PubMed Health⌕ Search

Biomedical subjects

M Arvigo

Publications and source records attributed to M Arvigo.

13 recordsLinked to original sources
PubMed2005

Effects of alpha-interferon on insulin-like growth factor-I, insulin-like growth factor-II and insulin-like growth factor binding protein-3 secretion by a human lung cancer cell line in vitro.

The aim of our study was to evaluate the effect of alpha-interferon (alpha-IFN) on cell growth and on the different IGF system components in a human non-small cell lung cancer line (Calu-6) in vitro. Our results confirm the release of IGF-I and IGF-II by these cells. The amount of IGF-II in conditioned media (10.25 +/- 3.95 nM/10(6) cells, mean +/- SE) was more than 10-fold higher than that of IGF-I. alpha-IFN treatment reduced IGF-II levels in the media, with a maximal effect between 1 and 10 U/ml (delta% of control: -31 and -55%, respectively, p < 0.05). IGF-I was significantly reduced at 0.5 U/ml (p < 0.01). No difference, however, was observed in IGF mRNA expression between untreated and alpha-IFN treated cells. An increase in IGF-I and IGF-II intracellular levels in alpha-IFN treated cultures was observed, suggesting that alpha-IFN can regulate the transfer of these peptides into the cells. Furthermore, IGF type-I and particularly type-lI receptor expression was increased after alpha-IFN treatment. IGFBP-3 was detected only in trace amounts in the conditioned media; however, it showed an increase after alpha-IFN treatment (+110% at 1 U/ml). IGFBP-3 mRNA expression showed a slight increase after treatment with 1 and 10 U/ml. alpha-IFN (1-10 U/ml) reduced the stimulatory effect of IGF-I on cell replication (p < 0.01), inhibited (p < 0.01) cell replication in untreated and in fetal calf serum (FCS)-stimulated cells, and increased apoptosis in Calu-6 cells. Our data suggest that alpha-IFN may exert its effects at the cellular level in part through modification of the local IGF system.

Antineoplastic Agents↗
PubMed2005

The IGF system and bone.

All components of the IGF systems and all regulatory mechanisms known are present and active in bone tissue. Osteoblasts synthesize IGF-I and IGF-II which have mitogenic effects on bone cells. Although the relative productions of IGF-I and IGF-II by osteoblasts are different depending on different bone districts and experimental conditions, it seems now that IGF-II is, in general, more expressed than IGF-I. The synthesis of IGFs is down-regulated by many locally produced growth factors, particularly trasforming growth factor beta (TGF-beta) and cortisol, and this probably accounts for the osteoporotic effects of this steroid, whereas PTH is stimulatory. Similarly to other tissues, IGFs action on bone is not only limited to cell replication but also to differentiated functions, such as production of collagen and matrix apposition. Binding proteins 2-5 have been demonstrated to be present in bone, the most expressed being IGFBP-4 and -5. Unlike IGFBP-4 which has an inhibiting effect on IGF actions, IGFBP-5 has a potentiating effect, both in vivo and in vitro, probably by binding directly to sites which are independent of the IGF receptor. The involvement of IGFBP proteases has also been demonstrated in human osteoblasts which are stimulated by IGF-II and TGF-beta. In a rat osteoblast cell culture that we studied, IGF-II and IGFBP-2 were the most abundant peptides of the IGF system released in cell medium, IGFBP-5 was abundantly expressed but bound to cell surface and cell matrix and IGF-I and IGFBP-3 were found at very low concentrations. All these peptides reach the maximum concentration in the first stage of maturation and gradually decrease in the following stages. Also IGFBP proteases, namely MMP-2, are important actors of the systems, being involved in the inactivation of IGFBPs in the late stages of maturation.

Animals↗
PubMed2005

Potential indications for somatostatin analogues: immune system and limphoproliferative disorders.

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.

Humans↗
PubMed1999

IGF-I production by adult rat hepatocytes is stimulated by transforming growth factor-alpha and transforming growth factor-beta1.

Previously, we have observed that epidermal growth factor (EGF), a potent mitogen for cultured hepatocytes, stimulates the production of IGF-I and IGF-binding proteins (IGFBPs) by cultured hepatocytes from adult rats. This study was undertaken to investigate the possibility that other growth factors of hepatic origin could specifically be involved in the regulation of IGF-I and IGFBP expression. The effects of transforming growth factor-alpha (TGF-alpha), through EGF receptors to induce a mitogenic response, and transforming growth factor-beta1 (TGF-beta1), produced by non-parenchymal liver cells and able to inhibit hepatocyte proliferation in vivo and in culture, have been studied in cultured adult rat hepatocytes. Our results demonstrate that TGF-alpha and TGF-beta1 significantly stimulate IGF-I and IGFBP secretion by cultured hepatocytes but no change in the abundance of IGF-I and IGFBP mRNAs was observed with respect to controls. Cycloheximide is able to inhibit both basal and TGF-stimulated release of IGF-I and a similar effect was elicited by octreotide, the somatostatin analog, known to directly affect hepatic IGF-I gene expression. Our findings show the role of the liver in the secretion of IGF-I and IGFBPs, not only under endocrine and nutritional control but also under autocrine and paracrine control.

Animals↗
PubMed1998

Effects of the neuropeptide Y on estradiol and progesterone secretion by human granulosa cells in culture.

OBJECTIVE: To investigate the possible effects of neuropeptide Y on steroid release by human granulosa cells in culture. DESIGN: Prospective study. SETTING: A university laboratory and the division of obstetrics and gynecology in a hospital. PATIENT(S): Sixteen normally ovulating women. INTERVENTION(S): Ovulation induction for IVF-ET with an LH-releasing hormone analogue and gonadotropins. MAIN OUTCOME MEASURE(S): E2 and progesterone were assayed in the media conditioned by granulosa cells with the use of a double-antibody RIA. RESULT(S): Neuropeptide Y stimulates E2 production in a dose-dependent fashion. Preincubation for 3 hours with hCG led to a statistically significant increase in neuropeptide Y-induced E2 secretion. In contrast, whereas 3 hours of preincubation with 10(-7) mol/L of neuropeptide Y did not elicit a statistically significant increase in hCG-induced E2 secretion, coincubation for 48 hours significantly increased hCG-stimulated secretion. Unlike E2, progesterone secretion did not undergo any statistically significant or dose-dependent variation after treatment with neuropeptide Y. CONCLUSION(S): Neuropeptide Y plays a role in human ovarian steroidogenesis directly at the level of the granulosa cells of the follicles in the early stage of luteinization. In this way, neuropeptide Y could play an important role in controlling the positive feedback effect exerted by the ovarian steroids on LH-releasing hormone and gonadotropins in humans.

Adult↗
PubMed1998

Decreased acid-labile subunit (ALS) levels by endotoxin in vivo and by interleukin-1beta in vitro.

The production by the liver of the three subunits of the growth hormone (GH)-dependent 150 kDa complex (IGF-I, IGF-binding protein-3 and acid-labile subunit or ALS) is primarily under the control of GH. Recent data have shown that, besides GH, endotoxin (LPS) and cytokines may regulate the liver IGF-I gene. To investigate the potential regulation of ALS by LPS, we measured serum ALS by immunoblot, 5 and 10 h after IP injection of LPS (250 or 750 microg/100 g BW vs saline), in 4-week-old female Wistar rats (four per group). Ten hours after injection, serum ALS levels were reduced by 57% (delta%) with the lower dose (P<0.05) and by 81% with the higher dose (P<0.01) by comparison with saline-treated rats. The decrease in ALS levels in response to LPS was not prevented by exogenous GH. To investigate the role of interleukin (IL)-1beta in the regulation of ALS, primary cultured rat hepatocytes were exposed to increasing concentrations of IL-1beta. Cell exposure to IL-1beta markedly decreased both basal and GH-stimulated ALS levels (-70%; P<0.01) in a dose-dependent fashion, with the half-maximal inhibitory effect at concentrations of 0.1 ng/ml. Our results show that endotoxin induces a rapid decline in circulating ALS that is potentially mediated through IL-1beta. By limiting the formation of the 150 kDa complex, this reduction in circulating ALS might contribute to the rapid decline in serum IGF-I observed in sepsis.

Animals↗
PubMed1997

Insulin-like growth factors (IGF-I and IGF-II) and IGF-binding protein-3 production by fibroblasts of patients with Turner's syndrome in culture.

Reports indicate that in plasma insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are normal in patients with Turner's syndrome (TS). The aim of our study was to evaluate both the spontaneous and the stimulated synthesis of these peptides by mesenchymal cells obtained from skin biopsies of patients affected with TS. We compared the ability of fibroblasts from six TS patients with that of fibroblasts from six age-matched control (C) subjects to synthesize in vitro IGF-I, IGF-II, and IGFBP-3 under basal and GH-, estradiol (E2)-, or GH- plus E2-stimulated conditions. Furthermore, we evaluated IGF-I, IGF-II, and IGFBP-3 messenger ribonucleic acid (mRNA) expression in fibroblasts from TS and C subjects. Fibroblasts obtained from TS patients release into the medium significantly lower amounts of IGF-I and IGF-II than C fibroblasts (P = 0.0435 and 0.0318, respectively). In TS fibroblasts, GH and E2 are able to induce a similar increase, although not significant, of IGF-I secretion into the medium (163 +/- 75% and 112 +/- 41% of control values). On the contrary, in C fibroblasts, GH is more effective (275 +/- 61%; P = 0.0277) than E2 (75 +/- 46%). In both cell lines, GH and E2 do not significantly modify IGF-II release. Interestingly, the medium conditioned by fibroblasts from TS contains, under basal conditions, significantly higher amounts (273 +/- 79 ng/1 x 10(6) cells) of IGFBP-3 than that from control fibroblasts (67 +/- 19 ng/1 x 10(6) cells; P = 0.0191). GH exerts a stimulatory effect, although it is not statistically significant, on IGFBP-3 secretion, particularly in control fibroblasts. By contrast, the effect of E2 is inhibitory in all TS fibroblast cell lines, although it does not reach statistical significance (P = 0.067). In agreement with these data, a reduced mRNA expression of the genes encoding for IGF peptides was evident in TS fibroblasts, whereas no significant difference could be demonstrated for IGFBP-3 mRNA. The results suggest a reduced autocrine/paracrine action of IGFs in TS and indicate that skin fibroblast cultures can give information on the local responsiveness to the treatment.

Adolescent↗
PubMed1997

Effect of the somatostatin analog, octreotide, and of other hormones on the release of the acid-labile subunit of the 150 kDa complex by rat hepatocyte in primary culture.

OBJECTIVE: In normal subjects, the major form of circulating IGF is the GH-dependent 150 kDa complex. The liver appears to be the main source of the three components of the 150 kDa complex and, in particular, hepatocytes synthesize the insulin-like growth factor (IGF) peptide and the acid-labile subunit (ALS), whereas Kupffer and sinusoidal endothelial cells produce IGF-binding protein-3 (IGFBG-3). We have studied the effects of the somatostatin analog octreotide, IGF-II des(1-3)IGF-I, transforming growth factor (TGF)-beta 1 and tri-iodothyronine (T3) on ALS secretion into the medium conditioned by rat hepatocytes in primary culture. METHODS: The regulation of ALS release was evaluated in the conditioned medium of adult rat hepatocytes exposed to increasing concentrations of test substances or to vehicle alone (control), after gel filtration in basic conditions, by immunoblot using an antiserum generated against the N-terminal 34 amino acids of human ALS. RESULTS: The results demonstrate that: 1) octreotide in vitro produces a dose-dependent inhibition of both basal and GH-stimulated ALS secretion into the hepatocyte conditioned medium; 2) the release of ALS by adult rat hepatocytes is not affected by the presence during the incubation of des(1-3)IGF-I or IGF-II; 3) an inhibitory effect, although only with very high doses, can be observed after treatment with TGF-beta 1; and 4) a small but significant increase of ALS released into the medium can be seen when hepatocytes are treated with T3. CONCLUSIONS: Evaluation of the effect of substances known to affect the production of IGF peptides, the IGFBPs, or both, on adult rat hepatocytes in primary culture revealed no powerful stimulator, but instead a potent inhibitor of ALS release/synthesis. Our data suggest that the effect of somatostatin on the 150 kDa complex is mediated not only by the reduction in GH concentration, but also by a direct inhibition of ALS release or synthesis.

Acids↗
PubMed1996

Interrelationships between follicle stimulating hormone and the growth hormone--insulin-like growth factor--IGF-binding proteins axes in human granulosa cells in culture.

As it has been hypothesized that IGF-binding proteins (IGFBPs) may have a role as autocrine/paracrine factors in regulating the local actions of the insulin-like growth factors (IGFs) in the ovary, we studied the production of the IGFBPs by human granulosa cells (GC) in culture and the role of IGFBP-3 in the modulation of ovarian cell responsiveness to IGF-I and FSH. To this purpose, human luteinizing GC were cultured in serum-free conditions for 24 h and subsequently submitted to increasing concentrations (2-8 nmol/l) of recombinant non-glycosylated or partially glycosylated IGF-BP-3 for 48 h, in the presence or absence of IGF-I, des(1-3)IGF-I- a truncated analog of human IGF-I with markedly reduced binding ability to IGFBPs - and FSH (5-20 mIU/ml). The results demonstrate that human GC release IGFBP-1-2 and -3 into the medium, and that FSH is able to inhibit this release, while GH is clearly inhibitory on IGFBP-1 and stimulatory on IGFBP-3. Both IGF-I and des(1-3)IGF-I significantly (p < 0.001) stimulate E2 production by human GC in culture in a manner comparable to that of FSH in the dose range used. Preincubation for 2 h at 22 C with IGFBP-3, to allow the formation of the IGF-IGFBP complex, drastically reduced the stimulatory effect of IGF-I but not that of des(1-3)IGF-I. IGFBP-3 was also able to inhibit the stimulatory effect of FSH. These data show that: i) the IGF peptide is less active when bound to IGFBP-3; ii) as IGFBP-3 does not affect the potency of des(1-3)IGF-I, its inhibitory action is exerted upstream of the membrane receptor binding; iii) as the action of IGFBP-3 is exerted by binding the IGF peptide, its inhibitory effect on FSH points out the role of the locally produced IGF-II in potentiating the FSH action on human GC.

Adult↗
PubMed1995

Effect of octreotide on circulating IGF-I chromatographic profile: evidence for an inhibitory action on the formation of the 150-kDa ternary complex.

OBJECTIVE: The increasing use in clinical practice of octreotide (a somatostatin analogue which inhibits the secretion of GH and other peptide hormones) led us to study the effects of this treatment on GH, insulin-like growth factors (IGF)-I and II and IGF-binding protein (IGFBP)-3, as well as on circulating IGFBP complexes in acromegalic patients. DESIGN: The circulating concentrations of GH, IGF-I, IGF-II and IGFBP-3 were measured in acromegalic patients before and after 3, 6, 9, and 12 months of treatment with octreotide (group I: n = 5), and compared with those found in a group of patients (group II) treated with bromocriptine (n = 3), cabergoline (n = 7) radiotherapy (n = 3) or surgical therapy (n = 2). In pools of serum obtained from patients treated with octreotide, dopaminergic drugs, surgery and radiation, before and after therapy, immunoreactive IGF-I and IGFBP-3 were also evaluated after Superdex 200 gel filtration in neutral conditions. RESULTS: Before treatment, the concentration of IGF-I and IGFBP-3 were above the normal range in all patients, while IGF-II levels were slightly reduced. After treatment with octreotide, IGF-I (P = 0.004), IGF-II (P = 0.02) and IGFBP-3 (P < 0.001) were significantly reduced as compared to basal levels. In subjects of group II, only IGF-I concentration was significantly reduced by the treatment (P = 0.02), and a negative correlation between IGF-I and IGF-II concentrations was found (r = -0.58, P < 0.0001). After gel filtration immunoreactive IGF-I and IGFBP-3 were found in the 150-kDa mol.wt. region in serum obtained from untreated patients and from treated patients of group II, while in the serum of octreotide-treated patients the IGF-I and IGFBP-3 peaks were shifted to the 60-kDa mol.wt. region, thus suggesting that the acid-labile subunit of the 150-kDa complex was drastically reduced. Since the GH concentrations in groups I and II were similar (M +/- SEM; 13.8 +/- 7.4 and 21.2 +/- 10.6 mU/l respectively), the marked reduction in acid-labile subunit in the octreotide treated patients can be explained by a direct inhibitory effect of somatostatin on the subunit. CONCLUSIONS: Octreotide exerts an inhibitory effect not only on IGF-I but also on IGF-II. The reduced formation of the 150-kDa complex probably causes an increased metabolic clearance rate of IGF peptides which can account for the reduced concentration of both IGFs after treatment with octreotide.

Acromegaly↗
PubMed1995

Effect of the acid-labile subunit on the binding of insulin-like growth factor (IGF)-binding protein-3 to [125I]IGF-I.

In normal subjects, the major form of circulating insulin-like growth factor (IGF) is the GH-dependent 150K complex. This complex is formed by the IGF peptide, the acid-stable binding protein IG-FBP-3, and the acid-labile subunit (ALS), which, although not binding IGF, appears to be necessary to reconstitute the complex in its natural form. The ALS was purified in our laboratory from human serum by ammonium sulfate precipitation, ion exchange chromatography using DEAE-Sephadex A-50, Concanavalin-A-Sepharose-4B chromatography, and two sequential gel filtrations by fast performance liquid chromatography. As demonstrated by gel permeation chromatography on fast performance liquid chromatography, incubation for 2 h at 20 C of this preparation with [125I]IGF-I and recombinant IGFBP-3 (rIGFBP-3) allows the reconstitution of a complex of about 150 kilodaltons. In these experimental conditions, the ALS is not only able to increase the mol wt of the complex, but also to greatly increase the amount of IGF-I bound; in the absence of ALS, radioactivity in the mol wt volume of the complexed forms was lower than that in the mol wt volume of the free form (percentage of total [125I]IGF-I: rIGFBP-3 alone, 15% and 44%; in the presence of ALS, 41% and 24%, respectively). In both charcoal and polyethylene glycol ligand binding assays, competitive binding curves for the displacement of [125I]IGF-I from rIGFBP-3 by increasing concentrations of unlabeled IGF-I showed an increased binding activity of rIGFBP-3 in the presence of ALS. The effect of ALS on rIGFBP-3-binding activity was dose dependent. These data show that the non-IGF-binding ALS subunit of the 150-kilodalton complex can play an important role in the regulation of IGF-I or IGF-II binding to rIGFBP-3 and, therefore, on the levels of free IGF peptide, possibly by inducing conformational changes in rIGFBP-3. In addition, ligand and immunoblot reveal that ALS and rIGFBP-3 are able to form a high mol wt complex in the absence of IGF peptide. On the basis of these data, ALS seems to have a more complex function than that of simply increasing the mol wt of the IGF-IGFBP-3 complex.

Binding, Competitive↗