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At least 397 records · Page 22Linked to original sources
PubMed2002

Co-expression of vascular endothelial growth factor and neuropilin-1 in ovine feto-placental artery endothelial cells.

Vascular endothelial growth factor (VEGF) is a key regulator for placental angiogenesis and vascular functions via activating two high affinity tyrosine-kinase receptors, VEGF receptor-1 (VEGFR-1) and -2 (VEGFR-2). Recently, a specific VEGF165 receptor, neuropilin-1 (NP-1), was also identified in endothelial cells and upon VEGF binding, NP-1, synergistically with VEGFR-2, enhances VEGF-induced cell proliferation and migration. To evaluate the role of VEGF and NP-1 in regulating fetoplacental angiogenesis and endothelial function, an ovine fetal placental artery endothelial (OFPAE) cell line was established. In this study, an OFPAE cell cDNA library was constructed. Two positive clones for VEGF and one for NP-1 were isolated from the OFPAE cell cDNA library, and their partial 3' sequences were identified. The sequence of VEGF cDNA insert had 98% homology to the reported ovine VEGF (GenBank accesssion # X89506). The partial NP-1 cDNA sequence included a portion of the protein coding region and a complete 3' untranslated region (UTR), and had 90% homology to human NP-1 (GenBank accession # AF016050). The predicted amino acid sequence of ovine NP-1 was 97-98% identical to human (GenBank accession # AAC12921.1), mouse (GenBank accession # NP_032763), and rat (GenBank accession # AAC53345.1) NP-1. Two CU-rich stabilizing and two consensus destabilizing elements 5'-AUUUA-3' were identified in the 3' UTR of ovine NP-1 cDNA sequence. These elements are the potential binding sites for mRNA-binding proteins which may regulate the stability of NP-1 mRNA. Expression of VEGF and NP-1 in OFPAE cells and fetal placentas was confirmed by Northern and Western blot analyses. Using PCR analysis, we also identified partial sequences of multiple VEGF isoforms (VEGF188, 183, 164, and 120) as well as VEGFR-1, VEGFR-2, and neuropilin-2 (NP-2) from the OFPAE cell cDNA library. These results indicate that multiple isoforms of VEGF are expressed in OFPAE cells. Moreover, we also identified, for the first time, a complete 3' UTR of NP-1 cDNA in any species. Together with expression of VEGF and VEGF receptors in OFPAE cells, we propose that there is an autocrine mechanism by which VEGF regulates fetal placental angiogenesis and other functions of endothelial cells.

Animals↗
PubMed1998

Calcitonin receptor mRNA expression in TT cells: effect of dexamethasone.

Among the four isoforms of the calcitonin receptor (CTR) described in humans, two differ by the presence of h-CTR1 or absence of h-CTR2 of 16 amino acids in the first intracellular loop. Both receptors are biologically active. The TT cell line derived from a human medullary carcinoma of the thyroid is characterized by the secretion of large amounts of calcitonin. We have recently shown that this cell line expresses h-CTR2. In the present work we have studied the expression of CTR during TT cell proliferation and used dexamethasone to modify calcitonin expression in order to establish if an autocrine regulation involving calcitonin and its receptor was functional in the TT cells. The expression of this receptor and of calcitonin during TT cell proliferation was studied by reverse transcriptase-polymerase chain reaction (RT-PCR). Dexamethasone, a potent inhibitor of TT cell proliferation, levels (day 6 of culture) specifically increased receptor levels from day 8 onwards. CT peptide and CT mRNA levels decreased or were similar during experimental time. CTR regulation by glucocorticoids is suggested in TT cells. Autocrine regulation of CTR is also suggested by relation between CT mRNA levels and CTR mRNA.

Autocrine Communication↗
PubMed1999

Indirect mechanisms and cascades of androgen action.

Androgens are the main hormones responsible for the induction of the male phenotype. This process involves a complex combination of reversible and irreversible effects. As for other steroid hormones, many of the effects of androgens are mediated by a specific intracellular receptor that interacts with cis-acting regulatory regions (AREs) in the affected genes. Apart from these direct effects, however, androgens may indirectly affect the expression of a variety of genes that do not necessarily contain AREs. Indirect effects may be related to androgen-induced changes in the concentration or activity of secondary transcription factors, autocrine and paracrine mediators, and circulating hormones. Such indirect effects may induce cascade-like actions and may play an important role in more complex effects of androgens involving coordinated responses of genes, cells and organs.

Androgens↗
PubMed2003

The insulin-like growth factor system and cancer.

The insulin-like growth factor (IGF) family of ligands, binding proteins and receptors is an important growth factor system involved in both the development of the organism and the maintenance of normal function of many cells of the body. The system also has powerful anti-apoptotic effects. More recently, evidence has accrued to demonstrate that the IGFs play an important role in cancer. Individuals with serum IGF-II levels in the upper quartile of the normal range (and IGF binding protein-3 levels in the lower quartiles) have a relative risk for developing breast, prostate, colon and lung cancer. IGF-II is commonly expressed by tumor cells and may act as an autocrine growth factor; occasionally even reaching target tissues and causing tumor-induced hypoglycemia. The IGF-I receptor is commonly (though not always) overexpressed in many cancers, and many recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and cell death; functions that are critical for cancer cell survival and metastases. In this review, many aspects of the IGF system and its relationship to cancer will be discussed.

Animals↗
PubMed2000

The endogenous survival promotion of axotomized rat corticospinal neurons by brain-derived neurotrophic factor is mediated via paracrine, rather than autocrine mechanisms.

The previously reported rescue of corticospinal neurons (CSN) from axotomy-induced death by intracortical glial cell line-derived neurotrophic factor (GDNF)- and neurotrophin-3 (NT-3)-infusions depends on endogenous cortical brain-derived neurotrophic factor (BDNF). The present study examines whether BDNF, GDNF, or NT-3 can stimulate an autocrine or paracrine BDNF-support of lesioned CSN. BDNF-infusions increase BDNF mRNA-expression throughout cortical layers 2-5 and NT-3-treatment results in upregulation of BDNF-transcripts in the upper cortical layers. In contrast, GDNF-treatment had no effect. While virtually all CSN express the BDNF-receptor trkB, less than half of them express BDNF, and these expression patterns are unchanged after axotomy and the different neurotrophic factor treatments. The findings suggest that axotomized CSN are supported via a paracrine BDNF-mechanism which can be stimulated by BDNF- and NT-3-, but not by GDNF.

Animals↗
PubMed2001

Cerebrospinal fluid from patients with neurodegenerative and neuroinflammatory diseases: no evidence for rat glial activation in vitro.

To determine the possible contribution of glial cells via oxidative stress/cytokine secretion in the pathogenesis of Parkinson's disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) the concentration of nitric oxide (NO) (by the Griess method) and Interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay) were measured in resting rat microglial and astrocytic cell culture supernatants stimulated by cerebrospinal fluid (CSF) (dilution 1:4, 1:10) from patients with the aforementioned diseases. Neither the concentration of NO (optical density at 450 nm: control, 0.036+/-0.006; MS, 0.034+/-0.008; AD, 0.031+/-0.006; PD, 0.02+/-0.01; lipopolysaccharide (LPS), 0.26+/-0.018) nor the amount of IL-6 (ng/ml: control, 0.112+/-0.026; PD, 0.12+/-0.027; MS, 0.123+/-0.008; ALS, 0.137+/-0.01; LPS, 1.81+/-0.11) differed in any disease group from those of unaffected controls. These findings suggest that the stimuli for inflammatory activation of glia are quite localized and not present in sufficient concentrations in the CSF of affected patients.

Astrocytes↗
PubMed2003

Expression pattern of glypican-1 mRNA after brain injury in mice.

Glypican-1, a heparan sulfate proteoglycan, is expressed in various tissues including developing and postnatal central nervous system. It serves as a receptor for heparin-binding molecules such as fibroblast growth factors (FGFs). We investigated whether glypican-1 was expressed after brain injury in adult mice. In situ hybridization study showed that glypican-1 mRNA was expressed in the region surrounding necrotic tissue, and that the signal intensity peaked 7 days after the cryo-injury. In addition, both FGF-2 and amyloid precursor protein (APP) were concurrently upregulated and colocalized with glypican-1 mRNA. Since FGF-2 and APP can bind to glypican-1 in vitro, the present study suggested that their autocrine/paracrine interactions with glypican-1 may be involved in neuronal regeneration and/or neurite-outgrowth inhibition after brain injury.

Amyloid beta-Protein Precursor↗
PubMed2002

Amplification of extracellular nucleotide-induced leukocyte(s) degranulation by contingent autocrine and paracrine mode of leukotriene-mediated chemokine receptor activation.

Extracellular nucleotide-induced stimulation and activation of peripheral blood leukocytes and subsequent degranulation play a critical role in immediate-type hypersensitivity reaction and other inflammatory diseases. The extracellular nucleotides stimulate a P2Y receptor(s) on human PMN with the pharmacological profile similar to that of the P2Y2 receptor. Upon activation of P2Y2, arachidonic acid, formed from the membrane bound lipids by phospholipase A2, which subsequently metabolized by 5-lipoxygenase to form the leukotrienes. Of the several leukotrienes generated, LTB(4) is a potent pro-inflammatory chemokine. Upon its release LTB(4) binds to the PMN in a paracrine manner and also other leukocytes such as monocytes at the site of vascular injury, leading to an accelerated rate of degranulation. It is known that LTA(4) formed in the 5-lipoxygenase pathway in PMN could be released from PMN by receptor-mediated transport. Upon its release, the monocytes, erythrocytes, platelet, endothelial or smooth muscle cells can take up LTA(4). The endogenous LTA(4) hydrolase form the LTB(4) from LTA(4) in erythrocytes, platelet, endothelial or smooth muscle cells. As in PMN, LTB(4) is released from these cells via receptor-mediated transport to the extracellular milieu. Thus, released LTB(4) most likely acts as potentially accelerating factor in PMN and MN degranulation through its receptor-specific binding. It is not known whether any LTB(4) receptor exists in cytoplasm in any given cell type and also, the existence of any other signaling cascade for the extracellular nucleotide-induced leukocyte degranulation. Thus, it is convincing that the extracellular nucleotides released from the activated platelets and other damaged cell types exacerbate the inflammatory response by leukotriene generation. In turn the leukotriene will act in both autocrine and paracrine manner to amplify the degranulation processes in leukocytes invoked by extracellular nucleotides.

Animals↗
PubMed2001

Involvement of the fibrogenic cytokines, TGF-beta and bFGF, in the pathogenesis of idiopathic myelofibrosis.

Idiopathic Myelofibrosis (IMF), is a chronic myeloproliferative disorder characterized by the association of myeloproliferation and myelofibrosis. The pathophysiological mechanisms resulting in this disease remain still unclear. The myeloproliferation appeared to result from the clonal amplification of hematopoietic progenitors. In contrast, fibroblasts participating in myelofibrosis were shown to be polyclonal, thus suggesting that myelofibrosis was a reactive process. We studied the role of two growth factors TGF-beta and bFGF, which display potent fibrogenic properties and are major regulators of primitive hematopoiesis, in IMF pathogenesis. We demonstrated an increase of TGF-beta and bFGF expression in circulating megakaryocytic cells and platelets, together with alterations of the expression of these cytokines and their receptors in hematopoietic CD34+ progenitor cells from IMF patients. Our results suggested that TGF-beta and bFGF are involved both in myelofibrosis and myeloproliferation which characterize IMF.

Autocrine Communication↗
PubMed1998

Marked elevation of brain natriuretic peptide levels in pericardial fluid is closely associated with left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to investigate whether atrial and brain natriuretic peptides (ANP and BNP, respectively) represent autocrine/paracrine factors and are accumulated in pericardial fluid. BACKGROUND: ANP and BNP, systemic hormones produced by the heart, have elevated circulating levels in patients with heart failure. Recent evidence suggests that the heart itself is one of the target organs for these peptides. METHODS: With an immunoreactive radiometric assay, we measured the concentrations of these peptides in plasma and pericardial fluid simultaneously in 28 patients during coronary artery bypass graft surgery. RESULTS: The pericardial levels of BNP were markedly elevated in patients with impaired left ventricular function. We investigated the correlation of ANP and BNP levels in plasma or pericardial fluid with left ventricular hemodynamic variables. None of the hemodynamic variables correlated with ANP levels in plasma or pericardial fluid. Both plasma and pericardial fluid levels of BNP were significantly related to left ventricular end-diastolic and systolic volume indexes (LVEDVI and LVESVI, respectively). In addition, BNP pericardial fluid levels had closer relations with LVEDVI (r = 0.679, p < 0.0001) and LVESVI (r = 0.686, p < 0.0001) than did BNP plasma levels (LVEDVI: r = 0.567, p = 0.0017; LVESVI: r = 0.607, p = 0.0010). BNP levels in pericardial fluid but not in plasma correlated with left ventricular end-diastolic pressure (r = 0.495, p = 0.0074). CONCLUSIONS: BNP levels in pericardial fluid served as more sensitive and accurate indicators of left ventricular dysfunction than did BNP levels in plasma. Thus, BNP may be secreted from the heart into the pericardial space in response to left ventricular dysfunction, and it may have a pathophysiologic role in heart failure as an autocrine/paracrine factor.

Aged↗
PubMed1998

PEDF (pigment epithelium-derived factor) promotes increase and maturation of pigment granules in pigment epithelial cells in neonatal albino rat retinal cultures.

Pigment Epithelium-Derived Factor (PEDF), purified from human retinal pigment epithelial (RPE) cell culture medium, is a neurotrophic factor which potentiates the differentiation of human Y-79 retinoblastoma cells and increases the survival of cerebellar granule cells. To investigate the effects of PEDF on non-transformed retinal cells, we used primary cultures of neonatal albino rat retinas, where the three principal cell types of the retinal layers (neuronal, glial and epithelial) were all present and focussed our attention on RPE cells, which are of special relevance for retinal pathophysiology. PEDF had a dramatic effect on these cells. They showed a modified phenotype, with larger dimensions, higher cytoplasmic spreading, presence of phagocytic vacuoles, development of wide intercellular contacts, and increase and maturation of pigment granules. These results suggest that PEDF may have a role in regulating RPE cell differentiation.

Animals↗
PubMed1999

FGF-9 is an autocrine/paracrine neurotrophic substance for spinal motoneurons.

Motoneurons need muscle-derived neurotrophic substances for their survival during the initial phase of their development, but after maturation they lose this requirement and can survive after axotomy. This suggests that some neurotrophic substances other than target-derived ones control the survival of motoneurons in adults. Because spinal motoneurons express fibroblast growth factor-9 (FGF-9) messenger RNA, we hypothesized that FGF-9 might be an autocrine or paracrine survival factor for motoneurons. FGF-9 promoted the survival of motoneurons and upregulated the choline acetyl-transferase (ChAT) activity in the dissociated cultures of ventral half of rat E13 spinal cord. Externally added FGF-9 was more effective in low density cultures, and polyclonal blocking antibody against FGF-9 significantly lowered the ChAT activity. Our results support an autocrine or paracrine role for FGF-9 in mediating the survival of spinal motoneurons. Non-target-derived neurotrophic substances for motoneurons including FGF-9 should be important in the pathogenesis of motor neuron disorders in the adults, especially amyotrophic lateral sclerosis.

Animals↗
PubMed2000

FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor.

We have purified and characterized a factor, from the conditioned medium of neural stem cell cultures, which is required for fibroblast growth factor 2's (FGF-2) mitogenic activity on neural stem cells. This autocrine/paracrine cofactor is a glycosylated form of cystatin C (CCg), whose N-glycosylation is required for its activity. We further demonstrated that, both in vitro and in vivo, neural stem cells undergoing cell division are immunopositive for cystatin C. Finally, we showed in vivo functional activity of CCg by demonstrating that the combined delivery of FGF-2 and CCg to the adult dentate gyrus stimulated neurogenesis. We propose that the process of neurogenesis is controlled by the cooperation between trophic factors and autocrine/paracrine cofactors, of which CCg is a prototype.

Animals↗
PubMed1998

Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons.

Arterial baroreceptors are mechanosensitive nerve endings in the aortic arch and carotid sinus that play a critical role in acute regulation of arterial blood pressure. A previous study has shown that nitric oxide (NO) or NO-related species suppress action potential discharge of baroreceptors. In the present study, we investigated the effects of NO on Na+ currents of isolated baroreceptor neurons in culture. Exogenous NO donors inhibited both tetrodotoxin (TTX) -sensitive and -insensitive Na+ currents. The inhibition was not mediated by cGMP but by NO interaction with channel thiols. Acute inhibition of NO synthase increased the Na+ currents. NO scavengers (hemoglobin and ferrous diethyldithiocarbamate) increased Na+ currents before but not after inhibition of NO synthase. Furthermore, NO production in the neuronal cultures was detected by chemiluminescence and immunoreactivity to the neuronal isoform of NO synthase was identified in fluorescently identified baroreceptor neurons. These results indicate that NO/NO-related species function as autocrine regulators of Na+ currents in baroreceptor neurons. Modulation of Na+ channels may represent a novel response to NO.

Animals↗
PubMed1998

Localized secretion of ATP and opioids revealed through single Ca2+ channel modulation in bovine chromaffin cells.

In bovine chromaffin cells, the Ca2+ channels involved in exocytosis are effectively inhibited by ATP and opioids that are coreleased with catecholamines during cell activity. This autocrine loop causes a delay in Ca2+ channel activation that is quickly removed by preceding depolarizations. Changes in Ca2+ channel gating by secreted products thus make it possible to correlate Ca2+ channel activity to secretory events. Here, using cell-attached patch recordings, we found a remarkable correlation between delayed Ca2+ channel openings and neurotransmitter secretion induced by either local or whole-cell Ba2+ stimulation. The action is specific for N- and P/Q-type channels and largely prevented by PTX and mixtures of purinergic and opioid receptor antagonists. Overall, our data provide evidence that exocytosis, viewed through the autocrine inhibition of non-L-type channels, is detectable in membrane patches of approximately 1 microm2 distributed over 30%-40% of the total cell surface, while Ca2+ channels and autoreceptors are uniformly distributed over most of the cell membrane.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

Autocrine growth hormone production prevents apoptosis and inhibits differentiation in C2C12 myoblasts.

Although C2C12 myoblasts express low levels of growth hormone receptor (GHR), we failed to see any effect of exogenous growth hormone (GH) on cell proliferation or differentiation. C2C12 cells stably overexpressing (sixfold) more in GHR (C2C12(GHR)) grew faster than parental cells in media containing 2% serum, and proliferated while parental cells died, in the absence of serum. These effects were independent of exogenous GH but were inhibited by anti-GH and anti-insulin-like growth factor (anti-IGF-1) antibodies, consistent with a local production of GH, which we confirmed by RT-PCR and radioimmunoassay. In C2C12(GHR) cells, we observed an increased activation of the Janus kinase 2 (Jak2), signal transducers and activator of transcription 5 (Stat5), mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) upon acute GH stimulation. GHR overexpression also inhibited the formation of myotubes and the expression of markers for myoblast differentiation. Taken together, our data suggest that GH acts as an autocrine factor in C2C12 cells, to enhance proliferation and to inhibit differentiation.

Animals↗
PubMed2000

Autocrine nerve growth factor in human keratinocytes.

Biologically active nerve growth factor (NGF) is synthesised and released by proliferating normal human keratinocytes. NGF up-regulates the expression of NGF mRNA in keratinocytes. Keratinocytes express both the low (p75)- and the high-affinity (TrkA) NGF-receptors, which are located in the basal layer of the epidermis. K252, a specific inhibitor of trk phosphorylation, blocks NGF-induced keratinocyte proliferation, in absence of exogenous NGF. Normal keratinocytes over-expressing TrkA proliferate better than control transfectants, while the NGF mimicking anti-Trk antibody induces an increased keratinocyte proliferation in Trk over-expressing cells as compared to mock transfected keratinocytes. In addition, NGF over-expressing keratinocytes proliferate better than mock transfected cells. K252, by blocking TrkA phosphorylation, induces apoptosis in normal keratinocytes, but not in keratinocytes over-expressing bcl-2. Furthermore, NGF transfected keratinocytes are protected from UV-B-induced keratinocyte apoptosis, by maintaining constant levels of Bcl-2 and Bcl-xL . Taken together these results support the concept of an autocrine survival system sustained by NGF and its high-affinity receptor in human keratinocytes. Because NGF and Trk levels are highly expressed in psoriasis. one could speculate that NGF autocrine system plays a role in the mechanisms associated with this and other hyperproliferative skin conditions, including cancer.

Apoptosis↗