kappa B (NF-kB), and Ki-67 proliferation index (PI) factors in Medullary thyroid carcinoma (MTC) tissue progression and their relationship with tumor angiogenesis. Immunohistochemical (IHC) analyses of PEDF expression in various human tumor samples and healthy tissues have shown that high levels of PEDF expression are associated with a positive prognosis, and low levels of PEDF suggest a poorer prognosis. With the completion of further studies showing the antitumor effects of PEDF on different types of cancer, PEDF’s potential as a therapeutic agent has become increasingly promising. To the best of our knowledge, the role of PEDF in tumor angiogenesis in MTC has not been previously investigated. Material and Methods: Thirty-seven tissue samples were retrospectively analyzed and sent/removed for pathology after total or subtotal thyroidectomy and archived between 01.01.2000 and 31.12.2015 in the Pathology Department of Hacettepe University. Relationships between categorical variables are analyzed using Pearson Chi-squared or Fisher’s Exact tests.The correlation between two numerical variables is analyzed using Spearman’s Rho correlation coefficient, and a comparison of numerical variables between two groups is made using the Mann-Whitney U test. Results: The clinicopathological features of the patients were evaluated as sporadic or hereditary, tumor node metastasis (TNM) staging, single or multifocal focus, recurrence or regional or distant metastasis, progression-free survival time (PFS), and appropriate pathology tissue samples were determined as PEDF, VEGF, NF-kB, Ki-67 staining was compared. As a result of this comparison, a moderate negative correlation was found between VEGF expression level and PFS (rho = - 0,407, p = 0,019). No statistically significant correlation was found between single or multifocal groups and Ki-67 proliferation index (PI) expression levels (p = 0.070), but this is a small p value, a variable that is likely to find significant differences in studies with larger sample groups.The relationship between PEDF, VEGF, NF- kB, Ki-67 PI factors and tumor angiogenesis as reflected by microvessel density (MVD) was also investigated. To this end, we correlated the expression levels of PEDF, VEGF, NF-kB, and Ki-67 staining of suitable pathology tissue samples of the patients with the results obtained from the staining with CD 31. As a result of this comparison, no statistically significant relationship was found. Conclusions: We demonstrated and described for the first time PEDF expression patterns in MTC tumor tissues. A direct relationship between PEDF expression level and angiogenesis, angiogenetic and clinicopathological factors does not seem to exist, at least as it pertains to the group studied. Further studies are required to fully elucidate mechanisms for tumor angiogenesis and invasion in MTC.

Potential therapeutic role for pigment epithelium-derived factor in post-menopausal breast cancer bone metastasis.

This review discusses key oestrogens associated with the circulating pre- and post-menopausal milieu and how they may impact intratumoral oestrogen levels and breast cancer (BC) metastasis. It also identifies critical steps in BC metastasis to bone from the viewpoint of pigment epithelium-derived factor (PEDF) function, and discusses the role of several associated pro-metastatic biomarkers in BC bone metastasis. PEDF is regulated by oestrogen in a number of oestrogen-sensitive tissues. Changes in circulating oestrogen levels associated with menopause may enhance the growth of BC bone metastases, leading to the establishment of a pre-metastatic niche. The establishment of such a pre-metastatic niche is driven by several key mediators, with pro-osteoclastic and pro-metastatic function which are upregulated by BC cells. These mediators appear to be regulated by oestrogen, as well as differentially affected by menopausal status. PEDF interacts with several pro-metastatic, pro-osteoclastic biomarkers, including C-X-C motif chemokine receptor 4 (CXCR4) and nuclear factor kappa B (NFκB) in BC bone metastasis. Mediators such as CXCR4 and MT1-MMP underpin the ability of PEDF to function as an antimetastatic in other cancers such as osteosarcoma, highlighting the possibility that this serpin could be used as a therapeutic against BC metastasis in future.

Pigment epithelium-derived factor downregulation in oestrogen receptor positive breast cancer bone metastases is associated with menopause

Pigment epithelium-derived factor (PEDF) has a critical role in bone development and anti-tumour function in breast cancer (BC). As the expression and role of PEDF in BC bone metastases is unknown, we aimed to characterise PEDF in primary and metastatic BC. Subcellular PEDF localisation was semi-quantitatively analysed via immunohistochemistry in patient-matched, archived formalin-fixed paraffin-embedded primary BC and liver, lung, and decalcified bone metastases specimens. PEDF localisation was evaluated in 23 metastatic BC patients diagnosed with ER+, human epidermal growth factor receptor-2 (HER2) negative BC or TNBC. Cytoplasmic (p = 0.019) and membrane (p = 0.048) PEDF was lower in bone metastases compared to primary ER+/HER2- BC. In contrast, nuclear PEDF scores were higher in metastases compared to primary TNBC (p = 0.027), and increased membrane PEDF in metastatic tissue had improved disease-free interval (p = 0.016). Nuclear PEDF was decreased in bone metastases compared to primary ER+//HER2- BC in post-menopausal patients (p = 0.029). These novel findings indicate PEDF plays a role in clinical BC metastasis. Significantly lower PEDF levels in the post-menopausal compared to pre-menopausal setting suggests future PEDF research may have greater clinical importance in the post-menopausal ER+/HER2- BC population.

The Role of PEDF in Reproductive Aging of the Ovary.

Reproductive aging is characterized by a decline in ovarian function and in oocytes’ quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36–44 years old and 9–10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients.

Pigment epithelium-derived factor, an anti-VEGF factor, delays ovarian cancer progression by alleviating polarization of tumor-associated macrophages.

Ovarian cancer (OC) is one of the most dangerous gynecological malignancies with no effective treatment so far. Pigment epithelium-derived factor (PEDF) has been reported to have ideal anti-tumor effects, but its relationship with the regulation of tumor-associated macrophage polarization is currently unclear. In this study, the mRNA expression of PEDF and macrophage markers were determined in OC tissues from clinic patients and five OC (A2780, SKOV3, CAOV3, OVCAR3, and OVCA433) cell lines through quantitative reverse transcription PCR. Afterwards, tumor growth, cell proliferation and apoptosis, and macrophage polarization in OC tumor-bearing mice with PEDF overexpression were recorded and investigated. Finally, the polarization of macrophages was explored in the presence of lentiviral PEDF overexpression, adipose triglyceride lipase (ATGL) and laminin receptor (LR) knockdown, and mitogen-activated protein kinase (MAPK) pathway inhibition. Our results suggest that PEDF mRNA level is significantly decreased in OC tissues and cells and has a significant negative correlation with OC progression and the level of tumor-related macrophage markers. Furthermore, OC tumors overexpressing PEDF show suppressed growth viability and increased apoptosis rate. The fluorescence activated cell sorting (FACS) analysis reveals that PEDF can promote macrophage polarization in OC tumors towards M1 subtype. Mechanistically, we found that ATGL and extracellular-regulated kinase 1/2 (ERK1/2) signaling are involved in the regulation of macrophage polarization in OC tumors by PEDF. Taken together, these data indicate that the role of PEDF in regulating the polarization of tumor-associated macrophages may make it a potential therapeutic strategy for the treatment of OC in the future.

Strategies to Attenuate Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Pigment Epithelium-Derived Factor.

The phenomenon of no-reflow seriously limits the therapeutic value of coronary recanalization and leads to poor prognosis. Recent studies have demonstrated the potential role of pigment epithelium-derived factor (PEDF) in stabilizing endothelial cell junction, reducing vascular permeability and maintaining a quiescent vasculature. In this study, intramyocardial gene delivery was performed 5 days before the acute myocardial infarction/recanalization experiment in male rats. Positron emission tomography perfusion imaging with 13N-NH3 indicated PEDF to promote microvascular reperfusion significantly 4 h postcoronary occlusion. PEDF was observed to maintain the stability of endothelial adherens junctions (AJs), thus preventing the occurrence of no-reflow. PEDF reduced the hypoxia-induced vascular endothelial (VE)-cadherin endocytosis through PEDF/LR/Src/VE-cadherin S665 axis in vitro, which was remarkably observed to maintain endothelial AJs. Generally, PEDF might function as a relevant target for therapeutic vasculoprotection by way of regulating the phosphorylation level of VE-cadherin according to our data, thus being crucial for preventing no-reflow.

Pigment epithelium-derived factor, a novel decidual natural killer cells-derived factor, protects decidual stromal cells via anti-inflammation and anti-apoptosis in early pregnancy

What is the role of pigment epithelium-derived factor (PEDF) from decidual natural killer (dNK) cells during early pregnancy? PEDF from dNK cells limits the lipopolysaccharide (LPS)-induced apoptosis and inflammation of decidual stromal cells (DSCs) to maintain DSCs homoeostasis and immune balance at the maternal-foetal interface during early pregnancy. dNK cells, which secrete PEDF, play critical roles during pregnancy via a series of key regulators. PEDF, a multifunctional endogenous glycoprotein, exhibits a wide range of biological actions upon angiogenesis, inflammation, metabolic homoeostasis, immunomodulation etc., providing potential clinical applications. Natural killer (NK) cells from decidua and peripheral blood as well as DSCs isolated from normal pregnancy (NP) during the first trimester (6-10 weeks) and the matched patients suffering recurrent miscarriage (RM) were studied. RNA-sequencing analysis of dNK cells was performed to screen for potential key genes involved in RM. The expression of PEDF in dNK cells in NP and RM was examined. A coculture system with LPS-stimulated DSCs and NK cell supernatants derived from NP or RM was established to explore the regulatory mechanisms of PEDF at the maternal-foetal interface. Peripheral blood and decidual tissues were obtained from women with NP (n = 61) and RM (n = 21). The expression levels of PEDF in NK cells and its receptor (PEDFR) on DSCs were analysed using flow cytometry, western blot and immunohistochemistry. Purified peripheral natural killer (pNK) cells were cocultured with DSCs or trophoblast cells or a combination of both cell types, and PEDF expression in pNK cells was then examined by flow cytometry. DSCs were treated with LPS, an outer-membrane component of Gram-negative bacteria, thereby mimicking an enhanced inflammatory status within decidua, and were cocultured with dNK cell supernatants from NP or RM. In the coculture system, plasmids expressing short hairpin RNA were used to silence PEDFR on DSCs and block the PEDF/PEDFR interaction. Inflammatory cytokines and apoptosis of DSCs treated as described above were assessed by flow cytometry. Western blotting was performed, and the specific signal pathway inhibitors were used to determine downstream PEDF/PEDFR signalling in early decidua. Markedly higher RNA (P < 0.001) and protein expression of PEDF (P < 0.01) was detected in normal dNK cells when compared with pNK cells. Compared with pNK cells cultured alone, PEDF expression in pNK cells was elevated after coculture with DSCs (P < 0.01) or trophoblast cells (P < 0.001). The increased pro-inflammatory cytokine, tumour necrosis factor-α and apoptosis of DSCs following LPS stimulation were suppressed by recombinant human PEDF (P < 0.001) or the supernatant of dNK cells derived from NP (P < 0.001). However, these effects were somewhat abrogated when the PEDF/PEDFR interaction was blocked with PEDFR short hairpin sRNA (P < 0.01). Furthermore, dNK cell-derived PEDF protected DSCs from LPS-induced inflammation via inhibition of nuclear factor kappa-B activation, while also protecting DSCs from LPS-induced apoptosis via promotion of extracellular signal-regulated kinase expression. Compared with NP, both significantly decreased PEDF RNA (P < 0.001) and protein expression (P < 0.001) in dNK cells, but not in pNK cells (P > 0.05), were detected in women with RM. PEDFR on DSCs was also decreased within RM compared with that within NP (P < 0.001). As a result, dNK cell-mediated anti-inflammation (P < 0.01) and anti-apoptosis (P < 0.05) for protection of LPS-treated DSCs was attenuated in patients suffering from RM. N/A. We cannot exclude the possibility that the differences in amounts of PEDF and its receptor in tissue from NP versus RM women could be caused by the miscarriage event in women with RM. Our experiments only involved human samples investigated in vitro. Experiments in animal models and human study cohorts are still needed to confirm these findings and further clarify the role of PEDF-PEDFR in NP and/or RM. To the best of our knowledge, this is the first study to demonstrate PEDF expression and function at the maternal-foetal interface in the first trimester, providing further evidence that PEDF exhibits functional diversity and has great potential for clinical application(s). The findings of selectively high expression of PEDF in normal dNK cells and the PEDF-mediated role of dNK cells during NP and RM help to further elucidate the immune mechanisms behind RM. This work was supported by the National Basic Research Programme of China (2017YFC1001403 and 2015CB943300), Nature Science Foundation from National Nature Science Foundation of China (NSFC; 31970859, 81630036, 81501334, 91542116, 31570920, 81490744 and 31171437), the Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2017-2), the Programme of Shanghai Academic/Technology Research Leader (17XD1400900) and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (STCSM; 12JC1401600). None of the authors has any conflict of interest to declare.

Elucidating the role of pigment epithelium-derived factor (PEDF) in metabolic PCOS models.

PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

PEDF promotes nuclear degradation of ATGL through COP1

Adipose triglyceride lipase (ATGL) plays a compelling role in hepatic lipid turnover and in the pathophysiology of non-alcoholic fatty liver disease. Hepatic ATGL is post-transcriptionally regulated by E3 ubiquitin ligase constitutive photomorphogenic1 (COP1) through polyubiquitylation and proteasomal degradation. However the physiological cue for COP1-mediated hepatocellular degradation of ATGL remained unknown. Here we checked for the role of pigment epithelium-derived factor (PEDF), a moonlighting hepatokine and the so-called ligand of ATGL for its stability in hepatocytes. We show that PEDF diminishes ATGL protein stability by promoting its proteasomal degradation in COP1-dependent manner. Despite being a secretory glycoprotein, PEDF is also sequestered in the nuclear compartment so as COP1. Interestingly, PEDF enhances nuclear import of predominantly cytosolic ATGL protein for its subsequent proteasomal degradation in the nucleus. PEDF also controls cell autonomous hepatocyte lipid accumulation and mobilization through COP1-ATGL axis, thereby unraveling a novel pathway for hepatic lipid metabolism.

Decreased PEDF Expression Promotes Adipogenic Differentiation through the Up-Regulation of CD36.

Adipogenesis is a tightly regulated cellular process that involves the action of multiple signaling pathways. Characterization of regulators that are associated with adipose development is crucial to understanding the mechanisms underlying obesity and other metabolic disorders. Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that was first described as a neurotrophic factor. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, was characterized as its binding partner. In this study, we investigated the downstream effects of PEDF on adipogenic differentiation using rat adipose-derived stem cells (AdSCs) and the mouse pre-adipocyte cell line 3T3-L1. Knocking down PEDF in differentiating cells resulted in elevated levels of ATGL and CD36, as well as other adipogenic markers, with a concomitant increase in adipocyte number. CD36, a scavenger receptor for a variety of ligands, regulated proliferation and lipogenic gene expression during adipogenesis. The CD36 increase due to PEDF down-regulation might be a result of elevated PPARγ. We further demonstrated that PEDF expression was regulated by dexamethasone, a synthetic glucocorticoid that is widely used for adipogenesis at the transcriptional level. Taken together, our findings highlight that PEDF negatively regulates adipogenesis through the regulation of various signaling intermediates, and it may play a crucial role in lipid metabolic disorders.

Pigment epithelium-derived factor inhibits lung cancer migration and invasion by upregulating exosomal thrombospondin 1

Exosomes are implicated in cancer cell development, migration and invasion. Pigment epithelium-derived factor (PEDF) is a secreted anticancer protein that can regulate lung cancer progression; however, the role of PEDF in non-small cell lung cancer (NSCLC), including metastasis and cancer cell-derived exosome secretion, is unclear. In this study, we analyzed the effects of PEDF on exosome-mediated migration, invasion, and tumorigenicity of cultured NSCLC cells. The results showed that PEDF overexpression significantly reduced NSCLC invasion and migration, while inducing cell aggregation, whereas PEDF knockdown had the opposite effects. Exosomes from NSCLC cells treated with recombinant PEDF had a significantly reduced ability to promote cancer cell motility, migration, and invasion compared to exosomes from untreated cells. Exosomes from PEDF-treated cells contained thrombospondin 1 (THBS1), which inhibited cytoskeletal remodeling and exosome-induced lung cancer cell motility, migration, and invasion. Furthermore, PEDF-overexpressing NSCLC cells formed smaller xenograft tumors with higher THBS1 expression compared to control tumors. Our findings indicate that PEDF decreases the metastatic potential of NSCLC cells through regulation of THBS1 release in cancer cell-derived exosomes, thus uncovering a new mechanism of lung cancer progression.

Role of Pigment Epithelium-Derived Factor in Arsenic-Induced Vascular Endothelial Dysfunction in a Rat Model.

Water-borne arsenicosis is caused by the consumption of excess levels of inorganic arsenic from drinking water and is a worldwide public health issue. Arsenic exposure has recently attracted extensive attention due to its damage to the cardiovascular system. Vascular endothelial dysfunction (VED) is recognized as an important cause of cardiovascular diseases. Pigment epithelium-derived factor (PEDF) plays an important role in maintaining endothelial function, and our previous studies suggested that PEDF may have role in arsenic-induced damage. In the present study, we established subchronic arsenic exposure (3months) rat model from drinking water at doses of 0, 2mg/L, 10mg/L, and 50mg/L, respectively. The results showed that the endothelial cells of the aortic arch were obviously damaged, the apoptosis rate increased, the vWF and iNOS levels increased, and the NO and TNOS levels significantly decreased in the arsenic exposure groups. Regardless of serum or aortic arch endothelium, PEDF levels in the arsenic exposure groups decreased compared to the control group. The oxidative stress level and key proteins associated with apoptosis such as Fas, FasL, P53, and p-p38 were then detected to explore the detailed mechanisms. The results showed that the P53 and p-p38 levels significantly increased in the 10mg/L and 50mg/L groups compared to the control group. The MDA content in the arsenic exposure groups increased markedly, whereas the SOD activity decreased significantly with the increased arsenic dose. Taken together, our study is the first to find that PEDF plays a protective role in arsenic-induced endothelial dysfunction through anti-oxidation and anti-apoptosis, and p38 and P53 may be promising target proteins.

Role of pigment epithelium-derived factor (PEDF) on arsenic-induced neuronal apoptosis

Chronic exposure to high levels of arsenic is closely associated with nervous system disorders that harm learning, memory, and intelligence. Studies have shown that the primary characteristic of brain damage is neuronal apoptosis. Arsenic induces apoptosis in a variety of nerve cells. Therefore, substance that inhibit apoptosis promise to mitigate arsenic toxicity. Pigment epithelium-derived factor (PEDF) is widely distributed in brain tissues and has various effects on neurons, including induction of apoptosis. Our previous study suggested that PEDF might augment arsenic-induced apoptosis in rat brains. In this study of 151 adults with normal, mild, moderate, and high exposure to arsenic, the measured serum PEDF levels were 15.46 ± 5.87 ng/mL, 17.33 ± 8.22 ng/mL, 19.43 ± 9.51 ng/mL and 21.65 ± 14.46 ng/mL, respectively. Multiple linear regression analysis revealed an independent positive correlation between serum PEDF levels and arsenic exposure in drinking water. To study the underlying mechanism of arsenic-induced apoptosis, we exposed PEDF-transfected PC12 cells to NaAsO2. We discovered that NaAsO2--induced mitochondrial apoptosis was enhanced in cells that over expressed PEDF. Moreover, p53 up regulated modulator of apoptosis (PUMA) gene and B-cell lymphoma 2 (Bcl-2) protein were primary factors in the progression of arsenic-induced apoptosis. Taken together, our results suggest that PEDF inhibition might mitigate arsenic toxicity to nerve cells.

Pigment epithelium derived factor (PEDF) expression in the male tract of Wistar rats

Pigment epithelium derived factor (PEDF) expression has been described in many organs as showing neurotrophic, anti-angiogenic, anti-apoptotic, anti-inflammatory, anti-oxidant and pro-cell survival properties. However, references to its activity in the male reproductive system are scarce. We aimed to characterize the expression of PEDF in the male reproductive tract of Wistar rats by using RT-PCR, western blot and immunostaining and also evaluate the effect of flutamide in PEDF expression. We found that PEDF is expressed in the epididymis, prostate and seminal vesicles in Wistar rats, but notably not in the testes. Under the effect of flutamide PEDF expression decreased, recovering by suppressing the antiandrogen. The epididymis is an essential organ in sperm maturation-storages. The role of PEDF in this physiological process has not been fully elucidated yet, but considering that in other systems PEDF has anti-apoptotic, anti-oxidants and pro-cell survival properties, its expression along the epididymis could play a role in the protection of spermatozoa while they are stored.

Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

ObjectivesSystemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1);...

Activation of Complement by Pigment Epithelium-Derived Factor in Rheumatoid Arthritis.

The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family. Using ELISA, we confirmed the presence of various amounts of complexes between PEDF and C4d in the SF from 30 RA patients, whereas none were detected in SF from control subjects. Correlation analyses suggested that, in arthritis patients, C4d-PEDF complexes found in sera arise from the joints, as well as from other tissues, and levels of the complexes did not differ in sera of RA patients and healthy controls. When immobilized, recombinant PEDF expressed in eukaryotic cells activated the classical complement pathway but not the alternative or lectin pathways. C1q protein was demonstrated to bind immobilized PEDF, and PEDF was shown to bind to immobilized C1q, in particular its head regions, which are known to interact with other activators of the classical pathway. Our results call for further investigation into the role of PEDF in inflammatory processes in the joint, which, in combination with classical complement activation, appears to be part of a (patho-)physiologic response.

P.2.f.018 - The plasma proteome following electroconvulsive therapy: a role for pigment epithelium-derived factor (PEDF) in depression and treatment response?

Multicore architectures were introduced to mitigate the issue of increase in power dissipation with clock frequency. Introduction of deeper pipelines, speculative threading etc. for single core systems were not able to bring much increase in performance as compared to their associated power overhead. However for multicore architectures performance scaling with number of cores has always been a challenge. The Amdahl’s law shows that the theoretical maximum speedup of a multicore architecture is not even close to the multiple of number of cores. With less amount of code in parallel having more number of cores for an application might just contribute in greater power dissipation instead of bringing some performance advantage. Therefore there is a need of an adaptive multicore architecture that can be tailored for the application in use for higher energy efficiency. In this paper a fuzzy logic based design space exploration technique is presented that is targeted to optimize a multicore architecture according to the workload requirements in order to achieve optimum balance between throughput and energy of the system.