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PubMed2002

Selenium deficiency increases the expression of inducible nitric oxide synthase in RAW 264.7 macrophages: role of nuclear factor-kappaB in up-regulation.

The inducible isoform of nitric oxide synthase (iNOS) is implicated in atherosclerosis, malignancy, rheumatoid arthritis, tissue and reperfusion injuries. A key determinant of the pro-oxidant versus protective effects of NO is the underlying redox status of the tissue. Selenoproteins, such as glutathione peroxidases (GPxs) and thioredoxin reductases, are key components of cellular defence and promote optimal antioxidant/oxidant balance. In this study, we have investigated the relationship between Se status, iNOS expression and NO production in Se-deficient and Se-supplemented RAW 264.7 macrophage cell lines. The cellular GPx activity, a measure of Se status, was 17-fold lower in Se-deficient RAW 264.7 cells and the total cellular oxidative tone, as assessed by flow cytometry with 2',7'-dichlorodihydrofluorescein diacetate, was higher in the Se-deficient cells than the Se-supplemented cells. Upon lipopolysaccharide (LPS) stimulation of these cells in culture, we found significantly higher iNOS transcript and protein expression levels with an increase in NO production in Se-deficient RAW 264.7 cells than the Se-supplemented cells. Electrophoretic mobility-shift assays, nuclear factor-kappaB (NF-kappaB)-luciferase reporter assays and Western blot analyses indicate that the increased expression of iNOS in Se deficiency could be due to an increased activation and consequent nuclear localization of the redox-sensitive transcription factor NF-kappaB. These results suggest an inverse relationship between cellular Se status and iNOS expression in LPS-stimulated RAW 264.7 cells and provide evidence for the beneficial effects of dietary Se supplementation in the prevention and/or treatment of oxidative-stress-mediated inflammatory diseases.

Animals↗
PubMed2000

Changes in CArG-binding protein A expression levels following injection(s) of the D1-dopamine agonist SKF-82958 in the intact and 6-hydroxydopamine-lesioned rat.

We recently characterized the rat brain homolog of mouse muscle CArG-binding protein A initially identified in C2 myogenic cells and showed an inverse temporal correlation between increased expression levels of this messenger RNA, c-fos and zif268 messenger RNA levels following the addition of nerve growth factor to PC12 cells. In addition, we found an inverse correlation between c-Fos protein and CArG-binding protein A messenger RNA levels in the lateral caudate-putamen of rats treated acutely and chronically with the D2 receptor antagonist fluphenazine (phenothiozine typical psychotic). To determine whether D1 receptor stimulation is also capable of inducing CArG-binding protein A up-regulation, drug naive or dopamine-depleted (i.e. 6-hydroxydopamine-lesioned) D1 hypersensitized rats (i.e. rats given repeated daily injections of SKF-82958 for 14days) were acutely injected with the D1 agonist SKF-82958 and examined using a combination of in situ hybridization for CArG binding protein A and immunocytochemistry for c-Fos. Both acutely treated animals and dopamine-depleted hypersensitized animals showed increases in CArG-binding protein A. Moderate increases were found in the medial caudate-putamen and nucleus accumbens core and shell regions following acute treatment whereas large increases in CArG-binding protein A expression levels were found in the medial and lateral caudate-putamen and the shell and core of the nucleus accumbens following hypersensitization. No change in CArG-binding protein A expression level was found in the dopamine-depleted, drug naive animals relative to controls. Regions of the basal ganglia where increases in CArG-binding protein A were detected following each treatment correlated perfectly with c-Fos protein induction. The results demonstrate that CArG-binding protein A responds to SKF-82958 and that the changes in CArG-binding protein A match perfectly with the pattern of c-Fos induction induced by the D1 agonist.

Animals↗
PubMed2006

AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3.

AMP-activated protein kinase (AMPK) is a key cellular sensor of reduced energy supply that is activated by increases in the cellular ratio of AMP/ATP. Phenformin and 5-aminoimidazole-4-carboxamide riboside (AICAR) are two drugs widely used to activate AMPK experimentally. In both differentiated hippocampal neurons and neuroblastoma SH-SY5Y cells we found that these two agents not only activated AMPK, but conversely greatly reduced the activating Ser/Thr phosphorylation of Akt. This blockade of Akt activity consequently lowered the inhibitory serine-phosphorylation of its substrates, glycogen synthase kinase-3alpha/beta (GSK3alpha/beta). An inhibitor of AMPK (Compound C) did not block dephosphorylation of Akt and GSK3. Thus, both drugs widely used to activate AMPK also caused dephosphorylation of Akt and of GSK3. The mechanism for Akt dephosphorylation caused by phenformin, but not AICAR, was due to inhibition of growth factor-induced signaling that leads to Akt phosphorylation. Stimulation of muscarinic receptors with carbachol in SH-SY5Y cells also activated AMPK and transiently caused dephosphorylation of Akt. These findings show that Akt dephosphorylation often occurs concomitantly with AMPK activation when cells are treated with phenformin or AICAR, indicating that these drugs do not only affect AMPK but also cause a coordinated inverse regulation of AMPK and Akt.

AMP-Activated Protein Kinases↗
PubMed1990

Modulation of endothelial cell phenotype by cyclic stretch: inhibition of collagen production.

Endothelial cells (EC) are constantly subjected to pulsatile stretch in vivo, but most studies of EC are performed under stationary tissue culture conditions. The aim of this study was to examine the effect of repetitive mechanical stretching on EC collagen production. Bovine EC were seeded in 35-mm flexible-bottom culture wells, allowed to attach for 24 hr, and then subjected to up to 24% elongation cyclic deformation, 3 cycles/min, 10 sec of elongation alternating with 10 sec of relaxation, for 5 days. Twenty-four hours prior to harvesting, serum-free media containing 50 microCi [3H]proline (PRO), an amino acid hydroxylated (OH) in collagen, and 50 micrograms/ml ascorbate were added per well. On Days 1, 3, and 5, the media and cells were collected, precipitated with TCA, sedimented, lyophilized, and analyzed by HPLC for OH-PRO and PRO. The results of this study indicate that EC production of collagen is inhibited with repetitive deformation. Since previous studies have shown that EC proliferation is increased after 3 cycles/min stretching, this supports the theory that collagen gene expression varies inversely with the proliferative state.

Animals↗
PubMed2000

Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer.

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-alpha (TNF-alpha), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0. 006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour.

Adult↗
PubMed1976

The effect of dibutyryl cyclic adenosine-3'-5'-monophosphate on protein secretion from the rat exocrine pancreas in vitro.

1 The mechanism by which dibutyryl cyclic adenosine-3'-5'-monophosphate (dibutyryl cyclic AMP) potentiates the secretory effect of carbachol in rat exocrine pancreas was investigated. 2 Dibutyryl cyclic AMP potentiated the secretory effect of carbachol only at carbachol concentrations greater than or equal to 10(-7) mol/l; was independent of carbachol at concentrations greater than 10(-7) mol/l and was inversely proportional to extracellular [Ca2+]. 3 Carbachol increased and dibutyryl cyclic AMP reduced the rate of 45Ca efflux from the tissue. 4 A-23187 stimulated 3H-protein release in the presence of Ca2+ and this effect was potentiated by dibutyryl cyclic AMP; the degree of potentiation was inversely proportional to extracellular [Ca2+]. At 10(-3) mol/l [Ca2+] the potentiation occurred only at ionophore concentrations less than or equal to 10(-6) mol/litre. 5 These results support the hypothesis that dibutyryl cyclic AMP potentiates the effect of secretagogues in rat exocrine pancreas by maintaining an elevated intracellular calcium concentration. It does so by inhibiting Ca2+ efflux. The results also suggest that the limiting factor in carbachol-stimulated secretion, at all concentrations of carbachol, is intracellular [Ca2+].

Animals↗
PubMed1987

The calcium antagonist nisoldipine and the calmodulin antagonist W-7 synergistically inhibit initiation of DNA synthesis in cultured arterial smooth muscle cells.

Cultured arterial smooth muscle cells go through a transition from a contractile to a synthetic phenotype. Morphologically, the transition includes a reduction in size of the myofilament bundles and the formation of an extensive rough endoplasmic reticulum and a large Golgi complex. Functionally, it leads to loss of contractility, onset of cellular proliferation, and secretion of extracellular matrix components. This change in differentiated characteristics under in vitro conditions has attracted attention because of its resemblance to the modification of the smooth muscle cells that occurs in vivo during atherogenesis. Here, transmission electron microscopy and [3H]-thymidine autoradiography were used to study the role of calcium ions in the control of phenotypic properties and growth of cultivated rat aortic smooth muscle cells. The calcium antagonist nisoldipine was found to lack distinct effect on the structural reorganization of the cells, but showed a moderate prohibitory effect on the start of DNA synthesis early in primary culture. In growth-arrested secondary cultures, nisoldipine inhibited induction of DNA synthesis by serum or platelet-derived growth factor (PDGF). The agent's effect was inversely related to the concentration of calcium ions in the extracellular medium and was partially counteracted by the calcium agonist BAY K 8644. In contrast, W-7, an antagonist of the calcium-binding protein calmodulin, potentiated the effect of nisoldipine and, at higher concentrations, inhibited induction of DNA synthesis in itself. The results suggest that the mitogenic stimulation of arterial smooth muscle cells involves a flux of calcium ions through the plasma membrane and requires participation of calmodulin.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Human homeobox HOXA7 regulates keratinocyte transglutaminase type 1 and inhibits differentiation.

Keratinocyte proliferation and differentiation result from expression of specific groups of genes regulated by unique combinations of transcription factors. To better understand these regulatory processes, we studied HOXA7 expression and its regulation of differentiation-specific keratinocyte genes. We isolated the homeobox transcription factor HOXA7 from keratinocytes through binding to a differentiation-dependent viral enhancer and analyzed its effect on endogenous differentiation-dependent genes, primarily transglutaminase 1. HOXA7 overexpression repressed transglutaminase 1-reporter activity. HOXA7 message markedly decreased, and transglutaminase RNA increased, upon phorbol ester-induced differentiation, in a protein kinase C-dependent manner. Overexpression of HOXA7 attenuated the transglutaminase 1 induction by phorbol ester, demonstrating that HOXA7 expression is inversely related to keratinocyte differentiation, and to transglutaminase 1 expression. Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. In keeping with these observations, epidermal growth factor receptor activation stimulated HOXA7 expression. HOX genes function in groups, and we found that HOXA5 and HOXB7 were also down-regulated by phorbol ester. These results provide the first example of protein kinase C-mediated homeobox gene regulation in keratinocytes, and new evidence that HOXA7, potentially in conjunction with HOXA5 and HOXAB7, silences differentiation-specific genes during keratinocyte proliferation, that are then released from inhibition in response to differentiation signals.

Amino Acid Sequence↗
PubMed1989

Effect of hypercalcemia-producing tumor on 1,25(OH)2D3 biosynthesis in athymic mice.

Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associated hypercalcemia (MAH), whereas murine models of MAH have high circulating 1,25(OH)2D3. To determine the effects of a hypercalcemia-producing tumor on circulating 1,25(OH)2D3, in vitro 25-hydroxyvitamin D1-hydroxylase (1OHase) activity was measured in kidneys from BALB/c athymic mice implanted with a hypercalcemia-producing human lung tumor. Twelve days of low-phosphorus diet (LPD) in control animals lowered serum phosphorus to levels found in tumor-bearing mice fed normal phosphorus diet (NPD; 4.1 +/- 0.3 vs. 4.4 +/- 0.7 mg/dl, P = NS) and increased 1OHase activity (1.6 +/- 0.2 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, NPD vs. LPD, P less than 0.05). 1OHase activity was greater in tumor-bearing animals fed NPD compared with control animals fed LPD (8.4 +/- 0.6 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, P less than 0.01). High-phosphorus intake suppressed 1OHase activity in both control and tumor-bearing animals. Seven days of parathyroid hormone infusion in control animals fed NPD raised serum calcium (9.4 +/- 0.2 vs. 13.3 +/- 1.6 mg/dl, P less than 0.05) and suppressed 1OHase activity (0.25 +/- 0.02 vs. 0.02 +/- 0.002 pmol.mg protein-1.5 min-1, P less than 0.001). The inverse relationship of serum phosphorus and 1OHase activity was much steeper in the tumor-bearing animals, with greater enzyme activity at comparable levels of serum phosphorus. The present study indicates that 1) factors produced by the tumor stimulate 1OHase activity, and 2) hypophosphatemia is required for expression of enhanced enzyme activity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1993

Glucagon stimulates insulin-like growth factor binding protein-1 secretion in healthy subjects, patients with pituitary insufficiency, and patients with insulin-dependent diabetes mellitus.

Glucagon (1-1.5 mg) was administrated iv as a bolus dose to healthy individuals (n = 7), patients with GH deficiency (n = 14), and patients with insulin-dependent diabetes mellitus (IDDM; n = 6). Thereafter, blood samples for determination of serum glucose, insulin, insulin-like growth factor-binding protein-1 (IGFBP-1), GH, and insulin-like growth factor-I (IGF-I) concentrations were collected for 180 min. IGFBP-1 concentrations increased significantly in response to glucagon, with maximal values observed at 90 min [in healthy subjects from 36 +/- 6 to 58 +/- 10 micrograms/L (P < 0.05), in GH-deficient patients from 36 +/- 4 to 54 +/- 6 micrograms/L (P < 0.001), and in IDDM patients from 115 +/- 18 to 167 +/- 27 micrograms/L (P < 0.05)]. The IGFBP-1 elevation was delayed in relation to the glucagon-induced increase in glucose and insulin concentrations. When the groups were combined, the individual IGFBP-1 peak value observed at 90 min was inversely correlated to the individual peak value of insulin observed at 15-30 min (r = -0.743; P < 0.001). In GH-deficient patients, serum GH concentrations remained undetectable (< 0.2 micrograms/L), and IGF-I concentrations were unchanged after the glucagon injection. In healthy subjects and IDDM patients, mean GH levels did not change significantly, whereas mean IGF-I concentrations decreased slightly at 30 min. In conclusion, glucagon increased serum IGFBP-1 concentrations in spite of increases in glucose and insulin. These results suggest that glucagon is a stimulator of IGFBP-1.

Adult↗
PubMed2000

Mobilization of CD34+ haematopoietic stem cells is associated with a functional inactivation of the integrin very late antigen 4.

The beta1 integrin very late antigen 4 (VLA-4) plays a central role in mobilization and homing of CD34+ cells. In this study, we examined the activation state of VLA-4 on CD34+ cells from bone marrow (BM) and peripheral blood (PB) by flow cytometry using a vascular cell adhesion molecule I-immunoglobulin (VCAM-I/IgG) fusion protein as soluble ligand. In an intraindividual analysis, we found a significantly reduced affinity and avidity of the VLA-4 receptor on CD34+ cells from PB during granulocyte colony-stimulating factor (G-CSF)-enhanced marrow recovery in comparison with steady-state BM. Moreover, the amount of circulating CD34+ cells during marrow recovery was inversely related to the activation state but not to the expression level of VLA-4, suggesting that a modulation of the functional state of VLA-4 is involved in the mobilization of CD34+ cells. Moreover, VLA-4 function on CD34+ cells from BM was associated with the maturation state of CD34+ cells as high-affinity VLA-4 receptors were observed on the vast majority of more primitive CD34+ cells. In addition, we found that Mg2+ ions as well as co-incubation of CD34+ cells with endothelial cells resulted in an activation of the VLA-4 receptor. In conclusion, modulation of the functional state of VLA-4 appears to be of relevance for the mobilization and homing of CD34+ haematopoietic stem cells.

Antigens, CD34↗
PubMed2003

Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes.

OBJECTIVE: To investigate the relationship of inflammation and endothelial activation with insulin resistance and adiposity in type 2 diabetes. METHODS AND RESULTS: Hundred and thirty-four (45 female) type 2 diabetic subjects aged 50-75 in the Fenofibrate Intervention and Event Lowering in Diabetes Study in Helsinki were examined before fenofibrate intervention. Fasting levels of circulating intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) (vascular cell adhesion molecule), ultra-sensitive C-reactive protein (CRP), human serum amyloid A (hSAA), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), secretory phospholipase A(2) IIA (PLA(2)), total, HDL and LDL cholesterol, triglycerides, P-glucose, HbA1c, and serum free insulin were determined. Insulin resistance was assessed by the homeostasis model. HOMA IR correlated significantly with all measures of adiposity and markers of inflammation and endothelial dysfunction. BMI was significantly associated with inflammation and endothelial activation, but with neither lipoproteins nor glycaemic control. After controlling for age, gender and BMI, HbA1c correlated significantly with CRP, hSAA, ICAM-1, E-selectin, and HOMA IR. HDL cholesterol correlated inversely with IL-6, M-CSF, E-selectin, and HOMA IR. HbA1c, phospholipase A(2), VCAM-1, and HDL cholesterol remained independent determinants of HOMA IR in the linear regression analysis controlled for age, gender, and BMI. CONCLUSION: Endothelial activation and acute-phase reaction correlate with insulin resistance and obesity in type 2 diabetic patients.

Acute-Phase Reaction↗
PubMed1990

Noncytotoxic activation of neutrophils by eosinophil granule major basic protein. Effect on superoxide anion generation and lysosomal enzyme release.

Eosinophil granule major basic protein (MBP) and neutrophils have each been implicated in the inflammatory late phase events of allergic disease. Based on this association and flow cytometric evidence presented in this report for MBP binding to neutrophils, we examined the ability of MBP to activate human neutrophils. Incubation of neutrophils with 0.5 to 3.0 microM MBP at room temperature produced a concentration-dependent chemiluminescence (CL) response that peaked after 50 to 70 min. Reduced-and-alkylated MBP, eosinophil cationic protein, and eosinophil-derived neurotoxin did not induce CL. MBP-induced CL was abrogated in the absence of Ca2+ and was absent in neutrophils isolated from two individuals with chronic granulomatous disease. MBP also stimulated release of superoxide anion (O2-) and lysozyme but not beta-glucuronidase or lactate dehydrogenase. Additionally, 1.5 microM MBP in combination with FMLP or platelet-activating factor stimulated a synergistic increase in O2- release from cytochalasin B-treated neutrophils. The degree of synergism with FMLP or platelet-activating factor was inversely related (p less than 0.005) to the level of MBP-induced O2- release. These results indicate that MBP activates neutrophils in a noncytolytic fashion and provide evidence that eosinophil-neutrophil collaboration may contribute to the pathogenesis observed in allergic late phase reactions.

Blood Proteins↗
PubMed1989

Action at a distance in Mu DNA transposition: an enhancer-like element is the site of action of supercoiling relief activity by integration host factor (IHF).

The first committed step in the in vitro strand transfer reaction of a mini-Mu donor molecule is the formation of a Type 1 complex in which the Mu ends are held together in a non-covalent protein-DNA complex. Efficient formation of this complex at high levels of donor supercoiling (sigma approximately -0.06) requires the Mu A and Escherichia coli HU proteins. At in vivo levels of supercoiling, efficient reaction also requires E. coli integration host factor (IHF). We demonstrate that this supercoiling relief activity of IHF is mediated through an IHF binding site in the Mu early promoter region. This site is part of a larger enhancer-like element which includes operator 1 (01) and part of operator 2 (02) with the IHF site in between. The enhancer-like element stimulates the initial rate of the in vitro reaction 100-fold and acts in a distance-independent fashion. Inversion of the orientation of the element results in a total loss of enhancer activity in the absence of IHF. However, a 10-fold stimulation in the initial rate of reaction is induced by the addition of IHF. Furthermore, correct helical phasing between 01 and 02 is required for maximal activity. The results indicate that a specific geometrical configuration of the enhancer-like element, which includes a sharp bend between 01 and 02, is required for optimal induction of synapsis.

Bacterial Proteins↗
PubMed1985

Stimulatory serum factors in aplastic anaemia. I. Serum 'releaser' activity for haemopoietic growth factors, a regulator?

Human serum contains an activity which enhances the release of colony stimulating and burst promoting activity (CSA and BPA). It is low in the majority of normal sera and was found elevated in patients with aplastic anaemia. The patient's 'response' to autologous serum releaser activity was measured by comparing CSA and BPA release by patient cells in percentage of release by normal cells. This 'response' was negatively correlated with serum releaser activity (P = 0.0035 for CSA-release, P less than 0.0001 for BPA-release), i.e. releaser activity was high, when factor release was low. This inverse relationship between releaser activity and the patient's response was also observed in four patients with pancytopenia of causes other than aplastic anaemia. We conclude that elevated serum releaser activity reflects a repair mechanisms which operates when CSA- and BPA-production is inadequate. Thus, releaser activity is likely to be a haemopoietic regulator.

Anemia, Aplastic↗
PubMed2001

JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells.

The Ras-related GTPase (Ral) is converted to the GTP-bound form by Ral guanine nucleotide dissociation stimulator (RalGDS), a putative effector protein of Ras. Recently, it was proven that Ral regulates c-Src activity and subsequent phosphorylation of its substrate, STAT3. Here, we show that STAT3 inversely regulates activation of Ral through induction of expression of RalGDS. To identify new leukemia inhibitory factor-induced genes, we have performed representational difference analysis using M1 mouse myeloid leukemia cells and cloned RalGDS. The expression of RalGDS and subsequent activation of RalA were clearly suppressed by a dominant negative form of STAT3 and a JAK inhibitor, JAB/SOCS1/SSI-1, indicating that RalGDS/RalA signaling requires the activation of the JAK/STAT3 pathway. An experiment using a Ras inhibitor demonstrated that full activation of RalA also requires activation of Ras. These results suggest a novel cross-talk between JAK/STAT3 and the Ras/RalGDS/Ral signaling pathways through gp130.

Acute-Phase Proteins↗
PubMed2006

The effects of IGF-I on bovine follicle development and IGFBP-2 expression are dose and stage dependent.

This study aimed to determine the effect of insulin-like growth factor-I (IGF-I) on early antral bovine follicular development, and the expression of insulin-like growth factor-binding protein-2 (IGFBP-2). Antral follicles separated into three different size groups were cultured for 6 days in medium supplemented with either a low (10 ng/ml) or high (1 microg/ml) dose of human recombinant IGF-I. Oestradiol production by follicles in all size ranges, cultured in the presence of the high concentration of IGF-I, significantly increased by day 6 (P < 0.05). Follicles in the smallest size range, 165-215 microm, cultured in a high dose of IGF-I, were found to be significantly increased in size (P < 0.01). Oocyte health of the largest follicles (281-380 microm) was significantly improved by the addition of IGF-I to the culture medium. mRNA expression of IGFBP-2 was decreased in the granulosa cells of follicles, size range 216-280 microm, cultured with a high dose of IGF-I (P < 0.05). Granulosa cells (P < 0.05) and oocytes (P < 0.01) of the largest follicles (281-380 microm) showed a decrease in IGFBP-2 expression (protein) when cultured in the control and low-IGF-I treatment groups. Therefore, the response of a bovine follicle to IGF-I is both dose and stage dependent. This work supports a role for IGF-I in modulating somatic and germ-cell maturation and development in early antral follicles. Furthermore, the inverse relationship between the level of IGF-I stimulation and IGFBP-2 expression suggests a local regulatory system modulating IGF-I availability.

Animals↗
PubMed2004

EGF mediates multiple signals: dependence on the conditions.

Epidermal growth factor (EGF) has been reported to both increase and decrease proliferation and apoptosis. In KB cells, EGF-induced alteration in proliferation and apoptosis are concentration and time dependent. High concentrations of EGF (10(-7) and 10(-8) M) stimulated proliferation and inhibited apoptosis at 24 h, with apoptosis increasing with prolonged exposure. Low concentrations of EGF (10(-10)-10(-11) M) inhibited apoptosis without affecting proliferation. EGFR protein expression was downregulated at high and upregulated at low EGF concentrations. Significant inverse correlation was shown between EGFR expression level and apoptosis. These results suggest the EGF receptor involvement in the modulation of apoptosis and the role of EGF anti-apoptotic effects in EGF-induced apoptosis.

Apoptosis↗