Expression of pigment epithelium-derived factor and tumor necrosis factor-α is correlated in bladder tumor and is related to tumor angiogenesis.

PubMed

Feng, Chen-Chen; Wang, Pao-Hsun; Ding, Qiang; Guan, Ming; Zhang, Yuan-Fang; Jiang, Hao-Wen; Wen, Hui; Wu, Zhong

2013-02-01

Angiogenesis is a pivotal process on which solid tumor growth is substantially dependent. Pigment epithelium-derived factor (PEDF) is the most potent natural anti-angiogenic factor, which has seldom been studied in bladder tumor, and whose functioning pathway remains unclear. We have thus investigated PEDF expression in relation to tumor necrosis factor-α (TNF-α) and microvessel density (MVD) with immunohistochemistry. Antibodies of PEDF and TNF-α were examined by Western blotting before immunohistochemistry. Sixty-four urothelial tumor sections and 23 normal controls were stained and expression of PEDF, TNF-α, and MVD were studied. Decreased PEDF expression and increased TNF-α expression was noticed in tumorous tissue compared with healthy urothelium. Lower PEDF expression was related to higher tumor grade but stage. Increased TNF-α expression was noticed in recurrent, larger tumors as well as in tumors with progression in grade and stage. Expression of PEDF and TNF-α was correlated in bladder tumor. PEDF or TNF-α was correlated with MVD negatively or positively, respectively, in cancerous tissue and tumorous grouping without correlation in papillary urothelial neoplasm of low malignant potential. Expressional change of PEDF and TNF-α is in relation to angiogenesis of bladder tumor, especially in bladder cancer development. Copyright © 2013 Elsevier Inc. All rights reserved.

Role of pigment epithelium-derived factor in the reproductive system.

PubMed

Chuderland, Dana; Ben-Ami, Ido; Bar-Joseph, Hadas; Shalgi, Ruth

2014-10-01

The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro- and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated. © 2014 Society for Reproduction and Fertility.

Pigment epithelium derived factor inhibits the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro.

PubMed

Sun, Yanmei; Che, Xuan; Zhu, Libo; Zhao, Mengdan; Fu, Guofang; Huang, Xiufeng; Xu, Hong; Hu, Fuqiang; Zhang, Xinmei

2012-01-01

Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF) is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF) expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by α-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis.

Pigment Epithelium Derived Factor Inhibits the Growth of Human Endometrial Implants in Nude Mice and of Ovarian Endometriotic Stromal Cells In Vitro

PubMed Central

Sun, Yanmei; Che, Xuan; Zhu, Libo; Zhao, Mengdan; Fu, Guofang; Huang, Xiufeng; Xu, Hong; Hu, Fuqiang; Zhang, Xinmei

2012-01-01

Angiogenesis is a prerequisite for the formation and development of endometriosis. Pigment epithelium derived factor (PEDF) is a natural inhibitor of angiogenesis. We previously demonstrated a reduction of PEDF in the peritoneal fluid, serum and endometriotic lesions from women with endometriosis compared with women without endometriosis. Here, we aim to investigate the inhibitory effect of PEDF on human endometriotic cells in vivo and in vitro. We found that PEDF markedly inhibited the growth of human endometrial implants in nude mice and of ovarian endometriotic stromal cells in vitro by up-regulating PEDF expression and down-regulating vascular endothelial growth factor (VEGF) expression. Moreover, apoptotic index was significantly increased in endometriotic lesions in vivo and endometriotic stromal cells in vitro when treated with PEDF. In mice treated with PEDF, decreased microvessel density labeled by Von Willebrand factor but not by α-Smooth Muscle Actin was observed in endometriotic lesions. And it showed no increase in PEDF expression of the ovary and uterus tissues. These findings suggest that PEDF gene therapy may be a new treatment for endometriosis. PMID:23028859

Cigarette Smoke-Related Hydroquinone Dysregulates MCP-1, VEGF and PEDF Expression in Retinal Pigment Epithelium in Vitro and in Vivo

PubMed Central

Pons, Marianne; Marin-Castaño, Maria E.

2011-01-01

Background Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly population. Debris (termed drusen) below the retinal pigment epithelium (RPE) have been recognized as a risk factor for dry AMD and its progression to wet AMD, which is characterized by choroidal neovascularization (CNV). The underlying mechanism of how drusen might elicit CNV remains undefined. Cigarette smoking, oxidative damage to the RPE and inflammation are postulated to be involved in the pathophysiology of the disease. To better understand the cellular mechanism(s) linking oxidative stress and inflammation to AMD, we examined the expression of pro-inflammatory monocyte chemoattractant protein-1 (MCP-1), pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial derived factor (PEDF) in RPE from smoker patients with AMD. We also evaluated the effects of hydroquinone (HQ), a major pro-oxidant in cigarette smoke on MCP-1, VEGF and PEDF expression in cultured ARPE-19 cells and RPE/choroids from C57BL/6 mice. Principal Findings MCP-1, VEGF and PEDF expression was examined by real-time PCR, Western blot, and ELISA. Low levels of MCP-1 protein were detected in RPE from AMD smoker patients relative to controls. Both MCP-1 mRNA and protein were downregulated in ARPE-19 cells and RPE/choroids from C57BL/6 mice after 5 days and 3 weeks of exposure to HQ-induced oxidative injury. VEGF protein expression was increased and PEDF protein expression was decreased in RPE from smoker patients with AMD versus controls resulting in increased VEGF/PEDF ratio. Treatment with HQ for 5 days and 3 weeks increased the VEGF/PEDF ratio in vitro and in vivo. Conclusion We propose that impaired RPE-derived MCP-1-mediated scavenging macrophages recruitment and phagocytosis might lead to incomplete clearance of proinflammatory debris and infiltration of proangiogenic macrophages which along with increased VEGF/PEDF ratio favoring angiogenesis might

Pigment epithelium-derived factor, insulin sensitivity, and adiposity in polycystic ovary syndrome: impact of exercise training.

PubMed

Joham, Anju E; Teede, Helena J; Hutchison, Samantha K; Stepto, Nigel K; Harrison, Cheryce L; Strauss, Boyd J; Paul, Eldho; Watt, Matthew J

2012-12-01

Pigment epithelium-derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight-matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non-PCOS weight-matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic-hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non-PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 ± 96.3 and 257.2 ± 64.3 mg.m(-2).min(-1)) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = -0.41, P = 0.03) and high-density lipoprotein (HDL) (r = -0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status.

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

PubMed Central

Wietecha, Mateusz S.; Król, Mateusz J.; Michalczyk, Elizabeth R.; Chen, Lin; Gettins, Peter G.

2015-01-01

During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury. PMID:26163443

Alginate Bead-Encapsulated PEDF Induces Ectopic Bone Formation In Vivo in the Absence of Co-Administered Mesenchymal Stem Cells.

PubMed

Elahy, Mina; Doschak, Michael R; Hughes, Jeffery D; Baindur-Hudson, Swati; Dass, Crispin R

2018-01-01

Bone defects can be severely debilitating and reduce quality of life. Osteoregeneration can alleviate some of the complications in bony defects. For therapeutic use in future, a single factor that can cause potent bone regeneration is highly preferred as it will be more costeffective, any off-target effects will be more easily monitored and potentially managed, and for ease of administration which would lead to better patient compliance and satisfaction. We demonstrate that pigment epithelium-derived factor (PEDF), one such factor that is known to be potent against angiogenesis, promotes osteoblastogenesis in mesenchymal stem cells in vitro, but does not need co-encapsulation of cells in alginate bead scaffolds for osteogeneration in vivo. Osteogenic differentiation by PEDF in vitro was confirmed with immunoblotting and immunocytochemical staining for bone markers (alkaline phosphatase, osteocalcin, osteopontin, collagen I), calcified mineral deposition, and assay for alkaline phosphatase activity. PEDF-mediated bone formation in a muscle pocket in vivo model was confirmed by microcomputed tomography (microCT), histology (haematoxylin and eosin, Alcian blue staining), immunostaining for bone markers and for collagen I-processing proteins (heat shock protein 47 and membrane type I matrix metalloproteinase). PEDF therefore presents itself as a promising biological for osteogeneration. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Increased expression of pigment epithelium-derived factor in aged mesenchymal stem cells impairs their therapeutic efficacy for attenuating myocardial infarction injury‡

PubMed Central

Liang, Hongliang; Hou, Huiyuan; Yi, Wei; Yang, Guodong; Gu, Chunhu; Lau, Wayne Bond; Gao, Erhe; Ma, Xinliang; Lu, Zifan; Wei, Xufeng; Pei, Jianming; Yi, Dinghua

2013-01-01

Aims Mesenchymal stem cells (MSCs) can ameliorate myocardial infarction (MI) injury. However, older-donor MSCs seem less efficacious than those from younger donors, and the contributing underlying mechanisms remain unknown. Here, we determine how age-related expression of pigment epithelium-derived factor (PEDF) affects MSC therapeutic efficacy for MI. Methods and results Reverse transcriptase–polymerized chain reaction  and enzyme-linked immunosorbent assay analyses revealed dramatically increased PEDF expression in MSCs from old mice compared to young mice. Morphological and functional experiments demonstrated significantly impaired old MSC therapeutic efficacy compared with young MSCs in treatment of mice subjected to MI. Immunofluorescent staining demonstrated that administration of old MSCs compared with young MSCs resulted in an infarct region containing fewer endothelial cells, vascular smooth muscle cells, and macrophages, but more fibroblasts. Pigment epithelium-derived factor overexpression in young MSCs impaired the beneficial effects against MI injury, and induced cellular profile changes in the infarct region similar to administration of old MSCs. Knocking down PEDF expression in old MSCs improved MSC therapeutic efficacy, and induced a cellular profile similar to young MSCs administration. Studies in vitro showed that PEDF secreted by MSCs regulated the proliferation and migration of cardiac fibroblasts. Conclusions This is the first evidence that paracrine factor PEDF plays critical role in the regulatory effects of MSCs against MI injury. Furthermore, the impaired therapeutic ability of aged MSCs is predominantly caused by increased PEDF secretion. These findings indicate PEDF as a promising novel genetic modification target for improving aged MSC therapeutic efficacy. PMID:21606086

Molecular phylogeny of the antiangiogenic and neurotrophic serpin, pigment epithelium derived factor in vertebrates

PubMed Central

Xu, Xuming; Zhang, Samuel Shao-Min; Barnstable, Colin J; Tombran-Tink, Joyce

2006-01-01

Background Pigment epithelium derived factor (PEDF), a member of the serpin family, regulates cell proliferation, promotes survival of neurons, and blocks growth of new blood vessels in mammals. Defining the molecular phylogeny of PEDF by bioinformatic analysis is one approach to understanding the link between its gene structure and its function in these biological processes. Results From a comprehensive search of available DNA databases we identified a single PEDF gene in all vertebrate species examined. These included four mammalian and six non-mammalian vertebrate species in which PEDF had not previously been described. A five gene cluster around PEDF was found in an approximate 100 kb region in mammals, birds, and amphibians. In ray-finned fish these genes are scattered over three chromosomes although only one PEDF gene was consistently found. The PEDF gene is absent in invertebrates including Drosophila melanogaster (D. melanogaster), Caenorhabditis elegans (C. elegans), and sea squirt (C. intestinalis). The PEDF gene is transcribed in all vertebrate phyla, suggesting it is biologically active throughout vertebrate evolution. The multiple actions of PEDF are likely conserved in evolution since it has the same gene structure across phyla, although the size of the gene ranges from 48.3 kb in X. tropicalis to 2.9 kb in fugu, with human PEDF at a size of 15.6 kb. A strong similarity in the proximal 200 bp of the PEDF promoter in mammals suggests the existence of a possible regulatory region across phyla. Using a non-synonymous/synonymous substitution rate ratio we show that mammalian and fish PEDFs have similar ratios of <0.13, reflecting a strong purifying selection of PEDF gene. A large number of repetitive transposable elements of the SINE and LINE class were found with random distribution in both the promoter and introns of mammalian PEDF. Conclusion The PEDF gene first appears in vertebrates and our studies suggest that the regulation and biological actions

Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: a novel mechanistic insight into progressive obesity.

PubMed

Dai, Zhiyu; Qi, Weiwei; Li, Cen; Lu, Juling; Mao, Yuling; Yao, Yachao; Li, Lei; Zhang, Ting; Hong, Honghai; Li, Shuai; Zhou, Ti; Yang, Zhonghan; Yang, Xia; Gao, Guoquan; Cai, Weibin

2013-09-05

Both elevated plasma free fatty acids (FFA) and accumulating triglyceride in adipose tissue are observed in the process of obesity and insulin resistance. This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Recent studies have demonstrated that pigment epithelium-derived factor (PEDF) contributes to elevated plasma FFA and insulin resistance in obese mice via the activation of adipose triglyceride lipase (ATGL). However, we found that PEDF downregulated adipose ATGL protein expression despite of enhancing lipolysis. Plasma PEDF and FFA were increased in associated with a progressive high-fat-diet, and those outcomes were also accompanied by fat accumulation and a reduction in adipose ATGL. Exogenous PEDF injection downregulated adipose ATGL protein expression and elevated plasma FFA, while endogenous PEDF neutralization significantly rescued the adipose ATGL reduction and also reduced plasma FFA in obese mice. PEDF reduced ATGL protein expression in a time- and dose-dependent manner in differentiated 3T3-L1 cells. Small interfering RNA-mediated PEDF knockdown and antibody-mediated PEDF blockage increased endogenous ATGL expression, and PEDF overexpression downregulated ATGL. PEDF resulted in a decreased half-life of ATGL and regulated ATGL degradation via ubiquitin-dependent proteasomal degradation pathway. PEDF stimulated lipolysis via ATGL using ATGL inhibitor bromoenol lactone, and PEDF also downregulated G0/G1 switch gene 2 (G0S2) expression, which is an endogenous inhibitor of ATGL activation. Overall, PEDF attenuated ATGL protein accumulation via proteasome-mediated degradation in adipocytes, and PEDF also promoted lipolysis by activating ATGL. Elevated PEDF may contribute to progressive obesity and insulin resistance via its dual regulation of ATGL. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pigment Epithelium Derived Factor Peptide Protects Murine Hepatocytes from Carbon Tetrachloride-Induced Injury

PubMed Central

Shih, Shou-Chuan; Ho, Tsung-Chuan; Chen, Show-Li; Tsao, Yeou-Ping

2016-01-01

Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and

High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling.

PubMed

Qi, Weiwei; Yang, Chuan; Dai, Zhiyu; Che, Di; Feng, Juan; Mao, Yuling; Cheng, Rui; Wang, Zhongxiao; He, Xuemin; Zhou, Ti; Gu, Xiaoqiong; Yan, Li; Yang, Xia; Ma, Jian-Xing; Gao, Guoquan

2015-04-01

Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride-induced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/β-catenin signaling. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Serum PEDF levels are decreased in a spontaneous animal model for human autoimmune uveitis.

PubMed

Zipplies, Johanna K; Hauck, Stefanie M; Schoeffmann, Stephanie; Amann, Barbara; Stangassinger, Manfred; Ueffing, Marius; Deeg, Cornelia A

2009-02-01

Identification of biomarkers is of critical relevance toward improving diagnosis and therapy of autoimmune disorders. Serum markers are a desirable choice as sera are easily accessible and the development of assays for routine clinical detection prompts feasible. Autoimmune uveitis, a recurrent disease affecting the eye, is characterized by returning inflammatory attacks of the inner eye followed by variable periods of quiescent stages. Spontaneous equine recurrent uveitis (ERU) is the equine equivalent and serves as a model for the human disease. To identify potential biomarker candidates, we first systematically compared the proteomes of individual ERU cases with healthy controls by proteomic profiling using 2-D difference-gel-electrophoresis (2-D DIGE) followed by tandem mass spectrometry. A total of seven differentially expressed proteins were identified. Besides the upregulation of IgG and the significant lower expression of albumin, Antithrombin III, and Vitamin D binding protein, we found complement components C1q and C4, to be downregulated in uveitic state. Interestingly, Pigment epithelium-derived factor (PEDF), a marker already detected by 2DE differential proteome analysis in ERU target tissues, vitreous and retina, was found to be also significantly downregulated in sera. The lower expression of PEDF in sera of horses with uveitis could be verified in a cohort of 116 ERU cases and 115 healthy controls. Our findings of a significant lower PEDF expression in ERU cases also in the periphery of the eye proves PEDF as a promising uveitis biomarker.

Human adipose-derived mesenchymal stromal cell pigment epithelium-derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells.

PubMed

Zolochevska, Olga; Shearer, Joseph; Ellis, Jayne; Fokina, Valentina; Shah, Forum; Gimble, Jeffrey M; Figueiredo, Marxa L

2014-03-01

Adipose-derived mesenchymal stromal cells (ASCs) are promising tools for delivery of cytotherapy against cancer. However, ASCs can exert profound effects on biological behavior of tumor cells. Our study aimed to examine the influence of ASCs on gene expression and epigenetic methylation profiles of prostate cancer cells as well as the impact of expressing a therapeutic gene on modifying the interaction between ASCs and prostate cancer cells. ASCs were modified by lentiviral transduction to express either green fluorescent protein as a control or pigment epithelium-derived factor (PEDF) as a therapeutic molecule. PC3 prostate cancer cells were cultured in the presence of ASC culture-conditioned media (CCM), and effects on PC3 or DU145. Ras cells were examined by means of real-time quantitative polymerase chain reaction, EpiTect methyl prostate cancer-focused real-time quantitative polymerase chain reaction arrays, and luciferase reporter assays. ASCs transduced with lentiviral vectors were able to mediate expression of several tumor-inhibitory genes, some of which correlated with epigenetic methylation changes on cocultured PC3 prostate cancer cells. When PC3 cells were cultured with ASC-PEDF CCM, we observed a shift in the balance of gene expression toward tumor inhibition, which suggests that PEDF reduces the potential tumor-promoting activity of unmodified ASCs. These results suggest that ASC-PEDF CCM can promote reprogramming of tumor cells in a paracrine manner. An improved understanding of genetic and epigenetic events in prostate cancer growth in response to PEDF paracrine therapy would enable a more effective use of ASC-PEDF, with the goal of achieving safer yet more potent anti-tumor effects. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Defining a mechanistic link between pigment epithelium-derived factor, docosahexaenoic acid, and corneal nerve regeneration.

PubMed

Pham, Thang Luong; He, Jiucheng; Kakazu, Azucena H; Jun, Bokkyoo; Bazan, Nicolas G; Bazan, Haydee E P

2017-11-10

The cornea is densely innervated to sustain the integrity of the ocular surface. Corneal nerve damage produced by aging, diabetes, refractive surgeries, and viral or bacterial infections impairs tear production, the blinking reflex, and epithelial wound healing, resulting in loss of transparency and vision. A combination of the known neuroprotective molecule, pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA), has been shown to stimulate corneal nerve regeneration, but the mechanisms involved are unclear. Here, we sought to define the molecular events of this effect in an in vivo mouse injury model. We first confirmed that PEDF + DHA increased nerve regeneration in the mouse cornea. Treatment with PEDF activates the phospholipase A 2 activity of the PEDF-receptor (PEDF-R) leading to the release of DHA; this free DHA led to enhanced docosanoid synthesis and induction of bdnf, ngf , and the axon growth promoter semaphorin 7a ( sema7a ), and as a consequence, their products appeared in the mouse tears. Surprisingly, corneal injury and treatment with PEDF + DHA induced transcription of neuropeptide y ( npy ), small proline-rich protein 1a ( sprr1a ), and vasoactive intestinal peptide ( vip ) in the trigeminal ganglia (TG). The PEDF-R inhibitor, atglistatin, blocked all of these changes in the cornea and TG. In conclusion, we uncovered here an active cornea-TG axis, driven by PEDF-R activation, that fosters axon outgrowth in the cornea. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Pigment epithelium-derived factor blocks tumor extravasation by suppressing amoeboid morphology and mesenchymal proteolysis.

PubMed

Ladhani, Omar; Sánchez-Martinez, Cristina; Orgaz, Jose L; Jimenez, Benilde; Volpert, Olga V

2011-07-01

Metastatic melanoma cells are highly adaptable to their in vivo microenvironment and can switch between protease-dependent mesenchymal and protease-independent amoeboid invasion to facilitate metastasis. Such adaptability can be visualized in vitro, when cells are cultured in conditions that recapitulate three-dimensional microenvironments. Using thick collagen layers in cell culture and in vivo extravasation assays, we found that pigment epithelium-derived factor (PEDF) suppressed lung extravasation of aggressive melanoma by coordinated regulation of cell shape and proteolysis. In cells grown on a thick collagen bed, PEDF overexpression and exogenous PEDF blocked the rapidly invasive, rounded morphology, and promoted an elongated, mesenchymal-like phenotype associated with reduced invasion. These changes in cell shape depended on decreased RhoA and increased Rac1 activation and were mediated by the up-regulation of Rac1-GEF, DOCK3 and down-regulation of Rac1-GAP, ARHGAP22. Surprisingly, we found that PEDF overexpression also blocked the trafficking of membrane-tethered, MT1-MMP to the cell surface through RhoA inhibition and Rac1 activation. In vivo, knockdown of Rac1 and DOCK3 or overexpression of MT1-MMP was sufficient to reverse the inhibitory effect of PEDF on extravasation. Using functional studies, we demonstrated that PEDF suppressed the rounded morphology and MT1-MMP surface localization through its antiangiongenic, 34-mer epitope and the recently identified PEDF receptor candidate, PNPLA2. Our findings unveil the coordinated regulation of cell shape and proteolysis and identify an unknown mechanism for PEDF's antimetastatic activity.

Pigment Epithelium-Derived Factor Blocks Tumor Extravasation by Suppressing Amoeboid Morphology and Mesenchymal Proteolysis12

PubMed Central

Ladhani, Omar; Sánchez-Martinez, Cristina; Orgaz, Jose L; Jimenez, Benilde; Volpert, Olga V

2011-01-01

Metastatic melanoma cells are highly adaptable to their in vivo microenvironment and can switch between protease-dependent mesenchymal and protease-independent amoeboid invasion to facilitate metastasis. Such adaptability can be visualized in vitro, when cells are cultured in conditions that recapitulate three-dimensional microenvironments. Using thick collagen layers in cell culture and in vivo extravasation assays, we found that pigment epithelium-derived factor (PEDF) suppressed lung extravasation of aggressive melanoma by coordinated regulation of cell shape and proteolysis. In cells grown on a thick collagen bed, PEDF overexpression and exogenous PEDF blocked the rapidly invasive, rounded morphology, and promoted an elongated, mesenchymal-like phenotype associated with reduced invasion. These changes in cell shape depended on decreased RhoA and increased Rac1 activation and were mediated by the up-regulation of Rac1-GEF, DOCK3 and down-regulation of Rac1-GAP, ARHGAP22. Surprisingly, we found that PEDF overexpression also blocked the trafficking of membrane-tethered, MT1-MMP to the cell surface through RhoA inhibition and Rac1 activation. In vivo, knockdown of Rac1 and DOCK3 or overexpression of MT1-MMP was sufficient to reverse the inhibitory effect of PEDF on extravasation. Using functional studies, we demonstrated that PEDF suppressed the rounded morphology and MT1-MMP surface localization through its antiangiongenic, 34-mer epitope and the recently identified PEDF receptor candidate, PNPLA2. Our findings unveil the coordinated regulation of cell shape and proteolysis and identify an unknown mechanism for PEDF's antimetastatic activity. PMID:21750657

Pigment epithelium-derived factor protects retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction

PubMed Central

Tian, Shu-Wei; Ren, Yuan; Pei, Jin-Zhi; Ren, Bai-Chao; He, Yuan

2017-01-01

AIM To investigate the potential of pigment epithelium-derived factor (PEDF) to protect the immortalized rat retinal ganglion cells-5 (RGC-5) exposed to CoCl2-induced chemical hypoxia. METHODS After being differentiated with staurosporine (SS), RGC-5 cells were cultured in four conditions: control group cells cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 100 µmol/mL streptomycin and penicillin (named as normal conditions); hypoxia group cells cultured in DMEM containing 300 µmol/mL CoCl2; cells in the group protected by PEDF were first pretreated with 100 ng/mL PEDF for 2h and then cultured in the same condition as hypoxia group cells; and PEDF group cells that were cultured in the presence of 100 ng/mL PEDF under normal conditions. The cell viability was assessed by MTT assay, the percentage of apoptotic cells was quantified using Annexin V-FITC apoptosis kit, and intra-cellar reactive oxygen species (ROS) was measured by dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe. The mitochondria-mediated apoptosis was also examined to further study the underlying mechanism of the protective effect of PEDF. The opening of mitochondrial permeability transition pores (mPTPs) and membrane potential (Δψm) were tested as cellular adenosine triphosphate (ATP) level and glutathione (GSH). Also, the expression and distribution of Cyt C and apoptosis inducing factor (AIF) were observed. RESULTS SS induced differentiation of RGC-5 cells resulting in elongation of their neurites and establishing contacts between outgrowths. Exposure to 300 µmol/mL CoCl2 triggered death of 30% of the total cells in cultures within 24h. At the same time, pretreatment with 100 ng/mL PEDF significantly suppressed the cell death induced by hypoxia (P<0.05). The apoptosis induced by treatment of CoCl2 was that induced cell death accompanied with increasing intra-cellar ROS and decreasing GSH and ATP level. PEDF pre-treatment suppressed these

Defects in subventricular zone pigmented epithelium-derived factor niche signaling in the senescence-accelerated mouse prone-8.

PubMed

Castro-Garcia, Paola; Díaz-Moreno, María; Gil-Gas, Carmen; Fernández-Gómez, Francisco J; Honrubia-Gómez, Paloma; Álvarez-Simón, Carmen Belén; Sánchez-Sánchez, Francisco; Cano, Juan Carlos Castillo; Almeida, Francisco; Blanco, Vicente; Jordán, Joaquín; Mira, Helena; Ramírez-Castillejo, Carmen

2015-04-01

We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model. © FASEB.

Pigment epithelium-derived factor stimulates skeletal muscle glycolytic activity through NADPH oxidase-dependent reactive oxygen species production.

PubMed

Carnagarin, Revathy; Carlessi, Rodrigo; Newsholme, Philip; Dharmarajan, Arun M; Dass, Crispin R

2016-09-01

Pigment epithelium-derived factor is a multifunctional serpin implicated in insulin resistance in metabolic disorders. Recent evidence suggests that exposure of peripheral tissues such as skeletal muscle to PEDF has profound metabolic consequences with predisposition towards chronic conditions such as obesity, type 2 diabetes, metabolic syndrome and polycystic ovarian syndrome. Chronic inflammation shifts muscle metabolism towards increased glycolysis and decreased oxidative metabolism. In the present study, we demonstrate a novel effect of PEDF on cellular metabolism in mouse cell line (C2C12) and human primary skeletal muscle cells. PEDF addition to skeletal muscle cells induced enhanced phospholipase A2 activity. This was accompanied with increased production of reactive oxygen species in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner that triggered a shift towards a more glycolytic phenotype. Extracellular flux analysis and glucose consumption assays demonstrated that PEDF treatment resulted in enhanced glycolysis but did not change mitochondrial respiration. Our results demonstrate that skeletal muscle cells express a PEDF-inducible oxidant generating system that enhances glycolysis but is sensitive to antioxidants and NADPH oxidase inhibition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study

PubMed Central

Ryan, K M; Glaviano, A; O'Donovan, S M; Kolshus, E; Dunne, R; Kavanagh, A; Jelovac, A; Noone, M; Tucker, G M; Dunn, M J; McLoughlin, D M

2017-01-01

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression. PMID:28350398

Electroconvulsive therapy modulates plasma pigment epithelium-derived factor in depression: a proteomics study.

PubMed

Ryan, K M; Glaviano, A; O'Donovan, S M; Kolshus, E; Dunne, R; Kavanagh, A; Jelovac, A; Noone, M; Tucker, G M; Dunn, M J; McLoughlin, D M

2017-03-28

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, yet its mechanism of action is not fully understood. Peripheral blood proteomic analyses may offer insights into the molecular mechanisms of ECT. Patients with a major depressive episode were recruited as part of the EFFECT-Dep trial (enhancing the effectiveness of electroconvulsive therapy in severe depression; ISRCTN23577151) along with healthy controls. As a discovery-phase study, patient plasma pre-/post-ECT (n=30) was analyzed using 2-dimensional difference in gel electrophoresis and mass spectrometry. Identified proteins were selected for confirmation studies using immunodetection methods. Samples from a separate group of patients (pre-/post-ECT; n=57) and matched healthy controls (n=43) were then used to validate confirmed changes. Target protein mRNA levels were also assessed in rat brain and blood following electroconvulsive stimulation (ECS), the animal model of ECT. We found that ECT significantly altered 121 protein spots with 36 proteins identified by mass spectrometry. Confirmation studies identified a post-ECT increase (P<0.01) in the antiangiogenic and neuroprotective mediator pigment epithelium-derived factor (PEDF). Validation work showed an increase (P<0.001) in plasma PEDF in depressed patients compared with the controls that was further increased post-ECT (P=0.03). PEDF levels were not associated with mood scores. Chronic, but not acute, ECS increased PEDF mRNA in rat hippocampus (P=0.02) and dentate gyrus (P=0.03). This study identified alterations in blood levels of PEDF in depressed patients and further alterations following ECT, as well as in an animal model of ECT. These findings implicate PEDF in the biological response to ECT for depression.

High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression

PubMed Central

Farnoodian, Mitra; Halbach, Caroline; Slinger, Cassidy; Pattnaik, Bikash R.; Sorenson, Christine M.

2016-01-01

Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis. PMID:27440660

Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration.

PubMed

Wang, Yujuan; Subramanian, Preeti; Shen, Defen; Tuo, Jingsheng; Becerra, S Patricia; Chan, Chi-Chao

2013-11-26

AMD (age-related macular degeneration) is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor) is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)]) mice, a model for progressive, focal rd (retinal degeneration). First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium) than WT (wild-type, C57BL/6N). Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 μg), followed by a subconjunctival injection of PEDF (3 μg) 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment.

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα.

PubMed

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-08-31

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer.

Promising Nanocarriers for PEDF Gene Targeting Delivery to Cervical Cancer Cells Mediated by the Over-expressing FRα

PubMed Central

Yang, Yuhan; He, Lili; Liu, Yongmei; Xia, Shan; Fang, Aiping; Xie, Yafei; Gan, Li; He, Zhiyao; Tan, Xiaoyue; Jiang, Chunling; Tong, Aiping; Song, Xiangrong

2016-01-01

Cervical cancer presents extremely low PEDF expression which is associated with tumor progression and poor prognosis. In this study, folate receptor α (FRα)-targeted nano-liposomes (FLP) were designed to enhance the anti-tumor effect by targeting delivery of exogenous PEDF gene to cervical cancer cells. The targeting molecule F-PEG-Chol was firstly synthesized by a novel simpler method. FLP encapsulating PEDF gene (FLP/PEDF) with a typical lipid-membrane structure were prepared by a film dispersion method. The transfection experiment found FLP could effectively transfect human cervical cancer cells (HeLa cells). FLP/PEDF significantly inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC cells) and suppressed adhension, invasion and migration of HeLa cells in vitro. In the abdominal metastatic tumor model of cervical cancer, FLP/PEDF administered by intraperitoneal injection exhibited a superior anti-tumor effect probably due to the up-regulated PEDF. FLP/PEDF could not only sharply reduce the microvessel density but also dramatically inhibit proliferation and markedly induce apoptosis of tumor cells in vivo. Moreover, the preliminary safety investigation revealed that FLP/PEDF had no obvious toxicity. These results clearly showed that FLP were desired carriers for PEDF gene and FLP/PEDF might represent a potential novel strategy for gene therapy of cervical cancer. PMID:27576898

A Novel In Vivo Model of Focal Light Emitting Diode-Induced Cone-Photoreceptor Phototoxicity: Neuroprotection Afforded by Brimonidine, BDNF, PEDF or bFGF

PubMed Central

García-Ayuso, Diego; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Bernal-Garro, José Manuel; Nieto-López, Leticia; Nadal-Nicolás, Francisco Manuel; Villegas-Pérez, María Paz; Wheeler, Larry A.; Vidal-Sanz, Manuel

2014-01-01

We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model

A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF.

PubMed

Ortín-Martínez, Arturo; Valiente-Soriano, Francisco Javier; García-Ayuso, Diego; Alarcón-Martínez, Luis; Jiménez-López, Manuel; Bernal-Garro, José Manuel; Nieto-López, Leticia; Nadal-Nicolás, Francisco Manuel; Villegas-Pérez, María Paz; Wheeler, Larry A; Vidal-Sanz, Manuel

2014-01-01

We have investigated the effects of light-emitting diode (LED)-induced phototoxicity (LIP) on cone-photoreceptors and their protection with brimonidine (BMD), brain-derived neurotrophic factor (BDNF), pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF) or basic fibroblast growth factor (bFGF). In anesthetized, dark adapted, adult albino rats a blue (400 nm) LED was placed perpendicular to the cornea (10 sec, 200 lux) and the effects were investigated using Spectral Domain Optical Coherence Tomography (SD-OCT) and/or analysing the retina in oriented cross-sections or wholemounts immune-labelled for L- and S-opsin and counterstained with the nuclear stain DAPI. The effects of topical BMD (1%) or, intravitreally injected BDNF (5 µg), PEDF (2 µg), CNTF (0.4 µg) or bFGF (1 µg) after LIP were examined on wholemounts at 7 days. SD-OCT showed damage in a circular region of the superotemporal retina, whose diameter varied from 1,842.4±84.5 µm (at 24 hours) to 1,407.7±52.8 µm (at 7 days). This region had a progressive thickness diminution from 183.4±5 µm (at 12 h) to 114.6±6 µm (at 7 d). Oriented cross-sections showed within the light-damaged region of the retina massive loss of rods and cone-photoreceptors. Wholemounts documented a circular region containing lower numbers of L- and S-cones. Within a circular area (1 mm or 1.3 mm radius, respectively) in the left and in its corresponding region of the contralateral-fellow-retina, total L- or S-cones were 7,118±842 or 661±125 for the LED exposed retinas (n = 7) and 14,040±1,860 or 2,255±193 for the fellow retinas (n = 7), respectively. BMD, BDNF, PEDF and bFGF but not CNTF showed significant neuroprotective effects on L- or S-cones. We conclude that LIP results in rod and cone-photoreceptor loss, and is a reliable, quantifiable model to study cone-photoreceptor degeneration. Intravitreal BDNF, PEDF or bFGF, or topical BMD afford significant cone neuroprotection in this model.

Pigment epithelium-derived factor upregulates collagen I and downregulates matrix metalloproteinase 2 in osteosarcoma cells, and colocalises to collagen I and heat shock protein 47 in fetal and adult bone.

PubMed

Alcantara, Marice B; Nemazannikova, Natalie; Elahy, Mina; Dass, Crispin R

2014-11-01

Pigment epithelium-derived factor (PEDF) has proven anti-osteosarcoma activity. However, the mechanism(s) underpinning its ability to reduce primary bone tumour (osteosarcoma) metastasis is unknown. Adult and fetal murine bone were immunostained for PEDF, collagen I (major protein in bone) and its processing proteins, heat shock protein 47 (HSP47, a chaperone protein for collagen I), membrane type I matrix metalloproteinase (MT1-MMP, a collagenase), and matrix metalloproteinase 2 (MMP-2, which is activated by MT1-MMP). Immunoblotting and immunocytochemistry were used to observe levels of the above biomarkers when human osteosarcoma cells were treated with PEDF. Immunohistochemical staining in adult and fetal bone mirrors collagen I. PEDF localised to ridges of trabecular bone in tibial cortex and to megakaryocytes within bone marrow. Second, we observed that PEDF upregulates collagen I, HSP47 and MT1-MMP, while downregulating MMP-2 in osteosarcoma cells in vitro. PEDF is a promising antagonist to osteosarcoma cell metastasis via downregulation of MMP-2, and can induce tumour cells to further adopt differentiative properties, thereby possibly reducing their aggressive growth in vitro and in vivo. © 2014 Royal Pharmaceutical Society.

Pigment epithelial-derived factor gene loaded novel COOH-PEG-PLGA-COOH nanoparticles promoted tumor suppression by systemic administration.

PubMed

Yu, Ting; Xu, Bei; He, Lili; Xia, Shan; Chen, Yan; Zeng, Jun; Liu, Yongmei; Li, Shuangzhi; Tan, Xiaoyue; Ren, Ke; Yao, Shaohua; Song, Xiangrong

2016-01-01

Anti-angiogenesis has been proposed as an effective therapeutic strategy for cancer treatment. Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous anti-angiogenic reagents discovered to date and PEDF gene therapy has been recognized as a promising treatment option for various tumors. There is an urgent need to develop a safe and valid vector for its systemic delivery. Herein, a novel gene delivery system based on the newly synthesized copolymer COOH-PEG-PLGA-COOH (CPPC) was developed in this study, which was probably capable of overcoming the disadvantages of viral vectors and cationic lipids/polymers-based nonviral carriers. PEDF gene loaded CPPC nanoparticles (D-NPs) were fabricated by a modified double-emulsion water-in-oil-in-water (W/O/W) solvent evaporation method. D-NPs with uniform spherical shape had relatively high drug loading (~1.6%), probably because the introduced carboxyl group in poly (D,L-lactide-co-glycolide) terminal enhanced the interaction of copolymer with the PEDF gene complexes. An excellent in vitro antitumor effect was found in both C26 and A549 cells treated by D-NPs, in which PEDF levels were dramatically elevated due to the successful transfection of PEDF gene. D-NPs also showed a strong inhibitory effect on proliferation of human umbilical vein endothelial cells in vitro and inhibited the tumor-induced angiogenesis in vivo by an alginate-encapsulated tumor cell assay. Further in vivo antitumor investigation, carried out in a C26 subcutaneous tumor model by intravenous injection, demonstrated that D-NPs could achieve a significant antitumor activity with sharply reduced microvessel density and significantly promoted tumor cell apoptosis. Additionally, the in vitro hemolysis analysis and in vivo serological and biochemical analysis revealed that D-NPs had no obvious toxicity. All the data indicated that the novel CPPC nanoparticles were ideal vectors for the systemic delivery of PEDF gene and might be widely

The VEGF and PEDF levels in the follicular fluid of patients co- treated with LETROZOLE and gonadotropins during the stimulation cycle.

PubMed

Haas, Jigal; Bassil, Rawad; Gonen, Noa; Meriano, Jim; Jurisicova, Andrea; Casper, Robert F

2018-05-29

Previous studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only. A single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits. The age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 μmol/l vs. 17.5 p = NS) were comparable between the two groups. The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17

PEDF as an anticancer drug and new treatment methods following the discovery of its receptors: A patent perspective

PubMed Central

Manalo, Katrina B.; Choong, Peter F.M.; Becerra, S. Patricia; Dass, Crispin R.

2014-01-01

Background Traditional forms of cancer therapy, which includes chemotherapy, have largely been overhauled due to the significant degree of toxicity they pose to normal, otherwise healthy tissue. It is hoped that use of biological agents, most of which are endogenously present in the body, will lead to safer treatment outcomes, without sacrificing efficacy. Objective The finding that PEDF, a naturally-occurring protein, was a potent angiogenesis inhibitor became the basis for studying the role of PEDF in tumours that are highly resistant to chemotherapy. The determination of the direct role of PEDF against cancer paved the way for understanding and developing PEDF as a novel drug. This review focuses on the patent applications behind testing the anticancer therapeutic effect of PEDF via its receptors as an antiangiogenic agent and as a direct anticancer agent. Conclusions The majority of the PEDF patents describe its and/or its fragments’ antiangiogenic ability and the usage of recombinant vectors as the mode of treatment delivery. PEDF’s therapeutic potential against different diseases and the discovery of its receptors opens possibilities for improving PEDF-based peptide design and drug delivery modes. PMID:21204726

Evaluation of pigment epithelium-derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes.

PubMed

Miyake, Masahiro; Yamashiro, Kenji; Nakanishi, Hideo; Nakata, Isao; Akagi-Kurashige, Yumiko; Kumagai, Kyoko; Oishi, Maho; Tsujikawa, Akitaka; Moriyama, Muka; Ohno-Matsui, Kyoko; Mochizuki, Manabu; Yoshimura, Nagahisa

2013-06-19

A case-control study in a relatively large cohort of highly myopic patients was conducted to explore the genetic background of the occurrence of choroidal neovascularization (CNV) secondary to high myopia. We evaluated three single nucleotide polymorphisms (SNPS) from two candidate genes: pigment epithelium-derived factor (PEDF) and complement factor I (CFI). The SNPs were selected based on previous reports. A total of 1082 unrelated highly myopic (i.e., axial length ≥ 26 mm in at least one eye) Japanese individuals with CNV (n = 478) and without CNV (n = 557) who were 50 years of age and older were genotyped by using an SNP assay. Multivariable logistic regression was conducted to adjust for age, sex, and axial length. compared with individuals without CNV, subjects with CNV were significantly older (P 0.01) and more likely to be female (P 0.01), but they did not have a significantly different axial length (P = 0.50). We did not find an association between the three SNPS and the occurrence of CNV. However, a subanalysis using extremely myopic patients (case: control = 284:317) revealed a marginal association of rs12603825 in the PEDF gene (P = 0.045). The contribution of rs1136287 in CFI was not found in any analysis. We demonstrated a marginal association of the PEDF SNP, rs12603825, with myopic CNV in extremely myopic patients. A further study using a larger cohort might elucidate a significant association; rs1136287 in CFI is less likely to be associated in Japanese individuals.

Heterogeneity of Metastatic Melanoma:  Correlation of MITF With Its Transcriptional Targets MLSN1, PEDF, HMB-45, and MART-1.

PubMed

Zand, Sarvenaz; Buzney, Elizabeth; Duncan, Lyn M; Dadras, Soheil S

2016-09-01

Histologic and molecular heterogeneity is well recognized in malignant melanoma; however, the diversity of expression of new and classic melanoma markers has not been correlated in serial sections of metastases. We examined and correlated the expression of microphthalmia transcription factor (MITF) with its transcriptional targets, including melastatin (MLSN1/TRPM1), pigment epithelium-derived factor (SERPINF1/PEDF), SILV/PMEL17/GP100 (human melanoma black 45 [HMB-45]), and melanoma antigen recognized by T cells 1 (MART-1)/MLANA, in 13 melanoma metastases in lymph nodes of 13 patients. The expression levels and patterns of marker expression were recorded by a semiquantitative, 4-point ordinal reactivity method. Our results showed a consistently robust and diffuse expression of MITF protein in 12 (92%) of 13 metastatic tumors compared with variable expression of MLSN1 (46%) messenger RNA or PEDF (75%), HMB-45 (54%), and MART-1 (46%) proteins. Overall, in melanoma lymph node metastases, MITF protein expression was not tightly correlated with its gene targets. Moreover, the immunoreactivity for MITF, compared with MART-1 and HMB-45, was retained, supporting immunohistochemical detection of MITF as a more sensitive method of detecting metastatic melanoma. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Comparison of the effects of letrozole and cabergoline on vascular permeability, ovarian diameter, ovarian tissue VEGF levels, and blood PEDF levels, in a rat model of ovarian hyperstimulation syndrome.

PubMed

Şahin, Nur; Apaydın, Nesin; Töz, Emrah; Sivrikoz, Oya Nermin; Genç, Mine; Turan, Gülüzar Arzu; Cengiz, Hakan; Eskicioğlu, Fatma

2016-05-01

To evaluate the effects of letrozole and cabergoline in a rat model of ovarian hyperstimulation syndrome (OHSS). In this prospective, controlled experimental study, the 28 female Wistar rats were divided into four subgroups (one non-stimulated control and three OHSS-positive groups: placebo, letrozole, and cabergoline). To induce OHSS, rats were injected with 10 IU of pregnant mare serum gonadotropin from day 29 to day 32 of life, followed by subcutaneous injection of 30 IU hCG on day 33. Letrozole rats received with a single dose of 0.1 mg/kg letrozole via oral gavage, on the hCG day. Cabergoline rats received with a single dose of 100 µg/kg cabergoline via oral gavage, on the hCG day. All animals were compared in terms of body weight, vascular permeability (VP), ovarian diameter, ovarian tissue VEGF expression (assessed via immunohistochemical staining), and blood pigment epithelium-derived growth factor (PEDF) levels. The OHSS-positive placebo group (group 2) exhibited the highest VP, ovarian diameter, extent of VEGF staining, and lowest PEDF level, as expected. No significant difference was evident between the letrozole and cabergoline groups in terms of any of body weight; VP; PEDF level; ovarian diameter; or the staining intensity of, or percentage staining for, VEGF in ovarian tissues. Letrozole and cabergoline were equally effective to prevent OHSS, reducing the ovarian diameter, VP, and PEDF and VEGF levels to similar extents.

A dock derived compound against laminin receptor (37 LR) exhibits anti-cancer properties in a prostate cancer cell line model.

PubMed

Umbaugh, Charles Samuel; Diaz-Quiñones, Adriana; Neto, Manoel Figueiredo; Shearer, Joseph J; Figueiredo, Marxa L

2018-01-19

Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals in endothelial cells and modulate angiogenesis. Recently, it was demonstrated that 37/67 LR modulates the anti-angiogenic potential of the secreted glycoprotein pigment epithelium-derived factor (PEDF). Restoration of PEDF balance is a desirable therapeutic outcome, and we sought to identify a small molecule that could recapitulate known signaling properties of PEDF but without the additional complications of peptide formulation or gene delivery safety validation. We used an in silico drug discovery approach to target the interaction interface between PEDF and 37 LR. Following cell based counter screening and binding validation, we characterized a hit compound's anti-viability, activation of PEDF signaling-related genes, anti-wound healing, and anti-cancer signaling properties. This hit compound has potential for future development as a lead compound for treating tumor growth and inhibiting angiogenesis.

Opposing Effects of Pigment Epithelium-Derived Factor on Breast Cancer Cell versus Neuronal Survival: Implication for Brain Metastasis and Metastasis-Induced Brain Damage

PubMed Central

Fitzgerald, Daniel P.; Subramanian, Preeti; Deshpande, Monika; Graves, Christian; Gordon, Ira; Qian, Yongzhen; Snitkovsky, Yeva; Liewehr, David J.; Steinberg, Seth M.; Paltán-Ortiz, José D.; Herman, Mary M.; Camphausen, Kevin; Palmieri, Diane; Becerra, S. Patricia; Steeg, Patricia S.

2011-01-01

Brain metastases are a significant cause of cancer patient morbidity and mortality, yet preventative and therapeutic options remain an unmet need. The cytokine PEDF is downregulated in resected human brain metastases of breast cancer compared to primary breast tumors, suggesting that restoring its expression might limit metastatic spread. Here we show that outgrowth of large experimental brain metastases from human 231-BR or murine 4T1-BR breast cancer cells was suppressed by PEDF expression, as supported by in vitro analyses as well as direct intracranial implantation. Notably, the suppressive effects of PEDF were not only rapid but independent of the effects of this factor on angiogenesis. Paralleling its cytotoxic effects on breast cancer cells, PEDF also exerted a pro-survival effect on neurons that shielded the brain from tumor-induced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. Our findings establish that PEDF as both a metastatic suppressor and a neuroprotectant in the the brain, highlighting its role as a double agent in limiting brain metastasis and its local consequences. PMID:22215693

[The correlation between the concentrations of VEGF and PEDF and Ca2+-PKC signaling pathways in human retinal pigment epithelial cells cultured in vitro after exposuring to blue light].

PubMed

Wang, Limin; Cai, Shanjun; Wu, Zhipeng; Gong, Xin; Lyu, Jianping; Su, Gang; Wang, Lili

2015-11-01

To investigate the concentrations of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), inositol triphosphate (IP3) and diacylglycerol (DAG) in human retinal pigment epithelium (RPE) cells after exposuring to blue light, and to explore the relationship with Ca2+-PKC signaling pathways, to evaluate the role of Ca2+-PKC signaling pathways of blue-light irradiation induced apoptosis in RPE cells. The fourth generation human RPE cells in vitro were exposured to blue light (2000±500 lux) for 6 hours, 24 hours prolongation of post-exposure culture. The concentrations of VEGF, PEDF, IP3 and DAG were assayed by enzyme linked immunosorbent assay (ELISA). Cells were randomly divided into 6 groups, group A (control), group B (exposure to blue light), group C (exposure to blue light+PMA), group D (exposure to blue light+Calphostin C), group E (exposure to blue light+Nifedipine), group F (exposure to blue light+Calphostin C+Nifedipine). Flow cytometry was used to detect the apoptosis rate of human RPE cells in A, B and F group. Comparing with group A (584.38±10.66), the concentration of VEGF in group B (700.70±5.88), group C (698.21±6.66) and group E (648.30±4.91) was higher, the difference was statistically significant (P=0.002, 0.002, 0.016). Comparing with group B (700.70±5.88), the concentration of VEGF in Group D (623.87±3.12) and E (648.30±4.91) was lower (P=0.001, 0.002). Comparing with group A (75.96±1.70), the concentration of PEDF in Group B (71.82±1.67) and C (72.43±0.58) was lower (P=0.004, 0.011), but the concentration of PEDF in Group D (86.31±1.35) and E (93.72±1.24) was higher (P=0.000, 0.000). Comparing with group B (71.82±1.67), the concentration of PEDF in Group D (86.31±1.35) and E (93.72±1.24) was higher (P=0.000, 0.000). Comparing with group A (7.70±0.29), the ratio of VEGF to PEDF in Group B (9.85±0.34) and Croup C (9.64±0.02) was higher (P=0.008, 0.027) Comparing with group B, The ratio of VEGF to PEDF

Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis c virus-associated insulin resistance.

PubMed

Kawaguchi, T; Yamagishi, S; Sata, M

2009-01-01

Recent clinical studies have shown that patients with chronic liver disease are insulin resistant. Of all etiologies of chronic liver disease including non-alcoholic fatty liver disease, the one that causes the most sever insulin resistance is hepatitis C virus (HCV) infection. Since insulin resistance promotes inflammatory and fibrogenic reactions in the liver, thus leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC) in patients with HCV infection, amelioration of insulin sensitivity may inhibit the progression of HCV-associated liver disease, and could improve the survival of these patients. HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and/or triglyceride accumulation-induced nuclear factor-kappaB (NF-kappaB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-kappaB and preservation of insulin signaling pathway. In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. We also discuss here which chemical structures could contribute to insulin-sensitization in patients with HCV infection.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Kyung-Jin; Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 110-799; Yun, Jang-Hyuk

Highlights: • PEDF was expressed and induced during the involuting phase of IH. • PEDF inhibited the cell growth of the involuting HemECs in an autocrine manner. • PEDF suppression restored the impaired cell growth of the involuting HemECs. - Abstract: Hemangioma is a benign tumor derived from abnormal blood vessel growth. Unlike other vascular tumor counterparts, a hemangioma is known to proliferate during its early stage but it is followed by a stage of involution where regression of the tumor occurs. The critical onset leading to the involution of hemangioma is currently not well understood. This study focused onmore » the molecular identities of the involution of hemangioma. We demonstrated that a soluble factor released from the involuting phase of hemangioma-derived endothelial cells (HemECs) and identified pigment epithelium-derived factor (PEDF) as an anti-angiogenic factor that was associated with the growth inhibition of the involuting HemECs. The growth inhibition of the involuting HemECs was reversed by suppression of PEDF in the involuting HemECs. Furthermore, we found that PEDF was more up-regulated in the involuting phase of hemangioma tissues than in the proliferating or the involuted. Taken together, we propose that PEDF accelerates the involution of hemangioma by growth inhibition of HemECs in an autocrine manner. The regulatory mechanism of PEDF expression could be a potential therapeutic target to treat hemangiomas.« less

Osteopontin and Other Regulators of Angiogenesis and Fibrogenesis in the Vitreous from Patients with Proliferative Vitreoretinal Disorders

PubMed Central

Abu El-Asrar, Ahmed M.; Imtiaz Nawaz, Mohd; Kangave, Dustan; Siddiquei, Mohammed Mairaj; Geboes, Karel

2012-01-01

The aim of this study was to determine the levels of the angiogenic and fibrogenic factors osteopontin (OPN), high-mobility group box-1 (HMGB1), and connective tissue growth factor (CTGF) and the antiangiogenic and antifibrogenic pigment epithelium-derived factor (PEDF) in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and rhegmatogenous retinal detachment with no PVR (RD). Vitreous samples from 48 PDR, 17 PVR and 30 RD patients were studied by enzyme-linked immunosorbent assay. OPN, HMGB1, CTGF, and PEDF levels were significantly higher in PDR patients than in RD patients (P < 0.001; 0.002; <0.001; <0.001, resp.). CTGF and PEDF levels were significantly higher in PVR patients than in RD patients (P < 0.001; 0.004, resp.). Exploratory logistic regression analysis identified significant associations between PDR and high levels of HMGB1, CTGF and PEDF, between PDR with active neovascularization and high levels of CTGF and PEDF, and between PDR with traction retinal detachment and high levels of HMGB1. In patients with PDR, there were significant correlations between the levels of PEDF and the levels of OPN (r = 0.544, P = 0.001), HMGB1 (r = 0.719, P < 0.001), and CTGF (r = 0.715, P < 0.001). In patients with PVR, there were significant correlations between the levels of OPN and the levels of HMGB1 (r = 0.484, P = 0.049) and PEDF (r = 0.559, P = 0.02). Our findings suggest that OPN, HMGB1, and CTGF contribute to the pathogenesis of proliferative vitreoretinal disorders and that increased levels of PEDF may be a response to counterbalance the activity of angiogenic and fibrogenic factors in PDR and PVR. PMID:23055574

Subconjunctival Bevacizumab Injection Impairs Corneal Innervations and Epithelial Wound Healing in Mice.

PubMed

Dong, Muchen; Di, Guohu; Zhang, Xiaoping; Zhou, Qingjun; Shi, Weiyun

2017-03-01

To investigate the effects of subconjunctival bevacizumab injection on the corneal nerve, sensitivity, and epithelial wound healing in mice. Adult C57BL/6 mice were treated with subconjunctival injection of 1, 2, 5, or 25 mg/mL bevacizumab. The corneal nerve was observed with whole-mount anti-β3-tubulin fluorescence staining. Corneal sensitivity was measured with a Cochet-Bonnet esthesiometer. The protein levels of pigment epithelium-derived factor (PEDF), nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were measured by ELISA. The corneal epithelial wound-healing rate was evaluated by fluorescein staining. The recovery of impaired mouse corneal innervations and epithelial wound-healing rate following bevacizumab injection was evaluated with the co-injection of PEDF, NGF, or CNTF. Subconjunctival bevacizumab injection caused apparent corneal nerve degeneration, attenuated corneal sensitivity, and delayed corneal epithelial wound healing and nerve regeneration in normal mice, which was more significant with increased concentration and times of the bevacizumab injection. However, the corneal nerve and sensitivity gradually improved and recovered in mice with a single injection of 1 to 5 mg/mL bevacizumab. Moreover, the bevacizumab injection significantly decreased the corneal PEDF, NGF, and CNTF content, whereas exogenous PEDF, NGF, or CNTF supplement attenuated impairment of the corneal nerve, sensitivity, and epithelial wound healing after subconjunctival bevacizumab injection. Subconjunctival bevacizumab injection impairs corneal innervations, epithelial wound healing, and nerve regeneration in normal mice, which may be caused by the reduction of neurotrophic factor content in the cornea.

Retinal pigment epithelium, age-related macular degeneration and neurotrophic keratouveitis.

PubMed

Bianchi, Enrica; Scarinci, Fabio; Ripandelli, Guido; Feher, Janos; Pacella, Elena; Magliulo, Giuseppe; Gabrieli, Corrado Balacco; Plateroti, Rocco; Plateroti, Pasquale; Mignini, Fiorenzo; Artico, Marco

2013-01-01

Age-related macular degeneration (AMD) is the leading cause of impaired vision and blindness in the aging population. The aims of our studies were to identify qualitative and quantitative alterations in mitochondria in human retinal pigment epithelium (RPE) from AMD patients and controls and to test the protective effects of pigment epithelium-derived factor (PEDF), a known neurotrophic and antiangiogenic substance, against neurotrophic keratouveitis. Histopathological alterations were studied by means of morphometry, light and electron microscopy. Unexpectedly, morphometric data showed that the RPE alterations noted in AMD may also develop in normal aging, 10-15 years later than appearing in AMD patients. Reduced tear secretion, corneal ulceration and leukocytic infiltration were found in capsaicin (CAP)-treated rats, but this effect was significantly attenuated by PEDF. These findings suggest that PEDF accelerated the recovery of tear secretion and also prevented neurotrophic keratouveitis and vitreoretinal inflammation. PEDF may have a clinical application in inflammatory and neovascular diseases of the eye.

Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration.

PubMed

Ioanna, Zygoula; Christian, Schori; Christian, Grimm; Daniel, Barthelmes

2018-02-01

Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins. Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA). The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients. nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases.

Common genetic variation in the SERPINF1 locus determines overall adiposity, obesity-related insulin resistance, and circulating leptin levels.

PubMed

Böhm, Anja; Ordelheide, Anna-Maria; Machann, Jürgen; Heni, Martin; Ketterer, Caroline; Machicao, Fausto; Schick, Fritz; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich; Staiger, Harald

2012-01-01

Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction.

PubMed

Moskowitz-Kassai, Eliza; Mackelaite, Lina; Chen, Jun; Patel, Kaushal; Dadhania, Darshana M; Gross, Steven S; Chander, Praveen; Delaney, Vera; Deng, Luqin; Chen, Ligong; Cui, Xiangqin; Suthanthiran, Manikkam; Goligorsky, Michael S

2012-02-01

We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria. In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors.

PubMed

Michalski, Dominik; Pitsch, Roman; Pillai, Deepu R; Mages, Bianca; Aleithe, Susanne; Grosche, Jens; Martens, Henrik; Schlachetzki, Felix; Härtig, Wolfgang

2017-01-01

Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.

Differential expression of anti-angiogenic factors and guidance genes in the developing macula.

PubMed

Kozulin, Peter; Natoli, Riccardo; O'Brien, Keely M Bumsted; Madigan, Michele C; Provis, Jan M

2009-01-01

anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IValpha2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by QRT-PCR. Localization of PEDF and Eph-A6 mRNAs in sections of macaque retina shows expression of both genes concentrates in the ganglion cell layer (GCL) at the developing fovea, consistent with an involvement in definition of the foveal avascular area. Because the axons of macular ganglion cells exit the retina from around 8 WG, we suggest that the axon guidance genes highly expressed at the macula at 19-20 WG are also involved in vascular patterning, along with PEDF and NPPB. Localization of both PEDF and Eph-A6 mRNAs to the GCL of the developing fovea supports this idea. It is possible that specialization of the macular vessels, including definition of the foveal avascular area, is mediated by processes that piggyback on axon guidance mechanisms in effect earlier in development. These findings may be useful to understand the vulnerability of the macula to degeneration and to develop new therapeutic strategies to inhibit neovascularization.

Differential expression of anti-angiogenic factors and guidance genes in the developing macula

PubMed Central

Kozulin, Peter; Natoli, Riccardo; O’Brien, Keely M. Bumsted; Madigan, Michele C.

2009-01-01

. Furthermore, we found significant upregulation of three anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IVα2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by QRT–PCR. Localization of PEDF and Eph-A6 mRNAs in sections of macaque retina shows expression of both genes concentrates in the ganglion cell layer (GCL) at the developing fovea, consistent with an involvement in definition of the foveal avascular area. Conclusions Because the axons of macular ganglion cells exit the retina from around 8 WG, we suggest that the axon guidance genes highly expressed at the macula at 19–20 WG are also involved in vascular patterning, along with PEDF and NPPB. Localization of both PEDF and Eph-A6 mRNAs to the GCL of the developing fovea supports this idea. It is possible that specialization of the macular vessels, including definition of the foveal avascular area, is mediated by processes that piggyback on axon guidance mechanisms in effect earlier in development. These findings may be useful to understand the vulnerability of the macula to degeneration and to develop new therapeutic strategies to inhibit neovascularization. PMID:19145251

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

PubMed

Nishimon, Shohei; Ohnuma, Tohru; Takebayashi, Yuto; Katsuta, Narimasa; Takeda, Mayu; Nakamura, Toru; Sannohe, Takahiro; Higashiyama, Ryoko; Kimoto, Ayako; Shibata, Nobuto; Gohda, Tomohito; Suzuki, Yusuke; Yamagishi, Sho-Ichi; Tomino, Yasuhiko; Arai, Heii

2017-06-02

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. Copyright © 2017

Genetic variants in pigment epithelium-derived factor influence response of polypoidal choroidal vasculopathy to photodynamic therapy.

PubMed

Nakata, Isao; Yamashiro, Kenji; Yamada, Ryo; Gotoh, Norimoto; Nakanishi, Hideo; Hayashi, Hisako; Tsujikawa, Akitaka; Otani, Atsushi; Ooto, Sotaro; Tamura, Hiroshi; Saito, Masaaki; Saito, Kuniharu; Iida, Tomohiro; Oishi, Akio; Kurimoto, Yasuo; Matsuda, Fumihiko; Yoshimura, Nagahisa

2011-07-01

with the AA genotype showed significantly worse visual prognosis after PDT (P = 0.013). Pigment epithelium-derived factor (SERPINF1 or PEDF) polymorphisms may influence the initial response to and visual prognosis after PDT for PCV. Our findings may lead to understanding the pathogenesis of PCV and modification of the effects of PDT. Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

γ-Secretase Inhibition of Murine Choroidal Neovascularization Is Associated with Reduction of Superoxide and Proinflammatory Cytokines

PubMed Central

Qi, Xiaoping; Cai, Jun; Ruan, Qing; Liu, Li; Boye, Sanford L.; Chen, Zhijuan; Hauswirth, William W.; Ryals, Renee C.; Shaw, Lynn; Caballero, Sergio; Grant, Maria B.

2012-01-01

Purpose. This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines. Methods. γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angiogenesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA. Results. γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. Conclusions. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression during CNV. PMID:22205609

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.

PubMed

Moh, Mei Chung; Sum, Chee Fang; Tavintharan, Subramaniam; Pek, Sharon Li Ting; Yeoh, Lee Ying; Ng, Xiaowei; Lee, Simon Biing Ming; Tang, Wern Ee; Lim, Su Chi

2017-07-01

This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications. Copyright © 2016. Published by Elsevier Inc.

The Antibiotic-free pFAR4 Vector Paired with the Sleeping Beauty Transposon System Mediates Efficient Transgene Delivery in Human Cells.

PubMed

Pastor, Marie; Johnen, Sandra; Harmening, Nina; Quiviger, Mickäel; Pailloux, Julie; Kropp, Martina; Walter, Peter; Ivics, Zoltán; Izsvák, Zsuzsanna; Thumann, Gabriele; Scherman, Daniel; Marie, Corinne

2018-06-01

The anti-angiogenic and neurogenic pigment epithelium-derived factor (PEDF) demonstrated a potency to control choroidal neovascularization in age-related macular degeneration (AMD) patients. The goal of the present study was the development of an efficient and safe technique to integrate, ex vivo, the PEDF gene into retinal pigment epithelial (RPE) cells for later transplantation to the subretinal space of AMD patients to allow continuous PEDF secretion in the vicinity of the affected macula. Because successful gene therapy approaches require efficient gene delivery and stable gene expression, we used the antibiotic-free pFAR4 mini-plasmid vector to deliver the hyperactive Sleeping Beauty transposon system, which mediates transgene integration into the genome of host cells. In an initial study, lipofection-mediated co-transfection of HeLa cells with the SB100X transposase gene and a reporter marker delivered by pFAR4 showed a 2-fold higher level of genetically modified cells than when using the pT2 vectors. Similarly, with the pFAR4 constructs, electroporation-mediated transfection of primary human RPE cells led to 2.4-fold higher secretion of recombinant PEDF protein, which was still maintained 8 months after transfection. Thus, our results show that the pFAR4 plasmid is a superior vector for the delivery and integration of transgenes into eukaryotic cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Osteogenesis Imperfecta Type VI in Individuals from Northern Canada.

PubMed

Ward, Leanne; Bardai, Ghalib; Moffatt, Pierre; Al-Jallad, Hadil; Trejo, Pamela; Glorieux, Francis H; Rauch, Frank

2016-06-01

Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.

Nerves and neovessels inhibit each other in the cornea.

PubMed

Ferrari, Giulio; Hajrasouliha, Amir R; Sadrai, Zahra; Ueno, Hiroki; Chauhan, Sunil K; Dana, Reza

2013-01-28

To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea. b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining. No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed. Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis.

Nerves and Neovessels Inhibit Each Other in the Cornea

PubMed Central

Ferrari, Giulio; Hajrasouliha, Amir R.; Sadrai, Zahra; Ueno, Hiroki; Chauhan, Sunil K.; Dana, Reza

2013-01-01

Purpose. To evaluate the regulatory cross-talk of the vascular and neural networks in the cornea. Methods. b-FGF micropellets (80 ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day 7, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation, corneas were harvested for ELISA (VEGFR3 and pigment epithelium-derived factor [PEDF]) and for quantitative RT-PCR (VEGFR3, PEDF, and CD45). PEDF, VEGFR3, beta-3 tubulin, CD45, CD11b, and F4/80 expression in the cornea were evaluated using immunostaining. Results. No nerves were detected in the areas subject to corneal neovascularization, whereas they persisted in the areas that were neovessel-free. Conversely, 7 days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 in the corneal epithelial layer. Finally, an inflammatory cell infiltrate, including macrophages, was observed. Conclusion. Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far-reaching implications in understanding angiogenesis. PMID:23307967

On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion.

PubMed

Rodríguez-Piñeiro, A M; Blanco-Prieto, S; Sánchez-Otero, N; Rodríguez-Berrocal, F J; de la Cadena, M Páez

2010-06-16

The current imperative need for new biomarkers of non-small cell lung cancer (NSCLC) prompted us to compare the proteome of serum and pleural effusion samples from cancer patients with those with benign lung diseases as pneumonia or tuberculosis. Samples were prefractionated through affinity chromatography prior to 2D-DIGE to detect proteins with altered expression in cancer patients. Overall, we identified more potential biomarkers in pleural effusion, which is closer to the affected organ, than in serum. Nevertheless, in both cases principal component analysis demonstrated that the pattern of significantly altered proteins discriminates between disease groups. The biomarker candidates comprise proteins increased in malignant pleural effusions as gelsolin and the metalloproteinase inhibitor 2, and others with lower levels as S100-A8 and S100-A9. The most interesting protein was the pigment epithelium-derived factor (PEDF), which is related to angiogenesis inhibition, and was significantly overexpressed both in serum and pleural effusion from NSCLC patients. More than 12 PEDF isoforms were specifically immunodetected in both fluids in 2-D blots, most of them overexpressed in NSCLC. Thus, further validation would be ideally directed to quantify individual PEDF isoforms, as it may be only one or some of them the ones altered in the cancer process. Copyright 2010 Elsevier B.V. All rights reserved.

Factors, fiction and endothelium-derived hyperpolarizing factor.

PubMed

Sandow, Shaun L

2004-09-01

1. The principal mediators of vascular tone are neural, endothelial and physical stimuli that result in the initiation of dilator and constrictor responses to facilitate the control of blood pressure. Two primary vasodilatory stimuli produced by the endothelium are nitric oxide (NO) and prostaglandins. An additional endothelium-dependent vasodilatory mechanism is characterized as the hyperpolarization-mediated relaxation that remains after the inhibition of the synthesis of NO and prostaglandins. This mechanism is due to the action of a so-called endothelium-derived hyperpolarizing factor (EDHF) and is dependent on either the release of diffusible factor(s) and/or to a direct contact-mediated mechanism. 2. Most evidence supports the concept that 'EDHF' activity is dependent on contact-mediated mechanisms. This involves the transfer of an endothelium-derived electrical current, as an endothelium-derived hyperpolarization (EDH), through direct heterocellular coupling of endothelial cells and smooth muscle cells via myoendothelial gap junctions (MEGJ). However, there is a lack of consensus with regard to the nature and mechanism of action of EDHF/EDH (EDH(F)), which has been shown to vary within and between vascular beds, as well as among species, strains, sex and during development, ageing and disease. 3. In addition to actual heterogeneity in EDH(F), further heterogeneity has resulted from the less-than-optimal design, analysis and interpretation of data in some key papers in the EDHF literature; with such views being perpetuated in the subsequent literature. 4. The focus of the present brief review is to examine what factors are proposed as EDH(F) and highlight the correlative structural and functional studies from our laboratory that demonstrate an integral role for MEGJ in the conduction of EDH, which account for the heterogeneity in EDH(F), while incorporating the reported diffusible mechanisms in the regulation of this activity. Furthermore, in addition to the

Dietary Weight Loss and Exercise Effects on Serum Biomarkers of Angiogenesis in Overweight Postmenopausal Women: A Randomized Controlled Trial.

PubMed

Duggan, Catherine; Tapsoba, Jean de Dieu; Wang, Ching-Yun; McTiernan, Anne

2016-07-15

Obese and sedentary persons have an increased risk for cancer, but underlying mechanisms are poorly understood. Angiogenesis is common to adipose tissue formation and remodeling, and to tumor vascularization. A total of 439 overweight/obese, healthy, postmenopausal women [body mass index (BMI) > 25 kg/m(2)] ages 50-75 years, recruited between 2005 and 2008 were randomized to a 4-arm 12-month randomized controlled trial, comparing a caloric restriction diet arm (goal: 10% weight loss, N = 118), aerobic exercise arm (225 minutes/week of moderate-to-vigorous activity, N = 117), a combined diet + exercise arm (N = 117), or control (N = 87) on circulating levels of angiogenic biomarkers. VEGF, plasminogen activator inhibitor-1 (PAI-1), and pigment epithelium-derived factor (PEDF) were measured by immunoassay at baseline and 12 months. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity. Participants randomized to the diet + exercise arms had statistically significantly greater reductions in PAI-1 at 12 months compared with controls (-19.3% vs. +3.48%, respectively, P < 0.0001). Participants randomized to the diet and diet + exercise arms had statistically significantly greater reductions in PEDF (-9.20%, -9.90%, respectively, both P < 0.0001) and VEGF (-8.25%, P = 0.0005; -9.98%, P < 0.0001, respectively) compared with controls. There were no differences in any of the analytes in participants randomized to the exercise arm compared with controls. Increasing weight loss was statistically significantly associated with linear trends of greater reductions in PAI-1, PEDF, and VEGF. Weight loss is significantly associated with reduced circulating VEGF, PEDF, and PAI-1, and could provide incentive for reducing weight as a cancer prevention method in overweight and obese individuals. Cancer Res; 76(14); 4226-35. ©2016 AACR. ©2016 American Association for Cancer Research.

Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

PubMed Central

Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

2013-01-01

Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

Platelet-derived growth factor inhibits platelet activation in heparinized whole blood.

PubMed

Selheim, F; Holmsen, H; Vassbotn, F S

1999-08-15

We previously have demonstrated that human platelets have functionally active platelet-derived growth factor alpha-receptors. Studies with gel-filtered platelets showed that an autocrine inhibition pathway is transduced through this tyrosine kinase receptor during platelet activation. The physiological significance of this inhibitory effect of platelet-derived growth factor on gel-filtered platelets activation is, however, not known. In the present study, we investigated whether platelet-derived growth factor inhibits platelet activation under more physiological conditions in heparinized whole blood, which represents a more physiological condition than gel-filtered platelets. Using flow cytometric assays, we demonstrate here that platelet-derived growth factor inhibits thrombin-, thrombin receptor agonist peptide SFLLRN-, and collagen-induced platelet aggregation and shedding of platelet-derived microparticles from the platelet plasma membrane during platelet aggregation in stirred heparinized whole blood. The inhibitory effect of platelet-derived growth factor was dose dependent. However, under nonaggregating conditions (no stirring), we could not demonstrate any significant effect of platelet-derived growth factor on thrombin- and thrombin receptor agonist peptide-induced platelet surface expression of P-selectin. Our results demonstrate that platelet-derived growth factor appears to be a true antithrombotic agent only under aggregating conditions in heparinized whole blood.

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment.

PubMed

Smitka, Kvido; Marešová, Dana

2015-01-01

Adipose tissue is recognized as an active endocrine organ that produces a number of endocrine substances referred to as "adipokines" including leptin, adiponectin, adipolin, visfatin, omentin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), resistin, pigment epithelium-derived factor (PEDF), and progranulin (PGRN) which play an important role in the food intake regulation and significantly influence insulin sensitivity and in some cases directly affect insulin resistance in skeletal muscle, liver, and adipose tissue. The review summarizes current knowledge about adipose tissue-derived hormones and their influence on energy homeostasis regulation. The possible therapeutic potential of these adipokines in the treatment of insulin resistance, endothelial dysfunction, a pro-inflammatory response, obesity, eating disorders, progression of atherosclerosis, type 1 diabetes, and type 2 diabetes is discussed.

Contacting co-culture of human retinal microvascular endothelial cells alters barrier function of human embryonic stem cell derived retinal pigment epithelial cells.

PubMed

Skottman, H; Muranen, J; Lähdekorpi, H; Pajula, E; Mäkelä, K; Koivusalo, L; Koistinen, A; Uusitalo, H; Kaarniranta, K; Juuti-Uusitalo, K

2017-10-01

Here we evaluated the effects of human retinal microvascular endothelial cells (hREC) on mature human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells. The hESC-RPE cells (Regea08/017, Regea08/023 or Regea11/013) and hREC (ACBRI 181) were co-cultured on opposite sides of transparent membranes for up to six weeks. Thereafter barrier function, small molecule permeability, localization of RPE and endothelial cell marker proteins, cellular fine structure, and growth factor secretion of were evaluated. After co-culture, the RPE specific CRALBP and endothelial cell specific von Willebrand factor were appropriately localized. In addition, the general morphology, pigmentation, and fine structure of hESC-RPE cells were unaffected. Co-culture increased the barrier function of hESC-RPE cells, detected both with TEER measurements and cumulative permeability of FD4 - although the differences varied among the cell lines. Co-culturing significantly altered VEGF and PEDF secretion, but again the differences were cell line specific. The results of this study showed that co-culture with hREC affects hESC-RPE functionality. In addition, co-culture revealed drastic cell line specific differences, most notably in growth factor secretion. This model has the potential to be used as an in vitro outer blood-retinal barrier model for drug permeability testing. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

[Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

PubMed

Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

2014-01-01

Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

Biological Modulation of Mouse RPE Cells in Response to Subthreshold Diode Micropulse Laser Treatment.

PubMed

Li, Zhouyue; Song, Yanping; Chen, Xiao; Chen, Zhongshan; Ding, Qin

2015-11-01

Many clinical trials have demonstrated the effectiveness of subthreshold phototherapy with no visible damage in retinal vascular diseases, such as diabetic retinopathy. We aimed primarily to investigate the effect of subthreshold diode micropulse laser (SDM) treatment on mouse retinal pigmented epithelium (RPE) cells. The expression of angiogenesis-modulating cytokines in response to SDM was also explored. The least toxic laser dose was selected by measuring cell viability with MTT assay and 5 % duty cycle (DC) was chosen for use in further experiments. RPE cells were treated with laser-induced radiation ranging from 0 to 400 mW for 24 h. The apoptotic rate of RPE cells was assessed by flow cytometry. Expressions of vascular endothelial growth factor A (VEGF-A), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF), and pigment epithelium-derived factor (PEDF) were determined by Western Blotting and real-time PCR, respectively. After 24 h of laser irradiation, cell viability was reduced dose dependently and the effect was significant compared to the controls (P < 0.05). In addition, laser treatment with intensities of 100 and 200 mW with DC of 5 % produced no significant effect on cell viability and apoptosis as compared with the control group (P > 0.05). The protein and mRNA expressions of angiogenic stimulators (VEGF-A, TGF-β, and bFGF) were significantly down-regulated (P < 0.05), whereas those of the angiogenic inhibitor (PEDF) were up-regulated (P < 0.05). No significant difference was found between the cells treated with different intensities of laser radiation (P > 0.05). Our results showed that SDM treatment of the RPE cells suppressed the expression of choroid neovasculization-promoting cytokines and up-regulated the angiogenic inhibitor, PEDF without damaging the cells. Further investigation is needed to understand the mechanism and to optimize the use of SDM as a novel method of treatment for retinal vascular

Prospectives for Gene Therapy of Retinal Degenerations

PubMed Central

Thumann, Gabriele

2012-01-01

Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell

Long-Term Effects of Weight Loss and Exercise on Biomarkers Associated with Angiogenesis.

PubMed

Duggan, Catherine; Tapsoba, Jean de Dieu; Wang, Ching-Yun; Schubert, Karen E Foster; McTiernan, Anne

2017-12-01

Background: We tested the effect of weight loss on circulating levels of the angiogenic factors VEGF and pigment epithelium-derived factor (PEDF) in postmenopausal overweight/obese women, 18 months after completing a year-long 4-arm randomized controlled trial of behavioral weight loss and/or exercise versus control (i.e., 30 months postrandomization). Methods: The 439 overweight/obese, postmenopausal women, ages 50 to 75 years, were randomized to: diet (goal: 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), diet + exercise ( N = 117), or control ( N = 87). At 12 months, 399 women gave a blood sample; 156 returned at 30 months. Biomarkers were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for baseline BMI, age, and race/ethnicity. Results: Participants randomized to diet, exercise, and diet + exercise arms had greater reductions in VEGF at 30 months (-14.1% P = 0.02; -19.7% P = 0.003; -14.5% P = 0.002, respectively) versus controls (-4.5%). There were no statistically significant changes in PEDF in any intervention arm. Participants maintaining ≥10% of baseline weight loss at 30 months had greater reductions in VEGF versus those who gained weight/had no weight change (-22.3% vs. -10.2% respectively, P = 0.002). Participants maintaining any weight loss had significantly lower levels of PEDF at 30 months versus those who gained weight/no weight change. Conclusions: Sustained weight loss via diet and/or exercise results in reductions in angiogenic factors, and can be maintained up to 30-month follow-up. Limitations include relatively small numbers, and possible bias toward more successful weight loss among women who returned at 30 months. Impact: Maintaining weight loss can achieve long-term reductions in biomarkers of angiogenesis that can persist up to 18 months after completion of a weight loss intervention. Cancer Epidemiol Biomarkers Prev; 26(12); 1788-94. ©2017 AACR . �

Derivation of Sky-View Factors from LIDAR Data

NASA Technical Reports Server (NTRS)

Kidd, Christopher; Chapman, Lee

2013-01-01

The use of Lidar (Light Detection and Ranging), an active light-emitting instrument, is becoming increasingly common for a range of potential applications. Its ability to provide fine resolution spatial and vertical resolution elevation data makes it ideal for a wide range of studies. This paper demonstrates the capability of Lidar data to measure sky view factors (SVF). The Lidar data is used to generate a spatial map of SVFs which are then compared against photographically-derived SVF at selected point locations. At each location three near-surface elevations measurements were taken and compared with collocated Lidar-derived estimated. It was found that there was generally good agreement between the two methodologies, although with decreasing SVF the Lidar-derived technique tended to overestimate the SVF: this can be attributed in part to the spatial resolution of the Lidar sampling. Nevertheless, airborne Lidar systems can map sky view factors over a large area easily, improving the utility of such data in atmospheric and meteorological models.

Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair.

PubMed

Tilokee, Everad L; Latham, Nicholas; Jackson, Robyn; Mayfield, Audrey E; Ye, Bin; Mount, Seth; Lam, Buu-Khanh; Suuronen, Erik J; Ruel, Marc; Stewart, Duncan J; Davis, Darryl R

2016-07-01

First generation cardiac stem cell products provide indirect cardiac repair but variably produce key cardioprotective cytokines, such as stromal-cell derived factor 1α, which opens the prospect of maximizing up-front paracrine-mediated repair. The mesenchymal subpopulation within explant derived human cardiac stem cells underwent lentiviral mediated gene transfer of stromal-cell derived factor 1α. Unlike previous unsuccessful attempts to increase efficacy by boosting the paracrine signature of cardiac stem cells, cytokine profiling revealed that stromal-cell derived factor 1α over-expression prevented lv-mediated "loss of cytokines" through autocrine stimulation of CXCR4+ cardiac stem cells. Stromal-cell derived factor 1α enhanced angiogenesis and stem cell recruitment while priming cardiac stem cells to readily adopt a cardiac identity. As compared to injection with unmodified cardiac stem cells, transplant of stromal-cell derived factor 1α enhanced cells into immunodeficient mice improved myocardial function and angiogenesis while reducing scarring. Increases in myocardial stromal-cell derived factor 1α content paralleled reductions in myocyte apoptosis but did not influence long-term engraftment or the fate of transplanted cells. Transplantation of stromal-cell derived factor 1α transduced cardiac stem cells increased the generation of new myocytes, recruitment of bone marrow cells, new myocyte/vessel formation and the salvage of reversibly damaged myocardium to enhance cardiac repair after experimental infarction. Stem Cells 2016;34:1826-1835. © 2016 AlphaMed Press.

Sutureless Fixation of Amniotic Membrane for Therapy of Ocular Surface Disorders

PubMed Central

Kotomin, Ilya; Valtink, Monika; Hofmann, Kai; Frenzel, Annika; Morawietz, Henning; Werner, Carsten; Funk, Richard H. W.; Engelmann, Katrin

2015-01-01

Amniotic membrane is applied to the diseased ocular surface to stimulate wound healing and tissue repair, because it releases supportive growth factors and cytokines. These effects fade within about a week after application, necessitating repeated application. Generally, amniotic membrane is fixed with sutures to the ocular surface, but surgical intervention at the inflamed or diseased site can be detrimental. Therefore, we have developed a system for the mounting of amniotic membrane between two rings for application to a diseased ocular surface without surgical intervention (sutureless amniotic membrane transplantation). With this system, AmnioClip, amniotic membrane can be applied like a large contact lens. First prototypes were tested in an experiment on oneself for wearing comfort. The final system was tested on 7 patients in a pilot study. A possible influence of the ring system on the biological effects of amniotic membrane was analyzed by histochemistry and by analyzing the expression of vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF 2) and pigment epithelium-derived factor (PEDF) from amniotic membranes before and after therapeutic application. The final product, AmnioClip, showed good tolerance and did not impair the biological effects of amniotic membrane. VEGF-A and PEDF mRNA was expressed in amniotic membrane after storage and mounting before transplantation, but was undetectable after a 7-day application period. Consequently, transplantation of amniotic membranes with AmnioClip provides a sutureless and hence improved therapeutic strategy for corneal surface disorders. Trial Registration ClinicalTrials.gov NCT02168790 PMID:25955359

Job compensable factors and factor weights derived from job analysis data.

PubMed

Chi, Chia-Fen; Chang, Tin-Chang; Hsia, Ping-Ling; Song, Jen-Chieh

2007-06-01

Government data on 1,039 job titles in Taiwan were analyzed to assess possible relationships between job attributes and compensation. For each job title, 79 specific variables in six major classes (required education and experience, aptitude, interest, work temperament, physical demands, task environment) were coded to derive the statistical predictors of wage for managers, professionals, technical, clerical, service, farm, craft, operatives, and other workers. Of the 79 variables, only 23 significantly related to pay rate were subjected to a factor and multiple regression analysis for predicting monthly wages. Given the heterogeneous nature of collected job titles, a 4-factor solution (occupational knowledge and skills, human relations skills, work schedule hardships, physical hardships) explaining 43.8% of the total variance but predicting only 23.7% of the monthly pay rate was derived. On the other hand, multiple regression with 9 job analysis items (required education, professional training, professional certificate, professional experience, coordinating, leadership and directing, demand on hearing, proportion of shift working indoors, outdoors and others, rotating shift) better predicted pay and explained 32.5% of the variance. A direct comparison of factors and subfactors of job evaluation plans indicated mental effort and responsibility (accountability) had not been measured with the current job analysis data. Cross-validation of job evaluation factors and ratings with the wage rates is required to calibrate both.

Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta

PubMed Central

Becker, Jutta; Semler, Oliver; Gilissen, Christian; Li, Yun; Bolz, Hanno Jörn; Giunta, Cecilia; Bergmann, Carsten; Rohrbach, Marianne; Koerber, Friederike; Zimmermann, Katharina; de Vries, Petra; Wirth, Brunhilde; Schoenau, Eckhard; Wollnik, Bernd; Veltman, Joris A.; Hoischen, Alexander; Netzer, Christian

2011-01-01

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis. PMID:21353196

Brain-derived neurotrophic factor and its clinical implications

PubMed Central

Bathina, Siresha

2015-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus. PMID:26788077

On the derivation of the areal reduction factor of storms

NASA Astrophysics Data System (ADS)

Bacchi, Baldassare; Ranzi, Roberto

A stochastic derivation of the areal reduction factor (ARF) of the storm intensity is presented: it is based on the analysis of the crossing properties of the rainfall process aggregated in space and time. As a working hypothesis, the number of crossings of high rainfall intensity levels is assumed to be Poisson-distributed and a hyperbolic tail of the probability of exceedances of rainfall intensity has been adopted. These hypotheses are supported by the analysis of radar maps during an intense storm event which occurred in Northern Italy. The reduction factor derived from this analysis shows a power-law decay with respect to the area of integration and the duration of the storm. The areal reduction results as a function of the storm duration and of its frequency. A weak, but significant decrease of the areal reduction factor with respect to the return period is shown by the functions derived, and this result is consistent with that of some recent studies on this topic. The results derived, although preliminary, may find useful applications for the definition of the design storm in urban catchments of a size greater than some square kilometres and with duration of some hours.

N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor.

PubMed

Stamler, J; Mendelsohn, M E; Amarante, P; Smick, D; Andon, N; Davies, P F; Cooke, J P; Loscalzo, J

1989-09-01

Recent evidence suggests that endothelium-derived relaxing factor exhibits properties of nitric oxide. Like nitric oxide, it inhibits platelet function and mediates its effects by elevating intracellular cyclic GMP. In this study we have investigated the role of reduced thiol in the mechanism of action of endothelium-derived relaxing factor on platelets. Bovine aortic endothelial cells were grown on microcarrier beads and pretreated with aspirin before use. Endothelial cells stimulated with bradykinin or exposed to stirred medium expressed a dose-dependent inhibition of platelet aggregation that was potentiated by the reduced thiol, N-acetylcysteine. Endothelial cell-mediated platelet inhibition was attenuated by methylene blue. Inhibition of platelet aggregation by endothelial cells was associated with a rise in platelet intracellular cyclic GMP, an effect that was enhanced by N-acetylcysteine. These data show that 1) the reduced thiol N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor and 2) this effect is associated with increasing intracellular platelet cyclic GMP levels.

Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.

PubMed

Kos, L; Aronzon, A; Takayama, H; Maina, F; Ponzetto, C; Merlino, G; Pavan, W

1999-02-01

The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.

Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect.

PubMed

Mathijssen, Natascha C J; Masereeuw, Rosalinde; Holme, Pal Andre; van Kraaij, Marian G J; Laros-van Gorkom, Britta A P; Peyvandi, Flora; van Heerde, Waander L

2013-08-01

Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study. Ten factor VII deficient patients were treated with either recombinant activated (20 μg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points. Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII. Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products. Copyright © 2013 Elsevier Ltd. All rights reserved.

Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

PubMed

Bilgiç, Ayhan; Toker, Aysun; Işık, Ümit; Kılınç, İbrahim

2017-03-01

It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

Bone-Derived Growth Factors

PubMed Central

Capanna, R.; Campanacci, D.A.; De Biase, P.; Cuomo, P.; Lorenzoni, A.

2010-01-01

Bone regeneration is based on the synergy between osteconduction, osteoinduction and osteogenesis. In recent years, we have witnessed the birth and development of numerous osteoconductive substrates, created with the intention of replacing bone grafts, both autologous and homologous. Recently, attention has shifted to osteogenesis, in other words, to the study of mesenchymal cells and their differentiation into osteoblastic cell lines that can be cultured in vitro (as already seen with chondroblasts). Osteoinduction, too, has been shown to be equally important, ever since Urist’s 1967 study which drew attention to the demineralised bone matrix and its properties. The following twenty years led to the definition of bone morphogenetic protein (BMP) and finally to the marketing of the first ostegenic protein (OP-1) obtained by means of the gene recombination technique. The BMPs produced using this technique that, so far, have been shown to be most active are BMP-2 (Infuse) and BMP-7 (Osigraft). The BMPs are not the only molecules with osteoinductive capacity. Other molecules capable of influencing bone regeneration are: platelet-derived growth factors (PDGFs), the transforming growth factor-beta (TGF-β) family, insulin-like growth factor (IGF-I) and the acidic and basic fibroblast growth factors (FGFs). All these growth factors act in synergy with the BMPs, modulating their action and exerting an inductive and proliferative action on the cell lines responsible for regenerating the bone matrix. The literature has been literally invaded by studies, both experimental and preclinical, on these proteins (Termaat, 2005), and they have provided ample demonstration that the BMPs are effective in improving healing of fractures, pseudoarthrosis and spinal fusions. Important advantages of BMPs are the complete absence of risk of transmissible disease, given that they are produced using recombination technology; their purity, and thus absence of an immune response (although

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

PubMed Central

Autry, Anita E.

2012-01-01

Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development. PMID:22407616

Brain-Derived Neurotrophic Factor in the Airways

PubMed Central

Prakash, Y.S.; Martin, Richard J.

2014-01-01

In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target. PMID:24560686

Protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion.

PubMed

Zhai, S-Q; Guo, W; Hu, Y-Y; Yu, N; Chen, Q; Wang, J-Z; Fan, M; Yang, W-Y

2011-05-01

To explore the protective effects of brain-derived neurotrophic factor on the noise-damaged cochlear spiral ganglion. Recombinant adenovirus brain-derived neurotrophic factor vector, recombinant adenovirus LacZ and artificial perilymph were prepared. Guinea pigs with audiometric auditory brainstem response thresholds of more than 75 dB SPL, measured seven days after four hours of noise exposure at 135 dB SPL, were divided into three groups. Adenovirus brain-derived neurotrophic factor vector, adenovirus LacZ and perilymph were infused into the cochleae of the three groups, variously. Eight weeks later, the cochleae were stained immunohistochemically and the spiral ganglion cells counted. The auditory brainstem response threshold recorded before and seven days after noise exposure did not differ significantly between the three groups. However, eight weeks after cochlear perfusion, the group receiving brain-derived neurotrophic factor had a significantly decreased auditory brainstem response threshold and increased spiral ganglion cell count, compared with the adenovirus LacZ and perilymph groups. When administered via cochlear infusion following noise damage, brain-derived neurotrophic factor appears to improve the auditory threshold, and to have a protective effect on the spiral ganglion cells.

[Elucidating the molecular mechanism of prostate cancer progression under chronic hypoxia and development of the novel therapeutic approach].

PubMed

Nomura, Takeo; Yamasaki, Mutsushi; Mimata, Hiromitsu

2014-12-01

Cancer cells encounter a hypoxic microenvironment during tumor growth and progression. In addition, androgen-deprivation therapy against prostate cancer can develop secondary to a hypoxic condition caused by drastic blood supply reduction because androgen drives angiogenic inducers including vascular endothelial growth factor (VEGF) and inhibits angiogenesis inhibitor prostatic pigment epithelium-derived factor (PEDF). Extreme hypoxic conditions are not suitable for cancer survival, however, cancer cells soon adapt to a hypoxic environment and survive. We established a prostate cancer cell line cultured under chronic hypoxia and analyzed a castration-resistant phenotype. Here, the Vav3 was identified as a key oncogenic molecule associated with castration-resistance under chronic hypoxia. We analyzed the functions of Vav3 and Vav3-mediated signaling to establish a novel therapeutic target for castration-resistant prostate cancer.

Plasma brain-derived neurotrophic factor in women after bariatric surgery: a pilot study.

PubMed

Merhi, Zaher O; Minkoff, Howard; Lambert-Messerlian, Geralyn M; Macura, Jerzy; Feldman, Joseph; Seifer, David B

2009-04-01

Eighteen morbidly obese women had plasma brain-derived neurotrophic factor (BDNF) measured before bariatric surgery and 3 months postoperatively. We analyzed plasma BDNF levels in all the participants then subdivided according to menopausal status and type of surgery. Brain-derived neurotrophic factor decreased significantly in all the participants and in the premenopausal group when looked at in isolation.

Brain-derived neurotrophic factor and its receptors in Bergmann glia cells.

PubMed

Poblete-Naredo, Irais; Guillem, Alain M; Juárez, Claudia; Zepeda, Rossana C; Ramírez, Leticia; Caba, Mario; Hernández-Kelly, Luisa C; Aguilera, José; López-Bayghen, Esther; Ortega, Arturo

2011-12-01

Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been extensively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stimulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection. Copyright © 2011 Elsevier B.V. All rights reserved.

N-acetylcysteine does not influence the activity of endothelium-derived relaxing factor in vivo.

PubMed

Creager, M A; Roddy, M A; Boles, K; Stamler, J S

1997-02-01

Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol

Melatonin prevents retinal oxidative stress and vascular changes in diabetic rats

PubMed Central

Özdemir, G; Ergün, Y; Bakariş, S; Kılınç, M; Durdu, H; Ganiyusufoğlu, E

2014-01-01

Purpose To evaluate the role of melatonin, an antioxidant agent, in diabetic oxidative stress and vascular damage. Methods Diabetes was induced in 21 male Wistar rats by intraperitoneal (IP) administration of streptozotocin and then the rats were equally and randomly allocated to diabetic, melatonin, and vehicle groups. Seven healthy normal rats with similar features comprised the control group as the fourth group. All animals were followed for 12 weeks. The melatonin group received IP melatonin daily and the vehicle group received 2.5% ethanol IP at the last month. At the end of 12 weeks, the rats were killed and retinas were harvested. The retinas were investigated for the existence of hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor A (VEGF-A), and pigment epithelium-derived factor (PEDF) by ELISA. Retinal oxidative stress is quantitated by measuring nitrotyrosine and malondialdehyde levels. Retinal immunohistochemistry with antibody against CD31 antigen was carried out on retinal cross-sections. For statistics, ANOVA test was used for multiple comparisons. Results Hyperglycemia increased retinal oxidation as measured through levels of nitrotyrosine and malondialdehyde. Diabetic retinas are also associated with abnormal vascular changes such as dilatation and deformation. HIF-1α, VEGF-A, and PEDF were all increased because of diabetic injury. Melatonin showed a potential beneficial effect on retinopathy in diabetic rats. It decreased retinal nitrotyrosine and malondialdehyde levels, showing an antioxidative support. The vasculomodulator cytokines are decreased accordingly by melatonin therapy. Melatonin normalized retinal vascular changes as well. Conclusion Melatonin may show some advantage on diabetic vascular changes through decreasing oxidative stress and vessel-related cytokines. PMID:24924441

Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

PubMed

Shen, Weiyong; Chung, Sook H; Irhimeh, Mohammad R; Li, Shiying; Lee, So-Ra; Gillies, Mark C

2014-01-01

Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats. Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34(+) cells and mobilization of CD34(+)/VEGF-R2(+) cells as well as recruitment of CD34(+) cells into the retina were examined after EPO treatment. RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+) cells along with effective mobilization of CD34(+)/VEGF-R2(+) cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including regulation of retinal glia and

Systemic Administration of Erythropoietin Inhibits Retinopathy in RCS Rats

PubMed Central

Shen, Weiyong; Chung, Sook H.; Irhimeh, Mohammad R.; Li, Shiying; Lee, So-Ra; Gillies, Mark C.

2014-01-01

Objective Royal College of Surgeons (RCS) rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO) on retinopathy in RCS rats. Methods Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg) was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR), pro-neurotrophin 3 (pro-NT3), tumour necrosis factor-α (TNFα), pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A), the production of CD34+ cells and mobilization of CD34+/VEGF-R2+ cells as well as recruitment of CD34+ cells into the retina were examined after EPO treatment. Results RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34+ cells along with effective mobilization of CD34+/VEGF-R2+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. Conclusions Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple mechanisms including

Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

ERIC Educational Resources Information Center

Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

2012-01-01

Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

DTIC Science & Technology

2004-01-01

OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...Z39-18 ABSTRACT Title: THE INFLUENCE OF PLATELET-DERIVED GROWTH FACTOR AND FIBROBLAST GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND...GROWTH FACTOR 2 ON OLIGODENDROCYTE DEVELOPMENT AND REMYELINATION by Joshua C. Murtie Thesis/dissertation submitted to the

Evaluation of the rat bladder-derived relaxant factor by coaxial bioassay system.

PubMed

Bozkurt, Turgut Emrah; Sahin-Erdemli, Inci

2004-07-14

The release of bladder-derived relaxant factor in a coaxial bioassay system and the effects of reactive oxygen species were studied. After precontraction with phenylephrine (10(-6)-3x10(-6)) or 50 mM K+, acetylcholine (10(-8)-10(-3) M) induced relaxation in rat anococcygeus muscle mounted within rat bladder in a tissue bath. This relaxation was not altered by the removal of the urothelium or incubation with tetrodotoxin (10(-6) M). However, bupivacaine (10(-4) M) and lidocaine (3 x 10(-4) M) inhibited this response after raising the pH of the nutrient solution to 7.8, and oxybuprocaine (10(-4) M) exerted inhibitory effect at both physiological pH (7.4) and at pH 7.8. Exposure to electrolysis-generated reactive oxygen species or incubation with hydrogen peroxide and pyrogallol did not alter the acetylcholine response. Present results indicate that the bladder-derived relaxant factor does not behave like endothelium-derived hyperpolarizing factor, but its release may be associated with tetrodotoxin-resistant Na+ channels, which are probably in the neurons of the bladder rather than in the urothelium or detrusor muscle. Furthermore, reactive oxygen species do not interact with this relaxing factor, the exact nature and the physiological importance of which, however, remains to be established.

Adult hippocampus derived soluble factors induce a neuronal-like phenotype in mesenchymal stem cells.

PubMed

Rivera, Francisco J; Sierralta, Walter D; Minguell, Jose J; Aigner, Ludwig

2006-10-02

Bone marrow-derived mesenchymal stem cells (MSCs) are not restricted in their differentiation fate to cells of the mesenchymal lineage. They acquire a neural phenotype in vitro and in vivo after transplantation in the central nervous system. Here we investigated whether soluble factors derived from different brain regions are sufficient to induce a neuronal phenotype in MSCs. We incubated bone marrow-derived MSCs in conditioned medium (CM) derived from adult hippocampus (HCM), cortex (CoCM) or cerebellum (CeCM) and analyzed the cellular morphology and the expression of neuronal and glial markers. In contrast to muscle derived conditioned medium, which served as control, conditioned medium derived from the different brain regions induced a neuronal morphology and the expression of the neuronal markers GAP-43 and neurofilaments in MSCs. Hippocampus derived conditioned medium had the strongest activity. It was independent of NGF or BDNF; and it was restricted to the neuronal differentiation fate, since no induction of the astroglial marker GFAP was observed. The work indicates that soluble factors present in the brain are sufficient to induce a neuronal phenotype in MSCs.

BOREAS RSS-2 Extracted Reflectance Factors Derived from ASAS Imagery

NASA Technical Reports Server (NTRS)

Russell, C.; Hall, Forrest G. (Editor); Nickerson, Jaime (Editor); Dabney, P.; Kovalick, W.; Graham, D.; Bur, Michael; Irons, James R.; Tierney, M.

2000-01-01

The BOREAS RSS-2 team derived atmospherically corrected bidirectional reflectance factor means from multispectral, multiangle ASAS imagery for small homogeneous areas near several BOREAS sites. The ASAS imagery was acquired from the C-130 aircraft platform in 1994 and 1996. The data are stored in tabular ASCII files.

Derivation of the Korean radwaste scaling factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwang Yong Jee; Hong Joo Ahn; Se Chul Sohn

2007-07-01

The concentrations of several radionuclides in low and intermediate level radioactive waste (LILW) drums have to be determined before shipping to disposal facilities. A notice, by the Ministry of Science and Technology (MOST) of the Korean Government, related to the disposal of LILW drums came into effect at the beginning of 2005, with regards to a radionuclide regulation inside a waste drum. MOST allows for an indirect radionuclide assay using a scaling factor to measure the inventories due to the difficulty of nondestructively measuring the essential {alpha} and {beta}-emitting nuclides inside a drum. That is, a scaling factor calculated throughmore » a correlation of the {alpha} or {beta}-emitting nuclide (DTM, Difficult-To-Measure) with a {gamma}-emitting nuclide (ETM, Easy-To-Measure) which has systematically similar properties with DTM nuclides. In this study, radioactive wastes, such as spent resin and dry active waste which were generated at different sites of a PWR and a site of a PHWR type Korean NPP, were partially sampled and analyzed for regulated radionuclides by using radiochemical methods. According to a reactor type and a waste form, the analysis results of each radionuclide were classified. Korean radwaste scaling factor was derived from database of radionuclide concentrations. (authors)« less

Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

PubMed

Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

2017-06-01

The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment <25), the number of Met alleles in the brain-derived neurotrophic factor genotype was also an independent predictor of upper extremity motor outcome 3 months after stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 2017 American Heart Association, Inc.

Myeloma-derived macrophage inhibitory factor regulates bone marrow stromal cell-derived IL-6 via c-MYC.

PubMed

Piddock, Rachel E; Marlein, Christopher R; Abdul-Aziz, Amina; Shafat, Manar S; Auger, Martin J; Bowles, Kristian M; Rushworth, Stuart A

2018-05-16

Multiple myeloma (MM) remains an incurable malignancy despite the recent advancements in its treatment. The protective effects of the niche in which it develops has been well documented; however, little has been done to investigate the MM cell's ability to 're-program' cells within its environment to benefit disease progression. Here, we show that MM-derived macrophage migratory inhibitory factor (MIF) stimulates bone marrow stromal cells to produce the disease critical cytokines IL-6 and IL-8, prior to any cell-cell contact. Furthermore, we provide evidence that this IL-6/8 production is mediated by the transcription factor cMYC. Pharmacological inhibition of cMYC in vivo using JQ1 led to significantly decreased levels of serum IL-6-a highly positive prognostic marker in MM patients. Our presented findings show that MM-derived MIF causes BMSC secretion of IL-6 and IL-8 via BMSC cMYC. Furthermore, we show that the cMYC inhibitor JQ1 can reduce BMSC secreted IL-6 in vivo, irrespective of tumor burden. These data provide evidence for the clinical evaluation of both MIF and cMYC inhibitors in the treatment of MM.

Oxalobacter formigenes–Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells

PubMed Central

Arvans, Donna; Jung, Yong-Chul; Antonopoulos, Dionysios; Koval, Jason; Granja, Ignacio; Bashir, Mohamed; Karrar, Eltayeb; Roy-Chowdhury, Jayanta; Musch, Mark; Asplin, John; Chang, Eugene

2017-01-01

Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although Oxalobacter formigenes colonization is associated with reduced stone risk. O. formigenes interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, via an unknown secretagogue. The difficulties in sustaining O. formigenes colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of O. formigenes culture conditioned medium (CM) on apical 14C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, O. formigenes CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from Lactobacillus acidophilus did not. Treating the O. formigenes CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the O. formigenes–derived factors have molecular masses of 10–30 kDa. Treatment with the protein kinase A inhibitor H89 or the anion exchange inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid completely blocked the CM-induced oxalate transport. Knockdown of the oxalate transporter SLC26A6 also significantly restricted the induction of oxalate transport by CM. In a mouse model of primary hyperoxaluria type 1, rectal administration of O. formigenes CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that O. formigenes–derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with O. formigenes CM reflects the in vivo retention of biologic activity and the therapeutic potential of these factors. PMID:27738124

A note on the velocity derivative flatness factor in decaying HIT

NASA Astrophysics Data System (ADS)

Djenidi, L.; Danaila, L.; Antonia, R. A.; Tang, S.

2017-05-01

We develop an analytical expression for the velocity derivative flatness factor, F, in decaying homogenous and isotropic turbulence (HIT) starting with the transport equation of the third-order moment of the velocity increment and assuming self-preservation. This expression, fully consistent with the Navier-Stokes equations, relates F to the product between the second-order pressure derivative (∂2p /∂x2) and second-order moment of the longitudinal velocity derivative ((∂u/∂x ) 2), highlighting the role the pressure plays in the scaling of the fourth-order moment of the longitudinal velocity derivative. It is also shown that F has an upper bound which follows the integral of k*4Ep*(k* ) where Ep and k are the pressure spectrum and the wavenumber, respectively (the symbol * represents the Kolmogorov normalization). Direct numerical simulations of forced HIT suggest that this integral converges toward a constant as the Reynolds number increases.

Combining uncertainty factors in deriving human exposure levels of noncarcinogenic toxicants.

PubMed

Kodell, R L; Gaylor, D W

1999-01-01

Acceptable levels of human exposure to noncarcinogenic toxicants in environmental and occupational settings generally are derived by reducing experimental no-observed-adverse-effect levels (NOAELs) or benchmark doses (BDs) by a product of uncertainty factors (Barnes and Dourson, Ref. 1). These factors are presumed to ensure safety by accounting for uncertainty in dose extrapolation, uncertainty in duration extrapolation, differential sensitivity between humans and animals, and differential sensitivity among humans. The common default value for each uncertainty factor is 10. This paper shows how estimates of means and standard deviations of the approximately log-normal distributions of individual uncertainty factors can be used to estimate percentiles of the distribution of the product of uncertainty factors. An appropriately selected upper percentile, for example, 95th or 99th, of the distribution of the product can be used as a combined uncertainty factor to replace the conventional product of default factors.

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

PubMed

Puy, Cristina; Tucker, Erik I; Ivanov, Ivan S; Gailani, David; Smith, Stephanie A; Morrissey, James H; Gruber, András; McCarty, Owen J T

2016-01-01

Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma. Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.

Origin of platelet-derived growth factor in megakaryocytes in guinea pigs.

PubMed Central

Chernoff, A; Levine, R F; Goodman, D S

1980-01-01

Growth factor activity, as determined by the stimulation of [3H]thymidine incorporation into the DNA of quiescent 3T3 cells in culture, was found in lysates of guinea pig platelets and megakaryocytes. Quantitative dilution studies demonstrated that, of the cells present in the guinea pig bone marrow, only the megakaryocyte possessed quantitatively significant growth factor activity. The amount of activity present in one megakaryocyte was equivalent to that present in 1,000-5,000 platelets, a value approximately comparable to the number of platelets shed from a single megakaryocyte. It is suggested that guinea pig platelet-derived growth factor has its origin in the megakaryocyte. PMID:7358851

Biomimetic hybrid porous scaffolds immobilized with platelet derived growth factor-BB promote cellularization and vascularization in tissue engineering.

PubMed

Murali, Ragothaman; Ponrasu, Thangavel; Cheirmadurai, Kalirajan; Thanikaivelan, Palanisamy

2016-02-01

Development of hybrid scaffolds with synergistic combination of growth factor is a promising approach to promote early in vivo wound repair and tissue regeneration. Here, we show the rapid wound healing in Wistar albino rats using biomimetic collagen-poly(dialdehyde) guar gum based hybrid porous scaffolds covalently immobilized with platelet derived growth factor-BB. The immobilized platelet derived growth factor in the hybrid scaffolds not only enhance the total protein, collagen, hexosamine, and uronic acid contents in the granulation tissue but also provide stronger tissues. The wound closure analysis reveal that the complete epithelialization period is 15.4 ± 0.9 days for collagen-poly(dialdehyde) guar gum-platelet derived growth factor hybrid scaffolds, whereas it is significantly higher for control, collagen, collagen- poly(dialdehyde) guar gum and povidine-iodine treated groups. Further, the histological evaluation shows that the immobilized platelet derived growth factor in the hybrid scaffolds induced a more robust cellular and vascular response in the implanted site. Hence, we demonstrate that the collagen-poly(dialdehyde) guar gum hybrid scaffolds loaded with platelet derived growth factor stimulates chemotactic effects in the implanted site to promote rapid tissue regeneration and wound repair without the assistance of antibacterial agents. © 2015 Wiley Periodicals, Inc.

Proteomics-Derived Cerebrospinal Fluid Markers of Autopsy-Confirmed Alzheimer’s Disease

PubMed Central

Roher, Alex E.; Maarouf, Chera L.; Sue, Lucia I.; Hu, Yiran; Wilson, Jeffrey; Beach, Thomas G.

2010-01-01

The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers of neuropathologically-confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial 2-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), hemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF) while markers identified from the literature included Aβ1–40, Aβ1–42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by ELISA. The concentrations of Aβ1–42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1–42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1–42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1–42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1–42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1–42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1–42 alone was superior. PMID:19863188

SU-E-T-469: A Practical Approach for the Determination of Small Field Output Factors Using Published Monte Carlo Derived Correction Factors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calderon, E; Siergiej, D

2014-06-01

Purpose: Output factor determination for small fields (less than 20 mm) presents significant challenges due to ion chamber volume averaging and diode over-response. Measured output factor values between detectors are known to have large deviations as field sizes are decreased. No set standard to resolve this difference in measurement exists. We observed differences between measured output factors of up to 14% using two different detectors. Published Monte Carlo derived correction factors were used to address this challenge and decrease the output factor deviation between detectors. Methods: Output factors for Elekta's linac-based stereotactic cone system were measured using the EDGE detectormore » (Sun Nuclear) and the A16 ion chamber (Standard Imaging). Measurements conditions were 100 cm SSD (source to surface distance) and 1.5 cm depth. Output factors were first normalized to a 10.4 cm × 10.4 cm field size using a daisy-chaining technique to minimize the dependence of field size on detector response. An equation expressing the relation between published Monte Carlo correction factors as a function of field size for each detector was derived. The measured output factors were then multiplied by the calculated correction factors. EBT3 gafchromic film dosimetry was used to independently validate the corrected output factors. Results: Without correction, the deviation in output factors between the EDGE and A16 detectors ranged from 1.3 to 14.8%, depending on cone size. After applying the calculated correction factors, this deviation fell to 0 to 3.4%. Output factors determined with film agree within 3.5% of the corrected output factors. Conclusion: We present a practical approach to applying published Monte Carlo derived correction factors to measured small field output factors for the EDGE and A16 detectors. Using this method, we were able to decrease the percent deviation between both detectors from 14.8% to 3.4% agreement.« less

Binding affinities of vascular endothelial growth factor (VEGF) for heparin-derived oligosaccharides

PubMed Central

Zhao, Wenjing; McCallum, Scott A.; Xiao, Zhongping; Zhang, Fuming; Linhardt, Robert J.

2011-01-01

Heparin and heparan sulphate (HS) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS-binding to vascular endothelial growth factor (VEGF) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin-binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and that a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that VEGF binding affinity likely depends on the specific structural features of these oligosaccharides including their degree of sulphation and sugar ring stereochemistry and conformation. Notably, the unique 3-O-sulpho group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs. PMID:21658003

Image-derived input function with factor analysis and a-priori information.

PubMed

Simončič, Urban; Zanotti-Fregonara, Paolo

2015-02-01

Quantitative PET studies often require the cumbersome and invasive procedure of arterial cannulation to measure the input function. This study sought to minimize the number of necessary blood samples by developing a factor-analysis-based image-derived input function (IDIF) methodology for dynamic PET brain studies. IDIF estimation was performed as follows: (a) carotid and background regions were segmented manually on an early PET time frame; (b) blood-weighted and tissue-weighted time-activity curves (TACs) were extracted with factor analysis; (c) factor analysis results were denoised and scaled using the voxels with the highest blood signal; (d) using population data and one blood sample at 40 min, whole-blood TAC was estimated from postprocessed factor analysis results; and (e) the parent concentration was finally estimated by correcting the whole-blood curve with measured radiometabolite concentrations. The methodology was tested using data from 10 healthy individuals imaged with [(11)C](R)-rolipram. The accuracy of IDIFs was assessed against full arterial sampling by comparing the area under the curve of the input functions and by calculating the total distribution volume (VT). The shape of the image-derived whole-blood TAC matched the reference arterial curves well, and the whole-blood area under the curves were accurately estimated (mean error 1.0±4.3%). The relative Logan-V(T) error was -4.1±6.4%. Compartmental modeling and spectral analysis gave less accurate V(T) results compared with Logan. A factor-analysis-based IDIF for [(11)C](R)-rolipram brain PET studies that relies on a single blood sample and population data can be used for accurate quantification of Logan-V(T) values.

The use of autologous blood-derived growth factors in bone regeneration

PubMed Central

Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

2011-01-01

Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

Serum Brain-Derived Neurotrophic Factors in Taiwanese Patients with Drug-Naïve First-Episode Major Depressive Disorder: Effects of Antidepressants.

PubMed

Chiou, Yu-Jie; Huang, Tiao-Lai

2017-03-01

Brain-derived neurotrophic factors are known to be related to the psychopathology of major depressive disorder. However, studies focusing on drug-naïve first-episode patients are still rare. Over a 6-year period, we examined the serum brain-derived neurotrophic factors levels in patients with first-episode drug-naïve major depressive disorder and compared them with sex-matched healthy controls. We also investigated the relationships between serum brain-derived neurotrophic factors levels, suicidal behavior, and Hamilton Depression Rating Scale scores before and after a 4-week antidepressant treatment. The baseline serum brain-derived neurotrophic factors levels of 71 patients were significantly lower than those of the controls (P=.017), and the Hamilton Depression Rating Scale scores in 71 patients did not correlate with brain-derived neurotrophic factor levels. Brain-derived neurotrophic factor levels were significantly lower in 13 suicidal major depressive disorder patients than in 58 nonsuicidal major depressive disorder patients (P=.038). Among 41 followed-up patients, there was no alteration in serum brain-derived neurotrophic factors levels after treatment with antidepressants (P=.126). In receiver operating characteristic curve analysis of using pretreatment brain-derived neurotrophic factors to estimate the response to treatment, the area under the curve was 0.684. The most suitable cut-off point was 6.1 ng/mL (sensitivity=78.6%, specificity = 53.8%). Our data support the serum brain-derived neurotrophic factor levels in patients with drug-naïve first-episode major depressive disorder were lower than those in the healthy controls, and patients with pretreatment brain-derived neurotrophic factors >6.1 ng/mL were more likely to be responders. Although the relationship of our results to the mechanism of drug action and pathophysiology of depression remains unclear, the measure may have potential use as a predictor of response to treatment. In the future

Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer.

PubMed

Anan, K; Morisaki, T; Katano, M; Ikubo, A; Kitsuki, H; Uchiyama, A; Kuroki, S; Tanaka, M; Torisu, M

1996-03-01

Angiogenesis is a prerequisite for tumor growth and metastasis. Tumor angiogenesis may be mediated by several angiogenic factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha, and basic fibroblast growth factor. Differential mRNA expressions of VEGF, PDGF (A chain), transforming growth factor-alpha and basic fibroblast growth factor in 32 primary invasive breast tumors were examined by reverse transcriptase-polymerase chain reaction. We analyzed relationships between mRNA expressions of these angiogenic factors and the degree of angiogenesis, tumor size, and metastasis. Quantification of angiogenesis was achieved by the immunohistochemical staining of endothelial cells with antibody to CD31. VEGF and PDGF-A mRNAs were expressed more frequently in breast tumors than in nontumor breast tissues, whereas no difference was found in expression frequency of either transforming growth factor-alpha or basic fibroblast growth factor mRNA. Vascular counts in tumors correlated with each expression frequency of VEGF and PDGF-A mRNA. PDGF-A mRNA was expressed more frequently in tumors with lymph node metastasis than in those without metastasis. Expression of VEGF and PDGF mRNAs detected by reverse transcriptase-polymerase chain reaction in breast tumors correlates with tumor-related characteristics of angiogenesis and metastatic potential. Analysis of these mRNAs by reverse transcriptase-polymerase chain reaction may be useful for assessing the biologic behavior of a breast tumor before surgical treatment.

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium.

PubMed

Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Yalçın, Yaprak; Can, Güneş; Resmi, Halil; Akan, Pınar; Ergör, Gül; Aydemir, Omer; Cengisiz, Cengiz; Kerim, Doyuran

2014-09-01

Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Small sample size in different episodes and drug-free patients was the limitation of thestudy. Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of cigarette smoke on monocyte procoagulant activity: Focus on platelet-derived brain-derived neurotrophic factor (BDNF).

PubMed

Amadio, Patrizia; Baldassarre, Damiano; Sandrini, Leonardo; Weksler, Babette B; Tremoli, Elena; Barbieri, Silvia S

2017-01-01

Cigarette smoke (CS) activates platelets, promotes vascular dysfunction, and enhances Tissue Factor (TF) expression in blood monocytes favoring pro-thrombotic states. Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophins involved in survival, growth, and maturation of neurons, is released by activated platelets (APLTs) and plays a role in the cardiovascular system. The effect of CS on circulating levels of BDNF is controversial and the function of circulating BDNF in atherothrombosis is not fully understood. Here, we have shown that human platelets, treated with an aqueous extract of CS (CSE), released BDNF in a dose-dependent manner. In addition, incubation of human monocytes with BDNF or with the supernatant of platelets activated with CSE increased TF activity by a Tropomyosin receptor kinase B (TrkB)-dependent mechanism. Finally, comparing serum and plasma samples of 12 male never smokers (NS) and 29 male active smokers (AS) we observed a significant increase in microparticle-associated TF activity (MP-TF) as well as BDNF in AS, while in serum, BDNF behaved oppositely. Taken together these findings suggest that platelet-derived BDNF is involved in the regulation of TF activity and that CS plays a role in this pathway by favoring a pro-atherothrombotic state.

Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus.

PubMed

Teague, April M; Fields, David A; Aston, Christopher E; Short, Kevin R; Lyons, Timothy J; Chernausek, Steven D

2015-06-26

Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women. We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates. DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort. Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in

Characterization of male-derived factors inhibiting female sexual receptivity in Lygus hesperus

USDA-ARS?s Scientific Manuscript database

Newly mated females of the plant bug, Lygus hesperus Knight, enter a refractory period during which their sexual receptivity to courting males is greatly reduced for several days. This behavioral change appears to be induced by male-derived factors delivered in the spermatophore during copulation. T...

Brain-derived neurotrophic factor transgenic mice exhibit passive avoidance deficits, increased seizure severity and in vitro hyperexcitability in the hippocampus and entorhinal cortex.

PubMed

Croll, S D; Suri, C; Compton, D L; Simmons, M V; Yancopoulos, G D; Lindsay, R M; Wiegand, S J; Rudge, J S; Scharfman, H E

1999-01-01

Transgenic mice overexpressing brain-derived neurotrophic factor from the beta-actin promoter were tested for behavioral, gross anatomical and physiological abnormalities. Brain-derived neurotrophic factor messenger RNA overexpression was widespread throughout brain. Overexpression declined with age, such that levels of overexpression decreased sharply by nine months. Brain-derived neurotrophic factor transgenic mice had no gross deformities or behavioral abnormalities. However, they showed a significant passive avoidance deficit. This deficit was dependent on continued overexpression, and resolved with age as brain-derived neurotrophic factor transcripts decreased. In addition, the brain-derived neurotrophic factor transgenic mice showed increased seizure severity in response to kainic acid. Hippocampal slices from brain-derived neurotrophic factor transgenic mice showed hyperexcitability in area CA3 and entorhinal cortex, but not in dentate gyrus. Finally, area CA1 long-term potentiation was disrupted, indicating abnormal plasticity. Our data suggest that overexpression of brain-derived neurotrophic factor in the brain can interfere with normal brain function by causing learning impairments and increased excitability. The results also support the hypothesis that excess brain-derived neurotrophic factor could be pro-convulsant in the limbic system.

Multi-factor energy price models and exotic derivatives pricing

NASA Astrophysics Data System (ADS)

Hikspoors, Samuel

The high pace at which many of the world's energy markets have gradually been opened to competition have generated a significant amount of new financial activity. Both academicians and practitioners alike recently started to develop the tools of energy derivatives pricing/hedging as a quantitative topic of its own. The energy contract structures as well as their underlying asset properties set the energy risk management industry apart from its more standard equity and fixed income counterparts. This thesis naturally contributes to these broad market developments in participating to the advances of the mathematical tools aiming at a better theory of energy contingent claim pricing/hedging. We propose many realistic two-factor and three-factor models for spot and forward price processes that generalize some well known and standard modeling assumptions. We develop the associated pricing methodologies and propose stable calibration algorithms that motivate the application of the relevant modeling schemes.

Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.

PubMed Central

Gauldie, J; Richards, C; Harnish, D; Lansdorp, P; Baumann, H

1987-01-01

One of the oldest and most preserved of the homeostatic responses of the body to injury is the acute phase protein response associated with inflammation. The liver responds to hormone-like mediators by the increased synthesis of a series of plasma proteins called acute phase reactants. In these studies, we examined the relationship of hepatocyte-stimulating factor derived from peripheral blood monocytes to interferon beta 2 (IFN-beta 2), which has been cloned. Antibodies raised against fibroblast-derived IFN-beta having neutralizing activity against both IFN-beta 1 and -beta 2 inhibited the major hepatocyte-stimulating activity derived from monocytes. Fibroblast-derived mediator elicited the identical stimulated response in human HepG2 cells and primary rat hepatocytes as the monocyte cytokine. Finally, recombinant-derived human B-cell stimulatory factor type 2 (IFN-beta 2) from Escherichia coli induced the synthesis of all major acute phase proteins studied in human hepatoma HepG2 and primary rat hepatocyte cultures. These data demonstrate that monocyte-derived hepatocyte-stimulating factor and IFN-beta 2 share immunological and functional identity and that IFN-beta 2, also known as B-cell stimulatory factor and hybridoma plasmacytoma growth factor, has the hepatocyte as a major physiologic target and thereby is essential in controlling the hepatic acute phase response. Images PMID:2444978

A Histologically Distinctive Interstitial Pneumonia Induced by Overexpression of the Interleukin 6, Transforming Growth Factor β1, or Platelet-Derived Growth Factor B Gene

NASA Astrophysics Data System (ADS)

Yoshida, Mitsuhiro; Sakuma, Junko; Hayashi, Seiji; Abe, Kin'ya; Saito, Izumu; Harada, Shizuko; Sakatani, Mitsunoir; Yamamoto, Satoru; Matsumoto, Norinao; Kaneda, Yasufumi; Kishmoto, Tadamitsu

1995-10-01

Interstitial pneumonia is characterized by alveolitis with resulting fibrosis of the interstitium. To determine the relevance of humoral factors in the pathogenesis of interstitial pneumonia, we introduced expression vectors into Wistar rats via the trachea to locally overexpress humoral factors in the lungs. Human interleukin (IL) 6 and IL-6 receptor genes induced lymphocytic alveolitis without marked fibroblast proliferation. In contrast, overexpression of human transforming growth factor β1 or human platelet-derived growth factor B gene induced only mild or apparent cellular infiltration in the alveoli, respectively. However, both factors induced significant proliferation of fibroblasts and deposition of collagen fibrils. These histopathologic changes induced by the transforming growth factor β1 and platelet-derived growth factor B gene are partly akin to those changes seen in lung tissues from patients with pulmonary fibrosis and markedly contrast with the changes induced by overexpression of the IL-6 and IL-6 receptor genes that mimics lymphocytic interstitial pneumonia.

A Review: Proteomics in Retinal Artery Occlusion, Retinal Vein Occlusion, Diabetic Retinopathy and Acquired Macular Disorders.

PubMed

Cehofski, Lasse Jørgensen; Honoré, Bent; Vorum, Henrik

2017-04-28

Retinal artery occlusion (RAO), retinal vein occlusion (RVO), diabetic retinopathy (DR) and age-related macular degeneration (AMD) are frequent ocular diseases with potentially sight-threatening outcomes. In the present review we discuss major findings of proteomic studies of RAO, RVO, DR and AMD, including an overview of ocular proteome changes associated with anti-vascular endothelial growth factor (VEGF) treatments. Despite the severe outcomes of RAO, the proteome of the disease remains largely unstudied. There is also limited knowledge about the proteome of RVO, but proteomic studies suggest that RVO is associated with remodeling of the extracellular matrix and adhesion processes. Proteomic studies of DR have resulted in the identification of potential therapeutic targets such as carbonic anhydrase-I. Proliferative diabetic retinopathy is the most intensively studied stage of DR. Proteomic studies have established VEGF, pigment epithelium-derived factor (PEDF) and complement components as key factors associated with AMD. The aim of this review is to highlight the major milestones in proteomics in RAO, RVO, DR and AMD. Through large-scale protein analyses, proteomics is bringing new important insights into these complex pathological conditions.

Thyroxin treatment protects against white matter injury in the immature brain via brain-derived neurotrophic factor.

PubMed

Hung, Pi-Lien; Huang, Chao-Ching; Huang, Hsiu-Mei; Tu, Dom-Gene; Chang, Ying-Chao

2013-08-01

Low level of thyroid hormone is a strong independent risk factor for white matter (WM) injury, a major cause of cerebral palsy, in preterm infants. Thyroxin upregulates brain-derived neurotrophic factor during development. We hypothesized that thyroxin protected against preoligodendrocyte apoptosis and WM injury in the immature brain via upregulation of brain-derived neurotrophic factor. Postpartum (P) day-7 male rat pups were exposed to hypoxic ischemia (HI) and intraperitoneally injected with thyroxin (T4; 0.2 mg/kg or 1 mg/kg) or normal saline immediately after HI at P9 and P11. WM damage was analyzed for myelin formation, axonal injury, astrogliosis, and preoligodendrocyte apoptosis. Neurotrophic factor expression was assessed by real-time polymerase chain reaction and immunohistochemistry. Neuromotor functions were measured using open-field locomotion (P11 and P21), inclined plane climbing (P11), and beam walking (P21). Intracerebroventricular injection of TrkB-Fc or systemic administration of 7,8-dihydroxyflavone was performed. On P11, the HI group had significantly lower blood T4 levels than the controls. The HI group showed ventriculomegaly and marked reduction of myelin basic protein immunoreactivities in the WM. T4 (1 mg/kg) treatment after HI markedly attenuated axonal injury, astrocytosis, and microgliosis, and increased preoligodendrocyte survival. In addition, T4 treatment significantly increased myelination and selectively upregulated brain-derived neurotrophic factor expression in the WM, and improved neuromotor deficits after HI. The protective effect of T4 on WM myelination and neuromotor performance after HI was significantly attenuated by TrkB-Fc. Systemic 7,8-dihydroxyflavone treatment ameliorated hypomyelination after HI injury. T4 protects against WM injury at both pathological and functional levels via upregulation of brain-derived neurotrophic factor-TrkB signaling in the immature brain.

Platelet-rich plasma derived growth factors contribute to stem cell differentiation in musculoskeletal regeneration

NASA Astrophysics Data System (ADS)

Qian, Yun; Han, Qixin; Chen, Wei; Song, Jialin; Zhao, Xiaotian; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

2017-10-01

Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of platelet-rich plasma derived growth factors with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

Immunohistochemical examination of effects of kefir, koumiss and commercial probiotic capsules on platelet derived growth factor-c and platelet derived growth factor receptor-alpha expression in mouse liver and kidney.

PubMed

Bakir, B; Sari, E K; Aydin, B D; Yildiz, S E

2015-04-01

We investigated using immunohistochemistry the effects of kefir, koumiss and commercial probiotic capsules on the expression of platelet derived growth factor-c (PDGF-C) and platelet derived growth factor receptor-alpha (PDGFR-α) in mouse liver and kidney. Mice were assigned to four groups: group 1 was given commercial probiotic capsules, group 2 was given kefir, group 3 was given koumiss and group 4 was untreated. After oral administration for 15 days, body weights were recorded and liver and kidney tissue samples were obtained. Hematoxylin and eosin staining was used to examine histology. PDGF-C and PDGFR-α in liver and kidney were localized using the streptavidin-biotin peroxidase complex method (ABC). We found that the weights of the mice in the kefir, koumiss and commercial probiotic capsules groups increased compared to the control group. No differences in liver and kidney histology were observed in any of the experimental groups. Kefir, koumiss and the commercial probiotic preparation increased PDGF-C and PDGFR-α expression.

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

PubMed Central

Numakawa, Tadahiro; Odaka, Haruki; Adachi, Naoki

2017-01-01

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs. PMID:29099059

Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

DOE Office of Scientific and Technical Information (OSTI.GOV)

El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument

2013-02-21

Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation inmore » ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.« less

The effects of adolescent methylphenidate exposure on the behavioral and brain-derived neurotrophic factor response to nicotine.

PubMed

Cummins, Elizabeth D; Leedy, Kristen K; Dose, John M; Peterson, Daniel J; Kirby, Seth L; Hernandez, Liza J; Brown, Russell W

2017-01-01

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a "school day" regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45-P63 and tested after a three-day drug washout on the forced swim stress task on P67-P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44-P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

Prostate-derived Ets factor, an oncogenic driver in breast cancer.

PubMed

Sood, Ashwani K; Geradts, Joseph; Young, Jessica

2017-05-01

Prostate-derived Ets factor (PDEF), a member of the Ets family of transcription factors, differs from other family members in its restricted expression in normal tissues and its unique DNA-binding motif. These interesting attributes coupled with its aberrant expression in cancer have rendered PDEF a focus of increasing interest by tumor biologists. This review provides a current understanding of the characteristics of PDEF expression and its role in breast cancer. The bulk of the evidence is consistent with PDEF overexpression in most breast tumors and an oncogenic role for this transcription factor in breast cancer. In addition, high PDEF expression in estrogen receptor-positive breast tumors showed significant correlation with poor overall survival in several independent cohorts of breast cancer patients. Together, these findings demonstrate PDEF to be an oncogenic driver of breast cancer and a biomarker of poor prognosis in this cancer. Based on this understanding and the limited expression of PDEF in normal human tissues, the development of PDEF-based therapeutics for prevention and treatment of breast cancer is also discussed.

REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR MESSENGER RNA LEVELS IN AVIAN HYPOTHALAMIC SLICE CULTURES. (R825294)

EPA Science Inventory

Mechanisms regulating the expression of brain-derived neurotrophic factor, a member of the neurotrophin family, have been extensively studied in the rat cerebral cortex, hippocampus and cerebellum. In contrast, little is known regarding the regulation of this growth factor in ...

Stage specific requirement of platelet-derived growth factor receptor-α in embryonic development.

PubMed

Qian, Chen; Wong, Carol Wing Yan; Wu, Zhongluan; He, Qiuming; Xia, Huimin; Tam, Paul Kwong Hang; Wong, Kenneth Kak Yuen; Lui, Vincent Chi Hang

2017-01-01

Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures. To address the temporal requirement of Pdgfra in embryonic development. We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies. Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives. Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.

Multifaceted Therapeutic Benefits of Factors Derived From Dental Pulp Stem Cells for Mouse Liver Fibrosis.

PubMed

Hirata, Marina; Ishigami, Masatoshi; Matsushita, Yoshihiro; Ito, Takanori; Hattori, Hisashi; Hibi, Hideharu; Goto, Hidemi; Ueda, Minoru; Yamamoto, Akihito

2016-10-01

: Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl 4 )-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl 4 -induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl 4 -induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF. This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced

Angiogenic and angiostatic factors in the molecular control of angiogenesis.

PubMed

Distler, J H W; Hirth, A; Kurowska-Stolarska, M; Gay, R E; Gay, S; Distler, O

2003-09-01

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.

The effect of choosing three different C factor formulae derived from NDVI on a fully raster-based erosion modelling

NASA Astrophysics Data System (ADS)

Sulistyo, Bambang

2016-11-01

The research was aimed at studying the efect of choosing three different C factor formulae derived from NDVI on a fully raster-based erosion modelling of The USLE using remote sensing data and GIS technique. Methods applied was by analysing all factors affecting erosion such that all data were in the form of raster. Those data were R, K, LS, C and P factors. Monthly R factor was evaluated based on formula developed by Abdurachman. K factor was determined using modified formula used by Ministry of Forestry based on soil samples taken in the field. LS factor was derived from Digital Elevation Model. Three C factors used were all derived from NDVI and developed by Suriyaprasit (non-linear) and by Sulistyo (linear and non-linear). P factor was derived from the combination between slope data and landcover classification interpreted from Landsat 7 ETM+. Another analysis was the creation of map of Bulk Density used to convert erosion unit. To know the model accuracy, model validation was done by applying statistical analysis and by comparing Emodel with Eactual. A threshold value of ≥ 0.80 or ≥ 80% was chosen to justify. The research result showed that all Emodel using three formulae of C factors have coeeficient of correlation value of > 0.8. The results of analysis of variance showed that there was significantly difference between Emodel and Eactual when using C factor formula developed by Suriyaprasit and Sulistyo (non-linear). Among the three formulae, only Emodel using C factor formula developed by Sulistyo (linear) reached the accuracy of 81.13% while the other only 56.02% as developed by Sulistyo (nonlinear) and 4.70% as developed by Suriyaprasit, respectively.

Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning-Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor-Dependent Hippocampal Neurogenesis.

PubMed

Liu, Wen-Chung; Yang, San-Nan; Wu, Chih-Wei J; Chen, Lee-Wei; Chan, Julie Y H

2016-01-01

To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute carbon monoxide poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor in the hippocampus. Laboratory animal experiments. University/Medical center research laboratory. Adult, male Sprague-Dawley rats. Rats were divided into five groups: (1) non-carbon monoxide-treated control, (2) acute carbon monoxide poisoning, (3) acute carbon monoxide poisoning followed by 7-day hyperbaric oxygen treatment, (4) carbon monoxide + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute carbon monoxide poisoning followed by intracerebroventricular infusion of brain-derived neurotrophic factor. Acute carbon monoxide poisoning was achieved by exposing the rats to carbon monoxide at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after carbon monoxide poisoning. Recombinant human TrkB-Fc chimera or brain-derived neurotrophic factor was infused into the lateral ventricle via the implanted osmotic minipump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of brain-derived neurotrophic factor was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. Acute carbon monoxide poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67⁺, and doublecortin⁺ cells in the subgranular zone of the dentate gyrus. This

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells

PubMed Central

Choi, Nahyun; Shin, Soyoung; Song, Sun U.; Sung, Jong-Hyuk

2018-01-01

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal–regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration. PMID:29495622

Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells.

PubMed

Choi, Nahyun; Shin, Soyoung; Song, Sun U; Sung, Jong-Hyuk

2018-02-28

Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration.

Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis

ERIC Educational Resources Information Center

Saghazadeh, Amene; Rezaei, Nima

2017-01-01

Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity. Altered blood BDNF levels have been frequently identified in people with autism spectrum disorders (ASD). There are however wide discrepancies in the evidence. Therefore, we performed the present systematic review and meta-analysis aimed at…

Mitogenic and chondrogenic effects of fibroblast growth factor-2 in adipose-derived mesenchymal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiou, Michael; Xu Yue; Longaker, Michael T.

2006-05-05

Adipose-derived mesenchymal cells (AMCs) have demonstrated a great capacity for differentiating into bone, cartilage, and fat. Studies using bone marrow-derived mesenchymal cells (BMSCs) have shown that fibroblast growth factor (FGF)-2, a potent mitogenic factor, plays an important role in tissue engineering due to its effects in proliferation and differentiation for mesenchymal cells. The aim of this study was to investigate the function of FGF-2 in AMC chondrogenic differentiation and its possible contributions to cell-based therapeutics in skeletal tissue regeneration. Data demonstrated that FGF-2 significantly promoted the proliferation of AMCs and enhanced chondrogenesis in three-dimensional micromass culture. Moreover, priming AMCs withmore » treatment of FGF-2 at 10 ng/ml demonstrated that cells underwent chondrogenic phenotypic differentiation, possibly by inducing N-Cadherin, FGF-receptor 2, and transcription factor Sox9. Our results indicated that FGF-2 potentiates chondrogenesis in AMCs, similar to its functions in BMSCs, suggesting the versatile potential applications of FGF-2 in skeletal regeneration and cartilage repair.« less

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

PubMed

Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

2005-01-01

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Hypoxia enhances the protective effects of placenta-derived mesenchymal stem cells against scar formation through hypoxia-inducible factor-1α.

PubMed

Du, Lili; Lv, Runxiao; Yang, Xiaoyi; Cheng, Shaohang; Xu, Jing; Ma, Tingxian

2016-06-01

To explore the effect of placenta-derived mesenchymal stem cells on scar formation as well as the underlying mechanism. The isolated placenta-derived mesenchymal stem cells from mice were distributed in the wounded areas of scalded mouse models, attenuated inflammatory responses and decreased the deposition of collagens, thus performing a beneficial effect against scar formation. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells and hypoxia-inducible factor-1α was involved in the protective effect of placenta-derived mesenchymal stem cells in hypoxic condition. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells through hypoxia-inducible factor-1α and PMSCs may have a potential application in the treatment of wound.

Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1).

PubMed

Nagle, Dale G; Zhou, Yu-Dong

2006-01-01

Hypoxia-inducible factor-1 (HIF-1) is a key mediator of oxygen homeostasis that was first identified as a transcription factor that is induced and activated by decreased oxygen tension. Upon activation, HIF-1 upregulates the transcription of genes that promote adaptation and survival under hypoxic conditions. HIF-1 is a heterodimer composed of an oxygen-regulated subunit known as HIF-1alpha and a constitutively expressed HIF-1beta subunit. In general, the availability and activity of the HIF-1alpha subunit determines the activity of HIF-1. Subsequent studies have revealed that HIF-1 is also activated by environmental and physiological stimuli that range from iron chelators to hormones. Preclinical studies suggest that HIF-1 activation may be a valuable therapeutic approach to treat tissue ischemia and other ischemia/hypoxia-related disorders. The focus of this review is natural product-derived small molecule HIF-1 activators. Natural products, relatively low molecular weight organic compounds produced by plants, animals, and microbes, have been and continue to be a major source of new drugs and molecular probes. The majority of known natural product-derived HIF-1 activators were discovered through the pharmacological evaluation of specifically selected individual compounds. On the other hand, the combination of natural products chemistry with appropriate high-throughput screening bioassays may yield novel natural product-derived HIF-1 activators. Potent natural product-derived HIF-1 activators that exhibit a low level of toxicity and side effects hold promise as new treatment options for diseases such as myocardial and peripheral ischemia, and as chemopreventative agents that could be used to reduce the level of ischemia/reperfusion injury following heart attack and stroke.

Involvement of Brain-Derived Neurotrophic Factor in Late-Life Depression

PubMed Central

Dwivedi, Yogesh

2013-01-01

Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons, synaptic integrity, and synaptic plasticity. Evidence suggests that BDNF is involved in major depression, such that the level of BDNF is decreased in depressed patients and that antidepressants reverse this decrease. Stress, a major factor in depression, also modulates BDNF expression. These studies have led to the proposal of the neurotrophin hypothesis of depression. Late-life depression is associated with disturbances in structural and neural plasticity as well as impairments in cognitive behavior. Stress and aging also play a crucial role in late-life depression. Many recent studies have suggested that not only expression of BDNF is decreased in the serum/plasma of patients with late-life depression, but structural abnormalities in the brain of these patients may be associated with a polymorphism in the BDNF gene, and that there is a relationship between a BDNF polymorphism and antidepressant remission rates. This review provides a critical review of the involvement of BDNF in major depression, in general, and in late-life depression, in particular. PMID:23570887

Hypoxia and alkalinization inhibit endothelium-derived nitric oxide but not endothelium-derived hyperpolarizing factor responses in porcine coronary artery.

PubMed

Shimizu, S; Paul, R J

1999-10-01

We investigated the mechanisms by which hypoxia and alkalinization inhibit the endothelium-dependent relaxation to Substance P (SP) in porcine coronary artery. In a KCl contracture, the major component of the SP response is endothelium-derived nitric oxide (EDNO), whereas with receptor-mediated 9,11-dideoxy-llalpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) stimulation, the SP response is dependent on both EDNO and endothelium-derived hyperpolarization factor. Intracellular alkalinization by NH(4)Cl reduced the peak of SP responses when arteries were contracted with KCl, whereas with U46619 stimulation, the peak was little effected but the duration was shortened. In endothelial cell-denuded arteries, alkalinization with NH(4)Cl shifted the sodium nitroprusside concentration-relaxation relations rightward. The effects of NH(4)Cl in SP- and sodium nitroprusside-induced relaxations were attenuated by decreasing extracellular pH (pH(o)) from 7.4 to 7.2, which normalized intracellular pH (pH(i)) to control levels. In contrast, in U46619 contractures, the SP response in the presence of a NO synthase inhibitor was unaffected by NH(4)Cl. Moreover, hypoxia blunted but did not abolish the responses to SP for U46619 contractures; addition of KCl, however, abolished the SP response under hypoxia. Endothelial [Ca(2+)](i) was measured with fura-2 differentially loaded only into endothelial cells on intact arteries. Despite the attenuation of the SP response in KCl contractures by NH(4)Cl or hypoxia, endothelial [Ca(2+)](i) responses were unchanged. Our results suggest that hypoxia and alkalinization inhibit EDNO but not endothelium-derived hyperpolarization factor relaxations through a mechanism(s) not involving endothelial cell [Ca(2+)](i). Inhibition of EDNO relaxation by alkalinization with NH(4)Cl is likely to occur at the level of activation of guanylate cyclase and/or at a step downstream in smooth muscle.

Brain-Derived Neurotrophic Factor (BDNF) and Traumatic Brain Injury (Head and Spinal)

DTIC Science & Technology

2000-01-01

phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor- mediated survival and neuritogenesis of the neuroblastoma cell line ... SH - SY5Y , J. Neurochem. 73 (1999) 1409-1421. 15. Gottshalk, W.A., Jiang, H., Tartaglia, N., Feng, L., Figurov, A., Lu, B., Signaling mechanisms...NT-6), and neurotrophin-7 (NT-7) (4, 5, 24, 80). Neurotrophins are believed to promote their cell survival, growth, and differentiation effects

Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

USDA-ARS?s Scientific Manuscript database

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

USDA-ARS?s Scientific Manuscript database

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

Trophic factors from adipose tissue-derived multi-lineage progenitor cells promote cytodifferentiation of periodontal ligament cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sawada, Keigo; Takedachi, Masahide, E-mail: takedati@dent.osaka-u.ac.jp; Yamamoto, Satomi

Stem and progenitor cells are currently being investigated for their applicability in cell-based therapy for periodontal tissue regeneration. We recently demonstrated that the transplantation of adipose tissue-derived multi-lineage progenitor cells (ADMPCs) enhances periodontal tissue regeneration in beagle dogs. However, the molecular mechanisms by which transplanted ADMPCs induce periodontal tissue regeneration remain to be elucidated. In this study, trophic factors released by ADMPCs were examined for their paracrine effects on human periodontal ligament cell (HPDL) function. ADMPC conditioned medium (ADMPC-CM) up-regulated osteoblastic gene expression, alkaline phosphatase activity and calcified nodule formation in HPDLs, but did not significantly affect their proliferative response.more » ADMPCs secreted a number of growth factors, including insulin-like growth factor binding protein 6 (IGFBP6), hepatocyte growth factor and vascular endothelial growth factor. Among these, IGFBP6 was most highly expressed. Interestingly, the positive effects of ADMPC-CM on HPDL differentiation were significantly suppressed by transfecting ADMPCs with IGFBP6 siRNA. Our results suggest that ADMPCs transplanted into a defect in periodontal tissue release trophic factors that can stimulate the differentiation of HPDLs to mineralized tissue-forming cells, such as osteoblasts and cementoblasts. IGFBP6 may play crucial roles in ADMPC-induced periodontal regeneration. - Highlights: • ADMPC-derived humoral factors stimulate cytodifferentiation of HPDLs. • ADMPCs secret growth factors including IGFBP6, VEGF and HGF. • IGFBP6 is involved in the promotion effect of ADMPC-CM on HPDL cytodifferentiation.« less

A Review: Proteomics in Retinal Artery Occlusion, Retinal Vein Occlusion, Diabetic Retinopathy and Acquired Macular Disorders

PubMed Central

Cehofski, Lasse Jørgensen; Honoré, Bent; Vorum, Henrik

2017-01-01

Retinal artery occlusion (RAO), retinal vein occlusion (RVO), diabetic retinopathy (DR) and age-related macular degeneration (AMD) are frequent ocular diseases with potentially sight-threatening outcomes. In the present review we discuss major findings of proteomic studies of RAO, RVO, DR and AMD, including an overview of ocular proteome changes associated with anti-vascular endothelial growth factor (VEGF) treatments. Despite the severe outcomes of RAO, the proteome of the disease remains largely unstudied. There is also limited knowledge about the proteome of RVO, but proteomic studies suggest that RVO is associated with remodeling of the extracellular matrix and adhesion processes. Proteomic studies of DR have resulted in the identification of potential therapeutic targets such as carbonic anhydrase-I. Proliferative diabetic retinopathy is the most intensively studied stage of DR. Proteomic studies have established VEGF, pigment epithelium-derived factor (PEDF) and complement components as key factors associated with AMD. The aim of this review is to highlight the major milestones in proteomics in RAO, RVO, DR and AMD. Through large-scale protein analyses, proteomics is bringing new important insights into these complex pathological conditions. PMID:28452939

VR-10 Thrombospondin-1 Synthetic Polypeptide's Impact on Rhesus Choroid-Retinal Endothelial Cells.

PubMed

Tian, Run; Han, Fang; Yang, Jun; Zhao, Hai-Yan; Mei, Yan; Deng, Ai-Ping; Fang, Lin; Zhang, Xi-Rui

2018-01-01

. Compared with the control group, FasL mRNA expression was significantly increased in the 10 µg/ml synthetic peptide VR-10 treatment group; however, Bcl-2 mRNA expression was decreased. 5. Western blotting showed that RF/6A cells in the control group mainly expressed the 32 kD procaspase-3 forms. For the 10 µg/ml synthetic peptide, VR-10 treatment group, it showed decreased expression of procaspase-3 (32 kD) and concomitant increased expression of its shorter pro apoptotic forms (20 kD). Compared with the control group, Fas protein expression significantly increased in the 10 µg/ml synthetic peptide VR-10 treatment group. Synthetic peptide VR-10 had an inhibitory action on the proliferation and migration of RF/6A cells. VR-10 inhibited angiogenesis by its combined actions, which included up-regulating the expression of an anti-angiogenesis gene, namely, pigment epithelium-derived factor (PEDF), down-regulating the expression of the pro-angiogenic vascular endothelial growth factor (VEGF), and mediated endothelial cell apoptosis. © 2018 The Author(s). Published by S. Karger AG, Basel.

Differential Regulation of Brain-Derived Neurotrophic Factor Transcripts during the Consolidation of Fear Learning

ERIC Educational Resources Information Center

Ressler, Kerry J.; Rattiner, Lisa M.; Davis, Michael

2004-01-01

Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5[prime]-exon and a common 3[prime]-coding exon. This study describes novel evidence for the…

A glioma-derived analog to platelet-derived growth factor: demonstration of receptor competing activity and immunological crossreactivity.

PubMed Central

Nistér, M; Heldin, C H; Wasteson, A; Westermark, B

1984-01-01

A human clonal glioma cell line, U-343 MGa Cl 2, cultured under serum-free conditions, was found to release a factor that competed with 125I-labeled platelet-derived growth factor (125I-PDGF) for binding to human foreskin fibroblasts. The concentration of competing activity in conditioned medium was equal to 20-30 ng of PDGF per ml. The PDGF receptor competing activity had an elution position on Sephadex G-200 close to that of tracer PDGF. The same fractions in the chromatogram also contained growth-promoting activity and material active in a PDGF radioimmunoassay. Incubation of partially purified, 125I-labeled glioma factor with fibroblasts, or rabbit anti-PDGF serum, led to the selective binding of a component with an estimated Mr of 31,000, as shown by NaDodSO4/gel electrophoresis under nonreducing conditions. After reduction this component migrated as a Mr 18,000 protein. Thus, the behavior in NaDodSO4/gel electrophoresis was similar to that of PDGF. Furthermore, incubation of partially purified glioma factor with immobilized PDGF antibodies markedly decreased the amount of PDGF receptor competing activity remaining in the supernatant. These results suggest that the factor produced by glioma cells has structural, immunological, and functional resemblance to PDGF. We previously reported that a human osteosarcoma cell line produces a PDGF-like molecule with growth-promoting activity. Taken together with the recent finding that PDGF is homologous to the transforming gene product of simian sarcoma virus, our present data give additional support for the idea that an autocrine activation of the PDGF receptor may be operational in the growth of human tumors of mesenchymal or glial origin. Images PMID:6322178

Connective Tissue Growth Factor Promotes Efficient Generation of Human Induced Pluripotent Stem Cell‐Derived Choroidal Endothelium

PubMed Central

Songstad, Allison E.; Worthington, Kristan S.; Chirco, Kathleen R.; Giacalone, Joseph C.; Whitmore, S. Scott; Anfinson, Kristin R.; Ochoa, Dalyz; Cranston, Cathryn M.; Riker, Megan J.; Neiman, Maurine; Stone, Edwin M.; Mullins, Robert F.

2017-01-01

Abstract Age‐related macular degeneration (AMD) is a leading cause of irreversible blindness in the Western world. Although, the majority of stem cell research to date has focused on production of retinal pigment epithelial (RPE) and photoreceptor cells for the purpose of evaluating disease pathophysiology and cell replacement, there is strong evidence that the choroidal endothelial cells (CECs) that form the choriocapillaris vessels are the first to be lost in this disease. As such, to accurately evaluate disease pathophysiology and develop an effective treatment, production of patient‐specific, stem cell‐derived CECs will be required. In this study, we report for the first time a stepwise differentiation protocol suitable for generating human iPSC‐derived CEC‐like cells. RNA‐seq analysis of the monkey CEC line, RF/6A, combined with two statistical screens allowed us to develop media comprised of various protein combinations. In both screens, connective tissue growth factor (CTGF) was identified as the key component required for driving CEC development. A second factor tumor necrosis factor (TNF)‐related weak inducer of apoptosis receptor was also found to promote iPSC to CEC differentiation by inducing endogenous CTGF secretion. CTGF‐driven iPSC‐derived CEC‐like cells formed capillary tube‐like vascular networks, and expressed the EC‐specific markers CD31, ICAM1, PLVAP, vWF, and the CEC‐restricted marker CA4. In combination with RPE and photoreceptor cells, patient‐specific iPSC derived CEC‐like cells will enable scientists to accurately evaluate AMD pathophysiology and develop effective cell replacement therapies. Stem Cells Translational Medicine 2017;6:1533–1546 PMID:28474838

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection

PubMed Central

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments. PMID:28928987

Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection.

PubMed

Phillips, Cristy

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD) and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity) optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments.

An approximately factored incremental strategy for calculating consistent discrete aerodynamic sensitivity derivatives

NASA Technical Reports Server (NTRS)

Korivi, V. M.; Taylor, A. C., III; Newman, P. A.; Hou, G. J.-W.; Jones, H. E.

1992-01-01

An incremental strategy is presented for iteratively solving very large systems of linear equations, which are associated with aerodynamic sensitivity derivatives for advanced CFD codes. It is shown that the left-hand side matrix operator and the well-known factorization algorithm used to solve the nonlinear flow equations can also be used to efficiently solve the linear sensitivity equations. Two airfoil problems are considered as an example: subsonic low Reynolds number laminar flow and transonic high Reynolds number turbulent flow.

Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney.

PubMed

Wangensteen, Rosemary; Quesada, Andrés; Sainz, Juan; Duarte, Juan; Vargas, Félix; Osuna, Antonio

2002-05-24

The present study aimed to evaluate the contributions of endothelium-derived hyperpolarizing factor (EDHF), the nitric oxide (NO)-cGMP pathway, and prostaglandins to adrenomedullin-induced vasodilation in isolated rat kidney. Inhibition of the NO-cGMP pathway with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo-[4,3a]quinoxalin-1-one (ODQ) reduced the maximal vasodilator response to adrenomedullin by approximately 50%. Pretreatment of the vessels with the potassium channel inhibitor, tetraethylammonium or increased extracellular K(+), also decreased the maximal response to adrenomedullin by approximately 50%. The simultaneous administration of blockers of both endothelium-derived relaxing factors had a combined effect that almost suppressed adrenomedullin-induced vasodilation. The administration of indomethacin did not modify the renal response to adrenomedullin. Our results suggest that the vasodilator response to adrenomedullin in the isolated perfused kidney of rats is mediated by EDHF and NO to a similar extent. Our data also provide evidence that prostaglandins play no role in the vasodilator response to adrenomedullin in the renal vasculature.

Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity

PubMed Central

Kim, Youngmi; Kim, Eunhee; Wu, Qiulian; Guryanova, Olga; Hitomi, Masahiro; Lathia, Justin D.; Serwanski, David; Sloan, Andrew E.; Weil, Robert J.; Lee, Jeongwu; Nishiyama, Akiko; Bao, Shideng; Hjelmeland, Anita B.; Rich, Jeremy N.

2012-01-01

Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFRα alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFRβ (but not PDGFRα) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFRβ inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFRβ targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies. PMID:22661233

Changes in compressed neurons from dogs with acute and severe cauda equina constrictions following intrathecal injection of brain-derived neurotrophic factor-conjugated polymer nanoparticles☆

PubMed Central

Tan, Junming; Shi, Jiangang; Shi, Guodong; Liu, Yanling; Liu, Xiaohong; Wang, Chaoyang; Chen, Dechun; Xing, Shunming; Shen, Lianbing; Jia, Lianshun; Ye, Xiaojian; He, Hailong; Li, Jiashun

2013-01-01

This study established a dog model of acute multiple cauda equina constriction by experimental constriction injury (48 hours) of the lumbosacral central processes in dorsal root ganglia neurons. The repair effect of intrathecal injection of brain-derived neurotrophic factor with 15 mg encapsulated biodegradable poly(lactide-co-glycolide) nanoparticles on this injury was then analyzed. Dorsal root ganglion cells (L7) of all experimental dogs were analyzed using hematoxylin-eosin staining and immunohistochemistry at 1, 2 and 4 weeks following model induction. Intrathecal injection of brain-derived neurotrophic factor can relieve degeneration and inflammation, and elevate the expression of brain-derived neurotrophic factor in sensory neurons of compressed dorsal root ganglion. Simultaneously, intrathecal injection of brain-derived neurotrophic factor obviously improved neurological function in the dog model of acute multiple cauda equina constriction. Results verified that sustained intraspinal delivery of brain-derived neurotrophic factor encapsulated in biodegradable nanoparticles promoted the repair of histomorphology and function of neurons within the dorsal root ganglia in dogs with acute and severe cauda equina syndrome. PMID:25206593

Production of Human Monoclonal Rheumatoid Factor Secreting Hybridomas Derived from Rheumatoid Synovial Cells

DTIC Science & Technology

1989-01-01

lymphocytes obtained from patients with other We were then interested to see whether AD7 RF had types of arthritis who were seronegative were also...seropositive rheumatoid anhrius patients and from synowal cells in arthritis patients seroneganve for rheumatoidfactor. 1.0 Patients No. of hybridso 1gM RF...Production of human monoclonal rheumatoid factor secreting hybridomas derived from rheumatoid s’inovial cells 12. PEFTONAL AUTVOR(S) Robbins DL, Kenny

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

PubMed Central

Bertling, Anne; Brodde, Martin F.; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C.; Kelsch, Reinhard; Kehrel, Beate E.

2017-01-01

Background Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Methods Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Results Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Conclusion Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress. PMID:29070980

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4).

PubMed

Bertling, Anne; Brodde, Martin F; Visser, Mayken; Treffon, Janina; Fennen, Michelle; Fender, Anke C; Kelsch, Reinhard; Kehrel, Beate E

2017-09-01

Hemarthrosis, or bleeding into the joints, is a hallmark of hemophilia. Heme triggers oxidative stress, inflammation, and destruction of cartilage and bone. The haptoglobin-CD163-heme oxygenase-1 (HO-1) pathway circumvents heme toxicity through enzymatic degradation of heme and transcription of antioxidant genes. Plasma-derived factor concentrates contain many proteins that might impact on cellular pathways in joints, blood, and vessels. Activation of platelets from healthy volunteers was assessed by flow cytometry analysis of fibrinogen binding and CD62P expression. Platelet CXCL4 release was measured by ELISA. Human peripheral blood mononuclear cells were exposed to CXCL4 or platelet supernatants (untreated or pre-stimulated with factor VIII (FVIII) products) during their differentiation to macrophages and analyzed for CD163 expression. Some macrophage cultures were additionally incubated with autologous hemoglobin for 18 h for analysis of HO-1 expression. Platelet CXCL4 release was increased by all 8 tested plasma-derived FVIII products but not the 3 recombinant products. Macrophages exposed to supernatant from platelets treated with some plasma-derived FVIII products downregulated CD163 surface expression and failed to upregulate the athero- and joint protective enzyme HO-1 in response to hemoglobin. Plasma-derived FVIII products might promote bleeding-induced joint injury via generation of macrophages that are unable to counteract redox stress.

Brain-derived neurotrophic factor and Alzheimer's disease: physiopathology and beyond.

PubMed

Diniz, Breno Satler; Teixeira, Antonio Lucio

2011-12-01

Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF became a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have reported altered levels of BDNF in the circulation, i.e. serum or plasma, of patients with Alzheimer's disease (AD), and low BDNF levels in the CSF as predictor of future cognitive decline in healthy older subjects. Altered BDNF circulating levels have also been reported in other neurodegenerative and psychiatric disorders, hampering its use as a specific biomarker for AD. Therefore, BDNF seems to be an unspecific biomarker of neuropsychiatric disorders marked by neurodegenerative changes.

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) expression in colorectal cancer.

PubMed

Nagano, Hideki; Goi, Takanori; Koneri, Kenji; Hirono, Yasuo; Katayama, Kanji; Yamaguchi, Akio

2007-12-01

Vascular endothelial growth factor (VEGF) is known as an important factor in the growth and metastasis of cancer cells. In 2001, a novel angiogenesis factor, endocrine gland-derived vascular endothelial growth factor (EG-VEGF), was cloned. In this study, we investigated the expression of EG-VEGF in colorectal cancer, the relationship between its expression and clinicopathological factors, and the in vitro activity of EG-VEGF transfectants. We determined expression levels of EG-VEGF in 113 advanced colorectal cancers resected in our hospital by quantitative PCR, and compared the expression levels and clinicopathological findings by multivariate analyses. The expression of EG-VEGF mRNA was positive in 31 cancers and negative in 82 cancers. We found that compared with the negative expression of the EG-VEGF gene, its positive expression was more frequently associated with hematogenous metastasis, and was associated with a poorer survival rate. In addition, EG-VEGF transfectants showed a higher degree of in vitro tubular formation than control cells. We speculate that, in colorectal cancers, the EG-VEGF gene functions as an important factor in angiogenesis in primary and metastatic lesions, and consider that it is useful as a novel prognostic factor. EG-VEGF molecule-targeted therapy has the potential for improving survival rates.

The metastatic microenvironment: lung-derived factors control the viability of neuroblastoma lung metastasis.

PubMed

Maman, Shelly; Edry-Botzer, Liat; Sagi-Assif, Orit; Meshel, Tsipi; Yuan, Weirong; Lu, Wuyuan; Witz, Isaac P

2013-11-15

Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis, or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60-70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases. The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations-lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem-cell markers, morphology, and migratory capacity. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease. Copyright © 2013 UICC.

Role of platelet-derived growth factors in physiology and medicine

PubMed Central

Andrae, Johanna; Gallini, Radiosa; Betsholtz, Christer

2008-01-01

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have served as prototypes for growth factor and receptor tyrosine kinase function for more than 25 years. Studies of PDGFs and PDGFRs in animal development have revealed roles for PDGFR-α signaling in gastrulation and in the development of the cranial and cardiac neural crest, gonads, lung, intestine, skin, CNS, and skeleton. Similarly, roles for PDGFR-β signaling have been established in blood vessel formation and early hematopoiesis. PDGF signaling is implicated in a range of diseases. Autocrine activation of PDGF signaling pathways is involved in certain gliomas, sarcomas, and leukemias. Paracrine PDGF signaling is commonly observed in epithelial cancers, where it triggers stromal recruitment and may be involved in epithelial–mesenchymal transition, thereby affecting tumor growth, angiogenesis, invasion, and metastasis. PDGFs drive pathological mesenchymal responses in vascular disorders such as atherosclerosis, restenosis, pulmonary hypertension, and retinal diseases, as well as in fibrotic diseases, including pulmonary fibrosis, liver cirrhosis, scleroderma, glomerulosclerosis, and cardiac fibrosis. We review basic aspects of the PDGF ligands and receptors, their developmental and pathological functions, principles of their pharmacological inhibition, and results using PDGF pathway-inhibitory or stimulatory drugs in preclinical and clinical contexts. PMID:18483217

Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise.

PubMed

Borror, Andrew

2017-09-01

The mechanisms causing improved cognition following acute exercise are poorly understood. This article proposes that brain-derived neurotrophic factor (BDNF) is the main factor contributing to improved cognition following exercise. Additionally, it argues that cerebral blood flow (CBF) and oxidative stress explain the release of BDNF from cerebral endothelial cells. One way to test these hypotheses is to block endothelial function and measure the effect on BDNF levels and cognitive performance. The CBF and oxidative stress can also be examined in relationship to BDNF using a multiple linear regression. If these hypotheses are true, there would be a linear relationship between CBF+oxidative stress and BDNF levels as well as between BDNF levels and cognitive performance. The novelty of these hypotheses comes from the emphasis on the cerebral endothelium and the interplay between BDNF, CBF, and oxidative stress. If found to be valid, these hypotheses would draw attention to the cerebral endothelium and provide direction for future research regarding methods to optimize BDNF release and enhance cognition. Elucidating these mechanisms would provide direction for expediting recovery in clinical populations, such as stroke, and maintaining quality of life in the elderly. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells.

PubMed

Kemp, Kevin; Dey, Rimi; Cook, Amelia; Scolding, Neil; Wilkins, Alastair

2017-08-01

Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia.

Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages.

PubMed

Jin, Xueting; Kruth, Howard S

2016-06-30

A protocol is presented for cell culture of macrophage colony-stimulating factor (M-CSF) differentiated human monocyte-derived macrophages. For initiation of experiments, fresh or frozen monocytes are cultured in flasks for 1 week with M-CSF to induce their differentiation into macrophages. Then, the macrophages can be harvested and seeded into culture wells at required cell densities for carrying out experiments. The use of defined numbers of macrophages rather than defined numbers of monocytes to initiate macrophage cultures for experiments yields macrophage cultures in which the desired cell density can be more consistently attained. Use of cryopreserved monocytes reduces dependency on donor availability and produces more homogeneous macrophage cultures.

Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth factor and insulin-like growth factor-1.

PubMed

Mooney, R A; Freund, G G; Way, B A; Bordwell, K L

1992-11-25

Tyrosine phosphorylation is a mechanism of signal transduction shared by many growth factor receptors and oncogene products. Phosphotyrosine phosphatases (PTPases) potentially modulate or counter-regulate these signaling pathways. To test this hypothesis, the transmembrane PTPase CD45 (leukocyte common antigen) was expressed in the murine cell line C127. Hormone-dependent autophosphorylation of the platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) receptors was markedly reduced in cells expressing the transmembrane PTPase. Tyrosine phosphorylation of other PDGF-dependent phosphoproteins (160, 140, and 55 kDa) and IGF-1-dependent phosphoproteins (145 kDa) was similarly decreased. Interestingly, the pattern of growth factor-independent tyrosine phosphorylations was comparable in cells expressing the PTPase and control cells. This suggests a selectivity or accessibility of the PTPase limited to a subset of cellular phosphotyrosyl proteins. The maximum mitogenic response to PDGF and IGF-1 in cells expressing the PTPase was decreased by 67 and 71%, respectively. These results demonstrate that a transmembrane PTPase can both affect the tyrosine phosphorylation state of growth factor receptors and modulate proximal and distal cellular responses to the growth factors.

Angiogenesis is inhibitory for mammalian digit regeneration

PubMed Central

Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong

2014-01-01

Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862

More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder.

PubMed

Wang, Tzu-Yun; Lee, Sheng-Yu; Hu, Ming-Chuan; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Lin, Shih-Hsien; Li, Chia-Ling; Wang, Liang-Jen; Chen, Po See; Chen, Shih-Heng; Huang, San-Yuan; Tzeng, Nian-Sheng; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2017-11-01

Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p<0.001) main effect of diagnosis on inflammatory factors and BDNF expression in these groups. ASPD, SUDs, and ASPD+SUDs patients had significantly (p<0.001) higher TNF-α levels but lower TGF-β1 and BDNF levels. SUDs and ASPD+SUDs patients had higher IL-10 levels than did ASPD patients and HCs. There was no difference in IL-10 levels between HCs and ASPD. Moreover, subgrouping SUDs and ASPD±SUDs into opioid use disorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD±OUD groups than other SUDs (P≤0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration.

PubMed

Qian, Yun; Han, Qixin; Chen, Wei; Song, Jialin; Zhao, Xiaotian; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

2017-01-01

Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

A Bilayer Construct Controls Adipose-Derived Stem Cell Differentiation into Endothelial Cells and Pericytes without Growth Factor Stimulation

DTIC Science & Technology

2011-01-01

A Bilayer Construct Controls Adipose-Derived Stem Cell Differentiation into Endothelial Cells and Pericytes Without Growth Factor Stimulation...Ph.D.3 This work describes the differentiation of adipose-derived mesenchymal stem cells (ASC) in a composite hy- drogel for use as a vascularized...tissue from a single population of ASC. This work underscores the importance of the extracellular matrix in controlling stem cell phenotype. It is our

Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder☆

PubMed Central

Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

2013-01-01

The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression. PMID:25206732

Human buccal plate extraction socket regeneration with recombinant human platelet-derived growth factor BB or enamel matrix derivative.

PubMed

Nevins, Marc L; Camelo, Marcelo; Schupbach, Peter; Nevins, Myron; Kim, Soo-Woo; Kim, David M

2011-01-01

The objective of this study was to assess the osseous healing of buccal plate extraction socket defects. There were four cohorts: group A (mineral collagen bone substitute [MCBS] scaffold alone), group B (MCBS with recombinant human platelet-derived growth factor BB [rhPDGF-BB; 0.3 mg/mL]), group C (MCBS with enamel matrix derivative [EMD]), and group D (combination of EMD with bone ceramic). The primary outcome of bone quality was evaluated using light microscopy, backscatter scanning electron microscopy, and histomorphometrics. Reentry surgery provided an opportunity for clinical observation of the healed ridge morphology. Sixteen patients with buccal wall extraction socket defects were randomized into four treatment groups of equal size. Grafting was provided at the time of extraction with advancement of the buccal flap for primary closure. A trephine core biopsy of the implant site preparation was performed after 5 months for implant placement. Histologic examination identified new bone healing around the biomaterial scaffolds. Statistically significant differences in new bone formation were not observed among the treatment groups. There was a histomorphometric trend toward more new bone for the rhPDGF-BB-treated group (group B). This group had the most favorable ridge morphology for optimal implant placement.

An Empirically Derived Taxonomy of Factors Affecting Physicians' Willingness to Disclose Medical Errors

PubMed Central

Kaldjian, Lauris C; Jones, Elizabeth W; Rosenthal, Gary E; Tripp-Reimer, Toni; Hillis, Stephen L

2006-01-01

BACKGROUND Physician disclosure of medical errors to institutions, patients, and colleagues is important for patient safety, patient care, and professional education. However, the variables that may facilitate or impede disclosure are diverse and lack conceptual organization. OBJECTIVE To develop an empirically derived, comprehensive taxonomy of factors that affects voluntary disclosure of errors by physicians. DESIGN A mixed-methods study using qualitative data collection (structured literature search and exploratory focus groups), quantitative data transformation (sorting and hierarchical cluster analysis), and validation procedures (confirmatory focus groups and expert review). RESULTS Full-text review of 316 articles identified 91 impeding or facilitating factors affecting physicians' willingness to disclose errors. Exploratory focus groups identified an additional 27 factors. Sorting and hierarchical cluster analysis organized factors into 8 domains. Confirmatory focus groups and expert review relocated 6 factors, removed 2 factors, and modified 4 domain names. The final taxonomy contained 4 domains of facilitating factors (responsibility to patient, responsibility to self, responsibility to profession, responsibility to community), and 4 domains of impeding factors (attitudinal barriers, uncertainties, helplessness, fears and anxieties). CONCLUSIONS A taxonomy of facilitating and impeding factors provides a conceptual framework for a complex field of variables that affects physicians' willingness to disclose errors to institutions, patients, and colleagues. This taxonomy can be used to guide the design of studies to measure the impact of different factors on disclosure, to assist in the design of error-reporting systems, and to inform educational interventions to promote the disclosure of errors to patients. PMID:16918739

Fibroblast growth factor-2 stimulates adipogenic differentiation of human adipose-derived stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kakudo, Natsuko; Shimotsuma, Ayuko; Kusumoto, Kenji

2007-07-27

Adipose-derived stem cells (ASCs) have demonstrated a capacity for differentiating into a variety of lineages, including bone, cartilage, or fat, depending on the inducing stimuli and specific growth and factors. It is acknowledged that fibroblast growth factor-2 (FGF-2) promotes chondrogenic and inhibits osteogenic differentiation of ASCs, but thorough investigations of its effects on adipogenic differentiation are lacking. In this study, we demonstrate at the cellular and molecular levels the effect of FGF-2 on adipogenic differentiation of ASCs, as induced by an adipogenic hormonal cocktail consisting of 3-isobutyl-1-methylxanthine (IBMX), dexamethasone, insulin, and indomethacin. FGF-2 significantly enhances the adipogenic differentiation of humanmore » ASCs. Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor {gamma}2 (PPAR{gamma}2), a key transcription factor in adipogenesis, was upregulated. The results of FGF-2 supplementation suggest the potential applications of FGF-2 and ASCs in adipose tissue regeneration.« less

Thymocyte emigration is mediated by active movement away from stroma-derived factors

PubMed Central

Poznansky, Mark C.; Olszak, Ivona T.; Evans, Richard H.; Wang, Zhengyu; Foxall, Russell B.; Olson, Douglas P.; Weibrecht, Kathryn; Luster, Andrew D.; Scadden, David T.

2002-01-01

T cells leave the thymus at a specific time during differentiation and do not return despite elaboration of known T cell chemoattractants by thymic stroma. We observed differentiation stage–restricted egress of thymocytes from an artificial thymus in which vascular structures or hemodynamics could not have been playing a role. Hypothesizing that active movement of cells away from a thymic product may be responsible, we demonstrated selective reduction in emigration from primary thymus by inhibitors of active movement down a concentration gradient (chemofugetaxis). Immature intrathymic precursors were insensitive to an emigration signal, whereas mature thymocytes and peripheral blood T cells were sensitive. Thymic stroma was noted to elaborate at least two proteins capable of inducing emigration, one of which was stromal cell–derived factor-1. Thymic emigration is mediated, at least in part, by specific fugetaxis-inducing factors to which only mature cells respond. PMID:11956248

Mesenchymal Stem Cells Suppress Chronic Rejection in Heterotopic Small Intestine Transplant Rat Models Via Inhibition of CD68, Transforming Growth Factor- β1, and Platelet-Derived Growth Factor Expression.

PubMed

Li, Fuxin; Cao, Jisen; Zhao, Zhicheng; Li, Chuan; Qi, Feng; Liu, Tong

2017-04-01

Mesenchymal stem cells are easy to obtain and expand, with characteristics of low immunogenicity and strong tissue repair capacity. In this study, our aim was to investigate the role of mesenchymal stem cells in chronic immune rejection of heterotopic small intestine transplant in rats. After successfully constructing a rat chronic immune rejection model of heterotopic small intestine transplant, we infused mesenchymal stem cells into the animal recipients. We observed mesenchymal stem cell location in the recipients, recipient survival, pathology changes, and the expression of CD68, transforming growth factor β1, and platelet-derived growth factor C in the donor intestine. Mesenchymal stem cells inhibited the lymphocyte proliferation caused by concanavalin A in vitro. After stem cells were infused into recipients, they were mainly located in the donor intestine, as well as in the spleen and thymus. Recovery after transplant and pathology changes of the donor intestine in rats with stem cell infusion were better than in the control group; however, we observed no differences in survival time, accompanied by downregulated expression of CD68, transforming growth factor β1, and platelet-derived growth factor C. Mesenchymal stem cells, to a certain extent, could inhibit the process of chronic rejection. The mechanisms may include the inhibited function of these cells on lymphocyte proliferation, reduced infiltration of macrophages, and reduced expression of transforming growth factor β1 and platelet-derived growth factor C.

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

ERIC Educational Resources Information Center

Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

2013-01-01

Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

Emission factors for hydraulically fractured gas wells derived using well- and battery-level reported data for Alberta, Canada.

PubMed

Tyner, David R; Johnson, Matthew R

2014-12-16

A comprehensive technical analysis of available industry-reported well activity and production data for Alberta in 2011 has been used to derive flaring, venting, and diesel combustion greenhouse gas and criteria air contaminant emission factors specifically linked to drilling, completion, and operation of hydraulically fractured natural gas wells. Analysis revealed that in-line ("green") completions were used at approximately 53% of wells completed in 2011, and in other cases the majority (99.5%) of flowback gases were flared rather than vented. Comparisons with limited analogous data available in the literature revealed that reported total flared and vented natural gas volumes attributable to tight gas well-completions were ∼ 6 times larger than Canadian Association of Petroleum Producers (CAPP) estimates for natural gas well-completion based on wells ca. 2000, but 62% less than an equivalent emission factor that can be derived from U.S. EPA data. Newly derived emission factors for diesel combustion during well drilling and completion are thought to be among the first such data available in the open literature, where drilling-related emissions for tight gas wells drilled in Alberta in 2011 were found to have increased by a factor of 2.8 relative to a typical well drilled in Canada in 2000 due to increased drilling lengths. From well-by-well analysis of production phase flared, vented, and fuel usage natural gas volumes reported at 3846 operating tight gas wells in 2011, operational emission factors were developed. Overall results highlight the importance of operational phase GHG emissions at upstream well sites (including on-site natural gas fuel use), and the critical levels of uncertainty in current estimates of liquid unloading emissions.

Preferential Redistribution of Fine-Grained Particles in the Panama Basin and Potential Errors in 230Th-Derived Focusing Factors

NASA Astrophysics Data System (ADS)

Marcantonio, F.; Lyle, M. W.; Ibrahim, R.

2013-12-01

of the paired sites, with the higher MARs always at the potentially winnowed sites. The 'thick' Carnegie Ridge site has a 230Th-derived focusing factor of about 6. However, we believe that, given our observations of the radiocarbon-derived fluxes of sand, the high 230Th-derived focusing factor is likely an overestimate of the degree of focusing, and the average 230Th-derived MAR is likely an underestimate of the true MAR. Similarly, the biasing for the 'thin' Cocos site that has a 230Th-derived focusing factor of 0.2 (i.e., potential winnowing) is expected to be the opposite, namely, 230Th-derived fluxes are likely being overestimated there. The quantitative extent to which 230Th-derived focusing factors have been over- and under-estimated in the Panama Basin will be discussed. We hypothesize that size fractionation, as well as 230Th focusing errors, occur most frequently at lower current velocities where the fine and coarse fraction of the sediment components are more effectively sorted from each other.

Corallocins A-C, Nerve Growth and Brain-Derived Neurotrophic Factor Inducing Metabolites from the Mushroom Hericium coralloides.

PubMed

Wittstein, Kathrin; Rascher, Monique; Rupcic, Zeljka; Löwen, Eduard; Winter, Barbara; Köster, Reinhard W; Stadler, Marc

2016-09-23

Three new natural products, corallocins A-C (1-3), along with two known compounds were isolated from the mushroom Hericium coralloides. Their benzofuranone and isoindolinone structures were elucidated by spectral methods. All corallocins induced nerve growth factor and/or brain-derived neurotrophic factor expression in human 1321N1 astrocytes. Furthermore, corallocin B showed antiproliferative activity against HUVEC and human cancer cell lines MCF-7 and KB-3-1.

Platelet-derived growth factor-C and -D in the cardiovascular system and diseases.

PubMed

Lee, Chunsik; Li, Xuri

2018-08-01

The cardiovascular system is among the first organs formed during development and is pivotal for the formation and function of the rest of the organs and tissues. Therefore, the function and homeostasis of the cardiovascular system are finely regulated by many important molecules. Extensive studies have shown that platelet-derived growth factors (PDGFs) and their receptors are critical regulators of the cardiovascular system. Even though PDGF-C and PDGF-D are relatively new members of the PDGF family, their critical roles in the cardiovascular system as angiogenic and survival factors have been amply demonstrated. Understanding the functions of PDGF-C and PDGF-D and the signaling pathways involved may provide novel insights into both basic biomedical research and new therapeutic possibilities for the treatment of cardiovascular diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Are genetic variants in the platelet-derived growth factor [beta] gene associated with chronic pancreatitis?

PubMed

Muddana, Venkata; Park, James; Lamb, Janette; Yadav, Dhiraj; Papachristou, Georgios I; Hawes, Robert H; Brand, Randall; Slivka, Adam; Whitcomb, David C

2010-11-01

Platelet-derived growth factor [beta] (PDGF-[beta]) is a major signal in proliferation and matrix synthesis through activated pancreatic stellate cells, leading to fibrosis of the pancreas. Recurrent acute pancreatitis (RAP) seems to predispose to chronic pancreatitis (CP) in some patients but not others. We tested the hypothesis that 2 known PDGF-[beta] polymorphisms are associated with progression from RAP to CP. We also tested the hypothesis that PDGF-[beta] polymorphisms in combination with environmental risk factors such as alcohol and smoking are associated with CP. Three hundred eighty-two patients with CP (n = 176) and RAP (n = 206) and 251 controls were evaluated. Platelet-derived growth factor [beta] polymorphisms +286 A/G (rs#1800818) seen in 5'-UTR and +1135 A/C (rs#1800817) in first intron were genotyped using single-nucleotide polymorphism polymerase chain reaction approach and confirmed by DNA sequencing. The genotypic frequencies for PDGF-[beta] polymorphisms in positions +286 and +1135 were found to be similar in controls and patients with RAP and CP. There was no difference in genotypic frequencies among RAP, CP, and controls in subjects in the alcohol and smoking subgroups. Known variations in the PDGF-[beta] gene do not have a significant effect on promoting or preventing fibrogenesis in pancreatitis. Further evaluation of this important pathway is warranted.

Lens Epithelium-derived Growth Factor/p75 Interacts with the Transposase-derived DDE Domain of PogZ*S⃞

PubMed Central

Bartholomeeusen, Koen; Christ, Frauke; Hendrix, Jelle; Rain, Jean-Christophe; Emiliani, Stéphane; Benarous, Richard; Debyser, Zeger; Gijsbers, Rik; De Rijck, Jan

2009-01-01

Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a prominent cellular interaction partner of human immunodeficiency virus-1 (HIV-1) integrase, tethering the preintegration complex to the host chromosome. In light of the development of LEDGF/p75-integrase interaction inhibitors, it is essential to understand the cell biology of LEDGF/p75. We identified pogZ as new cellular interaction partner of LEDGF/p75. Analogous to lentiviral integrase, pogZ, a domesticated transposase, carries a DDE domain, the major determinant for LEDGF/p75 interaction. Using different in vitro and in vivo approaches, we corroborated the interaction between the C terminus of LEDGF/p75 and the DDE domain of pogZ, revealing an overlap in the binding of pogZ and HIV-1 integrase. Competition experiments showed that integrase is efficient in displacing pogZ from LEDGF/p75. Moreover, pogZ does not seem to play a role as a restriction factor of HIV. The finding that LEDGF/p75 is capable of interacting with a DDE domain protein that is not a lentiviral integrase points to a profound role of LEDGF/p75 in DDE domain protein function. PMID:19244240

Mechanisms of regulation of cell-mediated immunity. III. The characterization of azobenzenearsonate-specific suppressor T-cell- derived-suppressor factors

PubMed Central

1979-01-01

Delayed type hypersensitivity to the hapten azobenzenearsonate (ABA) can be induced and suppressed by the administration of hapten-coupled syngeneic spleen cells by the appropriate route. Suppressor T cells stimulated by the intravenous administration of ABA-coupled spleen cells have been shown to produce a discrete subcellular factor(s) which is capable of suppressing delayed type hypersensitivity to azobenzenearsonate in the mouse. Such suppressor factors may be produced by the mechanical disruption of suppressor cells or by placing such suppressor cells in culture for 24 h. The suppressor factor(s) (SF) derived from ABA-specific suppressor cells exhibit biological specificity for the suppression of ABA delayed type hypersensitivity (DTH), but not trinitro-phenyl DTH, as well as the capacity to bind to ABA immunoadsorbents. Passage of suppressor factor(s) over reverse immunoadsorbents utilizing a rabbit anti-mouse F(ab')2 antiserum demonstrated that the antigen-specific T-cell derived SF does not bear conventional immunoglobulin markers. The suppressor factor(s) are not immunoglobulin molecules was further demonstrated by the inability of anti-ABA antibodies to suppress ABA DTH. Gel filtration of ABA suppressor factor(s) showed that the majority of the suppressive activity was present in a fraction with molecular weight ranging between 6.8 x 10(4) and 3.3 x 10(4) daltons. We also analyzed for the presence of determinants encoded by the H-2 major histocompatibility complex (MHC) and found that immunoadsorbents prepared utilizing antisera capable of interacting with gene products of the whole or selected gene regions of H-2 MHC, i.e., B10.D2 anti-B10.A and B10 anti- B10.A immunoadsorbents, retained the suppressive activity of ABA-SF. Elution of such columns with glycine HCl buffers (pH 2.8) permitted recovery of specific suppressive activity. Taken collectively such data supports the notion that suppressor T-cell-derived ABA suppressor factors have antigen

Differential protein expression in Tree Shrew sclera during development of lens-induced myopia and recovery

PubMed Central

Norton, Thomas T.

2007-01-01

Purpose The tree shrew model of refractive development is particularly useful because, like humans, tree shrews have a fibrous sclera. Selective changes in some candidate extracellular matrix proteins and mRNAs have been found in the sclera during the development of, and recovery from, induced myopia. We undertook a more neutral proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry to identify scleral proteins that are differentially expressed during the development of, and recovery from, lens-induced myopia. Methods Five tree shrews (Tupaia glis belangeri) wore a monocular –5 D lens for 4 days, starting 24 days after natural eye opening. At the end of this time, all treated eyes had partially compensated for the lens and were –3.5±0.7 D (mean ± SEM) myopic relative to the untreated fellow control eyes. An additional five animals wore a –5 D lens for 11–13 days, followed by 4 days of recovery without the –5 D lens. The amount of recovery was 1.6±0.4 D. Scleral proteins from both groups were then isolated and resolved by two-dimensional gel electrophoresis and spots that were differentially expressed were identified by mass spectrometry. Results The scleral protein profile typically displayed ~700 distinct protein spots within the pH 5–8 range. Comparison of the treated-eye and control-eye scleras of the lens-compensation animals revealed five spots that were significantly differentially expressed in all five pairs of eyes; all were downregulated 1.2 to 1.7 fold in the treated eye. These proteins were identified as: pigment epithelium-derived factor (PEDF), procollagen I α1, procollagen I α2, and thrombospondin I (two spots). In the recovering eyes, the two thrombospondin I spots remained lower in abundance while PEDF and the procollagens were no longer downregulated. In addition, 78 kDa glucose-regulated protein (GRP 78), a member of the heat shock protein 70 family, was slightly upregulated 1.3 fold. Conclusions

Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation

PubMed Central

Stead, Rebecca; Musa, Moji G.; Bryant, Claire L.; Lanham, Stuart A.; Johnston, David A.; Reynolds, Richard; Torrens, Christopher; Fraser, Paul A.; Clough, Geraldine F.

2016-01-01

Objectives: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Methods: Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18–32 μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. Results: EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels. Conclusion: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a ‘second hit’ (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function. PMID:26682783

Developmental conditioning of endothelium-derived hyperpolarizing factor-mediated vasorelaxation.

PubMed

Stead, Rebecca; Musa, Moji G; Bryant, Claire L; Lanham, Stuart A; Johnston, David A; Reynolds, Richard; Torrens, Christopher; Fraser, Paul A; Clough, Geraldine F

2016-03-01

The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH : EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Developmentally conditioned changes in EDH : EDRF signalling pathways were investigated in cremaster arterioles (18-32  μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. EDH via intermediate (IKCa) and small (SKca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P < 0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P < 0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH : EDRF were associated with altered endothelial cell expression and localization of IKCa channels. This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IKCa signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function.

Regulation of Transforming Growth Factor β1, Platelet-Derived Growth Factor, and Basic Fibroblast Growth Factor by Silicone Gel Sheeting in Early-Stage Scarring.

PubMed

Choi, Jaehoon; Lee, Eun Hee; Park, Sang Woo; Chang, Hak

2015-01-01

Hypertrophic scars and keloids are associated with abnormal levels of growth factors. Silicone gel sheets are effective in treating and preventing hypertrophic scars and keloids. There has been no report on the change in growth factors in the scar tissue following the use of silicone gel sheeting for scar prevention. A prospective controlled trial was performed to evaluate whether growth factors are altered by the application of a silicone gel sheet on a fresh surgical scar. Four of seven enrolled patients completed the study. Transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were investigated immunohistochemically in biopsies taken from five scars at 4 months following surgery. In both the epidermis and the dermis, the expression of TGF-β1 (P=0.042 and P=0.042) and PDGF (P=0.043 and P=0.042) was significantly lower in the case of silicone gel sheet-treated scars than in the case of untreated scars. The expression of bFGF in the dermis was significantly higher in the case of silicone gel sheet-treated scars than in the case of untreated scars (P=0.042), but in the epidermis, the expression of bFGF showed no significant difference between the groups (P=0.655). The levels of TGF-β1, PDGF, and bFGF are altered by the silicone gel sheet treatment, which might be one of the mechanisms of action in scar prevention.

Zinc Interactions With Brain-Derived Neurotrophic Factor and Related Peptide Fragments.

PubMed

Travaglia, A; La Mendola, D

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal development and survival, synaptic plasticity, and cognitive function. Dysregulation of BDNF signaling is involved in several neurodegenerative disorders, including Alzheimer's disease. Alteration of metal ion homeostasis is observed both in normal aging and in many neurodegenerative diseases. Interestingly, there is a significant overlap between brain areas characterized by metal ion dyshomeostasis and those where BDNF exerts its biological activity. Therefore, it is reasonable to speculate that metal ions, especially zinc, can modulate the activity of BDNF. The synthesis of BDNF peptidomimetic can be helpful both to understand the molecular interaction of BDNF with metal ions and to develop new drugs for neurodegenerative diseases. © 2017 Elsevier Inc. All rights reserved.

Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

PubMed Central

Mariga, Abigail; Mitre, Mariela; Chao, Moses V.

2017-01-01

Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease. PMID:27015693

Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor.

PubMed

Nishimura, R; Li, W; Kashishian, A; Mondino, A; Zhou, M; Cooper, J; Schlessinger, J

1993-11-01

Autophosphorylation sites of growth factor receptors with tyrosine kinase activity function as specific binding sites for Src homology 2 (SH2) domains of signaling molecules. This interaction appears to be a crucial step in a mechanism by which receptor tyrosine kinases relay signals to downstream signaling pathways. Nck is a widely expressed protein consisting exclusively of SH2 and SH3 domains, the overexpression of which causes cell transformation. It has been shown that various growth factors stimulate the phosphorylation of Nck and its association with autophosphorylated growth factor receptors. A panel of platelet-derived growth factor (PDGF) receptor mutations at tyrosine residues has been used to identify the Nck binding site. Here we show that mutation at Tyr-751 of the PDGF beta-receptor eliminates Nck binding both in vitro and in living cells. Moreover, the Y751F PDGF receptor mutant failed to mediate PDGF-stimulated phosphorylation of Nck in intact cells. A phosphorylated Tyr-751 is also required for binding of phosphatidylinositol-3 kinase to the PDGF receptor. Hence, the SH2 domains of p85 and Nck share a binding site in the PDGF receptor. Competition experiments with different phosphopeptides derived from the PDGF receptor suggest that binding of Nck and p85 is influenced by different residues around Tyr-751. Thus, a single tyrosine autophosphorylation site is able to link the PDGF receptor to two distinct SH2 domain-containing signaling molecules.

Urinary brain-derived neurotrophic factor as a biomarker of executive functioning.

PubMed

Koven, Nancy S; Collins, Larisa R

2014-01-01

Neurotrophins such as brain-derived neurotrophic factor (BDNF) are vital for neuronal survival and adaptive plasticity. With high BDNF gene expression in the prefrontal cortex, BDNF is a potential regulatory factor for building and maintaining cognitive reserves. Recent studies suggest that individual differences in executive functioning, a broad cognitive domain reliant upon frontal lobe structure and function, are governed in part by variance in BDNF polymorphisms. However, as neurogenetic data are not necessarily indicative of in vivo neurochemistry, this study examines the relationship between executive functioning and the neurotransmitter by measuring peripheral BDNF levels. Fifty-two healthy young adults completed a battery of standardized executive function tests. BDNF levels, adjusted for creatinine, were quantified with enzyme-linked immunosorbent assay of urine samples taken at the time of testing. BDNF concentration was positively associated with cognitive flexibility but had no relationship with working memory, abstract reasoning/planning, self-monitoring/response inhibition, or fluency. These results individuate cognitive flexibility as the specific facet of executive functioning associated with in vivo BDNF levels. This study also validates urinary BDNF as a peripheral biomarker of cognition in healthy adults. © 2014 S. Karger AG, Basel.

[Risk factors associated with bacterial growth in derivative systems from cerebrospinal liquid in pediatric patients].

PubMed

de Jesús Vargas-Lares, José; Andrade-Aguilera, Angélica Rocío; Díaz-Peña, Rafael; Barrera de León, Juan Carlos

2015-01-01

To determine risk factors associated with bacterial growth in systems derived from cerebrospinal fluid in pediatric patients. Case and controls study from January to December 2012, in patients aged <16 years who were carriers of hydrocephalus and who required placement or replacement of derivative system. Cases were considered as children with cultures with bacterial growth and controls with negative bacterial growth. Inferential statistics with Chi-squared and Mann-Whitney U tests. Association of risk with odds ratio. We reviewed 746 registries, cases n=99 (13%) and controls n=647 (87%). Masculine gender 58 (57%) vs. feminine gender 297 (46%) (p=0.530). Age of cases: median, five months and controls, one year (p=0.02). Median weight, 7 vs. 10 kg (p=0.634). Surgical interventions: median n=2 (range, 1-8) vs. n=1 (range, 1-7). Infection rate, 13.2%. Main etiology ductal stenosis, n=29 (29%) vs. n=50 (23%) (p=0.530). Non-communicating, n=50 (51%) vs. 396 (61%) (p=0.456). Predominant microorganisms: enterobacteria, pseudomonas, and enterococcus. Non-use of iodized dressing OR=2.6 (range, 1.8-4.3), use of connector OR=6.8 (range, 1.9-24.0), System replacement OR=2.0 (range, 1.3-3.1), assistant without surgical facemask OR=9.7 (range, 2.3-42.0). Being a breastfeeding infant, of low weight, non-application of iodized dressing, use of connector, previous derivation, and lack of adherence to aseptic technique were all factors associated with ependymitis.

Recruitment of bone marrow-derived cells to the periodontal ligament via the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis.

PubMed

Kaku, M; Kitami, M; Rosales Rocabado, J M; Ida, T; Akiba, Y; Uoshima, K

2017-08-01

The periodontal ligament (PDL) is a non-mineralized connective tissue that exists between the alveolar bone and root surface cementum and plays important roles in tooth function. The PDL harbors a remarkable reserve of multipotent stem cells, which maintain various types of cells. However, the sources of these stem cells, other than their developmental origin, are not well understood. To elucidate the recruitment of bone marrow (BM)-derived stem cells in the PDL, green fluorescent protein (GFP)-expressing BM-derived cells were transplanted into the femoral BM of immunodeficient rats, and the distribution and expression of stem cell markers in the PDL were analyzed in vivo. To evaluate the functional significance of BM-derived cells to the PDL, tooth replantation was performed and the expression of stromal cell-derived factor (SDF)-1, a critical chemotactic signal for mesenchymal stem cell recruitment, was analyzed. To confirm the SDF-1-dependency of BM-derived cell migration to the PDL, PDL-conditioned medium (CM) was prepared, and BM-derived cell migration was analyzed using a transwell culture system. Four weeks after cell transplantation, GFP-positive cells were detected in the PDL, and some of them were also positive for stem cell markers (i.e., CD29, SSEA4, and αSMA). Seven days after tooth replantation, the number of GFP- and SDF-1-positive cells significantly increased in PDL. Concurrently, the concentration of SDF-1 and the number of colony-forming units of fibroblasts in peripheral blood were increased. BM-derived cell migration increased in PDL-CM and was inhibited by an inhibitor of C-X-C chemokine receptor type 4 (CXCR4), an SDF-1 receptor. These results indicate that stem cells and their progeny in PDL are not only derived from their developmental origin but are also supplied from the BM via the blood as the need arises. Moreover, this BM-derived cell recruitment appears to be regulated, at least partially, by the SDF-1/CXCR4 axis. © 2017 John Wiley

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.

PubMed

Ishii, Makoto; Iadecola, Costantino

2016-05-01

Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.

Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloidmore » fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.« less

Release kinetics of platelet-derived and plasma-derived growth factors from autologous plasma rich in growth factors.

PubMed

Anitua, Eduardo; Zalduendo, Mari Mar; Alkhraisat, Mohammad Hamdan; Orive, Gorka

2013-10-01

Many studies have evaluated the biological effects of platelet rich plasma reporting the final outcomes on cell and tissues. However, few studies have dealt with the kinetics of growth factor delivery by plasma rich in growth factors. Venous blood was obtained from three healthy volunteers and processed with PRGF-Endoret technology to prepare autologous plasma rich in growth factors. The gel-like fibrin scaffolds were then incubated in triplicate, in a cell culture medium to monitor the release of PDGF-AB, VEGF, HGF and IGF-I during 8 days of incubation. A leukocyte-platelet rich plasma was prepared employing the same technology and the concentrations of growth factors and interleukin-1β were determined after 24h of incubation. After each period, the medium was collected, fibrin clot was destroyed and the supernatants were stored at -80°C until analysis. The growth factor delivery is diffusion controlled with a rapid initial release by 30% of the bioactive content after 1h of incubation and a steady state release when almost 70% of the growth factor content has been delivered. Autologous fibrin matrix retained almost 30% of the amount of the growth factors after 8 days of incubation. The addition of leukocytes to the formula of platelet rich plasma did not increase the concentration of the growth factors, while it drastically increased the presence of pro-inflammatory IL-1β. Further studies employing an in vitro inflammatory model would be interesting to study the difference in growth factors and pro-inflammatory cytokines between leukocyte-free and leukocyte-rich platelet rich plasma. Copyright © 2013 Elsevier GmbH. All rights reserved.

Brain-Derived Neurotrophic Factor Gene Expression in Pediatric Bipolar Disorder: Effects of Treatment and Clinical Response

ERIC Educational Resources Information Center

Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Dwivedi, Yogesh; Pavuluri, Mani N.

2008-01-01

The study determines the gene expression of brain-derived neurotrophic factor (BDNF) in the lymphocytes of subjects with pediatric bipolar disorder (PBD) before and during treatment with mood stabilizers and in drug-free normal control subjects. Results indicate the potential of BDNF levels as a biomarker for PBD and as a treatment predictor and…

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that

Decreased Plasma Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Concentrations during Military Training

PubMed Central

Nibuya, Masashi; Ishida, Toru; Yamamoto, Tetsuo; Mukai, Yasuo; Mitani, Keiji; Tsumatori, Gentaro; Scott, Daniel; Shimizu, Kunio

2014-01-01

Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep. PMID:24586790

Brain-derived neurotrophic factor secreted by the cerebral endothelium: A new actor of brain function?

PubMed

Marie, Christine; Pedard, Martin; Quirié, Aurore; Tessier, Anne; Garnier, Philippe; Totoson, Perle; Demougeot, Céline

2018-06-01

Low cerebral levels of brain-derived neurotrophic factor (BDNF), which plays a critical role in many brain functions, have been implicated in neurodegenerative, neurological and psychiatric diseases. Thus, increasing BDNF levels in the brain is considered an attractive possibility for the prevention/treatment of various brain diseases. To date, BDNF-based therapies have largely focused on neurons. However, given the cross-talk between endothelial cells and neurons and recent evidence that BDNF expressed by the cerebral endothelium largely accounts for BDNF levels present in the brain, it is likely that BDNF-based therapies would be most effective if they also targeted the cerebral endothelium. In this review, we summarize the available knowledge about the biology and actions of BDNF derived from endothelial cells of the cerebral microvasculature and we emphasize the remaining gaps and shortcomings.

Inhibition of the mitogenic response to platelet-derived growth factor by terbinafine

DOE Office of Scientific and Technical Information (OSTI.GOV)

St. Denny, I.H.; Glinka, K.G.; Nemecek, G.M.

1987-05-01

Terbinafine (T;(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine), an antimycotic which inhibits fungal squalene epoxidase activity, was examined for its effects on platelet-derived growth factor (PDGF)-stimulated mitogenesis. The inclusion of 1.5-5{mu}M T in fibroblast incubation media was associated with increased ({sup 3}H)thymidine incorporation into DNA in the presence and absence of PDGF. However, T at concentrations above 6{mu}M reduced DNA synthesis in control and PDGF-exposed cultures to nearly undetectable levels. Under a phase-contrast microscope, fibroblasts appeared morphologically normal at T concentrations as high as 25 {mu}M. Neither the uptake of ({sup 3}H)thymidine nor the specific binding of {sup 125}I-PDGF to fibroblast receptors was significantly affected bymore » 10 {mu}M T. Furthermore, concentrations of T which antagonized the mitogenic response to PDGF also interfered with fibroblast growth factor-induced mitogenesis. Together, these data suggest that T has the ability to inhibit the in vitro action of PDGF via a post-receptor mechanism.« less

Student learning of upper-level thermal and statistical physics: The derivation and use of the Boltzmann factor

NASA Astrophysics Data System (ADS)

Thompson, John

2015-04-01

As the Physical Review Focused Collection demonstrates, recent frontiers in physics education research include systematic investigations at the upper division. As part of a collaborative project, we have examined student understanding of several topics in upper-division thermal and statistical physics. A fruitful context for research is the Boltzmann factor in statistical mechanics: the standard derivation involves several physically justified mathematical steps as well as the invocation of a Taylor series expansion. We have investigated student understanding of the physical significance of the Boltzmann factor as well as its utility in various circumstances, and identified various lines of student reasoning related to the use of the Boltzmann factor. Results from written data as well as teaching interviews suggest that many students do not use the Boltzmann factor when answering questions related to probability in applicable physical situations, even after lecture instruction. We designed an inquiry-based tutorial activity to guide students through a derivation of the Boltzmann factor and to encourage deep connections between the physical quantities involved and the mathematics. Observations of students working through the tutorial suggest that many students at this level can recognize and interpret Taylor series expansions, but they often lack fluency in creating and using Taylor series appropriately, despite previous exposure in both calculus and physics courses. Our findings also suggest that tutorial participation not only increases the prevalence of relevant invocation of the Boltzmann factor, but also helps students gain an appreciation of the physical implications and meaning of the mathematical formalism behind the formula. Supported in part by NSF Grants DUE-0817282, DUE-0837214, and DUE-1323426.

Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

EPA Science Inventory

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

KRAS Mutation and Epithelial-Macrophage Interplay in Pancreatic Neoplastic Transformation.

PubMed

Bishehsari, Faraz; Zhang, Lijuan; Barlass, Usman; Preite, Nailliw; Turturro, Sanja; Najor, Matthew S; Shetuni, Brandon B; Zayas, Janet P; Mahdavinia, Mahboobeh; Abukhdeir, Abde M; Keshavarzian, Ali

2018-05-14

Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased i) ductal to acinar gene expression ratios, ii) epithelial cells proliferation, and iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a pro-tumorigenic phenotype in macrophages. Altered macrophages decreased epithelial Pigment Epithelial Derived Factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) as well as in our human PDA specimens. Epithelium-macrophage cross talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a pro-tumorigenic phenotype in macrophages, in turn augmenting neoplastic growth. This article is protected by copyright. All rights reserved. © 2018 UICC.

Transforming growth factor β-activated kinase 1 negatively regulates interleukin-1α-induced stromal-derived factor-1 expression in vascular smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Bin; Li, Wei; Zheng, Qichang

Stromal-derived Factor-1 (SDF-1) derived from vascular smooth muscle cells (VSMCs) contributes to vascular repair and remodeling in various vascular diseases. In this study, the mechanism underlying regulation of SDF-1 expression by interleukin-1α (IL-1α) was investigated in primary rat VSMCs. We found IL-1α promotes SDF-1 expression by up-regulating CCAAT-enhancer-binding protein β (C/EBPβ) in an IκB kinase β (IKKβ) signaling-dependent manner. Moreover, IL-1α-induced expression of C/EBPβ and SDF-1 was significantly potentiated by knockdown of transforming growth factor β-activated kinase 1 (TAK1), an upstream activator of IKKβ signaling. In addition, we also demonstrated that TAK1/p38 mitogen-activated protein kinase (p38 MAPK) signaling exerted negativemore » effect on IL-1α-induced expression of C/EBPβ and SDF-1 through counteracting ROS-dependent up-regulation of nuclear factor erythroid 2-related factor 2 (NRF2). In conclusion, TAK1 acts as an important regulator of IL-1α-induced SDF-1 expression in VSMCs, and modulating activity of TAK1 may serve as a potential strategy for modulating vascular repair and remodeling. - Highlights: • IL-1α induces IKKβ signaling-dependent SDF-1 expression by up-regulating C/EBPβ. • Activation of TAK1 by IL-1α negatively regulates C/EBPβ-dependent SDF-1 expression. • IL-1α-induced TAK1/p38 MAPK signaling counteracts ROS-dependent SDF-1 expression. • TAK1 counteracts IL-1α-induced SDF-1 expression by attenuating NRF2 up-regulation.« less

Neural progenitor cell implants modulate vascular endothelial growth factor and brain-derived neurotrophic factor expression in rat axotomized neurons.

PubMed

Talaverón, Rocío; Matarredona, Esperanza R; de la Cruz, Rosa R; Pastor, Angel M

2013-01-01

Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might

l-Serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons

PubMed Central

Furuya, Shigeki; Tabata, Toshihide; Mitoma, Junya; Yamada, Keiko; Yamasaki, Miwako; Makino, Asami; Yamamoto, Toshifumi; Watanabe, Masahiko; Kano, Masanobu; Hirabayashi, Yoshio

2000-01-01

Glial cells support the survival and development of central neurons through the supply of trophic factors. Here we demonstrate that l-serine (l-Ser) and glycine (Gly) also are glia-derived trophic factors. These amino acids are released by astroglial cells and promote the survival, dendritogenesis, and electrophysiological development of cultured cerebellar Purkinje neurons. Although l-Ser and Gly are generally classified as nonessential amino acids, 3-phosphoglycerate dehydrogenase (3PGDH), a key enzyme for their biosynthesis, is not expressed in Purkinje neurons. By contrast, the Bergman glia, a native astroglia in the cerebellar cortex, highly expresses 3PGDH. These data suggest that l-Ser and Gly mediate the trophic actions of glial cells on Purkinje neurons. PMID:11016963

History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair.

PubMed

Walker, Melissa J; Xu, Xiao-Ming

2018-06-13

Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with other factors and cell transplantations, for repairing the injured spinal cord. As studies of recent decades strongly suggest that combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

Stability-Derivative Determination from Flight Data

NASA Technical Reports Server (NTRS)

Holowicz, Chester H.; Holleman, Euclid C.

1958-01-01

A comprehensive discussion of the various factors affecting the determination of stability and control derivatives from flight data is presented based on the experience of the NASA High-Speed Flight Station. Factors relating to test techniques, determination of mass characteristics, instrumentation, and methods of analysis are discussed. For most longitudinal-stability-derivative analyses simple equations utilizing period and damping have been found to be as satisfactory as more comprehensive methods. The graphical time-vector method has been the basis of lateral-derivative analysis, although simple approximate methods can be useful If applied with caution. Control effectiveness has been generally obtained by relating the peak acceleration to the rapid control input, and consideration must be given to aerodynamic contributions if reasonable accuracy is to be realized.. Because of the many factors involved In the determination of stability derivatives, It is believed that the primary stability and control derivatives are probably accurate to within 10 to 25 percent, depending upon the specific derivative. Static-stability derivatives at low angle of attack show the greatest accuracy.

Brain-Derived Neurotrophic Factor Deficiency Restricts Proliferation of Oligodendrocyte Progenitors Following Cuprizone-Induced Demyelination

PubMed Central

Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa; Song, Yeri; VonDran, Melissa W; DiCicco-Bloom, Emanuel

2015-01-01

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligodendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNF+/− mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNF+/+ and BDNF+/− mice were fed cuprizone-containing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRα)+ or NG2+ cells were counted. To monitor DNA synthesis, 5-ethynyl-2′-deoxyuridine (EdU) was injected intraperitoneally and colocalized with PDGFRα+ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRα or NG2. Labeling indices were determined in the BDNF+/+ and BDNF+/− animals. After 4 or 5 weeks of control feed, BDNF+/− mice exhibit similar numbers of OPCs compared with BDNF+/+ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNF+/+ mice were reduced in the BDNF+/− mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion. PMID:25586993

Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish.

PubMed

Cacialli, Pietro; Palladino, Antonio; Lucini, Carla

2018-06-01

Several mammalian animal models of traumatic brain injury have been used, mostly rodents. However, reparative mechanisms in mammalian brain are very limited, and newly formed neurons do not survive for long time. The brain of adult zebrafish, a teleost fish widely used as vertebrate model, possesses high regenerative properties after injury due to the presence of numerous stem cells niches. The ventricular lining of the zebrafish dorsal telencephalon is the most studied neuronal stem cell niche because its dorso-lateral zone is considered the equivalent to the hippocampus of mammals which contains one of the two constitutive neurogenic niches of mammals. To mimic TBI, stab wound in the dorso-lateral telencephalon of zebrafish was used in studies devoted to fish regenerative properties. Brain-derived neurotrophic factor, which is known to play key roles in the repair process after traumatic brain lesions, persists around the lesioned area of injured telencephalon of adult zebrafish. These results are extensively compared to reparative processes in rodent brain. Considering the complete repair of the damaged area in fish, it could be tempting to consider brain-derived neurotrophic factor as a factor contributing to create a permissive environment that enables the establishment of new neuronal population in damaged brain.

Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression

PubMed Central

Zhang, Jia-min; Feng, Fei-er; Wang, Qian-ming; Zhu, Xiao-lu; Fu, Hai-xia; Xu, Lan-ping; Liu, Kai-yan

2016-01-01

Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Mesenchymal stem cells (MSCs) from ITP patients (MSC-ITP) do not exhibit conventional proliferative abilities and thus exhibit defects in immunoregulation, suggesting that MSC impairment might be a mechanism involved in ITP. Platelet-derived growth factor (PDGF) improves growth and survival in various cell types. Moreover, PDGF promotes MSC proliferation. The aim of the present study was to analyze the effects of PDGF-BB on MSC-ITP. We showed that MSC-ITP expanded more slowly and appeared flattened and larger. MSC-ITP exhibited increased apoptosis and senescence compared with controls. Both the intrinsic and extrinsic pathways account for the enhanced apoptosis. P53 and p21 expression were upregulated in MSC-ITP, but inhibition of p53 with pifithrin-α markedly inhibited apoptosis and senescence. Furthermore, MSCs from ITP patients showed a lower capacity for inhibiting the proliferation of activated T cells inducing regulatory T cells (Tregs) and suppressing the synthesis of anti-glycoprotein (GP)IIb-IIIa antibodies. PDGF-BB treatment significantly decreased the expression of p53 and p21 and increased survivin expression in MSC-ITP. In addition, the apoptotic rate and number of senescent cells in ITP MSCs were reduced. Their impaired ability for inhibiting activated T cells, inducing Tregs, and suppressing the synthesis of anti-GPIIb-IIIa antibodies was restored after PDGF-BB treatment. In conclusion, we have demonstrated that PDGF-BB protects MSCs derived from ITP patients against apoptosis, senescence, and immunomodulatory defects. This protective effect of PDGF-BB is likely mediated via the p53/p21 pathway, thus potentially providing a new therapeutic approach for ITP. Significance Immune thrombocytopenia (ITP) is characterized by platelet destruction and megakaryocyte dysfunction. Platelet-derived growth factor (PDGF) improves growth and survival in various

Design, synthesis and screening studies of potent thiazol-2-amine derivatives as fibroblast growth factor receptor 1 inhibitors.

PubMed

Kumar, B V S Suneel; Lakshmi, Narasu; Kumar, M Ravi; Rambabu, Gundla; Manjashetty, Thimmappa H; Arunasree, Kalle M; Sriram, Dharmarajan; Ramkumar, Kavya; Neamati, Nouri; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Fibroblast growth factor receptor 1 (FGFR1) a tyrosine kinase receptor, plays important roles in angiogenesis, embryonic development, cell proliferation, cell differentiation, and wound healing. The FGFR isoforms and their receptors (FGFRs) considered as a potential targets and under intense research to design potential anticancer agents. Fibroblast growth factors (FGF's) and its growth factor receptors (FGFR) plays vital role in one of the critical pathway in monitoring angiogenesis. In the current study, quantitative pharmacophore models were generated and validated using known FGFR1 inhibitors. The pharmacophore models were generated using a set of 28 compounds (training). The top pharmacophore model was selected and validated using a set of 126 compounds (test set) and also using external validation. The validated pharmacophore was considered as a virtual screening query to screen a database of 400,000 virtual molecules and pharmacophore model retrieved 2800 hits. The retrieved hits were subsequently filtered based on the fit value. The selected hits were subjected for docking studies to observe the binding modes of the retrieved hits and also to reduce the false positives. One of the potential hits (thiazole-2-amine derivative) was selected based the pharmacophore fit value, dock score, and synthetic feasibility. A few analogues of the thiazole-2-amine derivative were synthesized. These compounds were screened for FGFR1 activity and anti-proliferative studies. The top active compound showed 56.87% inhibition of FGFR1 activity at 50 µM and also showed good cellular activity. Further optimization of thiazole-2-amine derivatives is in progress.

Statistical Analysis of Instantaneous Frequency Scaling Factor as Derived from Optical Disdrometer Measurements at VW Bands

NASA Technical Reports Server (NTRS)

Zemba, Michael; Nessel, James; Tarasenko, Nicholas; Lane, Steven

2017-01-01

Since October 2015, NASA Glenn Research Center (GRC) and the Air Force Research Laboratory (AFRL) have collaboratively operated an RF terrestrial link in Albuquerque, New Mexico to characterize atmospheric propagation phenomena at 72 and 84 GHz. The WV-band Terrestrial Link Experiment (WTLE) consists of coherent transmitters at each frequency on the crest of the Sandia Mountains and a corresponding pair of receivers in south Albuquerque. The beacon receivers provide a direct measurement of the link attenuation, while concurrent weather instrumentation provides a measurement of the atmospheric conditions.Among the available weather instruments is an optical disdrometer which yields an optical measurement of rain rate, as well as droplet size and velocity distributions (DSD, DVD). In particular, the DSD can be used to derive an instantaneous scaling factor (ISF) by which the measured data at one frequency can be scaled to another for example, scaling the 72 GHz to an expected 84 GHz timeseries. Given the availability of both the DSD prediction and the directly observed 84 GHz attenuation, WTLE is thus uniquely able assess DSD-derived instantaneous frequency scaling at the VW-bands. Previous work along these lines has investigated the DSD-derived ISF at Ka and Q-band (20 GHz to 40 GHz) using a satellite beacon receiver experiment in Milan, Italy [1-3]. This work will expand the investigation to terrestrial links in the VW-bands, where the frequency scaling factor is lower and where the link is also much more sensitive to attenuation by rain, clouds, and other atmospheric effects.

A nuclear factor kappa B-derived inhibitor tripeptide inhibits UVB-induced photoaging process.

PubMed

Oh, Jee Eun; Kim, Min Seo; Jeon, Woo-Kwang; Seo, Young Kwon; Kim, Byung-Chul; Hahn, Jang Hee; Park, Chang Seo

2014-12-01

Ultraviolet (UV) irradiation on the skin induces photoaging which is characterized by keratinocyte hyperproliferation, generation of coarse wrinkles, worse of laxity and roughness. Upon UV irradiation, nuclear factor kappa B (NF-κB) is activated which plays a key role in signaling pathway leading to inflammation cascade and this activation stimulates expression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1alpha (IL-1α) and a stress response gene cyclooxygenase-2 (COX-2). In addition, activation of NF-κB up-regulates the expression of matrix metalloprotease-1 (MMP-1) and consequently collagen in dermis is degraded. In this study, the effects of a NF-κB-derived inhibitor tripeptide on the UVB-induced photoaging and inflammation were investigated in vitro and in vivo. A NF-κB-derived inhibitor tripeptide (NF-κB-DVH) was synthesized based on the sequence of dimerization region of the subunit p65 of NF-κB. Its inhibitory activity was confirmed using chromatin immunoprecipitation assay and in situ proximate ligation assay. The effects of anti-photoaging and anti-inflammation were analyzed by Enzyme-linked immunosorbent assay (ELISA), immunoblotting and immunochemistry. NF-κB-DVH significantly decreased UV-induced expression of TNF-α, IL-1α, MMP-1 and COX-2 while increased production of type I procollagen. Results showed NF-κB-DVH had strong anti-inflammatory activity probably by inhibiting NF-κB activation pathway and suggested to be used as a novel agent for anti-photoaging. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

The Effect of Secretory Factors of Adipose-Derived Stem Cells on Human Keratinocytes

PubMed Central

Moon, Kyoung Mi; Park, Ye-Hyoung; Lee, Jae Seol; Chae, Yong-Byung; Kim, Moon-Moo; Kim, Dong-Soo; Kim, Byung-Woo; Nam, Soo-Wan; Lee, Jong-Hwan

2012-01-01

The beneficial effects of adipose-derived stem cell conditioned medium (ADSC-CM) on skin regeneration have been reported. Although the mechanism of how ADSC-CM promotes skin regeneration is unclear, ADSC-CM contained various growth factors and it is an excellent raw material for skin treatment. ADSC-CM produced in a hypoxia condition of ADSC—in other words, Advanced Adipose-Derived Stem cell Protein Extract (AAPE)—has great merits for skin regeneration. In this study, human primary keratinocytes (HKs), which play fundamental roles in skin tissue, was used to examine how AAPE affects HK. HK proliferation was significantly higher in the experimental group (1.22 μg/mL) than in the control group. DNA gene chip demonstrated that AAPE in keratinocytes (p < 0.05) notably affected expression of 290 identified transcripts, which were associated with cell proliferation, cycle and migration. More keratinocyte wound healing and migration was shown in the experimental group (1.22 μg/mL). AAPE treatment significantly stimulated stress fiber formation, which was linked to the RhoA-ROCK pathway. We identified 48 protein spots in 2-D gel analysis and selected proteins were divided into 64% collagen components and 30% non-collagen components as shown by the MALDI-TOF analysis. Antibody array results contained growth factor/cytokine such as HGF, FGF-1, G-CSF, GM-CSF, IL-6, VEGF, and TGF-β3 differing from that shown by 2-D analysis. Conclusion: AAPE activates HK proliferation and migration. These results highlight the potential of the topical application of AAPE in the treatment of skin regeneration. PMID:22312315

Downregulated Brain-Derived Neurotrophic Factor-Induced Oxidative Stress in the Pathophysiology of Diabetic Retinopathy.

PubMed

Behl, Tapan; Kotwani, Anita

2017-04-01

Brain-derived neurotrophic factor (BDNF), a member of neurotrophin growth factor family, physiologically mediates induction of neurogenesis and neuronal differentiation, promotes neuronal growth and survival and maintains synaptic plasticity and neuronal interconnections. Unlike the central nervous system, its secretion in the peripheral nervous system occurs in an activity-dependent manner. BDNF improves neuronal mortality, growth, differentiation and maintenance. It also provides neuroprotection against several noxious stimuli, thereby preventing neuronal damage during pathologic conditions. However, in diabetic retinopathy (a neuromicrovascular disorder involving immense neuronal degeneration), BDNF fails to provide enough neuroprotection against oxidative stress-induced retinal neuronal apoptosis. This review describes the prime reasons for the downregulation of BDNF-mediated neuroprotective actions during hyperglycemia, which renders retinal neurons vulnerable to damaging stimuli, leading to diabetic retinopathy. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Distinctive diet-tissue isotopic discrimination factors derived from the exclusive bamboo-eating giant panda.

PubMed

Han, Han; Wei, Wei; Nie, Yonggang; Zhou, Wenliang; Hu, Yibo; Wu, Qi; Wei, Fuwen

2016-11-01

Stable isotope analysis is very useful in animal ecology, especially in diet reconstruction and trophic studies. Differences in isotope ratios between consumers and their diet, termed discrimination factors, are essential for studies of stable isotope ecology and are species-specific and tissue-specific. Given the specialized bamboo diet and clear foraging behavior, here, we calculated discrimination factors for carbon and nitrogen isotopes from diet to tissues (tooth enamel, hair keratin and bone collagen) for the giant panda (Ailuropoda melanoleuca), a species derived from meat-eating ancestors. Our results showed that carbon discrimination factor obtained from giant panda tooth enamel (ε 13 C diet-enamel = 10.0‰) and nitrogen discrimination factors from hair keratin (Δ 15 N diet-hair = 2.2‰) and bone collagen (Δ 15 N diet-collagen = 2.3‰) were lower, and carbon discrimination factors from hair keratin (Δ 13 C diet-hair = 5.0‰) and bone collagen (Δ 13 C diet-collagen = 6.1‰) were higher than those of other mammalian carnivores, omnivores and herbivores. Such distinctive values are likely the result of a low-nutrient and specialized bamboo diet, carnivore-like digestive system and exceptionally low metabolism in giant pandas. © 2016 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

Effects of vitamin D(3)-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis.

PubMed

Kanda, Shigeru; Mochizuki, Yasushi; Miyata, Yasuyoshi; Kanetake, Hiroshi; Yamamoto, Nobuto

2002-09-04

The vitamin D(3)-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) activates tumoricidal macrophages against a variety of cancers indiscriminately. We investigated whether GcMAF also acts as an antiangiogenic factor on endothelial cells. The effects of GcMAF on angiogenic growth factor-induced cell proliferation, chemotaxis, and tube formation were examined in vitro by using cultured endothelial cells (murine IBE cells, porcine PAE cells, and human umbilical vein endothelial cells [HUVECs]) and in vivo by using a mouse cornea micropocket assay. Blocking monoclonal antibodies to CD36, a receptor for the antiangiogenic factor thrombospondin-1, which is also a possible receptor for GcMAF, were used to investigate the mechanism of GcMAF action. GcMAF inhibited the endothelial cell proliferation, chemotaxis, and tube formation that were all stimulated by fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor-A, or angiopoietin 2. FGF-2-induced neovascularization in murine cornea was also inhibited by GcMAF. Monoclonal antibodies against murine and human CD36 receptor blocked the antiangiogenic action of GcMAF on the angiogenic factor stimulation of endothelial cell chemotaxis. In addition to its ability to activate tumoricidal macrophages, GcMAF has direct antiangiogenic effects on endothelial cells independent of tissue origin. The antiangiogenic effects of GcMAF may be mediated through the CD36 receptor.

Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacNaughton, W.K.; Wallace, J.L.; Cirino, G.

1989-01-01

The role that nitric oxide, an endothelium-derived relaxing factor, may play in the regulation of gastric mucosal defense was investigated by assessing the potential protective actions of this factor against the damage caused by ethanol in an ex vivo chamber preparation of the rat stomach. Topical application of glyceryl trinitrate and sodium nitroprusside, which have been shown to release nitric oxide, markedly reduced the area of 70% ethanol-induced hemorrhagic damage. Topical application of a 0.01% solution of authentic nitric oxide also significantly reduced the severity of mucosal damage. Pretreatment with indomethacin precluded the involvement of endogenous prostaglandins in the protectivemore » effects of these agents. The protective effects of NO were transient, since a delay of 5 minutes between NO administration and ethanal administration resulted in a complete loss of the protective activity. The protection against ethanol afforded by 10 ug/ml nitroprusside could be completely reversed by intravenous infusion of either 1% methylene blue or 1 mM hemoglobin, both of which inhibit vasodilation induced by nitric oxide. Intravenous infusion of 1% methylene blue significantly increased the susceptibility of the mucosa to damage induced by topical 20% ethanol.« less

Sperm-derived factors enhance the in vitro developmental potential of haploid parthenotes.

PubMed

Nair, Ramya; Aboobacker, Shahin; Mutalik, Srinivas; Kalthur, Guruprasad; Adiga, Satish Kumar

2017-12-01

Parthenotes are characterized by poor in vitro developmental potential either due to the ploidy status or the absence of paternal factors. In the present study, we demonstrate the beneficial role of sperm-derived factors (SDF) on the in vitro development of mouse parthenotes. Mature (MII) oocytes collected from superovulated Swiss albino mice were activated using strontium chloride (SrCl2) in the presence or absence of various concentrations of SDF in M16 medium. The presence of SDF in activation medium did not have any significant influence on the activation rate. However, a significant increase in the developmental potential of the embryos and increased blastocyst rate (P < 0.01) was observed at 50 µg/ml concentration. Furthermore, the activated oocytes from this group exhibited early cleavage and cortical distribution of cortical granules that was similar to that of normally fertilized zygotes. Culturing 2-cell stage parthenotes in the presence of SDF significantly improved the developmental potential (P < 0.05) indicating that they also play a significant role in embryo development. In conclusion, artificial activation of oocytes with SDF can improve the developmental potential of parthenotes in vitro.

[BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF): NEUROBIOLOGY AND MARKER VALUE IN NEUROPSYCHIATRY].

PubMed

Levada, O A; Cherednichenko, N V

2015-01-01

In this review current publications about neurobiology and marker value of brain derived neurotrophic factor (BDNF) in neuropsychiatry are analyzed. It is shown that BDNF is an important member of the family of neurotrophins which widely represented in various structures of the CNS. In prenatal period BDNF is involved in all stages of neuronal networks formation, and in the postnatal period its main role is maintaining the normal brain architectonics, involvement in the processes of neurogenesis and realization of neuroprotective functions. BDNF plays an important role in learning and memory organization, food and motor behavior. BDNF brain expression decreases with age, as well as in degenerative and vascular dementias, affective, anxiety, and behavioral disorders. The reducing of BDNF serum, level reflects the decreasing of its cerebral expression and could be used as a neurobiological marker of these pathological processes but the rising of its concentration could indicate the therapy effectiveness.

Intervertebral disc degeneration-induced expression of pain-related molecules: glial cell-derived neurotropic factor as a key factor.

PubMed

Jung, Woon-Won; Kim, Hyun-Sook; Shon, Jong-Ryeul; Lee, Min; Lee, Sang-Heon; Sul, Donggeun; Na, Heung Sik; Kim, Joo Han; Kim, Byung-Jo

2011-10-01

Discogenic low back pain has been shown to develop into chronic intractable pain due to an unknown pathogenesis. To study the mechanism of discogenic pain, we analyzed the serial expression of pain-related molecules in the dorsal root ganglia (DRG) and thalamus using a newly developed rat model of disc degeneration. Ten microliters of complete Freund's adjuvant was injected into the L5-6 disc of male Sprague-Dawley rats for 10 minutes using a 26-gauge needle. Using a behavioral test, rats with significant pain were selected and subsequently serial gene expression of pain-related molecules in the DRG and the thalamus was analyzed by reverse transcriptase polymerase chain reaction. The expression of tumor necrosis factor-α and interleukin-1β significantly increased at 4 and 8 weeks in the DRG of rats with pain. Furthermore, interleukin-6 was significantly increased at 4 weeks in the DRG; however, these cytokines did not show a significant change in the thalamus. Calcitonin gene-related peptide and substance P were significantly increased in DRG at 4 and 8 weeks and in the thalamus at 2 and 4 weeks. The level of nerve growth factor-β did not significantly increase in the DRG or thalamus, whereas glial cell line-derived neurotropic factor (GDNF) was significantly increased at 2 weeks and was sustained through 8 weeks in both the DRG and thalamus. The disc degeneration rat model described herein led to significant pain of a chronic nature. The gradual and persistent increase of GDNF in both the thalamus and DRG suggests that GDNF might be a key factor in the development of intractable, chronic discogenic pain.

Isolation and expansion of human pluripotent stem cell-derived hepatic progenitor cells by growth factor defined serum-free culture conditions.

PubMed

Fukuda, Takayuki; Takayama, Kazuo; Hirata, Mitsuhi; Liu, Yu-Jung; Yanagihara, Kana; Suga, Mika; Mizuguchi, Hiroyuki; Furue, Miho K

2017-03-15

Limited growth potential, narrow ranges of sources, and difference in variability and functions from batch to batch of primary hepatocytes cause a problem for predicting drug-induced hepatotoxicity during drug development. Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells in vitro are expected as a tool for predicting drug-induced hepatotoxicity. Several studies have already reported efficient methods for differentiating hPSCs into hepatocyte-like cells, however its differentiation process is time-consuming, labor-intensive, cost-intensive, and unstable. In order to solve this problem, expansion culture for hPSC-derived hepatic progenitor cells, including hepatic stem cells and hepatoblasts which can self-renewal and differentiate into hepatocytes should be valuable as a source of hepatocytes. However, the mechanisms of the expansion of hPSC-derived hepatic progenitor cells are not yet fully understood. In this study, to isolate hPSC-derived hepatic progenitor cells, we tried to develop serum-free growth factor defined culture conditions using defined components. Our culture conditions were able to isolate and grow hPSC-derived hepatic progenitor cells which could differentiate into hepatocyte-like cells through hepatoblast-like cells. We have confirmed that the hepatocyte-like cells prepared by our methods were able to increase gene expression of cytochrome P450 enzymes upon encountering rifampicin, phenobarbital, or omeprazole. The isolation and expansion of hPSC-derived hepatic progenitor cells in defined culture conditions should have advantages in terms of detecting accurate effects of exogenous factors on hepatic lineage differentiation, understanding mechanisms underlying self-renewal ability of hepatic progenitor cells, and stably supplying functional hepatic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Brain-Derived Neurotrophic Factor in Patients with Huntington's Disease

PubMed Central

Zuccato, Chiara; Mariotti, Caterina; Valenza, Marta; Lahiri, Nayana; Wild, Edward J.; Sassone, Jenny; Ciammola, Andrea; Bachoud-Lèvi, Anne Catherine; Tabrizi, Sarah J.; Di Donato, Stefano; Cattaneo, Elena

2011-01-01

Reduced Brain-Derived Neurotrophic Factor (BDNF) levels have been described in a number of patho-physiological conditions, most notably, in Huntington's disease (HD), a progressive neurodegenerative disorder. Since BDNF is also produced in blood, we have undertaken the measurement of its peripheral levels in the attempt to identify a possible link with HD prognosis and/or its progression. Here we evaluated BDNF level in 398 blood samples including 138 controls, 56 preHD, and 204 HD subjects. We found that BDNF protein levels were not reliably different between groups, whether measured in plasma (52 controls, 26 preHD, 105 HD) or serum (39 controls, 5 preHD, 29 HD). Our experience, and a re-analysis of the literature highlighted that intra-group variability and methodological aspects affect this measurement, especially in serum. We also assessed BDNF mRNA levels in blood samples from 47 controls, 25 preHD, and 70 HD subjects, and found no differences among the groups. We concluded that levels of BDNF in human blood were not informative (mRNA levels or plasma protein level) nor reliable (serum protein levels) as HD biomarkers. We also wish to warn the scientific community in interpreting the significance of changes measured in BDNF protein levels in serum from patients suffering from different conditions. PMID:21857974

Specific growth stimulation of cultured smooth muscle cells from spontaneously hypertensive rats by platelet-derived growth factor A-chain homodimer.

PubMed Central

Resink, T J; Scott-Burden, T; Hahn, A W; Rouge, M; Hosang, M; Powell, J S; Bühler, F R

1990-01-01

Cultured vascular smooth muscle cells (VSMC)1 from spontaneously hypertensive rats (SHR) possess specific cell surface receptors for both homodimeric forms of platelet-derived growth factor (PDGF-AA and PDGF-BB), in contrast to cells from normotensive Wistar Kyoto (WKY) animals, which express receptors only for the B-chain form of PDGF. Stimulation of quiescent VSMC from SHR with PDGF-AA resulted in activation of S6-kinase and induction of phosphoinositide catabolism, as well as cellular proliferation when cultures were maintained for prolonged periods with daily supplementation of the growth factor. WKY-derived VSMC showed no response to PDGF-AA, which was consistent with their lack of specific receptors for this homodimer. The responsiveness of quiescent cells from SHR and WKY to the B-chain homodimer was similar. The enhanced growth responsiveness of SHR-derived cells to fetal calf serum, as compared with cells from their normotensive counterparts, may be accounted for in part by their expression of receptors for the AA homodimer of PDGF. PMID:1965150

THE RELATIONSHIP OF THE CHEMOTACTIC BEHAVIOR OF THE COMPLEMENT-DERIVED FACTORS, C3a, C5a, AND C567, AND A BACTERIAL CHEMOTACTIC FACTOR TO THEIR ABILITY TO ACTIVATE THE PROESTERASE 1 OF RABBIT POLYMORPHONUCLEAR LEUKOCYTES

PubMed Central

Becker, Elmer L.

1972-01-01

The inhibition profiles obtained when a series of p-nitrophenyl ethyl alkylphosphonates and of p-nitrophenyl ethyl chloroalkylphosphonates were used to interfere with the chemotactic activity of polymorphonuclear leukocytes stimulated by C3a, C5a, and bacterial factor were the same as found previously when C567 was the chemotactic agent. This indicates that as in the chemotactic activity induced by C567, an obligatory step in the chemotaxis caused by C3a, C5a, and bacterial factor is the activation of proesterase 1 of the rabbit polymorphonuclear leukocyte. C5a and C3a activate proesterase 1 of peripheral blood polymophonuclear leukocytes as measured by the increase of acetyl DL-phenylalanine β-naphthyl esterase activity. Attempts to detect in a like manner the proesterase 1 of the same leukocytes using bacterial factor under varying circumstances have consistently failed. It is concluded that bacterial factor, for unknown reasons, is unable to activate proesterase 1 to the same extent as the complement-derived chemotactic factors. The hypothesis of there being a quantitative difference in the ability of bacterial factor to activate proesterase 1 compared with the complement-derived factors explains the previous observations that bacterial factor can not deactivate to itself or to the complement-derived factors, although these latter factors can deactivate to themselves, to each other, and to the bacterial factor. The quantitative difference in the ability of bacterial factor to activate proesterase 1 compared to the complement-derived factors is also associated with and explains the finding that the maximal chemotactic activity attainable when bacterial factor is the chemotactic agent is distinctly less than that obtained using either C3a, C5a, or C567. These results indicate that the activation of proesterase 1 is a general requirement for the chemotactic activity of rabbit polymorphonuclear leukocytes with known macromolecular chemotactic agents and suggest

Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood-derived megakaryocytes.

PubMed

Gertz, Jacqueline M; McLean, Kelley C; Bouchard, Beth A

2018-05-15

Plasma- and platelet-derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet-derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34 + hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41 + cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34 + cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b + cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in α-granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood. © 2018 Wiley Periodicals, Inc.

Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis.

PubMed

Takagi, Satoshi; Takemoto, Ai; Takami, Miho; Oh-Hara, Tomoko; Fujita, Naoya

2014-08-01

The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy.

PubMed

Saligan, L N; Lukkahatai, N; Holder, G; Walitt, B; Machado-Vieira, R

2016-12-01

Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. FACT-F scores of 47 subjects decreased from baseline (43.95 ± 1.3) to mid-EBRT (38.36 ± 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (r s = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue.

Platelet-Derived Growth Factor-BB Stimulates Fibronectin Gene Expression in Fibroblasts Isolated from Rat Thoracic Aorta

DTIC Science & Technology

1994-06-13

MARYLAND 20814-4799 TEACHING HOSPITALS WALTER REED ARMY MEDtCA L CENTER APPROVAL SHEET NAVAL HOSPITAL. BETHESDA MALCOLM GROW AIR FORCE MEDICAL ...CENTER WILFORD HALL "IR FORCE MEDICAL CENTER Title of Dissertation: "Platelet-derived growth factor-BB stimulates fibronectin gene expression in...fascinating world of basic medical science. His dedication and pursuit of excellence in all facets of his work are standards by which I will guide my own

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway.

PubMed

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F

2017-02-16

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157-an inhibitor of PERK-effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy.

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway

PubMed Central

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B.; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F.

2017-01-01

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157—an inhibitor of PERK—effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy. PMID:28212323

Cascade bioassay evidence for the existence of urothelium-derived inhibitory factor in Guinea pig urinary bladder.

PubMed

Guan, Na N; Thor, Anna; Hallén, Katarina; Wiklund, N Peter; Gustafsson, Lars E

2014-01-01

Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intact or -denuded guinea pig urinary bladders were used as donor tissues, stimulated by intermittent application of carbachol before or during the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the adenosine/P1 nucleoside receptor antagonist 8-(p-sulfophenyl)theophylline (8-PST) or the cyclo-oxygenase inhibitor diclofenac infused to bath donor and bioassay tissues. The spontaneous contractions of bioassay ureters were unaltered by application of carbachol 1-5 µM in the presence of scopolamine 5-30 µM. When carbachol was applied over the urothelium-denuded bladder, the assay ureter contraction rate was unaltered. Introducing carbachol over the everted urothelium-intact bladder significantly inhibited the contraction frequency of the assay ureter, suggesting the transfer of an inhibitory activity from the bladder to the assay ureter. The transmissible inhibitory activity was not markedly antagonized by L-NAME, 8-PST or diclofenac, while L-NAME nearly abolished nitrite release from the urothelium-intact bladder preparations. We suggest that urothelium-derived inhibitory factor is a transmissible entity over a significant distance as demonstrated in this novel cascade superfusion assay and seems less likely to be nitric oxide, nitrite, an adenosine receptor agonist or subject to inhibition by administration of a cyclo-oxygenase inhibitor.

Morris Water Maze Training in Mice Elevates Hippocampal Levels of Transcription Factors Nuclear Factor (Erythroid-derived 2)-like 2 and Nuclear Factor Kappa B p65

PubMed Central

Snow, Wanda M.; Pahlavan, Payam S.; Djordjevic, Jelena; McAllister, Danielle; Platt, Eric E.; Alashmali, Shoug; Bernstein, Michael J.; Suh, Miyoung; Albensi, Benedict C.

2015-01-01

Research has identified several transcription factors that regulate activity-dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-κB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-κB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-κB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-κB, this study simultaneously evaluated protein levels of NF-κB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-κB p50 protein after training relative to controls, whereas NF-κB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-κB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory. PMID:26635523

Stromal cell derived factor-1alpha protects stem cell derived insulin-producing cells from glucotoxicity under high glucose conditions in-vitro and ameliorates drug induced diabetes in rats

PubMed Central

2013-01-01

Background Diabetes mellitus is affecting more than 300 million people worldwide. Current treatment strategies cannot prevent secondary complications. Stem cells due to their regenerative power have long been the attractive target for the cell-based therapies. Mesenchymal stem cells (MSCs) possess the ability to differentiate into several cell types and to escape immune recognition in vitro. MSCs can be differentiated into insulin-producing cells (IPCs) and could be an exciting therapy for diabetes but problems like poor engraftment and survivability need to be confronted. It was hypothesized that stromal cell derived factor- 1alpha (SDF-1alpha) will enhance therapeutic potential of stem cell derived IPCs by increasing their survival and proliferation rate. Methods Novel culture conditions were developed to differentiate bone marrow derived mesenchymal stem cells (BMSCs) into IPCs by using endocrine differentiation inducers and growth factors via a three stage protocol. In order to enhance their therapeutic potential, we preconditioned IPCs with SDF-1alpha. Results Our results showed that SDF-1alpha increases survival and proliferation of IPCs and protects them from glucotoxicity under high glucose conditions in vitro. SDF-1alpha also enhances the glucose responsive insulin secretion in IPCs in vitro. SDF-1alpha preconditioning reverses hyperglycemia and increase serum insulin in drug induced diabetic rats. Conclusions The differentiation of BMSCs into IPCs and enhancement of their therapeutic potential by SDF-1alpha preconditioning may contribute to cell based therapies for diabetes. PMID:23648189

5'-adenosine monophosphate is the neutrophil-derived paracrine factor that elicits chloride secretion from T84 intestinal epithelial cell monolayers.

PubMed Central

Madara, J L; Patapoff, T W; Gillece-Castro, B; Colgan, S P; Parkos, C A; Delp, C; Mrsny, R J

1993-01-01

Neutrophil transmigration across intestinal epithelia is thought to contribute to epithelial dysfunction and characterizes many inflammatory intestinal diseases. Neutrophils activated by factors, normally present in the lumen, release a neutrophil-derived secretagogue activity to which intestinal epithelia respond with an electrogenic chloride secretion, the transport event which underlies secretory diarrhea. Using sequential ultrafiltration, column chromatographic, and mass and Raman spectroscopic techniques, neutrophil-derived secretagogue was identified as 5'-AMP. Additional studies suggested that neutrophil-derived 5'-AMP is subsequently converted to adenosine at the epithelial cell surface by ecto-5'-nucleotidase and that adenosine subsequently activates intestinal secretion through adenosine receptors on the apical membrane of target intestinal epithelial cells. These findings suggest that this ATP metabolite may serve as a neutrophil-derived paracrine mediator that contributes to secretory diarrhea in states of intestinal inflammation. PMID:8486793

Platelet-derived-growth-factor-stimulated heterogeneous polyphosphoinositide metabolism and phosphate uptake in C3H fibroblasts.

PubMed Central

Holmsen, H; Male, R; Rongved, S; Langeland, N; Lillehaug, J

1989-01-01

Pig platelet-derived growth factor (PDGF) increased the rate of [32P]Pi uptake by murine fibroblasts, resulting in a 3-9-fold elevation of the specific radioactivity of ATP, PtdInsP, PtdInsP2, PtdIns and phosphatidic acid. The specific radioactivity was 10-60-fold higher in ATP than in the four phospholipids. These substances are therefore not in metabolic equilibrium, which complicates determination of inositol phospholipid turnover. PMID:2548480

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis.

PubMed

Stampanoni Bassi, Mario; Iezzi, Ennio; Marfia, Girolama A; Simonelli, Ilaria; Musella, Alessandra; Mandolesi, Georgia; Fresegna, Diego; Pasqualetti, Patrizio; Furlan, Roberto; Finardi, Annamaria; Mataluni, Giorgia; Landi, Doriana; Gilio, Luana; Centonze, Diego; Buttari, Fabio

2018-04-14

In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Our results suggest that PDGF could promote a

Endothelial cell colony forming units derived from malignant breast diseases are resistant to tumor necrosis factor-α-induced apoptosis.

PubMed

Chou, Chen-Pin; Jiang, Shih Sheng; Pan, Huay-Ben; Yen, Yi-Chen; Tseng, Hui-Hwa; Hung, Yu-Ting; Wang, Ssu-Han; Chen, Yu-Lin; Chen, Ya-Wen

2016-11-24

Mobilisation of endothelial progenitor cells (EPCs) from the bone marrow is a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be elevated in certain malignant states. Using flow cytometry and a Hill-based colony forming unit (CFU) assay, the present study indicated that higher levels of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2) double-positive EPCs, as well as increased formation of endothelial cell colony-forming units (EC-CFUs) are associated with benign and malignant breast diseases, providing possible indicators for breast disease detection. Gene expression profiles revealed a genetic difference between CD34 + VEGFR2 + EPCs and EC-CFUs. Decreased expression of tumour necrosis factor receptor 2 (TNFR2) signalling-related genes and inhibition of tumour necrosis factor (TNF)-induced signalling were demonstrated in EC-CFUs derived from patients with malignant breast disease in comparison with those from healthy controls. Interestingly, our data provided the first evidence that EC-CFUs derived from patients with malignant breast disease were resistant to TNF-α-induced apoptosis, indicating a plausible target for future therapeutic interventions.

Statistical Analysis of Instantaneous Frequency Scaling Factor as Derived from Optical Disdrometer Measurements at V/W Bands

NASA Technical Reports Server (NTRS)

Zemba, Michael; Nessel, James; Tarasenko, Nicholas; Lane, Steven

2017-01-01

Since October 2015, NASA Glenn Research Center (GRC) and the Air Force Research Laboratory (AFRL) have collaboratively operated an RF terrestrial link in Albuquerque, New Mexico to characterize atmospheric propagation phenomena at 72 and 84 GHz. The W/V-band Terrestrial Link Experiment (WTLE) consists of coherent transmitters at each frequency on the crest of the Sandia Mountains and a corresponding pair of receivers in south Albuquerque. The beacon receivers provide a direct measurement of the link attenuation, while concurrent weather instrumentation provides a measurement of the atmospheric conditions. Among the available weather instruments is an optical disdrometer which yields an optical measurement of rain rate, as well as droplet size and velocity distributions (DSD, DVD). In particular, the DSD can be used to derive an instantaneous scaling factor (ISF) by which the measured data at one frequency can be scaled to another - for example, scaling the 72 GHz to an expected 84 GHz timeseries. Given the availability of both the DSD prediction and the directly observed 84 GHz attenuation, WTLE is thus uniquely able assess DSD-derived instantaneous frequency scaling at the V/W-bands. Previous work along these lines has investigated the DSD-derived ISF at Ka and Q-band (20 GHz to 40 GHz) using a satellite beacon receiver experiment in Milan, Italy. This work will expand the investigation to terrestrial links in the V/W-bands, where the frequency scaling factor is lower and where the link is also much more sensitive to attenuation by rain, clouds, and other atmospheric effects.

Clinical and biological significance of hepatoma-derived growth factor in Ewing's sarcoma.

PubMed

Yang, Yang; Li, Hui; Zhang, Fenfen; Shi, Huijuan; Zhen, Tiantian; Dai, Sujuan; Kang, Lili; Liang, Yingjie; Wang, Jin; Han, Anjia

2013-11-01

We sought to investigate the clinicopathological significance and biological function of hepatoma-derived growth factor (HDGF) in Ewing's sarcoma. Our results showed that HDGF expression is up-regulated in Ewing's sarcoma. Nuclear HDGF expression is significantly associated with tumour volume (p < 0.001), metastases at diagnosis (p < 0.001), low overall survival rate (p < 0.001) and low disease-free survival rate (p < 0.001). HDGF knock-down results in significant reduction of Ewing's sarcoma cell growth, proliferation and enhances tumourigenesis, both in vitro and in vivo. Meanwhile, HDGF knock-down causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing's sarcoma cells. Ninety-eight candidate HDGF downstream genes were identified in Ewing's sarcoma cells using cDNA microarray analysis. In addition, we found that HDGF knock-down inhibited FLI1 expression in Ewing's sarcoma cells at the mRNA and protein levels. Our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing's sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing's sarcoma. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Identification of Regulatory Factors for Mesenchymal Stem Cell-Derived Salivary Epithelial Cells in a Co-Culture System

PubMed Central

Park, Yun-Jong; Koh, Jin; Gauna, Adrienne E.; Chen, Sixue; Cha, Seunghee

2014-01-01

Patients with Sjögren’s syndrome or head and neck cancer patients who have undergone radiation therapy suffer from severe dry mouth (xerostomia) due to salivary exocrine cell death. Regeneration of the salivary glands requires a better understanding of regulatory mechanisms by which stem cells differentiate into exocrine cells. In our study, bone marrow-derived mesenchymal stem cells were co-cultured with primary salivary epithelial cells from C57BL/6 mice. Co-cultured bone marrow-derived mesenchymal stem cells clearly resembled salivary epithelial cells, as confirmed by strong expression of salivary gland epithelial cell-specific markers, such as alpha-amylase, muscarinic type 3 receptor, aquaporin-5, and cytokeratin 19. To identify regulatory factors involved in this differentiation, transdifferentiated mesenchymal stem cells were analyzed temporarily by two-dimensional-gel-electrophoresis, which detected 58 protein spots (>1.5 fold change, p<0.05) that were further categorized into 12 temporal expression patterns. Of those proteins only induced in differentiated mesenchymal stem cells, ankryin-repeat-domain-containing-protein 56, high-mobility-group-protein 20B, and transcription factor E2a were selected as putative regulatory factors for mesenchymal stem cell transdifferentiation based on putative roles in salivary gland development. Induction of these molecules was confirmed by RT-PCR and western blotting on separate sets of co-cultured mesenchymal stem cells. In conclusion, our study is the first to identify differentially expressed proteins that are implicated in mesenchymal stem cell differentiation into salivary gland epithelial cells. Further investigation to elucidate regulatory roles of these three transcription factors in mesenchymal stem cell reprogramming will provide a critical foundation for a novel cell-based regenerative therapy for patients with xerostomia. PMID:25402494

Abnormal platelet-derived growth factor signaling accounting for lung hypoplasia in experimental congenital diaphragmatic hernia.

PubMed

Dingemann, Jens; Doi, Takashi; Ruttenstock, Elke; Puri, Prem

2010-10-01

The pathogenesis of pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) is not fully understood. Platelet-derived growth factor A (PDGFA) and platelet-derived growth factor receptor α (PDGFRα) play a crucial role in lung development. It has been reported that PDGF induces H(2)O(2)-production and that oxidative stress may be an important mechanism for the impaired lung development in the nitrofen rat model. We hypothesized that pulmonary expression of PDGFA and PDGFRα is altered in the nitrofen induced CDH model. Pregnant rats received 100 mg nitrofen or vehicle on gestational day 9 (D9) and were sacrificed on D15, D18 or D21. RNA was extracted from fetal left lungs and mRNA levels of PDGFA and PDGFRα were determined using real-time polymerase chain reaction. Immunohistochemistry for protein expression of PDGFA and PDGFRα was performed. Pulmonary H(2)O(2) was measured colorimetrically. mRNA levels of PDGFRα at D15 (4.50 ± 0.87) and PDGFA at D18 (2.90 ± 1.38) were increased in the nitrofen group (P < .05). Immunohistochemistry revealed increased pulmonary expression of PDGFRα and PDGFA. H(2)O(2) content was significantly higher in the nitrofen group. Increased expression of PDGFA and PDGFRα suggests that pulmonary hypoplasia in the nitrofen CDH model may be owing to PDGF-induced oxidative stress during lung development. Copyright © 2010 Elsevier Inc. All rights reserved.

Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy.

PubMed

Piñol-Jurado, Patricia; Gallardo, Eduard; de Luna, Noemi; Suárez-Calvet, Xavier; Sánchez-Riera, Carles; Fernández-Simón, Esther; Gomis, Clara; Illa, Isabel; Díaz-Manera, Jordi

2017-08-01

Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Regulation of cell growth by redox-mediated extracellular proteolysis of platelet-derived growth factor receptor beta.

PubMed

Okuyama, H; Shimahara, Y; Kawada, N; Seki, S; Kristensen, D B; Yoshizato, K; Uyama, N; Yamaoka, Y

2001-07-27

Redox-regulated processes are important elements in various cellular functions. Reducing agents, such as N-acetyl-l-cysteine (NAC), are known to regulate signal transduction and cell growth through their radical scavenging action. However, recent studies have shown that reactive oxygen species are not always involved in ligand-stimulated intracellular signaling. Here, we report a novel mechanism by which NAC blocks platelet-derived growth factor (PDGF)-induced signaling pathways in hepatic stellate cells, a fibrogenic player in the liver. Unlike in vascular smooth muscle cells, we found that reducing agents, including NAC, triggered extracellular proteolysis of PDGF receptor-beta, leading to desensitization of hepatic stellate cells toward PDGF-BB. This effect was mediated by secreted mature cathepsin B. In addition, type II transforming growth factor-beta receptor was also down-regulated. Furthermore, these events seemed to cause a dramatic improvement of rat liver fibrosis. These results indicated that redox processes impact the cell's response to growth factors by regulating the turnover of growth factor receptors and that "redox therapy" is promising for fibrosis-related disease.

Trophic factors from adipose tissue-derived multi-lineage progenitor cells promote cytodifferentiation of periodontal ligament cells.

PubMed

Sawada, Keigo; Takedachi, Masahide; Yamamoto, Satomi; Morimoto, Chiaki; Ozasa, Masao; Iwayama, Tomoaki; Lee, Chun Man; Okura, Hanayuki; Matsuyama, Akifumi; Kitamura, Masahiro; Murakami, Shinya

2015-08-14

Stem and progenitor cells are currently being investigated for their applicability in cell-based therapy for periodontal tissue regeneration. We recently demonstrated that the transplantation of adipose tissue-derived multi-lineage progenitor cells (ADMPCs) enhances periodontal tissue regeneration in beagle dogs. However, the molecular mechanisms by which transplanted ADMPCs induce periodontal tissue regeneration remain to be elucidated. In this study, trophic factors released by ADMPCs were examined for their paracrine effects on human periodontal ligament cell (HPDL) function. ADMPC conditioned medium (ADMPC-CM) up-regulated osteoblastic gene expression, alkaline phosphatase activity and calcified nodule formation in HPDLs, but did not significantly affect their proliferative response. ADMPCs secreted a number of growth factors, including insulin-like growth factor binding protein 6 (IGFBP6), hepatocyte growth factor and vascular endothelial growth factor. Among these, IGFBP6 was most highly expressed. Interestingly, the positive effects of ADMPC-CM on HPDL differentiation were significantly suppressed by transfecting ADMPCs with IGFBP6 siRNA. Our results suggest that ADMPCs transplanted into a defect in periodontal tissue release trophic factors that can stimulate the differentiation of HPDLs to mineralized tissue-forming cells, such as osteoblasts and cementoblasts. IGFBP6 may play crucial roles in ADMPC-induced periodontal regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with Trichuris suis ova therapy.

PubMed

Rosche, Berit; Werner, Jonas; Benzel, Friderike Joëlle; Harms, Lutz; Danker-Hopfe, Heidi; Hellweg, Rainer

2013-01-01

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05). © B. Rosche et al., published by EDP Sciences, 2013.

Cascade Bioassay Evidence for the Existence of Urothelium-Derived Inhibitory Factor in Guinea Pig Urinary Bladder

PubMed Central

Guan, Na N.; Thor, Anna; Hallén, Katarina; Wiklund, N. Peter; Gustafsson, Lars E.

2014-01-01

Our aim was to investigate whether guinea pig urothelium-derived bioactivities compatible with the existence of urothelium-derived inhibitory factor could be demonstrated by in vitro serial bioassay and whether purinergic P1 receptor agonists, nitric oxide, nitrite or prostaglandins might explain observed activities. In a cascade superfusion system, urothelium-denuded guinea pig ureters were used as bioassay tissues, recording their spontaneous rhythmic contractions in presence of scopolamine. Urothelium-intact or -denuded guinea pig urinary bladders were used as donor tissues, stimulated by intermittent application of carbachol before or during the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), the adenosine/P1 nucleoside receptor antagonist 8-(p-sulfophenyl)theophylline (8-PST) or the cyclo-oxygenase inhibitor diclofenac infused to bath donor and bioassay tissues. The spontaneous contractions of bioassay ureters were unaltered by application of carbachol 1–5 µM in the presence of scopolamine 5–30 µM. When carbachol was applied over the urothelium-denuded bladder, the assay ureter contraction rate was unaltered. Introducing carbachol over the everted urothelium-intact bladder significantly inhibited the contraction frequency of the assay ureter, suggesting the transfer of an inhibitory activity from the bladder to the assay ureter. The transmissible inhibitory activity was not markedly antagonized by L-NAME, 8-PST or diclofenac, while L-NAME nearly abolished nitrite release from the urothelium-intact bladder preparations. We suggest that urothelium-derived inhibitory factor is a transmissible entity over a significant distance as demonstrated in this novel cascade superfusion assay and seems less likely to be nitric oxide, nitrite, an adenosine receptor agonist or subject to inhibition by administration of a cyclo-oxygenase inhibitor. PMID:25084114

Quantitative structure-activity relationship and molecular docking of artemisinin derivatives to vascular endothelial growth factor receptor 1.

PubMed

Saeed, Mohamed E M; Kadioglu, Onat; Seo, Ean-Jeong; Greten, Henry Johannes; Brenk, Ruth; Efferth, Thomas

2015-04-01

The antimalarial drug artemisinin has been shown to exert anticancer activity through anti-angiogenic effects. For further drug development, it may be useful to have derivatives with improved anti-angiogenic properties. We performed molecular docking of 52 artemisinin derivatives to vascular endothelial growth factor receptors (VEGFR1, VEGFR2), and VEGFA ligand using Autodock4 and AutodockTools-1.5.7.rc1 using the Lamarckian genetic algorithm. Quantitative structure-activity relationship (QSAR) analyses of the compounds prepared by Corina Molecular Networks were performed using the Molecular Operating Environment MOE 2012.10. A statistically significant inverse relationship was obtained between in silico binding energies to VEGFR1 and anti-angiogenic activity in vivo of a test-set of artemisinin derivatives (R=-0.843; p=0.035). This served as a control experiment to validate molecular docking predicting anti-angiogenc effects. Furthermore, 52 artemisinin derivatives were docked to VEGFR1 and in selected examples also to VEGFR2 and VEGFA. Higher binding affinities were calculated for receptors than for the ligand. The best binding affinities to VEGFR1 were found for an artemisinin dimer, 10-dihydroartemisinyl-2-propylpentanoate, and dihydroartemisinin α-hemisuccinate sodium salt. QSAR analyses revealed significant relationships between VEGFR1 binding energies and defined molecular descriptors of 35 artemisinins assigned to the training set (R=0.0848, p<0.0001) and 17 derivatives assigned to the test set (R=0.761, p<0.001). Molecular docking and QSAR calculations can be used to identify novel artemisinin derivatives with anti-angiogenic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors.

PubMed

Rehman, Jalees; Li, Jingling; Orschell, Christie M; March, Keith L

2003-03-04

Endothelial progenitor cells (EPCs) have been isolated from peripheral blood and can enhance angiogenesis after infusion into host animals. It is not known whether the proangiogenic effects are a result of such events as endothelial differentiation and subsequent proliferation of EPCs or secondary to secretion of angiogenic growth factors. Human EPCs were isolated as previously described, and their phenotypes were confirmed by uptake of acetylated LDL and binding of ulex-lectin. EPC proliferation and surface marker expression were analyzed by flow cytometry, and conditioned medium was assayed for growth factors. The majority of EPCs expressed monocyte/macrophage markers such as CD14 (95.7+/-0.3%), Mac-1 (57.6+/-13.5%), and CD11c (90.8+/-4.9%). A much lower percentage of cells expressed the specific endothelial marker VE-cadherin (5.2+/-0.7%) or stem/progenitor-cell markers AC133 (0.16+/-0.05%) and c-kit (1.3+/-0.7%). Compared with circulating monocytes, cultured EPCs showed upregulation of monocyte activation and macrophage differentiation markers. EPCs did not demonstrate any significant proliferation but did secrete the angiogenic growth factors vascular endothelial growth factor, hepatocyte growth factor, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor. Our findings suggest that acetylated LDL(+)ulex-lectin(+) cells, commonly referred to as EPCs, do not proliferate but release potent proangiogenic growth factors. The majority of acetylated LDL(+)ulex-lectin(+) cells are derived from monocyte/macrophages. The findings of low proliferation and endothelial differentiation suggest that their angiogenic effects are most likely mediated by growth factor secretion. These findings may allow for development of novel angiogenic therapies relying on secreted growth factors or on recruitment of endogenous monocytes/macrophages to sites of ischemia.

Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder.

PubMed

Fontanari, Anna-Martha V; Andreazza, Tahiana; Costa, Ângelo B; Salvador, Jaqueline; Koff, Walter J; Aguiar, Bianca; Ferrari, Pamela; Massuda, Raffael; Pedrini, Mariana; Silveira, Esalba; Belmonte-de-Abreu, Paulo S; Gama, Clarissa S; Kauer-Sant'Anna, Marcia; Kapczinski, Flavio; Lobato, Maria Ines R

2013-10-01

Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disordersand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life. Copyright © 2013 Elsevier Ltd. All rights reserved.

The Use of Recombinant Human Platelet-Derived Growth Factor for Maxillary Sinus Augmentation.

PubMed

Kubota, Atsushi; Sarmiento, Hector; Alqahtani, Mohammed Saad; Llobell, Arturo; Fiorellini, Joseph P

The maxillary sinus augmentation procedure has become a predictable treatment to regenerate bone for implant placement. The purpose of this study was to evaluate the effect of recombinant human platelet-derived growth factor BB (rhPDGF-BB) combined with a deproteinized cancellous bovine bone graft for sinus augmentation. The lateral window approach was used for maxillary sinuses with minimal residual bone. After a healing period of 4 months, dental implants were placed and then restored following a 2-month osseointegration period. The result demonstrated increased bone height and ISQ values and a 100% survival rate. This study indicates that the addition of rhPDGF-BB to deproteinized cancellous bovine bone accelerated the healing period in maxillary sinuses with minimal native bone.

Factors influencing the antifolate activity of synthetic tea-derived catechins.

PubMed

Sáez-Ayala, Magalí; Fernández-Pérez, María Piedad; Chazarra, Soledad; Mchedlishvili, Nani; Tárraga-Tomás, Alberto; Rodríguez-López, José Neptuno

2013-07-16

Novel tea catechin derivatives have been synthesized, and a structure-activity study, related to the capacity of these and other polyphenols to bind dihydrofolate reductase (DHFR), has been performed. The data showed an effective binding between all molecules and the free enzyme, and the dissociation constants of the synthetic compounds and of the natural analogues were on the same order. Polyphenols with a catechin configuration were better DHFR inhibitors than those with an epicatechin configuration. Antiproliferative activity was also studied in cultured tumour cells, and the data showed that the activity of the novel derivatives was higher in catechin isomers. Derivatives with a hydroxyl group para on the ester-bonded gallate moiety presented a high in vitro binding to DHFR, but exhibited transport problems in cell culture due to ionization at physiologic pHs. The impact of the binding of catechins to serum albumin on their biological activity was also evaluated. The information provided in this study could be important for the design of novel medicinal active compounds derived from tea catechins. The data suggest that changes in their structure to avoid serum albumin interactions and to facilitate plasmatic membrane transport are essential for the intracellular functions of catechins.

Cardiac Nerve Growth Factor Overexpression Induces Bone Marrow-derived Progenitor Cells Mobilization and Homing to the Infarcted Heart.

PubMed

Meloni, Marco; Cesselli, Daniela; Caporali, Andrea; Mangialardi, Giuseppe; Avolio, Elisa; Reni, Carlotta; Fortunato, Orazio; Martini, Stefania; Madeddu, Paolo; Valgimigli, Marco; Nikolaev, Evgeni; Kaczmarek, Leszek; Angelini, Gianni D; Beltrami, Antonio P; Emanueli, Costanza

2015-12-01

Reparative response by bone marrow (BM)-derived progenitor cells (PCs) to ischemia is a multistep process that comprises the detachment from the BM endosteal niche through activation of osteoclasts and proteolytic enzymes (such as matrix metalloproteinases (MMPs)), mobilization to the circulation, and homing to the injured tissue. We previously showed that intramyocardial nerve growth factor gene transfer (NGF-GT) promotes cardiac repair following myocardial infarction (MI) in mice. Here, we investigate the impact of cardiac NGF-GT on postinfarction BM-derived PCs mobilization and homing at different time points after adenovirus-mediated NGF-GT in mice. Immunohistochemistry and flow cytometry newly illustrate the temporal profile of osteoclast and activation of MMP9, PCs expansion in the BM, and liberation/homing to the injured myocardium. NGF-GT amplified these responses and increased the BM levels of active osteoclasts and MMP9, which were not observed in MMP9-deficient mice. Taken together, our results suggest a novel role for NGF in BM-derived PCs mobilization/homing following MI.

Empirical Derivation of Correction Factors for Human Spiral Ganglion Cell Nucleus and Nucleolus Count Units.

PubMed

Robert, Mark E; Linthicum, Fred H

2016-01-01

Profile count method for estimating cell number in sectioned tissue applies a correction factor for double count (resulting from transection during sectioning) of count units selected to represent the cell. For human spiral ganglion cell counts, we attempted to address apparent confusion between published correction factors for nucleus and nucleolus count units that are identical despite the role of count unit diameter in a commonly used correction factor formula. We examined a portion of human cochlea to empirically derive correction factors for the 2 count units, using 3-dimensional reconstruction software to identify double counts. The Neurotology and House Histological Temporal Bone Laboratory at University of California at Los Angeles. Using a fully sectioned and stained human temporal bone, we identified and generated digital images of sections of the modiolar region of the lower first turn of cochlea, identified count units with a light microscope, labeled them on corresponding digital sections, and used 3-dimensional reconstruction software to identify double-counted count units. For 25 consecutive sections, we determined that double-count correction factors for nucleus count unit (0.91) and nucleolus count unit (0.92) matched the published factors. We discovered that nuclei and, therefore, spiral ganglion cells were undercounted by 6.3% when using nucleolus count units. We determined that correction factors for count units must include an element for undercounting spiral ganglion cells as well as the double-count element. We recommend a correction factor of 0.91 for the nucleus count unit and 0.98 for the nucleolus count unit when using 20-µm sections. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

Differences in Preferential Sorting of Fine Particles in the Panama Basin Over the Past 25 kyr: Effects on 230Th-derived Focusing Factors

NASA Astrophysics Data System (ADS)

Loveley, M. R.; Marcantonio, F.; Lyle, M. W.; Wang, J. K.

2013-12-01

In this study, we attempt to understand how preferential sorting of fine particles during redistribution processes in the Panama Basin affects the 230Th constant-flux proxy. Fine particles likely contain greater amounts of 230Th, so that preferential sorting of fine particles may bias sediment mass accumulation rates (MARs). We examined sediments that span the past 25 kyr from two new sediment cores retrieved within about 56 km of each other in the northern part of the basin (MV1013-01-'4JC', 5° 44.699'N 85° 45.498' W, 1730 m depth; MV1014-01-'8JC', 6° 14.038'N 86° 2.613' W, 1993 m depth). Core 4JC, closer to the ridge top that bounds the basin (Cocos Ridge), has a thin sediment drape, while the deeper core 8JC, has a thicker sediment drape and lies further from the ridge top. 230Th-derived focusing factors from 4JC are similar and suggest winnowing with average values of about 0.5 and 0.6 during the Holocene and the last glacial, respectively. For 8JC, calculated average focusing factors are significantly different and suggest focusing with values of about 2 during the Holocene and 4 during the last glacial. Since the two sites are close to each other, one would expect similar rain rates and, therefore, similar 230Th-derived MARs within similar windows of time, i.e., the rain rate should not vary significantly at each site temporally. In addition, the radiocarbon-derived sand (>63μm) MARs should behave similarly since coarser particles are likely not transported by bottom currents. Sand MARs are, indeed, similar during the Holocene and the last glacial at each site. During the last glacial, however, sand MARs are about a factor of 3 higher than those during the Holocene. On the other hand, there is little variability in the 230Th-derived MARs both spatially and temporally. We interpret the discrepancies between the radiocarbon-derived sand and 230Th-derived MARs as being due to preferential sorting of fine particles during the redistribution of sediments by

Injectable Biodegradable Polyurethane Scaffolds with Release of Platelet-derived Growth Factor for Tissue Repair and Regeneration

PubMed Central

Hafeman, Andrea E.; Li, Bing; Yoshii, Toshitaka; Zienkiewicz, Katarzyna; Davidson, Jeffrey M.; Guelcher, Scott A.

2013-01-01

Purpose The purpose of this work was to investigate the effects of triisocyanate composition on the biological and mechanical properties of biodegradable, injectable polyurethane scaffolds for bone and soft tissue engineering. Methods Scaffolds were synthesized using reactive liquid molding techniques, and were characterized in vivo in a rat subcutaneous model. Porosity, dynamic mechanical properties, degradation rate, and release of growth factors were also measured. Results Polyurethane scaffolds were elastomers with tunable damping properties and degradation rates, and they supported cellular infiltration and generation of new tissue. The scaffolds showed a two-stage release profile of platelet-derived growth factor, characterized by a 75% burst release within the first 24 h and slower release thereafter. Conclusions Biodegradable polyurethanes synthesized from triisocyanates exhibited tunable and superior mechanical properties compared to materials synthesized from lysine diisocyanates. Due to their injectability, biocompatibility, tunable degradation, and potential for release of growth factors, these materials are potentially promising therapies for tissue engineering. PMID:18516665

Posttraumatic Propofol Neurotoxicity Is Mediated via the Pro-Brain-Derived Neurotrophic Factor-p75 Neurotrophin Receptor Pathway in Adult Mice.

PubMed

Sebastiani, Anne; Granold, Matthias; Ditter, Anja; Sebastiani, Philipp; Gölz, Christina; Pöttker, Bruno; Luh, Clara; Schaible, Eva-Verena; Radyushkin, Konstantin; Timaru-Kast, Ralph; Werner, Christian; Schäfer, Michael K; Engelhard, Kristin; Moosmann, Bernd; Thal, Serge C

2016-02-01

The gamma-aminobutyric acid modulator propofol induces neuronal cell death in healthy immature brains by unbalancing neurotrophin homeostasis via p75 neurotrophin receptor signaling. In adulthood, p75 neurotrophin receptor becomes down-regulated and propofol loses its neurotoxic effect. However, acute brain lesions, such as traumatic brain injury, reactivate developmental-like programs and increase p75 neurotrophin receptor expression, probably to foster reparative processes, which in turn could render the brain sensitive to propofol-mediated neurotoxicity. This study investigates the influence of delayed single-bolus propofol applications at the peak of p75 neurotrophin receptor expression after experimental traumatic brain injury in adult mice. Randomized laboratory animal study. University research laboratory. Adult C57BL/6N and nerve growth factor receptor-deficient mice. Sedation by IV propofol bolus application delayed after controlled cortical impact injury. Propofol sedation at 24 hours after traumatic brain injury increased lesion volume, enhanced calpain-induced αII-spectrin cleavage, and increased cell death in perilesional tissue. Thirty-day postinjury motor function determined by CatWalk (Noldus Information Technology, Wageningen, The Netherlands) gait analysis was significantly impaired in propofol-sedated animals. Propofol enhanced pro-brain-derived neurotrophic factor/brain-derived neurotrophic factor ratio, which aggravates p75 neurotrophin receptor-mediated cell death. Propofol toxicity was abolished both by pharmacologic inhibition of the cell death domain of the p75 neurotrophin receptor (TAT-Pep5) and in mice lacking the extracellular neurotrophin binding site of p75 neurotrophin receptor. This study provides first evidence that propofol sedation after acute brain lesions can have a deleterious impact and implicates a role for the pro-brain-derived neurotrophic factor-p75 neurotrophin receptor pathway. This observation is important as sedation

Controllable Syntheses of MOF-Derived Materials.

PubMed

Zou, Kang-Yu; Li, Zuo-Xi

2018-05-02

Metal-organic frameworks (MOFs), as an important kind of porous inorganic-organic hybrid materials with inherent outstanding physicochemistry characteristics, can be widely applied as versatile precursors for the facile preparation of functional MOF-derived materials. However, there are plenty of sophisticated factors during the synthetic process, which is far from reaching the goal of effectively controlling the nature of MOF-derived materials (such as the composition, morphology and surface area). Therefore, it is urgently necessary to develop regular protocols and concepts for controllable syntheses of MOF-derived materials. In this minireview, we mainly summarize and analyze complicated factors in the fabrication of MOF-derived materials according to recently reported literatures, and this provides a new insight into the rational design and syntheses of MOF-derived materials. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Statistical Analysis of Instantaneous Frequency Scaling Factor as Derived From Optical Disdrometer Measurements At KQ Bands

NASA Technical Reports Server (NTRS)

Zemba, Michael; Nessel, James; Houts, Jacquelynne; Luini, Lorenzo; Riva, Carlo

2016-01-01

The rain rate data and statistics of a location are often used in conjunction with models to predict rain attenuation. However, the true attenuation is a function not only of rain rate, but also of the drop size distribution (DSD). Generally, models utilize an average drop size distribution (Laws and Parsons or Marshall and Palmer. However, individual rain events may deviate from these models significantly if their DSD is not well approximated by the average. Therefore, characterizing the relationship between the DSD and attenuation is valuable in improving modeled predictions of rain attenuation statistics. The DSD may also be used to derive the instantaneous frequency scaling factor and thus validate frequency scaling models. Since June of 2014, NASA Glenn Research Center (GRC) and the Politecnico di Milano (POLIMI) have jointly conducted a propagation study in Milan, Italy utilizing the 20 and 40 GHz beacon signals of the Alphasat TDP#5 Aldo Paraboni payload. The Ka- and Q-band beacon receivers provide a direct measurement of the signal attenuation while concurrent weather instrumentation provides measurements of the atmospheric conditions at the receiver. Among these instruments is a Thies Clima Laser Precipitation Monitor (optical disdrometer) which yields droplet size distributions (DSD); this DSD information can be used to derive a scaling factor that scales the measured 20 GHz data to expected 40 GHz attenuation. Given the capability to both predict and directly observe 40 GHz attenuation, this site is uniquely situated to assess and characterize such predictions. Previous work using this data has examined the relationship between the measured drop-size distribution and the measured attenuation of the link]. The focus of this paper now turns to a deeper analysis of the scaling factor, including the prediction error as a function of attenuation level, correlation between the scaling factor and the rain rate, and the temporal variability of the drop size

Statistical Analysis of Instantaneous Frequency Scaling Factor as Derived From Optical Disdrometer Measurements At KQ Bands

NASA Technical Reports Server (NTRS)

Zemba, Michael; Nessel, James; Houts, Jacquelynne; Luini, Lorenzo; Riva, Carlo

2016-01-01

The rain rate data and statistics of a location are often used in conjunction with models to predict rain attenuation. However, the true attenuation is a function not only of rain rate, but also of the drop size distribution (DSD). Generally, models utilize an average drop size distribution (Laws and Parsons or Marshall and Palmer [1]). However, individual rain events may deviate from these models significantly if their DSD is not well approximated by the average. Therefore, characterizing the relationship between the DSD and attenuation is valuable in improving modeled predictions of rain attenuation statistics. The DSD may also be used to derive the instantaneous frequency scaling factor and thus validate frequency scaling models. Since June of 2014, NASA Glenn Research Center (GRC) and the Politecnico di Milano (POLIMI) have jointly conducted a propagation study in Milan, Italy utilizing the 20 and 40 GHz beacon signals of the Alphasat TDP#5 Aldo Paraboni payload. The Ka- and Q-band beacon receivers provide a direct measurement of the signal attenuation while concurrent weather instrumentation provides measurements of the atmospheric conditions at the receiver. Among these instruments is a Thies Clima Laser Precipitation Monitor (optical disdrometer) which yields droplet size distributions (DSD); this DSD information can be used to derive a scaling factor that scales the measured 20 GHz data to expected 40 GHz attenuation. Given the capability to both predict and directly observe 40 GHz attenuation, this site is uniquely situated to assess and characterize such predictions. Previous work using this data has examined the relationship between the measured drop-size distribution and the measured attenuation of the link [2]. The focus of this paper now turns to a deeper analysis of the scaling factor, including the prediction error as a function of attenuation level, correlation between the scaling factor and the rain rate, and the temporal variability of the drop

Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

PubMed

Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

2015-12-01

Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

Grain Size Biasing of 230Th-derived Focusing Factors in the Panama Basin

NASA Astrophysics Data System (ADS)

Loveley, M. R.; Marcantonio, F.; Lyle, M. W.; Ibrahim, R.; Wang, J. K.; Hertzberg, J. E.

2014-12-01

In this study, we attempt to understand how differing grain size classes in Panama Basin sediments may create biasing of 230Th as a constant-flux proxy. Greater amounts of 230Th are contained in fine grained particles, which, if fractionated from coarser grained counterparts may lead to biasing of 230Th-derived mass accumulation rates (MARs) and sediment focusing factors. We examined sediments that span the past 25 kyr from four new sediment cores retrieved from two different localities close to the ridges that bound the Panama Basin. Each locality contained paired sites that were seismically interpreted to have undergone sediment redistribution, i.e., thick focused sites versus thin winnowed sites. Two sediment cores were retrieved from the northern part of the Panama basin, Cocos Ridge, (MV1014-01-"4JC", 5° 44.7'N 85° 45.5' W, 1730 m depth; MV1014-01-"8JC", 6° 14.0'N 86° 2.6' W, 1993 m depth), and two were retrieved from the southern part of the basin, Carnegie Ridge, (MV1014-02-"11JC", 0° 41.6'S 85° 20.0' W, 2452 m depth; MV1014-02-"17JC" 0° 10.8'S 85° 52.0' W, 2846 m depth). Cores 4JC and 11JC lie closer to the ridge tops of the Cocos and Carnegie Ridges, respectively, and have thin sediment drapes, while deeper cores, 8JC (Cocos) and 17JC (Carnegie), have thicker sediment drapes and lie downslope from the ridge top cores. Age-model-derived sand MARs, which likely represent the vertical rain of particles that cannot be transported by bottom currents, are similar at each of the paired sites in Holocene and glacial time slices. However, 230Th-normalized MARs are about 50% lower, on average at each of the paired sites during the same time slices. Both Holocene and glacial samples from "thin" cores (4,11JC) contain, surprisingly, significant amounts (up to 50%) of the 230Th within the coarse grained (>63 μm) fraction which makes up 40-70% of the bulk samples analyzed. On the contrary, Holocene and glacial samples from "thick" cores, (8,17JC), contain the

Characteristics of yak platelet derived growth factors-alpha gene and expression in brain tissues.

PubMed

Huang, Zhenhua; Pan, Yangyang; Liu, Penggang; Yu, Sijiu; Cui, Yan

2017-05-29

Platelet derived growth factors (PDGFs) are key components of autocrine and paracrine signaling, both of which play important roles in mammalian developmental processes. PDGF expression levels also relate to oxygen levels. The characteristics of yak PDGFs, which are indigenous to hypoxic environments, have not been clearly described until the current study. We amplified the open reading frame encoding yak (Bos grunniens) platelet derived growth factor-a (PDGFA) from a yak skin tissue cDNA library by reverse transcriptase polymerase chain reaction (PCR) using specific primers and Sanger dideoxy sequencing. Expression of PDGFA mRNA in different portions of yak brain tissue (cerebrum, cerebellum, hippocampus, and spinal cord) was detected by quantitative real-time PCR (qRT-PCR). PDGFA protein expression levels and its location in different portions of the yak brain were evaluated by western blot and immunohistochemistry. We obtained a yak PDGFA 755 bp cDNA gene fragment containing a 636 bp open reading frame, encoding 211 amino acids (GenBank: KU851801). Phylogenetic analysis shows yak PDGFA to be well conserved, having 98.1% DNA sequence identity to homologous Bubalus bubalus and Bos taurus PDGFA genes. However, eight nucleotides in the yak DNA sequence and four amino acids in the yak protein sequence differ from the other two species. PDGFA is widely expressed in yak brain tissue, and furthermore, PDGFA expression in the cerebrum and cerebellum are higher than in the hippocampus and spinal cord (p > 0.05). PDGFA was observed by immunohistochemistry in glial cells of the cerebrum, cerebellum, and hippocampus, as well as in pyramidal cells of the cerebrum, and Purkinje cell bodies of the hippocampus, but not in glial cells of the spinal cord. The PDGFA gene is well conserved in the animal kingdom; however, the yak PDGFA gene has unique characteristics and brain expression patterns specific to this high elevation species.

Sex Differences in Brain-Derived Neurotrophic Factor Signaling and Functions

PubMed Central

Chan, Chi Bun; Ye, Keqiang

2016-01-01

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that plays a critical role in numerous neuronal activities. Recent studies report that some functions or action mechanisms of BDNF vary in a sex-dependent manner. In particular, BDNF content in some brain parts and the tendency of developing BDNF-deficient-related diseases like depression is higher in female animals. With the support of other relevant studies, it is suggested that sex hormones or steroids can modulate the activities of BDNF, which may account for its functional discrepancy in different sexes. Indeed, the cross-talk between BDNF and sex steroids has been detected for decades and some sex steroids like estrogen have a positive regulatory effect to BDNF expression and signaling. Thus, the sex of animal models used is critical when studying the functions of BDNF in vivo. In this review, we will summarize our current findings on the difference in expression, signaling, and functions of BDNF between sexes. We will also discuss the potential mechanisms in mediating these differential responses with a specific emphasis on sex steroids. By presenting and discussing these findings, we encourage taking sex influences into consideration when designing experiments, interpreting results and drawing conclusions. PMID:27870419

Role of fibroblast-derived factors in the pathogenesis of melasma.

PubMed

Byun, J W; Park, I S; Choi, G S; Shin, J

2016-08-01

The hyperactive melanocytes present in melasma skin are confined to the epidermis, but epidermal ablation to treat melasma pigmentation may lead to disease recurrence and aggravation. Melanocyte function is regulated by interactions between melanocytes and neighbouring cells such as keratinocytes and fibroblasts. Because melasma skin usually shows dermal changes after exposure to sunlight, we hypothesized that sun-damaged fibroblasts might play a crucial role in the pathogenesis of melasma. In this study, the melanogenic role of primary cultured fibroblasts from human melasma skin was investigated. We explored whether primary cultured fibroblasts from melasma tissue have a melanogenic function on cultured human epidermal melanocytes and artificial skin. The cytokine profile derived from fibroblasts and their effect on the pigmented epidermal equivalents were investigated. Fibroblasts from the melasma lesion and perilesional skin increased melanogenesis in cultured human epidermal melanocytes and in artificial skin. Fibroblasts from the melasma lesion and perilesional skin secreted more nerve growth factor (NGF)-β than those in normal buttock skin, and also increased melanogenesis and the expression level of NGF-β in cultured human epidermal melanocytes and artificial skin. These results suggest that fibroblasts may play a role in melanogenesis and the pathogenesis of melasma. © 2016 British Association of Dermatologists.

Analysis of Activated Platelet-Derived Growth Factor β Receptor and Ras-MAP Kinase Pathway in Equine Sarcoid Fibroblasts

PubMed Central

Altamura, Gennaro; Corteggio, Annunziata; Nasir, Lubna; Yuan, Zheng Qiang; Roperto, Franco; Borzacchiello, Giuseppe

2013-01-01

Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1) and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor β receptor (PDGFβR) causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGFβR is phosphorylated and binds downstream molecules related to Ras-mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGFβR in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm. PMID:23936786

Inhibitory effects of polysaccharide extract from Spirulina platensis on corneal neovascularization

PubMed Central

Yang, Lingling; Wang, Yao; Zhou, Qingjun; Chen, Peng; Wang, Yiqiang; Wang, Ye; Liu, Ting

2009-01-01

Purpose To assess the effects of polysaccharide extract from Spirulina platensis (PSP) on corneal neovascularization (CNV) in vivo and in vitro. Methods PSP was extracted from dry powder of Spirulina platensis. Its anti-angiogenic activity was evaluated in the mouse corneal alkali burn model after topical administration of PSP four times daily for up to seven days. Corneal samples were processed for histochemical, immunohistochemical, and gene expression analyses. The effects of PSP on proliferation, migration, tube formation, and serine threonine kinase (AKT) and extracellular regulated kinase1/2 (ERK1/2) signaling levels in vascular endothelial cells were determined using 3-(4,5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) and carboxyfluorescein succinimidyl ester (CFSE) labeling assays, wound healing assay, Matrigel tube formation assay, and western blot. Results Topical application of PSP significantly inhibited CNV caused by alkali burn. Corneas treated with PSP showed reduced levels of platelet endothelial cell adhesion molecule (CD31) and stromal cell-derived factor 1 (SDF1) proteins, reduced levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-9 (MMP9), SDF1, and tumor necrosis factor-alpha (TNF-α) mRNAs, and an increased level of pigment epithelium-derived factor (PEDF) mRNA. These are parameters that have all been related to CNV and/or inflammation. In human vascular endothelial cells, PSP significantly inhibited proliferation, migration, and tube formation in a dose-dependent manner. Furthermore, PSP also decreased the levels of activated AKT and ERK 1/2. Conclusions These data suggest that polysaccharide extract from Spirulina platensis is a potent inhibitor of CNV and that it may be of benefit in the therapy of corneal diseases involving neovascularization and inflammation. PMID:19784394

The association between serum brain-derived neurotrophic factor and a cluster of cardiovascular risk factors in adolescents: The CHAMPS-study DK

PubMed Central

Tarp, Jakob; Andersen, Lars Bo; Gejl, Anne Kær; Huang, Tao; Peijs, Lone; Bugge, Anna

2017-01-01

Background and objective Cardiovascular disease and type 2 diabetes pose a global health burden. Therefore, clarifying the pathology of these risk factors is essential. Previous studies have found positive and negative associations between one or more cardiovascular risk factors and brain-derived neurotrophic factor (BDNF) probably due to diverse methodological approaches when analysing peripheral BDNF levels. Moreover, only a few studies have been performed in youth populations. Consequently, the main objective of this study was to examine the association between serum BDNF and a composite z-score consisting of six cardiovascular risk factors. A secondary aim was to examine the associations between serum BDNF and each of the six risk factors. Methods Four hundred and forty-seven apparently healthy adolescents between 11–17 years of age participated in this cross-sectional study. Cardiorespiratory fitness (CRF), anthropometrics, pubertal status, blood pressure (BP), serum BDNF, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), blood glucose and insulin were measured. Information about alcohol consumption and socio-economic status was collected via questionnaires. Associations were modelled using linear regression analysis. Results Serum BDNF was positively associated with the composite z-score in the total study sample (standardized beta coefficient (std.β) = 0.10, P = 0.037). In males, serum BDNF was positively associated with the composite z-score (Std. β = 0.14, P = 0.034) and HOMA-IR (Std. β = 0.19, P = 0.004), and negatively associated with CRF (Std. β = -0.15, P = 0.026). In females, BDNF was positively associated with TG (Std. β = 0.14, P = 0.030) and negatively associated with waist circumference (WC) (Std. β = -0.16, P = 0.012). Conclusion Serum BDNF was positively associated with a composite z-score of cardiovascular risk factors. This association seems to be mainly driven by the association between TG, HOMA-IR and serum BDNF, and

Derived Basic Ability Factors: A Factor Analysis Replication Study.

ERIC Educational Resources Information Center

Lee, Mickey, M.; Lee, Lynda Newby

The purpose of this study was to replicate the study conducted by Potter, Sagraves, and McDonald to determine whether their recommended analysis could separate criterion variables into similar factors that were stable from year to year and from school to school. The replication samples consisted of all students attending Louisiana State University…

Quantification of platelets and platelet derived growth factors from platelet-rich-plasma (PRP) prepared at different centrifugal force (g) and time.

PubMed

Arora, Satyam; Doda, Veena; Kotwal, Urvershi; Dogra, Mitu

2016-02-01

Platelet derived biomaterials represent a key source of cytokines and growth factors extensively used for tissue regeneration; wound healing and tissue repair. Our study was to quantify platelets and growth factors released by PRP when prepared at different centrifugal force (g) and time. Our study was approved by the institutional ethical committee. One hundred millilitres of whole blood (WB) was collected in bag with CPDA as the anticoagulant(AC); (14 mL for 100 mL WB ratio). Nine aliquots of 10 mL each were made from the bag and set of three aliquots were made a group. PRP was prepared at varying centrifugal force (group A: -110 g, group B: -208 g & group C: -440 g) & time (1: -5 min, 2: -10 min & 3: -20 min). Contents of each PRP prepared were analysed. Commercial sandwich ELISA kits were used to quantify the concentrations of CD62P (Diaclone SAS; France), Platelet derived growth factors-AB (Qayee-Bio; China), transforming growth factor-β1 (DRG; Germany) and vascular endothelial growth factor (Boster Immuno Leader; USA) released in each PRP prepared. Eight volunteers were enrolled in the study (24-30 years). The baseline blood counts of all the volunteers were comparable (p ≥ 0.05). Mean ± SD of platelet yield of all nine groups ranged from 17.2 ± 4.2% to 78.7 ± 5.7%. Each PRP was activated with calcified thromboplastin to quantify the growth factors released by them. Significantly higher (p < 0.05) transforming growth factor-β1 and vascular endothelial growth factor were released compared to the baseline. Our study highlights the variation in both force (g) and time results in changes at cellular level and growth factor concentrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prognostic value of platelet-derived growth factor-A (PDGF-A) in gastric carcinoma.

PubMed Central

Katano, M; Nakamura, M; Fujimoto, K; Miyazaki, K; Morisaki, T

1998-01-01

OBJECTIVE: Because our previous study indicated that PDGF-A mRNA expression in biopsy specimens might identify a subgroup of high-risk patients with gastric carcinoma, in this study we analyzed the prognostic value of platelet-derived growth factor-A (PDGF-A) gene expression in gastric carcinoma biopsy specimens. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to analyze the PDGF-A gene expression in 65 gastric carcinoma endoscopic biopsy specimens. The 65 patients were divided into a PDGF-A-positive group (29 patients) and a PDGF-A-negative group (36 patients). RESULTS: On the basis of 2-year follow-up data, the PDGF-A-positive group demonstrated a shorter overall survival rate compared with the PDGF-A-negative group (p < 0.0001). A similar correlation was found in 34 advanced-stage patients (p = 0.003) and in 24 advanced-stage patients who underwent a curative resection (p = 0.003). Multivariance analysis indicated that the transcription of PDGF-A gene is a potent prognostic factor that is independent of the traditional pathologic parameters. CONCLUSIONS: Expression of PDGF-A mRNA in gastric biopsy specimens may be a new preoperative prognostic parameter in gastric carcinoma. Images Figure 1. Figure 5. PMID:9527059

Growth factors in porcine full and partial thickness burn repair. Differing targets and effects of keratinocyte growth factor, platelet-derived growth factor-BB, epidermal growth factor, and neu differentiation factor.

PubMed Central

Danilenko, D. M.; Ring, B. D.; Tarpley, J. E.; Morris, B.; Van, G. Y.; Morawiecki, A.; Callahan, W.; Goldenberg, M.; Hershenson, S.; Pierce, G. F.

1995-01-01

The topical application of recombinant growth factors such as epidermal growth factor, platelet-derived growth factor-BB homodimer (rPDGF-BB), keratinocyte growth factor (rKGF), and neu differentiation factor has resulted in significant acceleration of healing in several animal models of wound repair. In this study, we established highly reproducible and quantifiable full and deep partial thickness porcine burn models in which burns were escharectomized 4 or 5 days postburn and covered with an occlusive dressing to replicate the standard treatment in human burn patients. We then applied these growth factors to assess their efficacy on several parameters of wound repair: extracellular matrix and granulation tissue production, percent reepithelialization, and new epithelial area. In full thickness burns, only rPDGF-BB and the combination of rPDGF-BB and rKGF induced significant changes in burn repair. rPDGF-BB induced marked extracellular matrix and granulation tissue production (P = 0.013) such that the burn defect was filled within several days of escharectomy, but had no effect on new epithelial area or reepithelialization. The combination of rPDGF-BB and rKGF in full thickness burns resulted in a highly significant increase in extracellular matrix and granulation tissue area (P = 0.0009) and a significant increase in new epithelial area (P = 0.007), but had no effect on reepithelialization. In deep partial thickness burns, rKGF induced the most consistent changes. Daily application of rKGF induced a highly significant increase in new epithelial area (P < 0.0001) but induced only a modest increase in reepithelialization (83.7% rKGF-treated versus 70.2% control; P = 0.016) 12 days postburn. rKGF also doubled the number of fully reepithelialized burns (P = 0.02) at 13 days postburn, at least partially because of marked stimulation of both epidermal and follicular proliferation as assessed by proliferating cell nuclear antigen expression. In situ hybridization for

Adenoviral modification of mouse brain derived endothelial cells, bEnd3, to induce apoptosis by vascular endothelial growth factor.

PubMed

Mitsuuchi, Y; Powell, D R; Gallo, J M

2006-02-09

A second generation genetically-engineered cell-based drug delivery system, referred to as apoptotic-induced drug delivery (AIDD), was developed using endothelial cells (ECs) that undergo apoptosis upon binding of vascular endothelial growth factor (VEGF) to a Flk-1:Fas fusion protein (FF). This new AIDD was redesigned using mouse brain derived ECs, bEnd3 cells, and an adenovirus vector in order to enhance and control the expression of FF. The FF was tagged with a HA epitope (FFHA) and designed to be coexpressed with green fluorescence protein (GFP) by the regulation of cytomegalovirus promoters in the adenovirus vector. bEnd3 cells showed favorable coexpression of FFHA and GFP consistent with the multiplicity of infection of the adenovirus. Immunofluorescence analysis demonstrated that FFHA was localized at the plasma membrane, whereas GFP was predominantly located in the cytoplasm of ECs. Cell death was induced by VEGF, but not by platelet derived growth factor or fibroblast growth factor in a dose-dependent manner (range 2-20 ng/ml), and revealed caspase-dependent apoptotic profiles. The FFHA expressing bEnd3 cells underwent apoptosis when cocultured with a glioma cell (SF188V+) line able to overexpress VEGF. The combined data indicated that the FFHA adenovirus system can induce apoptotic signaling in ECs in response to VEGF, and thus, is an instrumental modification to the development of AIDD.

Platelet-derived growth factor-dependent association of the GTPase-activating protein of Ras and Src.

PubMed Central

Schlesinger, T K; Demali, K A; Johnson, G L; Kazlauskas, A

1999-01-01

Here we report that the platelet-derived growth factor beta receptor (betaPDGFR) is not the only tyrosine kinase able to associate with the GTPase-activating protein of Ras (RasGAP). The interaction of non-betaPDGFR kinase(s) with RasGAP was dependent on stimulation with platelet-derived growth factor (PDGF) and seemed to require tyrosine phosphorylation of RasGAP. Because the tyrosine phosphorylation site of RasGAP is in a sequence context that is favoured by the Src homology 2 ('SH2') domain of Src family members, we tested the possibility that Src was the kinase that associated with RasGAP. Indeed, Src interacted with phosphorylated RasGAP fusion proteins; immunodepletion of Src markedly decreased the recovery of the RasGAP-associated kinase activity. Thus PDGF-dependent tyrosine phosphorylation of RasGAP results in the formation of a complex between RasGAP and Src. To begin to address the relevance of these observations, we focused on the consequences of the interaction of Src and RasGAP. We found that a receptor mutant that did not activate Src was unable to efficiently mediate the tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Taken together, these observations support the following hypothesis. When RasGAP is recruited to the betaPDGFR, it is phosphorylated and associates with Src. Once bound to RasGAP, Src is no longer able to promote the phosphorylation of PLCgamma. This hypothesis offers a mechanistic explanation for our previously published findings that the recruitment of RasGAP to the betaPDGFR attenuates the tyrosine phosphorylation of PLCgamma. Finally, these findings suggest a novel way in which RasGAP negatively regulates signal relay by the betaPDGFR. PMID:10567236

Rapid and Sensitive Detection of Brain-Derived Neurotrophic Factor with a Plasmonic Chip

NASA Astrophysics Data System (ADS)

Tawa, Keiko; Satoh, Mari; Uegaki, Koichi; Hara, Tomoko; Kojima, Masami; Kumanogoh, Haruko; Aota, Hiroyuki; Yokota, Yoshiki; Nakaoki, Takahiko; Umetsu, Mitsuo; Nakazawa, Hikaru; Kumagai, Izumi

2013-06-01

Plasmonic chips, which are grating replicas coated with thin metal layers and overlayers such as ZnO, were applied in immunosensors to improve their detection sensitivity. Fluorescence from labeled antibodies bound to plasmonic chips can be enhanced on the basis of a grating-coupled surface plasmon resonance (GC-SPR) field. In this study, as one of the representative candidate protein markers for brain disorders, the brain-derived neurotrophic factor (BDNF) was quantitatively measured by sandwich assay on a plasmonic chip and detected on our plasmonic chip in the concentration of 5-7 ng/mL within 40 min. Furthermore, BDNF was detected in the blood sera from three types of mice: wild-type mice and two types of mutant mice. This technique is promising as a new clinical diagnosis tool for brain disorders based on scientific evidence such as blood test results.

Expression of platelet-derived growth factor and its receptors in proliferative disorders of fibroblastic origin.

PubMed

Smits, A; Funa, K; Vassbotn, F S; Beausang-Linder, M; af Ekenstam, F; Heldin, C H; Westermark, B; Nistér, M

1992-03-01

Platelet-derived growth factor (PDGF) is known to stimulate the proliferation of connective tissue-derived cells in vitro. Less is known about its functions in vivo, and the role of PDGF in the development of human tumors has not been clarified. The authors have investigated the occurrence of PDGF and PDGF receptors in a series of proliferative disorders of fibroblastic origin using immunohistochemical and in situ hybridization techniques. High expression of PDGF beta-receptor mRNA and protein was found in the malignant tumors, and also in some benign lesions, such as dermatofibroma. In all these cases, benign as well as malignant, the PDGF B-chain mRNA, and less clearly, the PDGF A-chain mRNA, were coexpressed with the beta-receptor. In contrast, high expression of PDGF alpha-receptor mRNA was only found in fully malignant lesions, i.e., malignant fibrous histiocytoma. These data indicate that an autocrine growth stimulation via the PDGF beta-receptor could occur in an early phase of tumorigenesis, and may be a necessary but insufficient event for the progression into fully malignant human connective tissue lesions.

Expression of platelet-derived growth factor and its receptors in proliferative disorders of fibroblastic origin.

PubMed Central

Smits, A.; Funa, K.; Vassbotn, F. S.; Beausang-Linder, M.; af Ekenstam, F.; Heldin, C. H.; Westermark, B.; Nistér, M.

1992-01-01

Platelet-derived growth factor (PDGF) is known to stimulate the proliferation of connective tissue-derived cells in vitro. Less is known about its functions in vivo, and the role of PDGF in the development of human tumors has not been clarified. The authors have investigated the occurrence of PDGF and PDGF receptors in a series of proliferative disorders of fibroblastic origin using immunohistochemical and in situ hybridization techniques. High expression of PDGF beta-receptor mRNA and protein was found in the malignant tumors, and also in some benign lesions, such as dermatofibroma. In all these cases, benign as well as malignant, the PDGF B-chain mRNA, and less clearly, the PDGF A-chain mRNA, were coexpressed with the beta-receptor. In contrast, high expression of PDGF alpha-receptor mRNA was only found in fully malignant lesions, i.e., malignant fibrous histiocytoma. These data indicate that an autocrine growth stimulation via the PDGF beta-receptor could occur in an early phase of tumorigenesis, and may be a necessary but insufficient event for the progression into fully malignant human connective tissue lesions. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:1372158

Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases.

PubMed

Son, Bo-Ra; Marquez-Curtis, Leah A; Kucia, Magda; Wysoczynski, Marcin; Turner, A Robert; Ratajczak, Janina; Ratajczak, Mariusz Z; Janowska-Wieczorek, Anna

2006-05-01

Human mesenchymal stem cells (MSCs) are increasingly being considered in cell-based therapeutic strategies for regeneration of various organs/tissues. However, the signals required for their homing and recruitment to injured sites are not yet fully understood. Because stromal-derived factor (SDF)-1 and hepatocyte growth factor (HGF) become up-regulated during tissue/organ damage, in this study we examined whether these factors chemoattract ex vivo-expanded MSCs derived from bone marrow (BM) and umbilical cord blood (CB). Specifically, we investigated the expression by MSCs of CXCR4 and c-met, the cognate receptors of SDF-1 and HGF, and their functionality after early and late passages of MSCs. We also determined whether MSCs express matrix metalloproteinases (MMPs), including membrane type 1 (MT1)-MMP, matrix-degrading enzymes that facilitate the trafficking of hematopoietic stem cells. We maintained expanded BM- or CB-derived MSCs for up to 15-18 passages with monitoring of the expression of 1) various tissue markers (cardiac and skeletal muscle, neural, liver, and endothelial cells), 2) functional CXCR4 and c-met, and 3) MMPs. We found that for up to 15-18 passages, both BM- and CB-derived MSCs 1) express mRNA for cardiac, muscle, neural, and liver markers, as well as the vascular endothelial (VE) marker VE-cadherin; 2) express CXCR4 and c-met receptors and are strongly attracted by SDF-1 and HGF gradients; 3) express MMP-2 and MT1-MMP transcripts and proteins; and 4) are chemo-invasive across the reconstituted basement membrane Matrigel. These in vitro results suggest that the SDF-1-CXCR4 and HGF-c-met axes, along with MMPs, may be involved in recruitment of expanded MSCs to damaged tissues.

The Effect of Brain-Derived Neurotrophic Factor on Periodontal Furcation Defects

PubMed Central

Jimbo, Ryo; Tovar, Nick; Janal, Malvin N.; Mousa, Ramy; Marin, Charles; Yoo, Daniel; Teixeira, Hellen S.; Anchieta, Rodolfo B.; Bonfante, Estevam A.; Konishi, Akihiro; Takeda, Katsuhiro; Kurihara, Hidemi; Coelho, Paulo G.

2014-01-01

This study aimed to observe the regenerative effect of brain-derived neurotrophic factor (BDNF) in a non-human primate furcation defect model. Class II furcation defects were created in the first and second molars of 8 non-human primates to simulate a clinical situation. The defect was filled with either, Group A: BDNF (500 µg/ml) in high-molecular weight-hyaluronic acid (HMW-HA), Group B: BDNF (50 µg/ml) in HMW-HA, Group C: HMW-HA acid only, Group D: empty defect, or Group E: BDNF (500 µg/ml) in saline. The healing status for all groups was observed at different time-points with micro computed tomography. The animals were euthanized after 11 weeks, and the tooth-bone specimens were subjected to histologic processing. The results showed that all groups seemed to successfully regenerate the alveolar buccal bone, however, only Group A regenerated the entire periodontal tissue, i.e., alveolar bone, cementum and periodontal ligament. It is suggested that the use of BDNF in combination with a scaffold such as the hyaluronic acid in periodontal furcation defects may be an effective treatment option. PMID:24454754

Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid–stimulated migration of murine osteosarcoma LM8 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kubohara, Yuzuru, E-mail: ykuboha@juntendo.ac.jp; Department of Health Science, Juntendo University Graduate School of Health and Sports Science, Inzai 270-1695; Komachi, Mayumi

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), −2, and −3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5–20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC{sub 50} values of 5.5, 4.6, andmore » 4.2 μM, respectively. On the other hand, the IC{sub 50} values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. - Highlights: • LPA induces cell migration (invasion) in murine osteosarcoma LM8 cells. • DIFs are novel lead anti-tumor agents found in Dictyostelium discoideum. • We examined the effects of DIF derivatives on LPA-induced LM8 cell migration in vitro. • Some of the DIF derivatives inhibited LPA-induced LM8 cell migration.« less

Derivative chameleons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noller, Johannes, E-mail: johannes.noller08@imperial.ac.uk

2012-07-01

We consider generalized chameleon models where the conformal coupling between matter and gravitational geometries is not only a function of the chameleon field φ, but also of its derivatives via higher order co-ordinate invariants (such as ∂{sub μ}φ∂{sup μ}φ,□φ,...). Specifically we consider the first such non-trivial conformal factor A(φ,∂{sub μ}φ∂{sup μ}φ). The associated phenomenology is investigated and we show that such theories have a new generic mass-altering mechanism, potentially assisting the generation of a sufficiently large chameleon mass in dense environments. The most general effective potential is derived for such derivative chameleon setups and explicit examples are given. Interestingly thismore » points us to the existence of a purely derivative chameleon protected by a shift symmetry for φ → φ+c. We also discuss potential ghost-like instabilities associated with mass-lifting mechanisms and find another, mass-lowering and instability-free, branch of solutions. This suggests that, barring fine-tuning, stable derivative models are in fact typically anti-chameleons that suppress the field's mass in dense environments. Furthermore we investigate modifications to the thin-shell regime and prove a no-go theorem for chameleon effects in non-conformal geometries of the disformal type.« less

Analytic Couple Modeling Introducing Device Design Factor, Fin Factor, Thermal Diffusivity Factor, and Inductance Factor

NASA Technical Reports Server (NTRS)

Mackey, Jon; Sehirlioglu, Alp; Dynys, Fred

2014-01-01

A set of convenient thermoelectric device solutions have been derived in order to capture a number of factors which are previously only resolved with numerical techniques. The concise conversion efficiency equations derived from governing equations provide intuitive and straight-forward design guidelines. These guidelines allow for better device design without requiring detailed numerical modeling. The analytical modeling accounts for factors such as i) variable temperature boundary conditions, ii) lateral heat transfer, iii) temperature variable material properties, and iv) transient operation. New dimensionless parameters, similar to the figure of merit, are introduced including the device design factor, fin factor, thermal diffusivity factor, and inductance factor. These new device factors allow for the straight-forward description of phenomenon generally only captured with numerical work otherwise. As an example a device design factor of 0.38, which accounts for thermal resistance of the hot and cold shoes, can be used to calculate a conversion efficiency of 2.28 while the ideal conversion efficiency based on figure of merit alone would be 6.15. Likewise an ideal couple with efficiency of 6.15 will be reduced to 5.33 when lateral heat is accounted for with a fin factor of 1.0.

Serum brain-derived neurotrophic factor levels and personality traits in patients with major depression.

PubMed

Nomoto, Hiroshi; Baba, Hajime; Satomura, Emi; Maeshima, Hitoshi; Takebayashi, Naoko; Namekawa, Yuki; Suzuki, Toshihito; Arai, Heii

2015-03-04

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. Previous studies have demonstrated lower serum BDNF levels in patients with major depressive disorder (MDD) and reported an association between BDNF levels and depression-related personality traits in healthy subjects. The aim of the present study was to explore for a possible association between peripheral BDNF levels and personality traits in patients with MDD. In this cross-sectional study, a total of 123 inpatients with MDD (Diagnostic and Statistical Manual for Mental Disorders, 4th edition) at the Juntendo University Koshigaya Hospital were recruited. Serum levels of BDNF were measured. Personality traits were assessed using the 125-item short version of the Temperament and Character Inventory (TCI). Multiple regression analysis adjusted for age, sex, body mass index, dose of antidepressant, and depression severity showed that TCI Self-Directedness (SD) scores were negatively associated with serum BDNF levels (β = -0.23, p = 0.026). MDD patients who have low SD did not show the reduction in serum BDNF levels that is normally associated with depressive state. Our findings suggest that depression-related biological changes may not occur in these individuals.

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma

PubMed Central

Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-01-01

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion. PMID:28212546

Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma.

PubMed

Xiong, Ye; Liu, Liyun; Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

2017-04-11

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

Identification of gonadal soma-derived factor involvement in Monopterus albus (protogynous rice field eel) sex change.

PubMed

Zhu, Yefei; Wang, Chunlei; Chen, Xiaowu; Guan, Guijun

2016-07-01

We studied molecular events and potential mechanisms underlying the process of female-to-male sex transformation in the rice field eel (Monopterus albus), a protogynous hermaphrodite fish in which the gonad is initially a female ovary and transforms into male testes. We cloned and identified a novel gonadal soma derived factor (GSDF), which encodes a member of the transforming growth factor-beta superfamily. gsdf expression was measured in gonads of female, intersex and male with reverse transcription-PCR and gsdf's role in sex transformation was studied with qPCR, histological analysis and dual-color in situ hybridization assays and compared to other sex-related genes. gsdf was correlated to Sertoli cell differentiation, indicating involvement in testicular differentiation and sex transformation from female to male in this species. A unique expression pattern reveals a potential role of gsdf essential for the sex transformation of rice field eels.

Glial cell line-derived neurotrophic factor and endothelial cells promote self-renewal of rabbit germ cells with spermatogonial stem cell properties.

PubMed

Kubota, Hiroshi; Wu, Xin; Goodyear, Shaun M; Avarbock, Mary R; Brinster, Ralph L

2011-08-01

Previous studies suggest that exogenous factors crucial for spermatogonial stem cell (SSC) self-renewal are conserved among several mammalian species. Since glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2) are critical for rodent SSC self-renewal, we hypothesized that they might promote self-renewal of nonrodent SSCs. Therefore, we cultured testicular germ cells from prepubertal rabbits in the presence of GDNF and FGF2 and found they proliferated indefinitely as cellular clumps that displayed characteristics previously identified for rodent SSCs. The rabbit germ cells could not be maintained on mouse embryonic fibroblast (STO) feeders that support rodent SSC self-renewal in vitro but were rather supported on mouse yolk sac-derived endothelial cell (C166) feeder layers. Proliferation of rabbit germ cells was dependent on GDNF. Of critical importance was that clump-forming rabbit germ cells colonized seminiferous tubules of immunodeficient mice, proliferated for at least 6 mo, while retaining an SSC phenotype in the testes of recipient mice, indicating that they were rabbit SSCs. This study demonstrates that GDNF is a mitogenic factor promoting self-renewal that is conserved between rodent and rabbit SSCs; with an evolutionary separation of ∼ 60 million years. These findings provide a foundation to study the mechanisms governing SSC self-renewal in nonrodent species.

A novel antiangiogenic peptide derived from hepatocyte growth factor inhibits neovascularization in vitro and in vivo

PubMed Central

Xu, Yi; Zhao, Hui; Zheng, Ying; Gu, Qing; Ma, Jianxing

2010-01-01

Purpose To study the antiangiogenic activity of two small peptides (H-RN and H-FT) derived from the hepatocyte growth factor kringle 1 domain (HGF K1) using in vitro and in vivo assays. Methods RF/6A rhesus macaque choroid-retina endothelial cells were used for in vitro studies. The inhibiting effect of two peptides on a vascular endothelial growth factor (VEGF)-stimulated cell proliferation, cell migration, and endothelial cell tube formation were investigated. For in vivo assays, the antiangiogenic activity of H-RN and H-FT in the chick chorioallantoic membrane model (CAM) and a mice oxygen-induced retinopathy model (OIR) were studied. A recombinant mouse VEGF-neutralizing antibody, bevacizumab, and a scrambled peptide were used as two control groups in separate studies. Results H-RN effectively inhibited VEGF-stimulated RF/6A cell proliferation, migration, and tube formation on Matrigel™, while H-FT did not. H-RN was also able to inhibit angiogenesis when applied to the CAM, and had antineovascularization activity in the retinal neovascularization of a mouse OIR model when administrated as an intravitreous injection. The antiangiogenic activity of H-RN was not as strong as that of VEGF antibodies. The H-FT and scrambled peptide had no such activity. Conclusions H-RN, a new peptide derived from the HGF K1 domain, was shown to have antiangiogenic activity in vitro and in vivo. It may lead to new potential drug discoveries and the development of new treatments for pathological retinal angiogenesis. PMID:21031024

The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-Met, and platelet-derived growth factor receptor.

PubMed

Chen, Zhang-Hui; Yu, Yan P; Michalopoulos, George; Nelson, Joel; Luo, Jian-Hua

2015-01-16

Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and overexpressed in a variety of human malignancies. In this report, we show that MCM7 binds SF3B3. The binding motif is located in the N terminus (amino acids 221-248) of MCM7. Knockdown of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor, platelet-derived growth factor receptor, and c-Met. A dramatic drop of reporter gene expression of the oxytocin exon 1-intron-exon 2-EGFP construct was also identified in SF3B3 and MCM7 knockdown PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knockdown of SF3B3 and MCM7 leads to an increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-Met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, thus giving significant new insight into the oncogenic activity of this protein. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage

PubMed Central

Yang, Lu; Chen, Xufeng; Simet, Samantha M.; Hu, Guoku; Cai, Yu; Niu, Fang; Kook, Yeonhee

2016-01-01

Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell–substrate impedance sensing and FITC-dextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1α. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2–related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1α/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1α and PDGF-BB. Pharmacological blocking of HIF-1α significantly abrogated cocaine-mediated loss of Zo-1. Understanding the

Imatinib mesylate inhibits platelet derived growth factor stimulated proliferation of rheumatoid synovial fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sandler, Charlotta; Joutsiniemi, Saima; Lindstedt, Ken A.

Synovial fibroblast is the key cell type in the growth of the pathological synovial tissue in arthritis. Here, we show that platelet-derived growth factor (PDGF) is a potent mitogen for synovial fibroblasts isolated from patients with rheumatoid arthritis. Inhibition of PDGF-receptor signalling by imatinib mesylate (1 {mu}M) completely abrogated the PDGF-stimulated proliferation and inhibited approximately 70% of serum-stimulated proliferation of synovial fibroblasts. Similar extent of inhibition was observed when PDGF was neutralized with anti-PDGF antibodies, suggesting that imatinib mesylate does not inhibit pathways other than those mediated by PDGF-receptors. No signs of apoptosis were detected in synovial fibroblasts cultured inmore » the presence of imatinib. These results suggest that imatinib mesylate specifically inhibits PDGF-stimulated proliferation of synovial fibroblasts, and that inhibition of PDGF-receptors could represent a feasible target for novel antirheumatic therapies.« less

Combined Effects of Brain-Derived Neurotrophic Factor Immobilized Poly-Lactic-Co-Glycolic Acid Membrane with Human Adipose-Derived Stem Cells and Basic Fibroblast Growth Factor Hydrogel on Recovery of Erectile Dysfunction

PubMed Central

Lee, Seung Hwan; Kim, In Gul; Jung, Ae Ryang; Shrestha, Kshitiz Raj; Lee, Jin Ho; Park, Ki Dong; Chung, Byung Ha; Kim, Sae Woong; Kim, Ki Hean

2014-01-01

Erectile dysfunction (ED) is the most frequent long-term problem after radical prostatectomy. We aimed to evaluate whether the use of combination therapy with basic fibroblast growth factor (bFGF)-hydrogel on corpus cavernosum and with adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF)-immobilized poly-lactic-co-glycolic acid (PLGA) membrane on the cavernous nerve (CN) could improve erectile function in a rat model of bilateral cavernous nerve crush injury (BCNI). Rats were randomly divided into five groups (n=15 per group): a normal group (N group), a group receiving saline application after bilateral cavernous nerve crush injury (BCNI), a group undergoing bFGF-hydrogel injection in the corpus cavernosum after BCNI (bFGF), a group receiving ADSC application covered with BDNF-membrane after BCNI (ADSC/BDNF), and a group undergoing coadministration of bFGF-hydrogel injection and BDNF-membrane with ADSCs after BDNF (bFGF+ADSC/BDNF). Four weeks postoperatively, the erectile function was assessed by detecting the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP). Smooth muscle and collagen contents were measured using Masson's trichrome staining. Neuronal nitric oxide synthase (nNOS) expression in the dorsal penile nerve was detected by immunostaining. The protein expression of the α-smooth muscle actin (α-SMA) and the cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum were quantified by western blot and cGMP assay, respectively. In the bFGF+ADSC/BDNF group, the erectile function was significantly elevated compared with the BCNI and other treated groups and showed a significantly increased smooth muscle/collagen ratio, nNOS content, α-SMA expression, and cGMP level. In particular, there were no statistical differences in the ICP/MAP ratio, smooth muscle/collagen ratio, and α-SMA and cGMP levels between the bFGF+ADSC/BDNF group and normal group. Application of the BDNF-immobilized PLGA membrane with

Analysis of soluble factors in conditioned media derived from primary cultures of cirrhotic liver of biliary atresia.

PubMed

Yamazaki, Taisuke; Wakai, Mariko; Enosawa, Shin; Tokiwa, Takayoshi

2017-06-01

Biliary atresia (BA) is a rare and serious liver disease in newborn infants. Previously, we reported that non-parenchymal cell (NPC) fractions from cirrhotic liver of BA may contain hepatic stem/progenitor cells in primary culture of NPC fractions. In this study, NPC fractions were subjected to primary or passage culture and found that clusters of hepatocyte-like cells appear even without adding hepatocyte growth factor (HGF) to the culture medium, but not in their passage culture used as a control. Based on these findings, conditioned media (CMs) were collected and soluble factors in the CMs were analyzed in order to elucidate the mechanism of the appearance of hepatocyte-like cells or their clusters. A large amount of active HGF consisting of α and β chains was detected in CMs derived from primary culture, but not in CMs from passage culture, as determined by western blot analysis, bone morphogenetic protein (BMP)-4, oncostatin M (OSM), and transforming growth factor (TGF)-β1 were not detected in any of the CMs. The number of hepatocyte-like cells in primary culture tended to decrease following treatment with the HGF receptor c-Met inhibitor, SU11274 in a dose-dependent manner. Furthermore, the clusters of hepatocyte-like cells tended to increase in size and number when freshly isolated NPC fractions were cultured in the presence of 10% of CMs collected after 3-4 wk of primary culture. In conclusion, these findings indicate that CMs derived from primary culture of NPC fractions of BA liver contain a large amount of active HGF, which may activate hepatic stem/progenitor cells and promote the appearance of hepatocyte-like cells or their clusters through HGF/c-Met signaling. The present study would lead to cell therapy using the patient's own cells for the treatment of BA.

Effect of brain-derived neurotrophic factor (BDNF) on sperm quality of normozoospermic men.

PubMed

Safari, Hassan; Khanlarkhani, Neda; Sobhani, Aligholi; Najafi, Atefeh; Amidi, Fardin

2017-07-05

The neurotrophin family of proteins and their receptors act as important proliferative and pro-survival factors in differentiation of nerve cells and are thought to play key roles in the development of reproductive tissues and normal function of spermatozoa. The objective of the present study was to evaluate the effect of Brain-Derived Neurotrophic Factor (BDNF) on the sperm viability and motility, lipid peroxidation (LPO), mitochondrial activity and concentration of leptin, nitric oxide (NO) and insulin in normozoospermic men. Semen samples from 20 normozoospermic men were divided into three groups: (i) control, (ii) BDNF and (iii) BDNF + K252a. BDNF and K252a were added in the dose of 0.133 and 0.1 nM, respectively. Viability was assessed by eosin-nigrosin staining technique, and motility was observed by microscopy. NO concentration and mitochondrial activity were measured with flow cytometry, and LPO was analyzed using enzyme-linked immunosorbent assay (ELISA) kits. Results showed that exogenous BDNF at 0.133 nM could significantly (p < 0.05) influence viability, motility, NO concentration, mitochondrial activity and LPO content. Secretions of insulin and leptin by human sperm were increased in cells exposed to the exogenous BDNF, whereas viability, mitochondrial activity and insulin and leptin secretions were decreased in cells exposed to the K252.

Serum Brain-derived neurotrophic factor (BDNF): the severity and symptomatic dimensions of depression.

PubMed

Jevtović, Saša; Karlović, Dalibor; Mihaljević-Peleš, Alma; Šerić, Vesna; Vrkić, Nada; Jakšić, Nenad

2011-12-01

The aim of this study was to compare the concentration of serum Brain-derived neurotrophic factor (BDNF) in patients suffering from major depressive disorder (MDD) considering the severity of MDD episode defined by the Hamilton rating scale for depression (HAMD-17). The other aim was to research the connection between serum BDNF and the symptomatic dimensions of MDD. The study includes 139 participants with major depressive disorder (MDD). Diagnosis of MDD was set by DSM-IV-TR criteria. The severity of MDD was estimated with HAM-D-17 in the manner that mild episode was diagnosed if the score on HAMD-17 was up to 18, moderately severe 18-25 and severe over 25. Concentration of BDNF was determined by the ELISA method. This research could not find a difference in BDNF concentration considering the severity of the depressive disorder in groups suffering from mild, moderately severe and severe episodes of MDD (F=1.816; p=0.169). Factor analysis of HAMD-17 extracted four dimensions of depressive symptoms. None of the symptomatic dimensions was significantly related to BDNF concentration. Results of this study indicate that serum BDNF levels are not related to the severity of depression and its specific symptomatic dimensions. These findings support the idea of a complex relationship between BDNF concentration at the periphery and in the CNS.

Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy.

PubMed

Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C; Markworth, James F; Mendias, Christopher L

2017-03-01

The platelet-derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) mark fibroadipogenic progenitor cells/fibroblasts and pericytes in skeletal muscle, respectively. While the role that these cells play in muscle growth and development has been evaluated, it was not known whether the PDGF receptors activate signaling pathways that control transcriptional and functional changes during skeletal muscle hypertrophy. To evaluate this, we inhibited PDGFR signaling in mice subjected to a synergist ablation muscle growth procedure, and performed analyses 3 and 10 days after induction of hypertrophy. The results from this study indicate that PDGF signaling is required for fiber hypertrophy, extracellular matrix production, and angiogenesis that occur during muscle growth. © 2017 Federation of European Biochemical Societies.

Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells.

PubMed

Chen, Hui; Lombès, Marc; Le Menuet, Damien

2017-04-12

Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer's, Huntington's and Parkinson's diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.

Profiling ethanol-targeted transcription factors in human carcinoma cell-derived embryoid bodies.

PubMed

Mandal, Chanchal; Halder, Debasish; Chai, Jin Choul; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

2016-01-15

Fetal alcohol spectrum disorder is a collective term that represents fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not yet understood. Few insights have been gained from genetic and epigenetic studies of fetal alcohol spectrum disorder. Our aim was to profile the important molecular regulators of ethanol-related alterations of the genome. For this purpose, we have analyzed the gene expression pattern of human carcinoma cell-derived embryoid bodies in the absence or presence of ethanol. A cDNA microarray analysis was used to profile mRNA expression in embryoid bodies at day 7 with or without ethanol treatment. A total of 493 differentially expressed genes were identified in response to 50 mM ethanol exposure. Of these, 111 genes were up-regulated, and 382 were down-regulated. Gene ontology term enrichment analysis revealed that these genes are involved in important biological processes: neurological system processes, cognition, behavior, sensory perception of smell, taste and chemical stimuli and synaptic transmission. Similarly, the enrichment of disease-related genes included relevant categories such as neurological diseases, developmental disorders, skeletal and muscular disorders, and connective tissue disorders. Furthermore, we have identified a group of 26 genes that encode transcription factors. We validated the relative gene expression of several transcription factors using quantitative real time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanisms underlying the pathology of alcohol-mediated anomalies and facilitates further research. Copyright © 2015 Elsevier B.V. All rights reserved.

Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression.

PubMed

Li, Shi-Ting; Pan, Jing; Hua, Xu-Ming; Liu, Hong; Shen, Sa; Liu, Jia-Fu; Li, Bin; Tao, Bang-Bao; Ge, Xiao-Li; Wang, Xu-Hui; Shi, Juan-Hong; Wang, Xiao-Qiang

2014-02-01

Several lines of evidence demonstrated that endothelial nitric oxide synthase (eNOS) confers protective effects during cerebral ischemia. In this study, we explored the underlying cellular and molecular mechanisms of neuroprotection by eNOS. A series of in vivo and in vitro ischemic models were employed to study the role of eNOS in maintaining neuronal survival and to identify the downstream factors. The current data showed that pretreatment with a specific eNOS inhibitor, L-N5-(1-iminoethyl) ornithine (L-NIO), aggravated the neuronal loss in the rat cerebral ischemic model, accompanied by reduction in brain-derived neurotrophic factor (BDNF) level, which was consistent with the findings in an oxygen-glucose deprivation model (OGD) with two neuronal cells: primary rat cortical neurons and human neuroblastoma SH-SY5Y cells. Furthermore, the extensive neuronal loss induced by L-NIO was totally abolished by exogenous BDNF in both in vitro and in vivo models. On the other hand, eNOS overexpression through an adenoviral vector exerted a prominent protective effect on the neuronal cells subject to OGD, and the protective effect was totally abrogated by a neutralizing anti-BDNF antibody. Collectively, our results indicate that the neuroprotection of neuron-derived eNOS against the cerebral ischemia was mediated through the regulation of BDNF secretion. In conclusion, our discovery provides a novel explanation for the neuroprotective effect of eNOS under pathological ischemic conditions such as stroke. © 2014 John Wiley & Sons Ltd.

Macrophage-derived insulin-like growth factor-1 affects influenza vaccine efficacy through the regulation of immune cell homeostasis.

PubMed

Yoon, Il-Sub; Park, Hyelim; Kwak, Hye-Won; Woo Jung, Yong; Nam, Jae-Hwan

2017-08-24

The level of antibody production induced by a vaccine involves a variety of host factors. One of these, insulin-like growth factor-1 (IGF-1), plays an important role in lymphocyte maturation and antibody expression. Here, we investigated the role of macrophage-derived IGF-1 in the induction of influenza vaccine-specific antibodies using macrophage-derived IGF-1 gene knockout (MIKO) mice. The titers of vaccine-specific total immunoglobulin G (IgG) and IgG1 after immunization were about two- to fourfold lower in MIKO mice than in WT mice. Moreover, MIKO mice showed a relatively weak booster effect of repeated immunization. In contrast, antigen-nonspecific total IgG was about threefold higher in MIKO mice than in WT mice. After viral challenge, the viral titer and the pathological damage in lungs of MIKO mice were higher than those in WT mice despite vaccination. Interestingly, the proportions of proinflammatory immune cells including M1 macrophages, Th1 and Th17 cells was higher in unvaccinated MIKO mice than in unvaccinated WT mice. This suggests that nonspecific activation of immune cells may paradoxically impair the response to the vaccine. In addition, although the proportions of T follicular helper (Tfh) cells and GL-7 + germinal center (GC) B cells were higher in MIKO mice than in WT mice, the population of CD138 + B220 + antibody-secreting plasmablasts was lower in MIKO mice, which may be a cause of the low influenza-specific antibody titer in MIKO mice. Taken together, these results suggest that macrophage-derived IGF-1 might play an important role in the vaccine-triggered immune response by regulating immune cell homeostasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Defective heat shock factor 1 inhibits the growth of fibrosarcoma derived from simian virus 40/T antigen-transformed MEF cells

PubMed Central

JIANG, QIYING; ZHANG, ZHI; LI, SHULIAN; WANG, ZHAOYANG; MA, YUANFANG; HU, YANZHONG

2015-01-01

Heat shock factor 1 (Hsf1) serves an important role in regulating the proliferation of human tumor cell lines in vitro and tissue specific tumorigenesis in certain mouse models. However, its role in viral-oncogenesis remains to be fully elucidated. In the current study, the role of Hsf1 in fibroblastoma derived from simian virus 40/T antigen (SV40/TAG)-transformed mouse embryonic fibroblast (MEF) cell lines was investigated. Knockout of Hsf1 inhibited MEF cell proliferation in vitro and fibroblastoma growth and metastasis to the lungs in vivo in nude mice. Knockout of Hsf1 increased the protein expression levels of p53 and phosphorylated retinoblastoma protein (pRb), however reduced the expression of heat shock protein 25 (Hsp25) in addition to the expression of the angiogenesis markers vascular endothelial growth factor, cluster of differentiation 34 and factor VIII related antigen. Furthermore, immunoprecipitation indicated that knockout of Hsf1 inhibited the association between SV40/TAG and p53 or pRb. These data suggest that Hsf1 is involved in the regulation of SV40/TAG-derived fibroblastoma growth and metastasis by modulating the association between SV40/TAG and tumor suppressor p53 and pRb. The current study provides further evidence that Hsf1 may be a novel therapeutic target in the treatment of cancer. PMID:26352782

Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development.

PubMed

Casey, B J; Glatt, C E; Tottenham, N; Soliman, F; Bath, K; Amso, D; Altemus, M; Pattwell, S; Jones, R; Levita, L; McEwen, B; Magariños, A M; Gunnar, M; Thomas, K M; Mezey, J; Clark, A G; Hempstead, B L; Lee, F S

2009-11-24

There has been a dramatic rise in gene x environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.

From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)

PubMed Central

Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

2013-01-01

Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. PMID:24300402

Small field detector correction factors kQclin,Qmsr (fclin,fmsr) for silicon-diode and diamond detectors with circular 6 MV fields derived using both empirical and numerical methods.

PubMed

O'Brien, D J; León-Vintró, L; McClean, B

2016-01-01

The use of radiotherapy fields smaller than 3 cm in diameter has resulted in the need for accurate detector correction factors for small field dosimetry. However, published factors do not always agree and errors introduced by biased reference detectors, inaccurate Monte Carlo models, or experimental errors can be difficult to distinguish. The aim of this study was to provide a robust set of detector-correction factors for a range of detectors using numerical, empirical, and semiempirical techniques under the same conditions and to examine the consistency of these factors between techniques. Empirical detector correction factors were derived based on small field output factor measurements for circular field sizes from 3.1 to 0.3 cm in diameter performed with a 6 MV beam. A PTW 60019 microDiamond detector was used as the reference dosimeter. Numerical detector correction factors for the same fields were derived based on calculations from a geant4 Monte Carlo model of the detectors and the Linac treatment head. Semiempirical detector correction factors were derived from the empirical output factors and the numerical dose-to-water calculations. The PTW 60019 microDiamond was found to over-respond at small field sizes resulting in a bias in the empirical detector correction factors. The over-response was similar in magnitude to that of the unshielded diode. Good agreement was generally found between semiempirical and numerical detector correction factors except for the PTW 60016 Diode P, where the numerical values showed a greater over-response than the semiempirical values by a factor of 3.7% for a 1.1 cm diameter field and higher for smaller fields. Detector correction factors based solely on empirical measurement or numerical calculation are subject to potential bias. A semiempirical approach, combining both empirical and numerical data, provided the most reliable results.

Effect of brain-derived neurotrophic factor (BDNF) on hepatocyte metabolism.

PubMed

Genzer, Yoni; Chapnik, Nava; Froy, Oren

2017-07-01

Brain-derived neurotrophic factor (BDNF) plays crucial roles in the development, maintenance, plasticity and homeostasis of the central and peripheral nervous systems. Perturbing BDNF signaling in mouse brain results in hyperphagia, obesity, hyperinsulinemia and hyperglycemia. Currently, little is known whether BDNF affects liver tissue directly. Our aim was to determine the metabolic signaling pathways activated after BDNF treatment in hepatocytes. Unlike its effect in the brain, BDNF did not lead to activation of the liver AKT pathway. However, AMP protein activated kinase (AMPK) was ∼3 times more active and fatty acid synthase (FAS) ∼2-fold less active, suggesting increased fatty acid oxidation and reduced fatty acid synthesis. In addition, cAMP response element binding protein (CREB) was ∼3.5-fold less active together with its output the gluconeogenic transcript phosphoenolpyruvate carboxykinase (Pepck), suggesting reduced gluconeogenesis. The levels of glycogen synthase kinase 3b (GSK3b) was ∼3-fold higher suggesting increased glycogen synthesis. In parallel, the expression levels of the clock genes Bmal1 and Cry1, whose protein products play also a metabolic role, were ∼2-fold increased and decreased, respectively. In conclusion, BDNF binding to hepatocytes leads to activation of catabolic pathways, such as fatty acid oxidation. In parallel gluconeogenesis is inhibited, while glycogen storage is triggered. This metabolic state mimics that of after breakfast, in which the liver continues to oxidize fat, stops gluconeogenesis and replenishes glycogen stores. Copyright © 2017 Elsevier Ltd. All rights reserved.

Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

PubMed

Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

2017-05-30

A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

Phylogenetic analysis of platelet-derived growth factor by radio- receptor assay

PubMed Central

1982-01-01

Competition between 125I-labeled platelet-derived growth factor (PDGF) and unlabeled PDGF forms the basis of a specific "radio-receptor assay" for quantifying PDGF in clotted blood serum. Human clotted blood serum contains 15 ng/ml of PDGF by radio-receptor assay; this corresponds to a PDGF content of approximately 7.5 x 10(-5) pg per circulating platelet, a figure which is corroborated by purification data. Clotted blood sera from mammals, lower vertebrates and marine invertebrates were screened for homologues of human PDGF by radio-receptor assay. All tested specimens from phylum Chordata contain a mitogenic agent that competes with human PDGF for receptor binding. Sera from tunicates down on the chordate line of evolution and sera from all tested animals on the arthropod line of development were negative. The phylogenetic distribution of PDGF homologue does not correlate with platelet distribution since platelets and their precursor cell--the bone marrow megacaryocyte--are unique to the mammalian hematopoietic system. One anatomical feature appearing coordinately with PDGF on the vertebrate line of development is a pressurized circulatory system. The coincidental appearance of these features may lend support to the hypothesis that PDGF plays a role in maintenance and repair of the vascular lining in vivo. PMID:7142300

Specific Inhibitors of Platelet-Derived Growth Factor or Epidermal Growth Factor Receptor Tyrosine Kinase Reduce Pulmonary Fibrosis in Rats

PubMed Central

Rice, Annette B.; Moomaw, Cindy R.; Morgan, Daniel L.; Bonner, James C.

1999-01-01

The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by ∼50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases. PMID:10393853

Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients.

PubMed

van Geffen, Mark; Mathijssen, Natascha C J; Holme, Pål A; Laros-van Gorkom, Britta A P; van Kraaij, Marian G J; Masereeuw, Roselinde; Peyvandi, Flora; van Heerde, Waander L

2013-07-01

Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 μg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Music exposure differentially alters the levels of brain-derived neurotrophic factor and nerve growth factor in the mouse hypothalamus.

PubMed

Angelucci, Francesco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

2007-12-18

It has been reported that music may have physiological effects on blood pressure, cardiac heartbeat, respiration, and improve mood state in people affected by anxiety, depression and other psychiatric disorders. However, the physiological bases of these phenomena are not clear. Hypothalamus is a brain region involved in the regulation of body homeostasis and in the pathophysiology of anxiety and depression through the modulation of hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic functions are also influenced by the presence of the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are proteins involved in the growth, survival and function of neurons in the central nervous system. The aim of this study was to investigate the effect of music exposure in mice on hypothalamic levels of BDNF and NGF. We exposed young adult mice to slow rhythm music (6h per day; mild sound pressure levels, between 50 and 60 dB) for 21 consecutive days. At the end of the treatment mice were sacrificed and BDNF and NGF levels in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA). We found that music exposure significantly enhanced BDNF levels in the hypothalamus. Furthermore, we observed that music-exposed mice had decreased NGF hypothalamic levels. Our results demonstrate that exposure to music in mice can influence neurotrophin production in the hypothalamus. Our findings also suggest that physiological effects of music might be in part mediated by modulation of neurotrophins.

Glial cell line-derived neurotrophic factor promotes the development of adrenergic neurons in mouse neural crest cultures

PubMed Central

Maxwell, Gerald D.; Reid, Kate; Elefanty, Andrew; Bartlett, Perry F.; Murphy, Mark

1996-01-01

Growth of mouse neural crest cultures in the presence of glial cell line-derived neurotrophic factor (GDNF) resulted in a dramatic dose-dependent increase in the number of tyrosine hydroxylase (TH)-positive cells that developed when 5% chicken embryo extract was present in the medium. In contrast, growth in the presence of bone morphogenetic protein (BMP)-2, BMP-4, BMP-6, transforming growth factor (TGF) β1, TGF-β2, and TGF-β3 elicited no increase in the number of TH-positive cells. The TH-positive cells that developed in the presence of GDNF had neuronal morphology and contained the middle and low molecular weight neurofilament proteins. Numerous TH-negative cells with the morphology of neurons also were observed in GDNF-treated cultures. Analysis revealed that the period from 6 to 12 days in vitro was the critical time for exposure to GDNF to generate the increase in TH-positive cell number. The growth factors neurotrophin-3 and fibroblast growth factor-2 elicited increases in the number of TH-positive cells similar to that seen in response to GDNF. In contrast, nerve growth factor was unable to substitute for GDNF. These findings extend the previously reported biological activities of GDNF by showing that it can act on mouse neural crest cultures to promote the development of neurons. PMID:8917581

Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor.

PubMed

McFadden, Lisa M; Vieira-Brock, Paula L; Hanson, Glen R; Fleckenstein, Annette E

2014-08-01

Preclinical studies suggest that prior treatment with escalating doses of methamphetamine (METH) attenuates the persistent deficits in hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) function resulting from a subsequent 'binge' METH exposure. Previous work also demonstrates that brain-derived neurotrophic factor (BDNF) exposure increases SERT function. The current study investigated changes in hippocampal BDNF protein and SERT function in rats exposed to saline or METH self-administration prior to a binge exposure to METH or saline. Results revealed that METH self-administration increased hippocampal mature BDNF (mBDNF) immunoreactivity compared to saline-treated rats as assessed 24 h after the start of the last session. Further, mBDNF immunoreactivity was increased and SERT function was not altered in rats that self-administered METH prior to the binge METH exposure as assessed 24 h after the binge exposure. These results suggest that prior exposure to contingent METH increases hippocampal mBDNF, and this may contribute to attenuated deficits in SERT function.

Derivation and application of the energy dissipation factor in the design of fishways

USGS Publications Warehouse

Towler, Brett; Mulligan, Kevin; Haro, Alexander J.

2015-01-01

Reducing turbulence and associated air entrainment is generally considered advantageous in the engineering design of fish passage facilities. The well-known energy dissipation factor, or EDF, correlates with observations of the phenomena. However, inconsistencies in EDF forms exist and the bases for volumetric energy dissipation rate criteria are often misunderstood. A comprehensive survey of EDF criteria is presented. Clarity in the application of the EDF and resolutions to these inconsistencies are provided through formal derivations; it is demonstrated that kinetic energy represents only 1/3 of the total energy input for the special case of a broad-crested weir. Specific errors in published design manuals are identified and resolved. New, fundamentally sound, design equations for culvert outlet pools and standard Denil Fishway resting pools are developed. The findings underscore the utility of EDF equations, demonstrate the transferability of volumetric energy dissipation rates, and provide a foundation for future refinement of component-, species-, and life-stage-specific EDF criteria.

The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth.

PubMed

Bennewith, Kevin L; Huang, Xin; Ham, Christine M; Graves, Edward E; Erler, Janine T; Kambham, Neeraja; Feazell, Jonathan; Yang, George P; Koong, Albert; Giaccia, Amato J

2009-02-01

Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.

Transdifferentiation of brain-derived neurotrophic factor (BDNF)-secreting mesenchymal stem cells significantly enhance BDNF secretion and Schwann cell marker proteins.

PubMed

Bierlein De la Rosa, Metzere; Sharma, Anup D; Mallapragada, Surya K; Sakaguchi, Donald S

2017-11-01

The use of genetically modified mesenchymal stem cells (MSCs) is a rapidly growing area of research targeting delivery of therapeutic factors for neuro-repair. Cells can be programmed to hypersecrete various growth/trophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) to promote regenerative neurite outgrowth. In addition to genetic modifications, MSCs can be subjected to transdifferentiation protocols to generate neural cell types to physically and biologically support nerve regeneration. In this study, we have taken a novel approach by combining these two unique strategies and evaluated the impact of transdifferentiating genetically modified MSCs into a Schwann cell-like phenotype. After 8 days in transdifferentiation media, approximately 30-50% of transdifferentiated BDNF-secreting cells immunolabeled for Schwann cell markers such as S100β, S100, and p75 NTR . An enhancement was observed 20 days after inducing transdifferentiation with minimal decreases in expression levels. BDNF production was quantified by ELISA, and its biological activity tested via the PC12-TrkB cell assay. Importantly, the bioactivity of secreted BDNF was verified by the increased neurite outgrowth of PC12-TrkB cells. These findings demonstrate that not only is BDNF actively secreted by the transdifferentiated BDNF-MSCs, but also that it has the capacity to promote neurite sprouting and regeneration. Given the fact that BDNF production remained stable for over 20 days, we believe that these cells have the capacity to produce sustainable, effective, BDNF concentrations over prolonged time periods and should be tested within an in vivo system for future experiments. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Restoration of Long-Term Potentiation in Middle-Aged Hippocampus After Induction of Brain-Derived Neurotrophic Factor

PubMed Central

Rex, Christopher S.; Lauterborn, Julie C.; Lin, Ching-Yi; Kramár, Eniko A.; Rogers, Gary A.; Gall, Christine M.; Lynch, Gary

2006-01-01

Rex, Christopher S., Julie C. Lauterborn, Ching-Yi Lin, Eniko A. Kramár, Gary A. Rogers, Christine M. Gall, and Gary Lynch. Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor. J Neurophysiol 96: 677-685, 2006. First published May 17, 2006; doi:10.1152/jn.00336.2006. Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP. PMID:16707719

Open-path Emission Factors Derived from DOAS and FTIR Measurements in the Mexico City Metropolitan Area

NASA Astrophysics Data System (ADS)

Flores, E.; Grutter, M.; Galle, B.; Mellqvist, J.; Samuelsson, J.; Knighton, B.; Jobson, B. T.; Volkamer, R.; Molina, L. T.; Molina, M. J.

2004-12-01

Mobile sources are responsible for about 50% of VOC (volatile organic compounds) and about 70% of NOx emissions in the Mexico City Metropolitan Area (MCMA). A novel approach has been developed to derive emission factors for mobile sources that are representative of the overall vehicle fleet, using collocated open-path Differential Optical Absorption Spectroscopy (DOAS) and Fourier Transform Infrared (FTIR) spectroscopic measurements. Measurements were recorded at two sites within the MCMA: (1) research-grade DOAS and FTIR systems were operated at the Mexican National Research and Training Center (CENICA) in Iztapalapa, (2) a research grade FTIR was operated at La Merced. In addition, point-sampling with a proton transfer reaction mass spectrometer (PTR-MS) was performed on the same location and the calibration standards for the PTR-MS and the DOAS instruments were cross-calibrated. The DOAS measured speciated aromatic hydrocarbons, including benzene, toluene, m-xylene, p-xylene, ethylbenzene (and mono-substituted alkylbenzenes), benzaldehyde, phenol, and p-cresol. The DOAS detection of aromatic hydrocarbons in the UV/vis spectral range between 250 to 310 nm suffers from the interference of molecular oxygen, and a novel approach is being presented that enables measurement of absolute concentrations of the above species. Further, HONO, NO2, SO2 and HCHO were measured at longer wavelengths. In combination with FTIR measurements of CO, CO2, NO, HCHO, ethylene, ethene, and total alkane, average emission factors for NOx, SO2 and numerous hydrocarbons were derived and scaled with fuel sales data to estimate total emissions of the vehicle fleet in the MCMA. The advantages and limitations of this low-cost emission inventory for mobile sources are decsribed.

Adipose-derived cells.

PubMed

Meliga, Emanuele; Strem, Brian M; Duckers, H J; Serruys, Patrick W

2007-01-01

Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1alpha, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 10(6) stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebo-controlled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI.

Platelets Contain Tissue Factor Pathway Inhibitor-2 Derived from Megakaryocytes and Inhibits Fibrinolysis*

PubMed Central

Vadivel, Kanagasabai; Ponnuraj, Sathya-Moorthy; Kumar, Yogesh; Zaiss, Anne K.; Bunce, Matthew W.; Camire, Rodney M.; Wu, Ling; Evseenko, Denis; Herschman, Harvey R.; Bajaj, Madhu S.; Bajaj, S. Paul

2014-01-01

Tissue factor pathway inhibitor-2 (TFPI-2) is a homologue of TFPI-1 and contains three Kunitz-type domains and a basic C terminus region. The N-terminal domain of TFPI-2 is the only inhibitory domain, and it inhibits plasma kallikrein, factor XIa, and plasmin. However, plasma TFPI-2 levels are negligible (≤20 pm) in the context of influencing clotting or fibrinolysis. Here, we report that platelets contain significant amounts of TFPI-2 derived from megakaryocytes. We employed RT-PCR, Western blotting, immunohistochemistry, and confocal microscopy to determine that platelets, MEG-01 megakaryoblastic cells, and bone marrow megakaryocytes contain TFPI-2. ELISA data reveal that TFPI-2 binds factor V (FV) and partially B-domain-deleted FV (FV-1033) with Kd ∼9 nm and binds FVa with Kd ∼100 nm. Steady state analysis of surface plasmon resonance data reveal that TFPI-2 and TFPI-1 bind FV-1033 with Kd ∼36–48 nm and bind FVa with Kd ∼252–456 nm. Further, TFPI-1 (but not TFPI-1161) competes with TFPI-2 in binding to FV. These data indicate that the C-terminal basic region of TFPI-2 is similar to that of TFPI-1 and plays a role in binding to the FV B-domain acidic region. Using pull-down assays and Western blots, we show that TFPI-2 is associated with platelet FV/FVa. TFPI-2 (∼7 nm) in plasma of women at the onset of labor is also, in part, associated with FV. Importantly, TFPI-2 in platelets and in plasma of pregnant women inhibits FXIa and tissue-type plasminogen activator-induced clot fibrinolysis. In conclusion, TFPI-2 in platelets from normal or pregnant subjects and in plasma from pregnant women binds FV/Va and regulates intrinsic coagulation and fibrinolysis. PMID:25262870

Covalently immobilized platelet-derived growth factor-BB promotes angiogenesis in biomimetic poly(ethylene glycol) hydrogels

PubMed Central

Saik, Jennifer E.; Gould, Daniel J.; Watkins, Emily M.; Dickinson, Mary E.; West, Jennifer L.

2011-01-01

The field of tissue engineering is severely limited by a lack of microvascularization in tissue engineered constructs. Biomimetic poly(ethylene glycol) hydrogels containing covalently immobilized platelet-derived growth factor BB (PDGF-BB) were developed to promote angiogenesis. Poly(ethylene glycol) hydrogels resist protein absorption and subsequent non-specific cell adhesion, thus providing a “blank slate”, which can be modified through the incorporation of cell adhesive ligands and growth factors. PDGF-BB is a key angiogenic protein able to support neovessel stabilization by inducing functional anastomoses and recruiting pericytes. Due to the widespread effects of PDGF in the body and a half-life of only 30 min in circulating blood, immobilization of PDGF-BB may be necessary. In this work bioactive, covalently immobilized PDGF-BB was shown to induce tubulogenesis on two-dimensional modified surfaces, migration in three-dimensional (3D) degradable hydrogels and angiogenesis in a mouse cornea micro-pocket angiogenesis assay. Covalently immobilized PDGF-BB was also used in combination with covalently immobilized fibroblast growth factor-2, which led to significantly increased endothelial cell migration in 3D degradable hydrogels compared with the presentation of each factor alone. When a co-culture of endothelial cells and mouse pericyte precursor 10T1/2 cells was seeded onto modified surfaces tubule formation was independent of surface modifications with covalently immobilized growth factors. Furthermore, the combination of soluble PDGF-BB and immobilized PDGF-BB induced a more robust vascular response compared with soluble PDGF-BB alone when implanted into an in vivo mouse cornea micropocket angiogenesis assay. Based on these results, we believe bioactive hydrogels can be tailored to improve the formation of functional microvasculature for tissue engineering. PMID:20801242

Allograft Bone: What Is the Role of Platelet-Derived Growth Factor in Hindfoot and Ankle Fusions.

PubMed

Scott, Ryan T; McAlister, Jeffrey E; Rigby, Ryan B

2018-01-01

Arthrodesis of the ankle or foot is a common procedure for chronic pain and disability. Nonunion remains a prevalent complication among arthrodesis procedures. Some patients present with an inherent risk of developing a nonunion. Allograft biologics have gained popularity in an effort to reduce complications such as nonunion. Various biologics bring unique properties while maintaining a singular purpose. Platelet-derived growth factor (PDGF) may be introduced into a fusion site to facilitate healthy bony consolidation. The purpose of this article is to review the benefits and modalities of PDGF and how it can improve patient outcomes in ankle and hindfoot fusions. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of brain-derived and glial cell line-derived neurotrophic factors on startle response and disrupted prepulse inhibition in mice of DBA/2J inbred strain.

PubMed

Naumenko, Vladimir S; Bazovkina, Daria V; Morozova, Maryana V; Popova, Nina K

2013-08-29

Prepulse inhibition (PPI), the reduction in acoustic startle reflex when it is preceded by weak prepulse stimuli, is a measure of critical to normal brain functioning sensorimotor gating. PPI deficit was shown in a variety of psychiatric disorders including schizophrenia, and in DBA/2J mouse strain. In the current study, we examined the effects of brain-derived (BDNF) and glial cell line-derived (GDNF) neurotrophic factors on acoustic startle response and PPI in DBA/2J mice. It was found that BDNF (300 ng, i.c.v.) significantly increased amplitude of startle response and restored disrupted PPI in 7 days after acute administration. GDNF (800 ng, i.c.v.) did not produce significant alteration neither in amplitude of startle response nor in PPI in DBA/2J mice. The reversal effect of BDNF on PPI deficit was unusually long-lasting: significant increase in PPI was found 1.5 months after single acute BDNF administration. Long-term ameliorative effect BDNF on disrupted PPI suggested the implication of epigenetic mechanism in BDNF action on neurogenesis. BDNF rather than GDNF could be a perspective drug for the treatment of sensorimotor gating impairments. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Glycan structure of Gc Protein-derived Macrophage Activating Factor as revealed by mass spectrometry.

PubMed

Borges, Chad R; Rehder, Douglas S

2016-09-15

Disagreement exists regarding the O-glycan structure attached to human vitamin D binding protein (DBP). Previously reported evidence indicated that the O-glycan of the Gc1S allele product is the linear core 1 NeuNAc-Gal-GalNAc-Thr trisaccharide. Here, glycan structural evidence is provided from glycan linkage analysis and over 30 serial glycosidase-digestion experiments which were followed by analysis of the intact protein by electrospray ionization mass spectrometry (ESI-MS). Results demonstrate that the O-glycan from the Gc1F protein is the same linear trisaccharide found on the Gc1S protein and that the hexose residue is galactose. In addition, the putative anti-cancer derivative of DBP known as Gc Protein-derived Macrophage Activating Factor (GcMAF, which is formed by the combined action of β-galactosidase and neuraminidase upon DBP) was analyzed intact by ESI-MS, revealing that the activating E. coli β-galactosidase cleaves nothing from the protein-leaving the glycan structure of active GcMAF as a Gal-GalNAc-Thr disaccharide, regardless of the order in which β-galactosidase and neuraminidase are applied. Moreover, glycosidase digestion results show that α-N-Acetylgalactosamindase (nagalase) lacks endoglycosidic function and only cleaves the DBP O-glycan once it has been trimmed down to a GalNAc-Thr monosaccharide-precluding the possibility of this enzyme removing the O-glycan trisaccharide from cancer-patient DBP in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Reprogramming of Sheep Fibroblasts into Pluripotency under a Drug-Inducible Expression of Mouse-Derived Defined Factors

PubMed Central

Li, Yang; Cang, Ming; Lee, Andrew Stephen; Zhang, Kehua; Liu, Dongjun

2011-01-01

Animal embryonic stem cells (ESCs) provide powerful tool for studies of early embryonic development, gene targeting, cloning, and regenerative medicine. However, the majority of attempts to establish ESC lines from large animals, especially ungulate mammals have failed. Recently, another type of pluripotent stem cells, known as induced pluripotent stem cells (iPSCs), have been successfully generated from mouse, human, monkey, rat and pig. In this study we show sheep fibroblasts can be reprogrammed to pluripotency by defined factors using a drug-inducible system. Sheep iPSCs derived in this fashion have a normal karyotype, exhibit morphological features similar to those of human ESCs and express AP, Oct4, Sox2, Nanog and the cell surface marker SSEA-4. Pluripotency of these cells was further confirmed by embryoid body (EB) and teratoma formation assays which generated derivatives of all three germ layers. Our results also show that the substitution of knockout serum replacement (KSR) with fetal bovine serum in culture improves the reprogramming efficiency of sheep iPSCs. Generation of sheep iPSCs places sheep on the front lines of large animal preclinical trials and experiments involving modification of animal genomes. PMID:21253598

Lactoferrin-derived peptides and Lactoferricin chimera inhibit virulence factor production and biofilm formation in Pseudomonas aeruginosa.

PubMed

Xu, G; Xiong, W; Hu, Q; Zuo, P; Shao, B; Lan, F; Lu, X; Xu, Y; Xiong, S

2010-10-01

To investigate the bactericidal activity of lactoferrin-derived peptides and a new LF-derived peptides chimera (LFchimera) against P. aeruginosa and the influence on virulence factors of P. aeruginosa. Lactoferricin (LFcin) and lactoferrampin (LFampin) are highly bioactive peptides isolated from the N-terminal region of lactoferrin (LF) by pepsin digestion. In this study, we designed LFchimera containing LFcin amino acids 17-30 and LFampin amino acids 268-284. Pseudomonas aeruginosa cells were incubated in medium with peptides at different concentrations, and then the assays of viability, pyocyanin, elastase activity and biofilm formation of P. aeruginosa were performed. We found that the concentration-dependent antibactericidal activity and down-regulating pyocyanin, elastase and biofilm formation of LFchimera were significantly stronger than those of LF, LFcin, LFampin or LFcin plus LFampin. Our results indicated that LF, LFcin, LFampin and LFchimera were potential candidates to combat P. aeruginosa, and LFchimera was the most effective in them. The new LFchimera has better activity against P. aeruginosa than LF, LFcin and LFampin and may be a promising new compound for treatment of P. aeruginosa infection. © 2010 The Authors. Journal compilation © 2010 The Society for Applied Microbiology.

Not just fractal surfaces, but surface fractal aggregates: Derivation of the expression for the structure factor and its applications

NASA Astrophysics Data System (ADS)

Besselink, R.; Stawski, T. M.; Van Driessche, A. E. S.; Benning, L. G.

2016-12-01

Densely packed surface fractal aggregates form in systems with high local volume fractions of particles with very short diffusion lengths, which effectively means that particles have little space to move. However, there are no prior mathematical models, which would describe scattering from such surface fractal aggregates and which would allow the subdivision between inter- and intraparticle interferences of such aggregates. Here, we show that by including a form factor function of the primary particles building the aggregate, a finite size of the surface fractal interfacial sub-surfaces can be derived from a structure factor term. This formalism allows us to define both a finite specific surface area for fractal aggregates and the fraction of particle interfacial sub-surfaces at the perimeter of an aggregate. The derived surface fractal model is validated by comparing it with an ab initio approach that involves the generation of a "brick-in-a-wall" von Koch type contour fractals. Moreover, we show that this approach explains observed scattering intensities from in situ experiments that followed gypsum (CaSO4 ṡ 2H2O) precipitation from highly supersaturated solutions. Our model of densely packed "brick-in-a-wall" surface fractal aggregates may well be the key precursor step in the formation of several types of mosaic- and meso-crystals.

Neer Award 2018: Platelet-derived growth factor receptor α co-expression typifies a subset of platelet-derived growth factor receptor β-positive progenitor cells that contribute to fatty degeneration and fibrosis of the murine rotator cuff.

PubMed

Jensen, Andrew R; Kelley, Benjamin V; Mosich, Gina M; Ariniello, Allison; Eliasberg, Claire D; Vu, Brandon; Shah, Paras; Devana, Sai K; Murray, Iain R; Péault, Bruno; Dar, Ayelet; Petrigliano, Frank A

2018-04-10

After massive tears, rotator cuff muscle often undergoes atrophy, fibrosis, and fatty degeneration. These changes can lead to high surgical failure rates and poor patient outcomes. The identity of the progenitor cells involved in these processes has not been fully elucidated. Platelet-derived growth factor receptor β (PDGFRβ) and platelet-derived growth factor receptor α (PDGFRα) have previously been recognized as markers of cells involved in muscle fibroadipogenesis. We hypothesized that PDGFRα expression identifies a fibroadipogenic subset of PDGFRβ + progenitor cells that contribute to fibroadipogenesis of the rotator cuff. We created massive rotator cuff tears in a transgenic strain of mice that allows PDGFRβ + cells to be tracked via green fluorescent protein (GFP) fluorescence. We then harvested rotator cuff muscle tissues at multiple time points postoperatively and analyzed them for the presence and localization of GFP + PDGFRβ + PDGFRα + cells. We cultured, induced, and treated these cells with the molecular inhibitor CWHM-12 to assess fibrosis inhibition. GFP + PDGFRβ + PDGFRα + cells were present in rotator cuff muscle tissue and, after massive tears, localized to fibrotic and adipogenic tissues. The frequency of PDGFRβ + PDGFRα + cells increased at 5 days after massive cuff tears and decreased to basal levels within 2 weeks. PDGFRβ + PDGFRα + cells were highly adipogenic and significantly more fibrogenic than PDGFRβ + PDGFRα - cells in vitro and localized to adipogenic and fibrotic tissues in vivo. Treatment with CWHM-12 significantly decreased fibrogenesis from PDGFRβ + PDGFRα + cells. PDGFRβ + PDGFRα + cells directly contribute to fibrosis and fatty degeneration after massive rotator cuff tears in the mouse model. In addition, CWHM-12 treatment inhibits fibrogenesis from PDGFRβ + PDGFRα + cells in vitro. Clinically, perioperative PDGFRβ + PDGFRα + cell inhibition may limit rotator cuff tissue degeneration and, ultimately

Recombinant Rabbit Leukemia Inhibitory Factor and Rabbit Embryonic Fibroblasts Support the Derivation and Maintenance of Rabbit Embryonic Stem Cells

PubMed Central

Xue, Fei; Ma, Yinghong; Chen, Y. Eugene; Zhang, Jifeng; Lin, Tzu-An; Chen, Chien-Hong; Lin, Wei-Wen; Roach, Marsha; Ju, Jyh-Cherng; Yang, Lan; Du, Fuliang

2012-01-01

Abstract The rabbit is a classical experimental animal species. A major limitation in using rabbits for biomedical research is the lack of germ-line-competent rabbit embryonic stem cells (rbESCs). We hypothesized that the use of homologous feeder cells and recombinant rabbit leukemia inhibitory factor (rbLIF) might improve the chance in deriving germ-line-competent rbES cells. In the present study, we established rabbit embryonic fibroblast (REF) feeder layers and synthesized recombinant rbLIF. We derived a total of seven putative rbESC lines, of which two lines (M5 and M23) were from culture Condition I using mouse embryonic fibroblasts (MEFs) as feeders supplemented with human LIF (hLIF) (MEF+hLIF). Another five lines (R4, R9, R15, R21, and R31) were derived from Condition II using REFs as feeder cells supplemented with rbLIF (REF+rbLIF). Similar derivation efficiency was observed between these two conditions (8.7% vs. 10.2%). In a separate experiment with 2×3 factorial design, we examined the effects of feeder cells (MEF vs. REF) and LIFs (mLIF, hLIF vs. rbLIF) on rbESC culture. Both Conditions I and II supported satisfactory rbESC culture, with similar or better population doubling time and colony-forming efficiency than other combinations of feeder cells with LIFs. Rabbit ESCs derived and maintained on both conditions displayed typical ESC characteristics, including ESC pluripotency marker expression (AP, Oct4, Sox2, Nanog, and SSEA4) and gene expression (Oct4, Sox2, Nanog, c-Myc, Klf4, and Dppa5), and the capacity to differentiate into three primary germ layers in vitro. The present work is the first attempt to establish rbESC lines using homologous feeder cells and recombinant rbLIF, by which the rbESCs were derived and maintained normally. These cell lines are unique resources and may facilitate the derivation of germ-line-competent rbESCs. PMID:22775411

Recombinant rabbit leukemia inhibitory factor and rabbit embryonic fibroblasts support the derivation and maintenance of rabbit embryonic stem cells.

PubMed

Xue, Fei; Ma, Yinghong; Chen, Y Eugene; Zhang, Jifeng; Lin, Tzu-An; Chen, Chien-Hong; Lin, Wei-Wen; Roach, Marsha; Ju, Jyh-Cherng; Yang, Lan; Du, Fuliang; Xu, Jie

2012-08-01

The rabbit is a classical experimental animal species. A major limitation in using rabbits for biomedical research is the lack of germ-line-competent rabbit embryonic stem cells (rbESCs). We hypothesized that the use of homologous feeder cells and recombinant rabbit leukemia inhibitory factor (rbLIF) might improve the chance in deriving germ-line-competent rbES cells. In the present study, we established rabbit embryonic fibroblast (REF) feeder layers and synthesized recombinant rbLIF. We derived a total of seven putative rbESC lines, of which two lines (M5 and M23) were from culture Condition I using mouse embryonic fibroblasts (MEFs) as feeders supplemented with human LIF (hLIF) (MEF+hLIF). Another five lines (R4, R9, R15, R21, and R31) were derived from Condition II using REFs as feeder cells supplemented with rbLIF (REF+rbLIF). Similar derivation efficiency was observed between these two conditions (8.7% vs. 10.2%). In a separate experiment with 2×3 factorial design, we examined the effects of feeder cells (MEF vs. REF) and LIFs (mLIF, hLIF vs. rbLIF) on rbESC culture. Both Conditions I and II supported satisfactory rbESC culture, with similar or better population doubling time and colony-forming efficiency than other combinations of feeder cells with LIFs. Rabbit ESCs derived and maintained on both conditions displayed typical ESC characteristics, including ESC pluripotency marker expression (AP, Oct4, Sox2, Nanog, and SSEA4) and gene expression (Oct4, Sox2, Nanog, c-Myc, Klf4, and Dppa5), and the capacity to differentiate into three primary germ layers in vitro. The present work is the first attempt to establish rbESC lines using homologous feeder cells and recombinant rbLIF, by which the rbESCs were derived and maintained normally. These cell lines are unique resources and may facilitate the derivation of germ-line-competent rbESCs.

The fibroblast-derived paracrine factor neuregulin-1 has a novel role in regulating the constitutive color and melanocyte function in human skin

PubMed Central

Choi, Wonseon; Wolber, Rainer; Gerwat, Wolfram; Mann, Tobias; Batzer, Jan; Smuda, Christoph; Liu, Hongfang; Kolbe, Ludger; Hearing, Vincent J.

2010-01-01

Interactions between melanocytes and neighboring cells in the skin are important in regulating skin color in humans. We recently demonstrated that the less pigmented and thicker skin on the palms and soles is regulated by underlying fibroblasts in those areas, specifically via a secreted factor (DKK1) that modulates Wnt signaling. In this study, we tested the hypothesis that dermal fibroblasts regulate the constitutive skin color of individuals ranging from very light to very dark. We used microarray analysis to compare gene expression patterns in fibroblasts derived from lighter skin types compared to darker skin types, with a focus on secreted proteins. We identified a number of genes that differ dramatically in expression and, among the expressed proteins, neuregulin-1, which is secreted by fibroblasts derived from dark skin, effectively increases the pigmentation of melanocytes in tissue culture and in an artificial skin model and regulates their growth, suggesting that it is one of the major factors determining human skin color. PMID:20736300

Brain derived neurotrophic factor (BDNF) and autism spectrum disorders (ASD) in childhood.

PubMed

Bryn, V; Halvorsen, B; Ueland, T; Isaksen, J; Kolkova, K; Ravn, K; Skjeldal, O H

2015-07-01

Neurotrophic factors are essential regulators of neuronal maturation including synaptic synthesis. Among those, Brain derived neurotrophic factor (BDNF) has been in particular focus in the understanding of autism spectrum disorders (ASD). The aim of our study was to investigate whether BNDF could be used as diagnostic/biological marker for ASD. For this purpose we examined the plasma levels of BDNF and the precursors pro- BDNF in patients with ASD and compared it with non-autistic controls; determined whether there was a correlation between the BDNF and proBDNF levels and clinical severity. We also investigated the coding region of BDNF identify for well-variations which could be associated to ASD. The 65 ASD patients (51 boys) were enrolled from a recent completed epidemiological survey covering two counties (Oppland and Hedmark) in Norway. The mean age of the total number of children who participated in this study was 11,7 years. 30 non-autistic children were included as controls, 14 boys and 16 girls. The mean age was 11.3 years. Exclusion criteria for control group were individuals suffering from either neurological, endocrine, or immune insuffiency. Patients with ASD were characterized by moderately but significantly elevated plasma levels of BDNF compared to matched controls. No differences were observed in the proBDNF level between patients and controls. Within the ASD group, children with intellectual disability demonstrated increased BDNF, but not proBDNF levels, while the presence of ADHD had no impact on circulating proBDNF or BDNF. No further associations between plasma proBDNF or BDNF and other clinical demographics were observed. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

In Vitro Expression of Cytokeratin 19 in Adipose-Derived Stem Cells Is Induced by Epidermal Growth Factor.

PubMed

Chen, Shangliang; Wang, Mingzhu; Chen, Xinglu; Chen, Shaolian; Liu, Li; Zhu, Jianbin; Wang, Jinhui; Yang, Xiaorong; Cai, Xiangsheng

2018-06-21

BACKGROUND Cytokeratin 19 (CK19) is a typical epithelial marker. In this study, we determined whether epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF) could enhance CK19 expression in adipose-derived stem cells (ADSCs), thereby inducing the differentiation of ADSCs into epithelial-like cells. MATERIAL AND METHODS ADSCs were isolated from perinephric fat, and the expression of CD29, CD90, and CD105 was confirmed. Following isolation, ADSCs were cultured in static medium or medium containing EGF or bFGF. RESULTS Flow cytometry revealed that EGF and bFGF could alter mesenchymal stem cell markers as well as the cell cycle of ADSCs. Western blotting and immunofluorescence revealed that after 14 days, EGF treatment enhanced the expression of CK19 in ADSCs. CONCLUSIONS Our findings offer important insight for the clinical use of ADSCs in the generation of epithelial-like cells in the future.

Exploring Factors Related to Young Children's Word-Meaning Derivations during Read-Alouds

ERIC Educational Resources Information Center

Christ, Tanya; Wang, X. Christine; Chiu, Ming Ming

2017-01-01

This study explores how child and text clues were related to 31 kindergarteners' word-meaning derivation outcomes for 372 words presented in books read aloud to children. Data were analyzed using a multilevel, cross-classification, ordered logit model. Children showed no word-meaning derivation 40% of the time, indicating a need for instruction.…

New sulfurated derivatives of cinnamic acids and rosmaricine as inhibitors of STAT3 and NF-κB transcription factors.

PubMed

Gabriele, Elena; Brambilla, Dario; Ricci, Chiara; Regazzoni, Luca; Taguchi, Kyoko; Ferri, Nicola; Asai, Akira; Sparatore, Anna

2017-12-01

A set of new sulfurated drug hybrids, mainly derived from caffeic and ferulic acids and rosmaricine, has been synthesized and their ability to inhibit both STAT3 and NF-κB transcription factors have been evaluated. Results showed that most of the new hybrid compounds were able to strongly and selectively bind to STAT3, whereas the parent drugs were devoid of this ability at the tested concentrations. Some of them were also able to inhibit the NF-κB transcriptional activity in HCT-116 cell line and inhibited HCT-116 cell proliferation in vitro with IC 50 in micromolar range, thus suggesting a potential anticancer activity. Taken together, our study described the identification of new derivatives with dual STAT3/NF-κB inhibitory activity, which may represent hit compounds for developing multi-target anticancer agents.

Biosynthesis and intracellular transport of the receptor for platelet-derived growth factor.

PubMed Central

Claesson-Welsh, L; Rönnstrand, L; Heldin, C H

1987-01-01

The biosynthesis of the receptor for platelet-derived growth factor (PDGF) was examined in metabolically labeled human foreskin fibroblasts. The receptor was synthesized as a 145-kDa precursor, which, when incubated with endo-beta-N-acetylglucosaminidase H (endo H), underwent a 15-kDa decrease in molecular mass. This indicates that the size of the core protein is about 130 kDa and that the 145-kDa form represents a receptor precursor carrying high-mannose N-linked oligosaccharide groups. Within 15 min after synthesis, the receptor was converted to a 165-kDa form. This form was entirely resistant to endo H treatment and probably represents a receptor molecule that has undergone further posttranslational modification, including O-linked glycosylation. Subsequently, within 30 min, a molecule of 170 kDa--i.e., the size of the mature receptor--appeared. A slightly larger molecule, of 175 kDa, which could be immunoprecipitated from PDGF-stimulated 32P-labeled cells, probably represents a receptor further modified by autophosphorylation. The 170-kDa molecule had an isoelectric point of about 4.5. Addition of PDGF increased the turnover rate of the 170-kDa PDGF receptor. Images PMID:2827155

Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.

PubMed

Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

2016-01-15

Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace. Copyright © 2015 Elsevier B.V. All rights reserved.

Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells

PubMed Central

2012-01-01

Background We recently isolated and identified Zizimin2 as a functional factor that is highly expressed in murine splenic germinal center B cells after immunization with T-cell-dependent antigen. Zizimin2 was revealed to be a new family member of Dock (dedicator of cytokinesis), Dock11, which is the guanine nucleotide exchange factor for Cdc42, a low-molecular-weight GTPase. However, the molecular function of Zizimin2 in acquired immunity has not been elucidated. Results In this study, we show that the protein expression of Zizimin2, which is also restricted to lymphoid tissues and lymphocytes, is reduced in aged mice. Over-expression of full-length Zizimin2 induced filopodial formation in 293T cells, whereas expression of CZH2 domain inhibited it. Stimulation of Fcγ receptor and Toll-like receptor 4 triggered Zizimin2 up-regulation and Cdc42 activation in bone marrow-derived dendritic cells. Conclusions These data suggest that Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. PMID:22494997

Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter

PubMed Central

Vana, Adam C.; Flint, Nicole C.; Harwood, Norah E.; Le, Tuan Q.; Fruttiger, Marcus; Armstrong, Regina C.

2009-01-01

In multiple sclerosis, remyelination becomes limited after repeated or prolonged episodes of demyelination. To test the effect of platelet-derived growth factor-A (PDGF-A) in recovery from chronic demyelination we induced corpus callosum demyelination using cuprizone treatment in hPDGF-A transgenic (tg) mice with the human PDGF-A gene under control of an astrocyte-specific promoter. After chronic demyelination and removal of cuprizone from the diet, remyelination and oligodendrocyte density improved significantly in hPDGF-A tg mice compared with wild-type mice. In hPDGF-A tg mice, oligodendrocyte progenitor density and proliferation values were increased in the corpus callosum during acute demyelination but not during chronic demyelination or the subsequent recovery period, compared with hPDGF-A tg mice without cuprizone or to treatment-matched wild-type mice. Proliferation within the subventricular zone and subcallosal zone was elevated throughout cuprizone treatment but was not different between hPDGF-A tg and wild-type mice. Importantly, hPDGF-A tg mice had reduced apoptosis in the corpus callosum during the recovery period after chronic demyelination. Therefore, PDGF-A may support oligodendrocyte generation and survival to promote remyelination of chronic lesions. Furthermore, preventing oligodendrocyte apoptosis may be important not only during active demyelination but also for supporting the generation of new oligodendrocytes to remyelinate chronic lesions. PMID:17984680

Further purification of human pituitary-derived chondrocyte growth factor: heparin-binding and cross-reactivity with antiserum to basic FGF.

PubMed

Too, C K; Murphy, P R; Hamel, A M; Friesen, H G

1987-05-14

The previously described human pituitary-derived chondrocyte growth factor (CGF), mitogenic for rabbit fetal chondrocytes, was found to bind to heparin-Sepharose and was eluted with 1.5M NaCl. Further characterization of CGF demonstrated a molecular weight of 18-20 kD and cross-reactivity with antiserum to synthetic bovine basic fibroblast growth factor (FGF1-24). When human pituitaries were homogenized in 0.15 ammonium sulfate (pH 5.5) and the extract chromatographed on heparin-Sepharose, 98% of the mitogenic activity was adsorbed to heparin and eluted with 3M NaCl. These findings indicate that CGF is closely related or identical to basic FGF and that the bulk of mitogenic activity in the human pituitary extracts binds to heparin.

Signal Factors Secreted by 2D and Spheroid Mesenchymal Stem Cells and by Cocultures of Mesenchymal Stem Cells Derived Microvesicles and Retinal Photoreceptor Neurons

PubMed Central

Mao, Mao; Zhou, Liang

2017-01-01

We aim to identify levels of signal factors secreted by MSCs cultured in 2D monolayers (2D-MSCs), spheroids (spheroids MSCs), and cocultures of microvesicles (MVs) derived from 2D-MSCs or spheroid MSCs and retinal photoreceptor neurons. We seeded 2D-MSCs, spheroid MSCs, and cells derived from spheroids MSCs at equal numbers. MVs isolated from all 3 culture conditions were incubated with 661W cells. Levels of 51 signal factors in conditioned medium from those cultured conditions were quantified with bead-based assay. We found that IL-8, IL-6, and GROα were the top three most abundant signal factors. Moreover, compared to 2D-MSCs, levels of 11 cytokines and IL-2Rα were significantly increased in conditioned medium from spheroid MSCs. Finally, to test if enhanced expression of these factors reflects altered immunomodulating activities, we assessed the effect of 2D-MSC-MVs and 3D-MSC-MVs on CD14+ cell chemoattraction. Compared to 2D-MSC-MVs, 3D-MSC-MVs significantly decreased the chemotactic index of CD14+ cells. Our results suggest that spheroid culture conditions improve the ability of MSCs to selectively secrete signal factors. Moreover, 3D-MSC-MVs also possessed an enhanced capability to promote signal factors secretion compared to 2D-MSC-MVs and may possess enhanced immunomodulating activities and might be a better regenerative therapy for retinal degenerative diseases. PMID:28194184

The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

PubMed

Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

2017-01-01

Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle

PubMed Central

Hartman, William; Helan, Martin; Smelter, Dan; Sathish, Venkatachalem; Thompson, Michael; Pabelick, Christina M.; Johnson, Bruce; Prakash, Y. S.

2015-01-01

Background Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). Methods and Results 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. Conclusions Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy. PMID:26192455

Brain-derived-neurotrophic-factor (BDNF) stress response in rats bred for learned helplessness.

PubMed

Vollmayr, B; Faust, H; Lewicka, S; Henn, F A

2001-07-01

Stress-induced elevation of glucocorticoids is accompanied by structural changes and neuronal damage in certain brain areas. This includes reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus which can be prevented by chronic electroconvulsive seizures and antidepressant drug treatment. In the last years we have bred two strains of rats, one which reacts with congenital helplessness to stress (cLH), and one which congenitally does not acquire helplessness when stressed (cNLH). After being selectively bred for more than 40 generations these strains have lost their behavioural plasticity including their sensitivity to antidepressant treatment. We show here that in cLH rats, acute immobilization stress does not induce a reduction of BDNF expression in the hippocampus which is observed in Sprague--Dawley and cNLH rats. All animals tested exhibited elevated corticosterone levels when stressed, an indication, that in cLH rats regulation of BDNF expression in the hippocampal formation is uncoupled from corticosterone increase induced through stress. This may explain the lack of adaptive responses in this strain.

Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder.

PubMed

Poletti, S; Aggio, V; Hoogenboezem, T A; Ambrée, O; de Wit, H; Wijkhuijs, A J M; Locatelli, C; Colombo, C; Arolt, V; Drexhage, H A; Benedetti, F

2017-02-01

Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P<0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment. BD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Differential procoagulant activity of microparticles derived from monocytes, granulocytes, platelets and endothelial cells: impact of active tissue factor.

PubMed

Shustova, Olga N; Antonova, Olga A; Golubeva, Nina V; Khaspekova, Svetlana G; Yakushkin, Vladimir V; Aksuk, Svetlana A; Alchinova, Irina B; Karganov, Mikhail Y; Mazurov, Alexey V

2017-07-01

: Microparticles released by activated/apoptotic cells exhibit coagulation activity as they express phosphatidylserine and some of them - tissue factor. We compared procoagulant properties of microparticles from monocytes, granulocytes, platelets and endothelial cells and assessed the impact of tissue factor in observed differences. Microparticles were sedimented (20 000g, 30 min) from the supernatants of activated monocytes, monocytic THP-1 cells, granulocytes, platelets and endothelial cells. Coagulation activity of microparticles was examined using plasma recalcification assay. The size of microparticles was evaluated by dynamic light scattering. Tissue factor activity was measured by its ability to activate factor X. All microparticles significantly accelerated plasma coagulation with the shortest lag times for microparticles derived from monocytes, intermediate - for microparticles from THP-1 cells and endothelial cells, and the longest - for microparticles from granulocytes and platelets. Average diameters of microparticles ranged within 400-600 nm. The largest microparticles were produced by endothelial cells and granulocytes, smaller - by monocytes, and the smallest - by THP-1 cells and platelets. The highest tissue factor activity was detected in microparticles from monocytes, lower activity - in microparticles from endothelial cells and THP-1 cells, and no activity - in microparticles from platelets and granulocytes. Anti-tissue factor antibodies extended coagulation lag times for microparticles from monocytes, endothelial cells and THP-1 cells and equalized them with those for microparticles from platelets and granulocytes. Higher coagulation activity of microparticles from monocytes, THP-1 cells and endothelial cells in comparison with microparticles from platelets and granulocytes is determined mainly by the presence of active tissue factor.

The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone.

PubMed

Motamedi, Shima; Karimi, Isaac; Jafari, Fariba

2017-06-01

The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome (MetS) and neurodegenerative diseases (NDD) like Alzheimer's disease, Huntington's disease, Parkinson's disease and depression. If one factor plays an essential role in the pathogenesis of two diseases, it can be concluded that there might be a common root in these two diseases, as well. This review was aimed to highlight the crucial roles of BDNF in the pathogenesis of MetS and NDD and to introduce sole prophylactic or therapeutic applications, BDNF gene therapy and BDFN administration, in controlling MetS and NDD.

Umbilical Cord Blood-Derived Mesenchymal Stem Cells Inhibit, But Adipose Tissue-Derived Mesenchymal Stem Cells Promote, Glioblastoma Multiforme Proliferation

PubMed Central

Akimoto, Keiko; Kimura, Kenichi; Nagano, Masumi; Takano, Shingo; To'a Salazar, Georgina; Yamashita, Toshiharu

2013-01-01

Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms—promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source

Reliability of vascular geometry factors derived from clinical MRA

NASA Astrophysics Data System (ADS)

Bijari, Payam B.; Antiga, Luca; Steinman, David A.

2009-02-01

Recent work from our group has demonstrated that the amount of disturbed flow at the carotid bifurcation, believed to be a local risk factor for carotid atherosclerosis, can be predicted from luminal geometric factors. The next step along the way to a large-scale retrospective or prospective imaging study of such local risk factors for atherosclerosis is to investigate whether these geometric features are reproducible and accurate from routine 3D contrast-enhanced magnetic resonance angiography (CEMRA) using a fast and practical method of extraction. Motivated by this fact, we examined the reproducibility of multiple geometric features that are believed important in atherosclerosis risk assessment. We reconstructed three-dimensional carotid bifurcations from 15 clinical study participants who had previously undergone baseline and repeat CEMRA acquisitions. Certain geometric factors were extracted and compared between the baseline and the repeat scan. As the spatial resolution of the CEMRA data was noticeably coarse and anisotropic, we also investigated whether this might affect the measurement of the same geometric risk factors by simulating the CEMRA acquisition for 15 normal carotid bifurcations previously acquired at high resolution. Our results show that the extracted geometric factors are reproducible and faithful, with intra-subject uncertainties well below inter-subject variabilities. More importantly, these geometric risk factors can be extracted consistently and quickly for potential use as disturbed flow predictors.

Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.

PubMed

Mandage, Rajendra; Telford, Marco; Rodríguez, Juan Antonio; Farré, Xavier; Layouni, Hafid; Marigorta, Urko M; Cundiff, Caitlin; Heredia-Genestar, Jose Maria; Navarro, Arcadi; Santpere, Gabriel

2017-01-01

Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV-mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies.

Stromal derived factor-1 regulates bone morphogenetic protein 2-induced osteogenic differentiation of primary mesenchymal stem cells

PubMed Central

Hosogane, Naobumi; Huang, Zhiping; Rawlins, Bernard A.; Liu, Xia; Boachie-Adjei, Oheneba; Boskey, Adele L.; Zhu, Wei

2010-01-01

Stromal derived factor-1 (SDF-1) is a chemokine signaling molecule that binds to its transmembrane receptor CXC chemokine receptor-4 (CXCR4). While we previously detected that SDF-1 was co-required with bone morphogenetic protein 2 (BMP2) for differentiating mesenchymal C2C12 cells into osteoblastic cells, it is unknown whether SDF-1 is similarly involved in the osteogenic differentiation of mesenchymal stem cells (MSCs). Therefore, here we examined the role of SDF-1 signaling during BMP2-induced osteogenic differentiation of primary MSCs that were derived from human and mouse bone marrow. Our data showed that blocking of the SDF-1/CXCR4 signal axis or adding SDF-1 protein to MSCs significantly affected BMP2-induced alkaline phosphatase (ALP) activity and osteocalcin (OCN) synthesis, markers of preosteoblasts and mature osteoblasts, respectively. Moreover, disrupting the SDF-1 signaling impaired bone nodule mineralization during terminal differentiation of MSCs. Furthermore, we detected that blocking of the SDF-1 signaling inhibited the BMP2-induced early expression of Runt-related factor-2 (Runx2) and osterix (Osx), two “master” regulators of osteogenesis, and the SDF-1 effect was mediated via intracellular Smad and Erk activation. In conclusion, our results demonstrated a regulatory role of SDF-1 in BMP2-induced osteogenic differentiation of MSCs, as perturbing the SDF-1 signaling affected the differentiation of MSCs towards osteoblastic cells in response to BMP2 stimulation. These data provide novel insights into molecular mechanisms underlying MSC osteogenesis, and will contribute to the development of MSC therapies for enhancing bone formation and regeneration in broad orthopaedic situations. PMID:20362069

Application of platelet derived growth factor-BB and diabetic wound healing: the relationship with oxidative events.

PubMed

Gökşen, Sibel; Balabanlı, Barbaros; Coşkun-Cevher, Şule

2017-05-01

The reasons that cause delay in wound healing in diabetes are a decrease in the level of growth factors secretion, an increase in the destruction of growth factors and in oxidative stress. Platelet derived growth factor (PDGF) is one of the important growth factors that play a role in all phases of wound healing. This study investigates time-dependent effects of topically PDGF-BB administration on oxidative events on the healing of dorsolateral-excisional wounds in diabetic rats. Forty-two female Wistar-albino rats with streptozotocin-induced diabetes were divided into four groups: control group, untreated group, chitosan-treated group, chitosan + PDGF-BB-treated group. Two identical full-thickness excisional skin wounds were made under anaesthesia in all rats except for the control group. In the PDGF-BB-treated and chitosan-treated groups, the wounds were treated topically PDGF-BB (7 ng/mL, single daily dose) and blank chitosan gel (equal amount) after wounding, respectively. After these administrations, on day 3 and day 7 of wound healing, rats were sacrificed. Thiobarbituric acid reactive substances, glutathione, nitric oxide, ascorbic acid levels, and superoxide dismutase activity in wound tissues were spectrophotometrically measured. PDGF-BB administration significantly increased TBARS levels and non-enzymatic antioxidant levels in early phase of diabetic wound healing. PDGF-BB dramatically reduced NO x levels on day 3 and sharply increased NO x levels on day 7 of wound healing. Consequently, PDGF-BB administration can be effective on oxidative balance in the early phase of diabetic wound healing.

Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice.

PubMed

Kocabayoglu, Peri; Zhang, David Y; Kojima, Kensuke; Hoshida, Yujin; Friedman, Scott L

2016-06-01

Hepatic stellate cells (HSCs) activate during injury to orchestrate the liver's inflammatory and fibrogenic responses. A critical feature of HSC activation is the rapid induction of beta platelet-derived growth factor (β-PDGFR), which drives cellular fibrogenesis and proliferation; in contrast, normal liver has minimal β-PDGFR expression. While the role of β-PDGFR is well established in liver injury, its expression and contribution during liver regeneration are unknown. The aim of this study was to determine whether β-PDGFR is induced during liver regeneration following partial hepatectomy (pHx), and to define its contribution to the regenerative response. Control mice or animals with HSC-specific β-PDGFR-depletion underwent two-thirds pHx followed by assessment of hepatocyte proliferation and expression of β-PDGFR. RNA-sequencing from whole liver tissue of both groups after pHx was used to uncover pathways regulated by β-PDGFR signalling in HSCs. Beta platelet-derived growth factor expression on HSCs was up-regulated within 24 h following pHx in control mice, whereas absence of β-PDGFR blunted the expansion of HSCs. Mice lacking β-PDGFR displayed prolonged increases of transaminase levels within 72 h following pHx. Hepatocyte proliferation was impaired within the first 24 h based on Ki-67 and PCNA expression in β-PDGFR-deficient mice. This was associated with dysregulated growth in the β-PDGFR-deficient mice based on RNAseq with pathway analysis, and real-time quantitative PCR, which demonstrated reduced expression of Hgf, Igfbp1, Mapk and Il-6. Beta platelet-derived growth factor is induced in HSCs following surgical pHx and its deletion in HSCs leads to prolonged liver injury. However, there is no significant difference in liver regeneration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Separation of [Rh-103m]-rhodocene derivatives from the parent [103Ru]ruthenocene derivatives and their organ distribution].

PubMed

Wenzel, M; Wu, Y F

1987-01-01

The radioactive decay of [103Ru]ruthenocene derivatives leads to 103mRh labelled rhodocinium derivatives, which can be separated by the extraction of a lipophilic solution of the ruthenocen derivate with water. The separation factor 103mRh/103Ru reaches values of 32:1 Rh3+ ions are not liberated and extracted. The organ distribution of the 103mRh labelled rhodocinium derivatives gained from ruthenocene and from N-isopropyl-ruthenocene amphetamine is different from the distribution of the parent ruthenocene compound. The liver and kidney uptake of the rhodocinium-amphetamine is much higher than the uptake with ruthenocene amphetamine.

[Analysis of factors related to the number of mesenchymal stem cells derived from synovial fluid of the temporomandibular joint].

PubMed

Sun, Y P; Zheng, Y H; Zhang, Z G

2017-06-09

Objective: To analyze related factors on the number of mesenchymal stem cells in the synovial fluid of the temporomandibular joint (TMJ) and provide an research basis for understanding of the source and biological role of mesenchymal stem cells derived from synovial fluid in TMJ. Methods: One hundred and twenty-two synovial fluid samples from 91 temporomandibular disorders (TMD) patients who visited in Department of TMJ Center, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University from March 2013 to December 2013 were collected in this study, and 6 TMJ synovial fluid samples from 6 normal volunteers who were studying in the North Campus of Sun Yat-sen University were also collected, so did their clinical information. Then the relation between the number of mesenchymal stem cells derived from synovial fluid and the health status of the joints, age of donor, disc perforation, condylar bony destruction, blood containing and visual analogue scale score of pain were investigated using Mann-Whitney U test and Spearman rank correlation test. Results: The number of mesenchymal stem cells derived from synovial fluid had no significant relation with visual analogue scale score of pain ( r= 0.041, P= 0.672), blood containing ( P= 0.063), condylar bony destruction ( P= 0.371). Linear correlation between the number of mesenchymal stem cells derived from synovial fluid and age of donor was very week ( r= 0.186, P= 0.043). The number of mesenchymal stem cells up-regulated when the joint was in a disease state ( P= 0.001). The disc perforation group had more mesenchymal stem cells in synovial fluid than without disc perforation group ( P= 0.042). Conclusions: The number of mesenchymal stem cells derived from synovial fluid in TMJ has no correlation with peripheral blood circulation and condylar bony destruction, while has close relation with soft tissue structure damage of the joint.

Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume.

PubMed

Mondelli, Valeria; Cattaneo, Annamaria; Murri, Martino Belvederi; Di Forti, Marta; Handley, Rowena; Hepgul, Nilay; Miorelli, Ana; Navari, Serena; Papadopoulos, Andrew S; Aitchison, Katherine J; Morgan, Craig; Murray, Robin M; Dazzan, Paola; Pariante, Carmine M

2011-12-01

Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this cross-sectional case-control study was to investigate potential causes and consequences of reduced BDNF expression in these patients by examining the association between BDNF levels and measures of stress, inflammation, and hippocampal volume in first-episode psychosis. Brain-derived neurotrophic factor, interleukin (IL)-6, and tumor necrosis factor (TNF)-α messenger RNA levels were measured in the leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, all aged 18 to 65 years, recruited between January 2006 and December 2008. Patients were recruited from inpatient and outpatient units of the South London and Maudsley National Health Service Foundation Trust in London, United Kingdom, and the healthy controls were recruited from the same catchment area via advertisement and volunteer databases. In these same subjects, we measured salivary cortisol levels and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. Patients had reduced BDNF (effect size, d = 1.3; P < .001) and increased IL-6 (effect size, d = 1.1; P < .001) and TNF-α (effect size, d = 1.7; P < .001) gene expression levels when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R(2) = 0.23, P = .009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels all significantly and independently predicted a smaller left hippocampal volume (adjusted R(2) = 0.71, P < .001). Biological

Correlates of early pregnancy serum brain-derived neurotrophic factor in a Peruvian population.

PubMed

Yang, Na; Levey, Elizabeth; Gelaye, Bizu; Zhong, Qiu-Yue; Rondon, Marta B; Sanchez, Sixto E; Williams, Michelle A

2017-12-01

Knowledge about factors that influence serum brain-derived neurotrophic factor (BDNF) concentrations during early pregnancy is lacking. The aim of the study is to examine the correlates of early pregnancy serum BDNF concentrations. A total of 982 women attending prenatal care clinics in Lima, Peru, were recruited in early pregnancy. Pearson's correlation coefficient was calculated to evaluate the relation between BDNF concentrations and continuous covariates. Analysis of variance and generalized linear models were used to compare the unadjusted and adjusted BDNF concentrations according to categorical variables. Multivariable linear regression models were applied to determine the factors that influence early pregnancy serum BDNF concentrations. In bivariate analysis, early pregnancy serum BDNF concentrations were positively associated with maternal age (r = 0.16, P < 0.001) and early pregnancy body mass index (BMI) (r = 0.17, P < 0.001), but inversely correlated with gestational age at sample collection (r = -0.21, P < 0.001) and C-reactive protein (CRP) concentrations (r = -0.07, P < 0.05). In the multivariable linear regression model, maternal age (β = 0.11, P = 0.001), early pregnancy BMI (β = 1.58, P < 0.001), gestational age at blood collection (β = -0.33, P < 0.001), and serum CRP concentrations (β = -0.57, P = 0.002) were significantly associated with early pregnancy serum BDNF concentrations. Participants with moderate antepartum depressive symptoms (Patient Health Questionnaire-9 (PHQ-9) score ≥ 10) had lower serum BDNF concentrations compared with participants with no/mild antepartum depressive symptoms (PHQ-9 score < 10). Maternal age, early pregnancy BMI, gestational age, and the presence of moderate antepartum depressive symptoms were statistically significantly associated with early pregnancy serum BDNF concentrations in low-income Peruvian women. Biological changes of CRP during pregnancy may affect serum

N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor.

PubMed

O'Sullivan, J M; Aguila, S; McRae, E; Ward, S E; Rawley, O; Fallon, P G; Brophy, T M; Preston, R J S; Brady, L; Sheils, O; Chion, A; O'Donnell, J S

2016-12-01

Essentials von Willebrands factor (VWF) glycosylation plays a key role in modulating in vivo clearance. VWF glycoforms were used to examine the role of specific glycan moieties in regulating clearance. Reduction in sialylation resulted in enhanced VWF clearance through asialoglycoprotein receptor. Progressive VWF N-linked glycan trimming resulted in increased macrophage-mediated clearance. Click to hear Dr Denis discuss clearance of von Willebrand factor in a free presentation from the ISTH Academy SUMMARY: Background Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. Objective To define the molecular mechanisms through which VWF N-linked glycan structures influence in vivo clearance. Methods By use of a series of exoglycosidases, different plasma-derived VWF (pd-VWF) glycoforms were generated. In vivo clearance of these glycoforms was then assessed in VWF -/- mice in the presence or absence of inhibitors of asialoglycoprotein receptor (ASGPR), or following clodronate-induced macrophage depletion. Results Reduced amounts of N-linked and O-linked sialylation resulted in enhanced pd-VWF clearance modulated via ASGPR. In addition to this role of terminal sialylation, we further observed that progressive N-linked glycan trimming also resulted in markedly enhanced VWF clearance. Furthermore, these additional N-linked glycan effects on clearance were ASGPR-independent, and instead involved enhanced macrophage clearance that was mediated, at least in part, through LDL receptor-related protein 1. Conclusion The carbohydrate determinants expressed on VWF regulate susceptibility to proteolysis by ADAMTS-13. In addition, our findings now further demonstrate that non-sialic acid carbohydrate

Platelet-Derived Growth Factor C Is Upregulated in Human Uterine Fibroids and Regulates Uterine Smooth Muscle Cell Growth1

PubMed Central

Suo, Guangli; Jiang, Yong; Cowan, Bryan; Wang, Jean Y.J.

2009-01-01

Leiomyomata uteri (i.e., uterine fibroids) are benign tumors arising from the abnormal growth of uterine smooth muscle cells (SMCs). We show here that the expression of platelet-derived growth factor C (PDGFC) is higher in approximately 80% of uterine fibroids than in adjacent myometrial tissues examined. Increased expression of PDGFC is also observed in fibroid-derived SMCs (fSMCs) relative to myometrial-derived SMCs (mSMCs). Recombinant bioactive PDGFCC homodimer stimulates the growth of fSMCs and mSMCs in ex vivo cultures and prolongs the survival of fSMCs in Matrigel plugs implemented subcutaneously in immunocompromised mice. The knockdown of PDGF receptor-alpha (PDGFRA) through lentiviral-mediated RNA interference reduces the growth of fSMCs and mSMCs in ex vivo cultures and in Matrigel implants. Furthermore, two small molecule inhibitors of the PDGFR tyrosine kinase (i.e., imatinib and dasatinib) exerted negative effects on fSMC and mSMC growth in ex vivo cultures, albeit at concentrations that cannot be achieved in vivo. These results suggest that the PDGFCC/PDGFRA signaling module plays an important role in fSMC and mSMC growth, and that the upregulation of PDGFC expression may contribute to the clonal expansion of fSMCs in the development of uterine fibroids. PMID:19553600

New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

PubMed Central

Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

2014-01-01

Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

Low-level laser therapy promotes dendrite growth via upregulating brain-derived neurotrophic factor expression

NASA Astrophysics Data System (ADS)

Meng, Chengbo; He, Zhiyong; Xing, Da

2014-09-01

Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via the increase of both BDNF mRNA and protein expression. In addition, dendrite growth was improved after LLLT, characterized by upregulation of PSD95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT can ameliorate Aβ-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Aβ-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of Alzheimer's disease.

Gc protein-derived macrophage activating factor (GcMAF): isoelectric focusing pattern and tumoricidal activity.

PubMed

Mohamad, Saharuddin Bin; Nagasawa, Hideko; Sasaki, Hideyuki; Uto, Yoshihiro; Nakagawa, Yoshinori; Kawashima, Ken; Hori, Hitoshi

2003-01-01

Gc protein is the precursor for Gc protein-derived macrophage activating factor (GcMAF), with three phenotypes: Gc1f, Gc1s and Gc2, based on its electrophoretic mobility. The difference in electrophoretic mobility is because of the difference in its posttranslational sugar moiety composition. We compared the difference between Gc protein and GcMAF electrophoretic mobility using the isoelectric focusing (IEF) method. The tumoricidal activity of GcMAF-treated macrophage was evaluated after coculture with L-929 cell. The tumoricidal mechanism was investigated using TNF bioassay and nitric oxide (NO) release. The difference in Gc protein and GcMAF electrophoretic mobility was detected. The tumoricidal activity of GcMAF-treated macrophage was detected, but no release of TNF and NO was detected. The difference of isoelectric focusing mobility in Gc protein and GcMAF would be useful to develop a GcMAF detection method. GcMAF increased macrophage tumoricidal activity but TNF and NO release were not involved in the mechanism.

Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.

PubMed

Presta, Marco; Oreste, Pasqua; Zoppetti, Giorgio; Belleri, Mirella; Tanghetti, Elena; Leali, Daria; Urbinati, Chiara; Bugatti, Antonella; Ronca, Roberto; Nicoli, Stefania; Moroni, Emanuela; Stabile, Helena; Camozzi, Maura; Hernandez, German Andrés; Mitola, Stefania; Dell'Era, Patrizia; Rusnati, Marco; Ribatti, Domenico

2005-01-01

Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives. Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane. LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.

Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid-stimulated migration of murine osteosarcoma LM8 cells.

PubMed

Kubohara, Yuzuru; Komachi, Mayumi; Homma, Yoshimi; Kikuchi, Haruhisa; Oshima, Yoshiteru

2015-08-07

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), -2, and -3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5-20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC50 values of 5.5, 4.6, and 4.2 μM, respectively. On the other hand, the IC50 values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.

Elevated expression of brain-derived neurotrophic factor facilitates visual imprinting in chicks.

PubMed

Suzuki, Keiko; Maekawa, Fumihiko; Suzuki, Shingo; Nakamori, Tomoharu; Sugiyama, Hayato; Kanamatsu, Tomoyuki; Tanaka, Kohichi; Ohki-Hamazaki, Hiroko

2012-12-01

With the aim of elucidating the neural mechanisms of early learning, we studied the role of brain-derived neurotrophic factor (BDNF) in visual imprinting in birds. The telencephalic neural circuit connecting the visual Wulst and intermediate medial mesopallium is critical for imprinting, and the core region of the hyperpallium densocellulare (HDCo), situated at the center of this circuit, has a key role in regulating the activity of the circuit. We found that the number of BDNF mRNA-positive cells in the HDCo was elevated during the critical period, particularly at its onset, on the day of hatching (P0). After imprinting training on P1, BDNF mRNA-positive cells in the HDCo increased in number, and tyrosine phosphorylation of TrkB was observed. BDNF infusion into the HDCo at P1 induced imprinting, even with a weak training protocol that does not normally induce imprinting. In contrast, K252a, an antagonist of Trk, inhibited imprinting. Injection of BDNF at P7, after the critical period, did not elicit imprinting. These results suggest that BDNF promotes the induction of imprinting through TrkB exclusively during the critical period. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

PubMed Central

Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

2016-01-01

Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy. PMID:27701410

A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression.

PubMed

Ustach, Carolyn V; Taube, Marcus E; Hurst, Newton J; Bhagat, Sunita; Bonfil, R Daniel; Cher, Michael L; Schuger, Lucia; Kim, Hyeong-Reh Choi

2004-03-01

The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH(2)-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the beta-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer.

A Potential Oncogenic Activity of Platelet-Derived Growth Factor D in Prostate Cancer Progression

PubMed Central

Ustach, Carolyn V.; Taube, Marcus E.; Hurst, Newton J.; Bhagat, Sunita; Bonfil, R. Daniel; Cher, Michael L.; Schuger, Lucia; Kim, Hyeong-Reh Choi

2014-01-01

The platelet-derived growth factor (PDGF) proteins are potent stimulators of cell proliferation/transformation and play a major role in cell-cell communication. For over two decades, PDGFs were thought to exist as three dimeric polypeptides (the homodimers AA and BB and the heterodimer AB). Recently, however, the PDGF C and D chains were discovered in a BLAST search of the expressed sequence tag databases. The PDGF CC and DD dimers have a unique two-domain structure with an NH2-terminal CUB (compliment subcomponents C1r/C1s, Uegf, and Bmp1) domain and a COOH-terminal PDGF/vascular endothelial growth factor domain. Whereas secreted PDGF AA, BB, and AB readily activate their cell surface receptors, it was suggested that extracellular proteolytic removal of the CUB domain is required for the PDGF/vascular endothelial growth factor domain of PDGF CC and DD to activate PDGF receptors. In the present study, we examined the processing of latent PDGF D into its active form and the effects of PDGF D expression on prostate cancer progression. We show that LNCaP cells auto-activate latent PDGF DD into the active PDGF domain, which can induce phosphorylation of the β-PDGF receptor and stimulates LNCaP cell proliferation in an autocrine manner. Additionally, LNCaP-PDGF D-conditioned medium induces migration of the prostate fibroblast cell line 1532-FTX, indicating LNCaP-processed PDGF DD is active in a paracrine manner as well. In a severe combined immunodeficient mouse model, PDGF DD expression accelerates early onset of prostate tumor growth and drastically enhances prostate carcinoma cell interaction with surrounding stromal cells. These demonstrate a potential oncogenic activity of PDGF DD in the development and/or progression of prostate cancer. PMID:14996732

Biota Modeling in EPA's Preliminary Remediation Goal and Dose Compliance Concentration Calculators for Use in EPA Superfund Risk Assessment: Explanation of Intake Rate Derivation, Transfer Factor Compilation, and Mass Loading Factor Sources

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manning, Karessa L.; Dolislager, Fredrick G.; Bellamy, Michael B.

The Preliminary Remediation Goal (PRG) and Dose Compliance Concentration (DCC) calculators are screening level tools that set forth Environmental Protection Agency's (EPA) recommended approaches, based upon currently available information with respect to risk assessment, for response actions at Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) sites, commonly known as Superfund. The screening levels derived by the PRG and DCC calculators are used to identify isotopes contributing the highest risk and dose as well as establish preliminary remediation goals. Each calculator has a residential gardening scenario and subsistence farmer exposure scenarios that require modeling of the transfer of contaminants frommore » soil and water into various types of biota (crops and animal products). New publications of human intake rates of biota; farm animal intakes of water, soil, and fodder; and soil to plant interactions require updates be implemented into the PRG and DCC exposure scenarios. Recent improvements have been made in the biota modeling for these calculators, including newly derived biota intake rates, more comprehensive soil mass loading factors (MLFs), and more comprehensive soil to tissue transfer factors (TFs) for animals and soil to plant transfer factors (BV's). New biota have been added in both the produce and animal products categories that greatly improve the accuracy and utility of the PRG and DCC calculators and encompass greater geographic diversity on a national and international scale.« less

Plasma Rich in Growth Factors Induces Cell Proliferation, Migration, Differentiation, and Cell Survival of Adipose-Derived Stem Cells

PubMed Central

Mellado-López, Maravillas; Griffeth, Richard J.; Meseguer-Ripolles, Jose; García, Montserrat

2017-01-01

Adipose-derived stem cells (ASCs) are a promising therapeutic alternative for tissue repair in various clinical applications. However, restrictive cell survival, differential tissue integration, and undirected cell differentiation after transplantation in a hostile microenvironment are complications that require refinement. Plasma rich in growth factors (PRGF) from platelet-rich plasma favors human and canine ASC survival, proliferation, and delaying human ASC senescence and autophagocytosis in comparison with serum-containing cultures. In addition, canine and human-derived ASCs efficiently differentiate into osteocytes, adipocytes, or chondrocytes in the presence of PRGF. PRGF treatment induces phosphorylation of AKT preventing ASC death induced by lethal concentrations of hydrogen peroxide. Indeed, AKT inhibition abolished the PRGF apoptosis prevention in ASC exposed to 100 μM of hydrogen peroxide. Here, we show that canine ASCs respond to PRGF stimulus similarly to the human cells regarding cell survival and differentiation postulating the use of dogs as a suitable translational model. Overall, PRGF would be employed as a serum substitute for mesenchymal stem cell amplification to improve cell differentiation and as a preconditioning agent to prevent oxidative cell death. PMID:29270200

Plasma Rich in Growth Factors Induces Cell Proliferation, Migration, Differentiation, and Cell Survival of Adipose-Derived Stem Cells.

PubMed

Mellado-López, Maravillas; Griffeth, Richard J; Meseguer-Ripolles, Jose; Cugat, Ramón; García, Montserrat; Moreno-Manzano, Victoria

2017-01-01

Adipose-derived stem cells (ASCs) are a promising therapeutic alternative for tissue repair in various clinical applications. However, restrictive cell survival, differential tissue integration, and undirected cell differentiation after transplantation in a hostile microenvironment are complications that require refinement. Plasma rich in growth factors (PRGF) from platelet-rich plasma favors human and canine ASC survival, proliferation, and delaying human ASC senescence and autophagocytosis in comparison with serum-containing cultures. In addition, canine and human-derived ASCs efficiently differentiate into osteocytes, adipocytes, or chondrocytes in the presence of PRGF. PRGF treatment induces phosphorylation of AKT preventing ASC death induced by lethal concentrations of hydrogen peroxide. Indeed, AKT inhibition abolished the PRGF apoptosis prevention in ASC exposed to 100  μ M of hydrogen peroxide. Here, we show that canine ASCs respond to PRGF stimulus similarly to the human cells regarding cell survival and differentiation postulating the use of dogs as a suitable translational model. Overall, PRGF would be employed as a serum substitute for mesenchymal stem cell amplification to improve cell differentiation and as a preconditioning agent to prevent oxidative cell death.

Platelet-derived growth factor A mRNA in platelets is associated with the degree of hepatic fibrosis in chronic hepatitis C.

PubMed

Tanikawa, Aline Aki; Grotto, Rejane Maria Tommasini; Silva, Giovanni Faria; Ferrasi, Adriana Camargo; Sarnighausen, Valéria Cristina Rodrigues; Pardini, Maria Inês de Moura Campos

2017-01-01

Transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor (PDGF) are the main cytokines related to hepatic fibrogenesis. RNA isolated from the platelets and hepatic tissue of 43 HCV carriers was used for quantitative polymerase chain reaction to determine TGFB1, PDGFA, and PDGFB RNA expression. The mRNA expression of PDGFA in platelets was significantly lower in the group with advanced fibrosis than in the group with early-stage fibrosis. TGFB1 was more frequently expressed in platelets than in hepatic tissue, which was different from PDGFB. A pathway mediated by overexpression of TGFB1 via PDGFA in megakaryocytes could be involved in the development of fibrosis.

Microbiota-Derived Metabolic Factors Reduce Campylobacteriosis in Mice.

PubMed

Sun, Xiaolun; Winglee, Kathryn; Gharaibeh, Raad Z; Gauthier, Josee; He, Zhen; Tripathi, Prabhanshu; Avram, Dorina; Bruner, Steven; Fodor, Anthony; Jobin, Christian

2018-05-01

Campylobacter jejuni, a prevalent foodborne bacterial pathogen, exploits the host innate response to induce colitis. Little is known about the roles of microbiota in C jejuni-induced intestinal inflammation. We investigated interactions between microbiota and intestinal cells during C jejuni infection of mice. Germ-free C57BL/6 Il10 -/- mice were colonized with conventional microbiota and infected with a single dose of C jejuni (10 9 colony-forming units/mouse) via gavage. Conventional microbiota were cultured under aerobic, microaerobic, or anaerobic conditions and orally transplanted into germ-free Il10 -/- mice. Colon tissues were collected from mice and analyzed by histology, real-time polymerase chain reaction, and immunoblotting. Fecal microbiota and bile acids were analyzed with 16S sequencing and high-performance liquid chromatography with mass spectrometry, respectively. Introduction of conventional microbiota reduced C jejuni-induced colitis in previously germ-free Il10 -/- mice, independent of fecal load of C jejuni, accompanied by reduced activation of mammalian target of rapamycin. Microbiota transplantation and 16S ribosomal DNA sequencing experiments showed that Clostridium XI, Bifidobacterium, and Lactobacillus were enriched in fecal samples from mice colonized with microbiota cultured in anaerobic conditions (which reduce colitis) compared with mice fed microbiota cultured under aerobic conditions (susceptible to colitis). Oral administration to mice of microbiota-derived secondary bile acid sodium deoxycholate, but not ursodeoxycholic acid or lithocholic acid, reduced C jejuni-induced colitis. Depletion of secondary bile acid-producing bacteria with antibiotics that kill anaerobic bacteria (clindamycin) promoted C jejuni-induced colitis in specific pathogen-free Il10 -/- mice compared with the nonspecific antibiotic nalidixic acid; colitis induction by antibiotics was associated with reduced level of luminal deoxycholate. We identified a

Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in Drosophila.

PubMed

Zheng, Huimei; Wang, Xuexiang; Guo, Pengfei; Ge, Wanzhong; Yan, Qinfeng; Gao, Weiqiang; Xi, Yongmei; Yang, Xiaohang

2017-05-01

In Drosophila, fat-body remodeling accompanied with fat mobilization is an ecdysone-induced dynamic process that only occurs during metamorphosis. Here, we show that the activated Drosophila platelet-derived growth factor/VEGF receptor (PVR) is sufficient to induce shape changes in the fat body, from thin layers of tightly conjugated polygonal cells to clusters of disaggregated round-shaped cells. These morphologic changes are reminiscent of those seen during early pupation upon initiation of fat-body remodeling. Activation of PVR also triggers an early onset of lipolysis and mobilization of internal storage, as revealed by the appearance of small lipid droplets and up-regulated lipolysis-related genes. We found that PVR displays a dynamic expression pattern in the fat body and peaks at the larval-prepupal transition under the control of ecdysone signaling. Removal of PVR, although it does not prevent ecdysone-induced fat-body remodeling, causes ecdysone signaling to be up-regulated. Our data reveal that PVR is active in a dual-secured mechanism that involves an ecdysone-induced fat-body remodeling pathway and a reinforced PVR pathway for effective lipid mobilization. Ectopic expression of activated c-kit-the mouse homolog of PVR in the Drosophila fat body-also results in a similar phenotype. This may suggest a novel function of c-kit as it relates to lipid metabolism in mammals.-Zheng, H., Wang, X., Guo, P., Ge, W., Yan, Q., Gao, W., Xi, Y., Yang, X. Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in Drosophila . © FASEB.

Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor.

PubMed

Fujimoto, Takuya; Imaeda, Yasuhiro; Konishi, Noriko; Hiroe, Katsuhiko; Kawamura, Masaki; Textor, Garret P; Aertgeerts, Kathleen; Kubo, Keiji

2010-05-13

Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice.

PubMed

Yoneda, Mitsugu; Sugimoto, Naotoshi; Katakura, Masanori; Matsuzaki, Kentaro; Tanigami, Hayate; Yachie, Akihiro; Ohno-Shosaku, Takako; Shido, Osamu

2017-01-01

Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Theobromine works as a phosphodiesterase (PDE) inhibitor to increase intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the cAMP-response element-binding protein (CREB), which is involved in a large variety of brain processes, including the induction of the brain-derived neurotrophic factor (BDNF). BDNF supports cell survival and neuronal functions, including learning and memory. Thus, cAMP/CREB/BDNF pathways play an important role in learning and memory. Here, we investigated whether orally administered theobromine could act as a PDE inhibitor centrally and affect cAMP/CREB/BDNF pathways and learning behavior in mice. The mice were divided into two groups. The control group (CN) was fed a normal diet, whereas the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 30 days. We measured the levels of theobromine, phosphorylated vasodilator-stimulated phosphoprotein (p-VASP), phosphorylated CREB (p-CREB), and BDNF in the brain. p-VASP was used as an index of cAMP increases. Moreover, we analyzed the performance of the mice on a three-lever motor learning task. Theobromine was detectable in the brains of TB mice. The brain levels of p-VASP, p-CREB, and BDNF were higher in the TB mice compared with those in the CN mice. In addition, the TB mice performed better on the three-lever task than the CN mice did. These results strongly suggested that orally administered theobromine acted as a PDE inhibitor in the brain, and it augmented the cAMP/CREB/BDNF pathways and motor learning in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Mutation of Gonadal soma-derived factor induces medaka XY gonads to undergo ovarian development.

PubMed

Imai, Takuto; Saino, Kentaro; Matsuda, Masaru

2015-11-06

Gonochoristic species have a bipotential gonad that develops into a testis or an ovary. In species whose sex is determined by a genetic factor, the expression of a sex-determining gene is the first cue that directs the development of a bipotential gonad. Subsequent expression of downstream genes induces the gonad to develop into a testis or an ovary. The TGF-ß family member Gonadal soma-derived factor (Gsdf) is thought to be an important gene for gonadal development in teleost fish, and it is expressed at higher levels in the testis than in the ovary from early to mature stages. However, there is little functional information about the gene. In this study, we targeted the Gsdf coding region in the medaka fish Oryzias latipes using transcription activator-like effector nucleases (TALENs) and studied the phenotypes of the Gsdf mutant medaka. Although normal and heterozygous XY gonads developed into a testis, all XY gonads with a homozygous mutation in Gsdf developed into an ovary at early developmental stages. However, two-thirds of Gsdf mutant XY gonads developed into testes in the adult stages. These results demonstrate that although a gonad can develop into a complete testis in the absence of Gsdf, Gsdf function is critical for directing the bipotential gonad at early developmental stages. Therefore, Gsdf is an endogenous inducer of testicular development similar to a master sex-determining gene. Copyright © 2015 Elsevier Inc. All rights reserved.

The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12-p13.1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schindelhauer, D.; Schuffenhauer, S.; Meitinger, T.

1995-08-10

The gene coding for glial cell line derived neurotrophic factor (GDNF) has biological properties that may have potential as a treatment for Parkinson`s and motoneuron diseases. Using the NIGMS Mapping Panel 2, we have localized the GDNF gene to human chromosome 5p12-p13.1. Large NruI and NotI fragments on chromosome 5 will facilitate the construction of a long-range map of the region. 26 refs., 1 fig., 1 tab.

Determinants of brain-derived neurotrophic factor (BDNF) in umbilical cord and maternal serum.

PubMed

Flöck, A; Weber, S K; Ferrari, N; Fietz, C; Graf, C; Fimmers, R; Gembruch, U; Merz, W M

2016-01-01

Brain-derived neurotrophic factor (BDNF) plays a fundamental role in brain development; additionally, it is involved in various aspects of cerebral function, including neurodegenerative and psychiatric diseases. Involvement of BDNF in parturition has not been investigated. The aim of our study was to analyze determinants of umbilical cord BDNF (UC-BDNF) concentrations of healthy, term newborns and their respective mothers. This cross-sectional prospective study was performed at a tertiary referral center. Maternal venous blood samples were taken on admission to labor ward; newborn venous blood samples were drawn from the umbilical cord (UC), before delivery of the placenta. Analysis was performed with a commercially available immunoassay. Univariate analyses and stepwise multivariate regression models were applied. 120 patients were recruited. UC-BDNF levels were lower than maternal serum concentrations (median 641 ng/mL, IQR 506 vs. median 780 ng/mL, IQR 602). Correlation between UC- and maternal BDNF was low (R=0.251, p=0.01). In univariate analysis, mode of delivery (MoD), gestational age (GA), body mass index at delivery, and gestational diabetes were determinants of UC-BDNF (MoD and smoking for maternal BDNF, respectively). Stepwise multivariate regression analysis revealed a model with MoD and GA as determinants for UC-BDNF (MoD for maternal BDNF). MoD and GA at delivery are determinants of circulating BDNF in the mother and newborn. We hypothesize that BDNF, like other neuroendocrine factors, is involved in the neuroendocrine cascade of delivery. Timing and mode of delivery may exert BDNF-induced effects on the cerebral function of newborns and their mothers. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons

PubMed Central

Noble, Emily E.; Mavanji, Vijayakumar; Little, Morgan R.; Billington, Charles J.; Kotz, Catherine M.; Wang, ChuanFeng

2014-01-01

Background Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. Methods To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for seven weeks of exercise intervention. Results Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p<0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. Conclusions These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. PMID:24755094

Exercise reduces diet-induced cognitive decline and increases hippocampal brain-derived neurotrophic factor in CA3 neurons.

PubMed

Noble, Emily E; Mavanji, Vijayakumar; Little, Morgan R; Billington, Charles J; Kotz, Catherine M; Wang, ChuanFeng

2014-10-01

Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p<0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. Published by Elsevier Inc.

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

NASA Technical Reports Server (NTRS)

Askari, Arman T.; Unzek, Samuel; Popovic, Zoran B.; Goldman, Corey K.; Forudi, Farhad; Kiedrowski, Matthew; Rovner, Aleksandr; Ellis, Stephen G.; Thomas, James D.; DiCorleto, Paul E.;

Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor.

PubMed

Miyamoto, Nobukazu; Maki, Takakuni; Shindo, Akihiro; Liang, Anna C; Maeda, Mitsuyo; Egawa, Naohiro; Itoh, Kanako; Lo, Evan K; Lok, Josephine; Ihara, Masafumi; Arai, Ken

2015-10-14

Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF. The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However

Cost function approach for estimating derived demand for composite wood products

Treesearch

T. C. Marcin

1991-01-01

A cost function approach was examined for using the concept of duality between production and input factor demands. A translog cost function was used to represent residential construction costs and derived conditional factor demand equations. Alternative models were derived from the translog cost function by imposing parameter restrictions.

Suppression of human monocyte tissue factor induction by red wine phenolics and synthetic derivatives of resveratrol.

PubMed

Kaur, Gurjeet; Roberti, Marinella; Raul, Francis; Pendurthi, Usha R

2007-01-01

Prevention of cardiovascular disease through nutritional supplements is growing in popularity throughout the world. Multiple epidemiologic studies found that moderate consumption of alcohol, particularly red wine, lowers mortality rates from coronary heart diseases (CHD). Chronic inflammation and atherosclerosis associated with CHD culminate in aberrant intravascular expression of tissue factor (TF), which triggers blood coagulation leading to thrombosis, a major cause for heart attack. We showed earlier that two red wine phenolics, resveratrol and quercetin, suppressed TF induction in endothelial cells. In the present study, we investigated efficacy of seven resveratrol derivatives, which were shown to be effective in regulating cancer cell growth in vitro at much lower concentrations than the parent compound resveratrol, in inhibiting TF induction in peripheral blood mononuclear cells (PBMCs). We also tested possible synergistic effects of resveratrol and quercetin with the other major red wine phenolics in suppression of lipopolysaccharide-induced TF expression in human PBMCs. We found that several resveratrol derivatives were 2- to 10-fold more efficient than resveratrol in inhibiting TF induction. Our study found no evidence for synergism among red wine polyphenolics. These data suggest that structural alterations of resveratrol can be effective in producing potent antithrombotic agents that will have therapeutic potential in the improvement of cardiovascular health and prevention of CHD. Among major red wine phenolics, quercetin appears to be the predominant suppressor of TF induction.

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

PubMed

Xu, Danfeng; Lian, Di; Wu, Jing; Liu, Ying; Zhu, Mingjie; Sun, Jiaming; He, Dake; Li, Ling

2017-08-04

Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay. Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti

Deriving depth-dependent light escape efficiency and optical Swank factor from measured pulse height spectra of scintillators.

PubMed

Howansky, Adrian; Peng, Boyu; Lubinsky, Anthony R; Zhao, Wei

2017-03-01

Pulse height spectroscopy has been used by investigators to deduce the imaging properties of scintillators. Pulse height spectra (PHS) are used to compute the Swank factor, which describes the variation in scintillator light output per x-ray interaction. The spread in PHS measured below the K-edge is related to the optical component of the Swank factor, i.e., variations in light escape efficiency from different depths of x-ray interaction in the scintillator, denoted ε¯(z). Optimizing scintillators for medical imaging applications requires understanding of these optical properties, as they determine tradeoffs between parameters such as x-ray absorption, light yield, and spatial resolution. This work develops a model for PHS acquisition such that the effect of measurement uncertainty can be removed. This method allows ε¯(z) to be quantified on an absolute scale and permits more accurate estimation of the optical Swank factor of scintillators. The pulse height spectroscopy acquisition chain was modeled as a linear system of stochastic gain stages. Analytical expressions were derived for signal and noise propagation through the PHS chain, accounting for deterministic and stochastic aspects of x-ray absorption, scintillation, and light detection with a photomultiplier tube. The derived expressions were used to calculate PHS of thallium-doped cesium iodide (CsI) scintillators using parameters that were measured, calculated, or known from literature. PHS were measured at 25 and 32 keV of CsI samples designed with an optically reflective or absorptive backing, with or without a fiber-optic faceplate (FOP), and with thicknesses ranging from 150-1000 μm. Measured PHS were compared with calculated PHS, then light escape model parameters were varied until measured and modeled results reached agreement. Resulting estimates of ε¯(z) were used to calculate each scintillator's optical Swank factor. For scintillators of the same optical design, only minor differences in

Deriving depth-dependent light escape efficiency and optical Swank factor from measured pulse height spectra of scintillators

PubMed Central

Howansky, Adrian; Peng, Boyu; Lubinsky, Anthony R.; Zhao, Wei

2017-01-01

Purpose Pulse height spectroscopy has been used by investigators to deduce the imaging properties of scintillators. Pulse height spectra (PHS) are used to compute the Swank factor, which describes the variation in scintillator light output per x-ray interaction. The spread in PHS measured below the K-edge is related to the optical component of the Swank factor, i.e. variations in light escape efficiency from different depths of x-ray interaction in the scintillator, denoted ε̄(z). Optimizing scintillators for medical imaging applications requires understanding of these optical properties, as they determine tradeoffs between parameters such as x-ray absorption, light yield, and spatial resolution. This work develops a model for PHS acquisition such that the effect of measurement uncertainty can be removed. This method allows ε̄(z) to be quantified on an absolute scale and permits more accurate estimation of the optical Swank factor of scintillators. Methods The pulse height spectroscopy acquisition chain was modeled as a linear system of stochastic gain stages. Analytical expressions were derived for signal and noise propagation through the PHS chain, accounting for deterministic and stochastic aspects of x-ray absorption, scintillation, and light detection with a photomultiplier tube. The derived expressions were used to calculate PHS of thallium-doped cesium iodide (CsI) scintillators using parameters that were measured, calculated, or known from literature. PHS were measured at 25 and 32 keV of CsI samples designed with an optically-reflective or absorptive backing, with or without a fiber-optic faceplate (FOP), and with thicknesses ranging from 150–1000 μm. Measured PHS were compared with calculated PHS, then light escape model parameters were varied until measured and modeled results reached agreement. Resulting estimates of ε̄(z) were used to calculate each scintillator’s optical Swank factor. Results For scintillators of the same optical design

The Effects of Acute Exercise on Memory and Brain-Derived Neurotrophic Factor (BDNF).

PubMed

Etnier, Jennifer L; Wideman, Laurie; Labban, Jeffrey D; Piepmeier, Aaron T; Pendleton, Daniel M; Dvorak, Kelly K; Becofsky, Katie

2016-08-01

Acute exercise benefits cognition, and some evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in this effect. The purpose of this study was to explore the dose-response relationship between exercise intensity, memory, and BDNF. Young adults completed 3 exercise sessions at different intensities relative to ventilator threshold (Vt) (VO 2max , Vt - 20%, Vt + 20%). For each session, participants exercised for approximately 30 min. Following exercise, they performed the Rey Auditory Verbal Learning Test (RAVLT) to assess short-term memory, learning, and long-term memory recall. Twenty-four hours later, they completed the RAVLT recognition trial, which provided another measure of long-term memory. Blood was drawn before exercise, immediately postexercise, and after the 30-min recall test. Results indicated that long-term memory as assessed after the 24-hr delay differed as a function of exercise intensity with the largest benefits observed following maximal intensity exercise. BDNF data showed a significant increase in response to exercise; however, there were no differences relative to exercise intensity and there were no significant associations between BDNF and memory. Future research is warranted so that we can better understand how to use exercise to benefit cognitive performance.

Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis.

PubMed

Saghazadeh, Amene; Rezaei, Nima

2017-04-01

Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity. Altered blood BDNF levels have been frequently identified in people with autism spectrum disorders (ASD). There are however wide discrepancies in the evidence. Therefore, we performed the present systematic review and meta-analysis aimed at qualitative and quantitative synthesis of studies that measured blood BDNF levels in ASD and control subjects. Observational studies were identified through electronic database searching and also hand-searching of reference lists of relevant articles. A total of 183 papers were initially identified for review and eventually twenty studies were included in the meta-analysis. A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

12 CFR 217.34 - OTC derivative contracts.

Code of Federal Regulations, 2014 CFR

2014-01-01

... net present value of the amount of unpaid premiums. Table 1 to § 217.34—Conversion Factor Matrix for... single OTC derivative contract is the greater of the mark-to-fair value of the OTC derivative contract or... with a negative mark-to-fair value, is calculated by multiplying the notional principal amount of the...

In Situ Blood Vessel Regeneration Using SP (Substance P) and SDF (Stromal Cell-Derived Factor)-1α Peptide Eluting Vascular Grafts.

PubMed

Shafiq, Muhammad; Zhang, Qiuying; Zhi, Dengke; Wang, Kai; Kong, Deling; Kim, Dong-Hwee; Kim, Soo Hyun

2018-05-31

The objective of this study was to develop small-diameter vascular grafts capable of eluting SDF (stromal cell-derived factor)-1α-derived peptide and SP (substance P) for in situ vascular regeneration. Polycaprolactone (PCL)/collagen grafts containing SP or SDF-1α-derived peptide were fabricated by electrospinning. SP and SDF-1α peptide-loaded grafts recruited significantly higher mesenchymal stem cells than that of the control group. The in vivo potential of PCL/collagen, SDF-1, and SP grafts was assessed by implanting them in a rat abdominal aorta for up to 4 weeks. All grafts remained patent as observed using color Doppler and stereomicroscope. Host cells infiltrated into the graft wall and the neointima was formed in peptides-eluting grafts. The lumen of the SP grafts was covered by the endothelial cells with cobblestone-like morphology, which were elongated in the direction of the blood flow, as discerned using scanning electron microscopy. Moreover, SDF-1α and SP grafts led to the formation of a confluent endothelium as evaluated using immunofluorescence staining with von Willebrand factor antibody. SP and SDF-1α grafts also promoted smooth muscle cell regeneration, endogenous stem cell recruitment, and blood vessel formation, which was the most prominent in the SP grafts. Evaluation of inflammatory response showed that 3 groups did not significantly differ in terms of the numbers of proinflammatory macrophages, whereas SP grafts showed significantly higher numbers of proremodeling macrophages than that of the control and SDF-1α grafts. SDF-1α and SP grafts can be potential candidates for in situ vascular regeneration and are worthy for future investigations. © 2018 American Heart Association, Inc.

Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Granulocyte Colony-Stimulating Factor Prolong the Survival of Neutrophils Infiltrating Bronchoalveolar Subtype Pulmonary Adenocarcinoma

PubMed Central

Wislez, Marie; Fleury-Feith, Jocelyne; Rabbe, Nathalie; Moreau, Joelle; Cesari, Danielle; Milleron, Bernard; Mayaud, Charles; Antoine, Martine; Soler, Paul; Cadranel, Jacques

2001-01-01

We evaluated the role of the tumor environment in the regulation of apoptosis of tumor-infiltrating neutrophils, the number of which correlates negatively with outcome, in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We examined three different parameters of apoptosis, namely morphological aspect, annexin-V expression, and DNA fragmentation. Bronchoalveolar lavage fluid (BALF) supernatants from patients with BAC significantly inhibited the 24-hour spontaneous apoptosis of normal peripheral blood neutrophils in vitro compared to BALF supernatants from control patients (64 ± 4% versus 90 ± 2% measured by annexin-V flow cytometry, P = 0.04). The alveolar neutrophil count correlated positively with the granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations in the patient’s BALF. Furthermore, neutralizing antibodies (Abs) against GM-CSF and G-CSF significantly inhibited BALF anti-apoptotic activity (15 to 40% and 34 to 63% inhibition, respectively), whereas neutralizing Abs against interleukin (IL)-8, IL-6, IL-1β and tumor necrosis factor-α had no significant effect. In an attempt to identify the cell origin of anti-apoptotic cytokines, we tested in vitro the effect of BAC cells (A549 cell line and primary culture derived from a patient’s BAC tumor) on the apoptosis of peripheral blood neutrophils. Cell-free supernatants from tumor cells did not inhibit neutrophil apoptosis. In contrast, cell-free supernatants from tumor cells previously exposed to conditioned media from peripheral blood mononuclear cells and alveolar macrophages significantly inhibited spontaneous neutrophil apoptosis. This inhibition was partially lifted when conditioned media from mononuclear cells were previously treated with Abs against IL-1β and tumor necrosis factor-α. As in vivo, neutralizing Abs against GM-CSF significantly inhibited the anti-apoptotic activity of cell culture supernatants

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

PubMed

Das, Undurti N

2013-10-01

Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process. Copyright © 2013 Elsevier Inc. All rights reserved.

Trauma profile in Egyptian adolescents with first-episode schizophrenia: relation to psychopathology and plasma brain-derived neurotrophic factor.