Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] induces differentiation and inhibits proliferation in many cell types including bone cells. These effects may be mediated by the modulation of the insulin-like growth factor (IGF) regulatory system. Therefore we investigated the effects of 1,25-(OH)2D3 on transcript and protein levels of both IGF-I and IGF binding proteins (IGFBPs) in clonal mouse osteoblasts. Subconfluent cultures were treated in serum-free medium with 1,25-(OH)2D3. Secreted IGF-I was measured using a RIA under conditions eliminating the interference of IGFBPs. 1,25-(OH)2D3 (10(-11)-10(-8) M) inhibited IGF-I release in a dose dependent manner at 24 h (maximally to 30 +/- 5% of control, mean +/- SEM of seven independent experiments). In a time course study IGF-I increased in the media of control cultures over a 48-h period, while IGF-I secretion was completely prevented from 6 h onward in 1,25-(OH)2D3 treated cultures. Northern blot analysis revealed four IGF-I transcripts of 0.9, 1.8, 4.4, and 7.5 kilobases (kb). 1,25-(OH)2D3 decreased levels of the 7.5 kb IGF-I transcript from 4-48 h, with maximal inhibition occurring at 24 h (25% of control). Western ligand blots of the culture medium demonstrated secretion of a 25-kilodalton IGFBP, which comprised greater than or equal to 90% of the secreted IGFBPs. The 25-kilodalton IGFBP had previously been shown to have sequence similarity with IGFBP-4, a binding protein which inhibits the action of IGFs on bone cells. 1,25-(OH)2D3 treatment increased secretion of IGFBP-4 up to 14-fold over 24 h. 1,25-(OH)2D3 also increased IGFBP-4 (2.2 kb) transcript levels within 30 min, with the maximal stimulation of 8-fold occurring after 8 h. [3H]Thymidine incorporation into cells was inhibited by 1,25-(OH)2D3 both under basal and serum-stimulated conditions. Our results are consistent with the hypothesis that the effects of 1,25-(OH)2D3 on osteoblast proliferation may be mediated in part by decreased levels of IGF-I and increased concentrations of inhibitory IGFBP-4. It is proposed that this alteration in the IGF system may be an important functional autocrine or paracrine switch in the transition of osteoblasts from states of proliferation to differentiation.
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PMID:1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. 172 89

The liver is thought to be the major source of circulating insulin-like growth factor (IGF-I) and IGF-binding protein-1 (IGFBP-1), whereas the primary production site of circulating IGFBP-3 remains unknown. As other tissues may contribute to the circulating pool of IGF-I and IGFBP, the aim of the present study was to assess the hepatic and renal arterio-venous difference and production rates of IGF-I, IGFBP-1, IGFBP-3, and GH in cirrhotic patients (n = 22) and matched control subjects (n = 27). IGFBP-1 and -3, IGF-I, and GH levels were measured by RIA in hepatic, renal, and peripheral veins and in the femoral artery. Levels of IGFBP-1 to -4 were additionally determined by Western ligand blotting. Hepatic venous IGFBP-1 was significantly increased in the cirrhotic patients (mean +/- SEM, 33.6 +/- 9.1 vs. 10.4 +/- 1.9 micrograms/L; P < 0.001), and arterio-renal-venous extraction was significant in both patients (6 +/- 2%; P < 0.01) and controls (11 +/- 1%; P < 0.001). Conversely, IGFBP-3 was decreased in the cirrhotic patients (1265 +/- 149 vs. 2712 +/- 137 micrograms/L; P < 0.001). IGFBP-3 correlated significantly with the wedged hepatic venous pressure (r = -0.49; P < 0.05), serum aspartate aminotransferase (r = -0.66; P < 0.01), serum bilirubin (r = -0.65; P < 0.01), serum albumin (r = 0.64; P < 0.01), and the Child score (r = -0.57; P < 0.01). IGF-I was significantly lower in the cirrhotics (57 +/- 10 vs. 143 +/- 11 micrograms/L; P < 0.001). No significant IGFBP-3 proteolysis was demonstrated in cirrhotics or controls. No significant differences were found in the values obtained simultaneously from hepatic, renal, and brachial veins or femoral artery, which suggests that no major net production or release of IGFBP-3 or IGF-I occurs in these tissues. No differences in IGFBP-2 or IGFBP-4 determined by Western ligan blot were found between patients and controls. The IGF-I concentrations correlated significantly with parameters of biochemical liver function. Basal GH concentrations were significantly higher in the cirrhotics (1.19 +/- 0.13 vs. 0.58 +/- 0.08 micrograms/L; P < 0.001). A significant hepatic disposal of GH was found in the patients (P < 0.05) and controls (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Concentrations, release, and disposal of insulin-like growth factor (IGF)-binding proteins (IGFBP), IGF-I, and growth hormone in different vascular beds in patients with cirrhosis. 753

In neonatal rats, systemic administration of epidermal growth factor (EGF) results in reduced body weight gain and decreased levels of circulating IGF-I, which suggests that it be involved in the EGF-induced growth retardation. We investigated the effect of 4 weeks of EGF administration on circulating free and total IGF-I and IGF-binding proteins (IGFBPs) in adult rats treated with saline (controls), 30 (low dose group) and 150 (high dose group) microgram/kg/day EGF. Serum IGF-I was determined in ultrafiltrates (free) and acid-ethanol extracts (total), and serum IGFBPs using Western ligand blotting, which yielded four distinct molecular bands. The IGFBPs were tentatively identified as IGFBP-3 (a double band at 42 and 38 kDa), IGFBP-1 and/or IGFBP-2 (a single band at 30 kDa) and IGFBP-4 (a single band at 24 kDa). EGF administration did not change the body weight, tibia length, or liver, heart and lung weight. In contrast, serum total IGF-I and IGFBP-3 decreased dose-dependently: total IGF-I averaged 1470 +/- 100 micrograms/l (controls; mean +/- SEM), 1030 +/- 60 micrograms/l (low dose group; P < 0.005) and 760 +/- 40 micrograms/l (high dose group; P < 0.005), whereas differences between IGFBP-3 levels reached significance (P < 0.05) between controls and high dose rats, only. When compared to controls, levels of IGFBP-1 and/or IGFBP-2 were increased in the low dose group (P < 0.05), but unchanged in the high dose group. IGFBP-4 was unaffected by EGF. Free IGF-I averaged 74 +/- 6 micrograms/l in controls, and was reduced to 35 +/- 6 micrograms/l (low dose group; P < 0.005) and 57 +/- 5 micrograms/l (high dose group; P < 0.05). Free IGF-I was inversely correlated (r = -0.49, P < 0.05) with IGFBP-1 and/or IGFBP-2. We conclude that in adult rats prolonged EGF administration has a marked depressing effect on circulating total and free IGF-I. Nevertheless, we did not observe any somatic growth retardation.
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PMID:The effect of epidermal growth factor on circulating levels of free and total IGF-I and IGF-binding proteins in adult rats. 871 50

We compared the effects of exogenous insulin and porcine ST (pST) on follicular development after weaning. Crossbred primiparous sows received saline (1.5 mL i.m.; n = 9), insulin (.4 IU/kg BW s.c.; Eli Lilly Lente Iletin II; n = 10), or pST (40 microg/kg BW i.m.; n = 10) from d 1 to 5 after weaning (d 0). Ovaries were collected, the diameter of each follicle > or = 2 mm was measured, and fluid from the 20 largest follicles was assessed for IGF-I, IGF binding proteins (IGFBP), estradiol, progesterone, and testosterone. The total number (27.7, 25.3, and 29.1 for saline, insulin, and pST, respectively; SEM = 3.2) and average diameter (4.7, 5.2, and 5.5 mm for saline, insulin, and pST treatments, respectively; SEM = .3 mm) of ovarian follicles were not affected by insulin or pST treatment. The pST and insulin increased follicular fluid estradiol and testosterone in medium and large follicles compared to fluid from saline-treated sows, but the increase was greater for insulin than for pST treatment (treatment x size interaction, P < .01). Similarly, progesterone concentrations in follicular fluid were higher in medium and large follicles after insulin treatment, and pST treatment induced higher progesterone concentrations in small follicles and increasingly lower concentrations of progesterone in medium and large follicles (treatment x size interaction, P < .0007) compared to saline treatment. Follicular fluid IGF-I was greater (treatment x health interaction, P < .0001) in atretic and nonatretic follicles from pST-treated sows than in those from insulin- and saline-treated sows. Follicular fluid IGFBP-2 (tendency, P < .07) and IGFBP, possibly representing IGFBP-5 (30 kDa) and IGFBP-4 (22 kDa), were higher in atretic follicles than in nonatretic follicles (P < .05), whereas IGFBP-3 was not influenced by health status. The 30- and 22-kDa IGFBP were also influenced by treatment, increasing due to pST compared with saline or insulin treatments (P < .008). Follicular fluid IGFBP-2 and IGFBP-3 were not influenced by treatment. In conclusion, pST and insulin positively influenced follicular steroidogenesis and possibly follicular development, although through different mechanisms.
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PMID:Comparative effects of insulin and porcine somatotropin on postweaning follicular development in primiparous sows. 962 54

The IGF family plays an important role in implantation and placental physiology. IGF-II is abundantly expressed by placental trophoblasts, and IGF binding protein (IGFBP)-4, a potent inhibitor of IGF actions, is the second most abundant IGFBP in the placental bed, expressed exclusively by the maternal decidua. Proteolysis of IGFBP-4 results in decreased affinity for IGF peptides, thereby enhancing IGF actions. In the current study, we have identified the IGFBP-4 protease and its inhibitor in human trophoblast and decidualized endometrial stromal cell cultures, and we have investigated their regulation in an effort to understand control of IGF-II bioavailability at the placental-decidual interface in human implantation. IGFBP-4 protease activity was detected in conditioned media (CM) from human trophoblasts and decidualized endometrial stromal cells using (125)I-IGFBP-4 substrate. Identification of the IGFBP-4 protease as pregnancy-associated plasma protein-A (PAPP-A) was confirmed by specific immunoinhibition and immunodepletion of the IGFBP-4 protease activity with specific PAPP-A antibodies. The IGFBP-4 protease activity was IGF-II-dependent in trophoblast CM. In decidualized stromal CM, PAPP-A/IGFBP-4 protease activity was also IGF-II-dependent, but was evident only when IGF-II was added in molar excess of the predominant IGFBP in decidualized stromal cell CM, IGFBP-1, supporting bioavailable IGF-II as a key cofactor of IGFBP-4 proteolysis by PAPP-A. Cultured first and second trimester human trophoblasts (n = 5) secreted PAPP-A into CM with mean +/- SEM levels of 172.4 +/- 32.8 mIU/liter.10(5) cells, determined by specific ELISA. PAPP-A in trophoblast CM (n = 3) and did not change in the presence of IGF-II (1-100 ng/ml). Cultured human endometrial stromal cells (n = 4) secreted low levels of PAPP-A (6.25 +/- 3.6 mIU/liter.10(5) cells). A physiological inhibitor of PAPP-A, the proform of eosinophil major basic protein (proMBP), was detected in trophoblast CM at levels of 1853 +/- 308 mIU/liter.10(5) cells, determined by specific ELISA, and was nearly undetectable in CM of human endometrial stromal cells. Upon in vitro decidualization of endometrial stromal cells with progesterone, PAPP-A levels in CM increased nearly 9-fold without a concomitant change in proMBP. In contrast to the experiments with trophoblasts, IGF-II and the IGF analogues, Leu(27) IGF-II, and Des (1-6) IGF-II, resulted in a dose-dependent decrease of PAPP-A levels in decidualized endometrial stromal CM by 70-90%, and a dose-dependent increase in proMBP of 14- to 41-fold. The data demonstrate conclusively that the IGF-II-dependent IGFBP-4 protease of human trophoblast and decidual origin is PAPP-A. Furthermore, the differential regulation of decidual PAPP-A and proMBP by insulin-like peptides supports a role for trophoblast-derived IGF-II as a paracrine regulator of these maternal decidual products that have the potential to regulate IGF-II bioavailability at the trophoblast-decidual interface. Overall, the data underscore potential roles for a complex family of enzyme (PAPP-A), substrate (IGFBP-4), inhibitor (proMBP), and cofactor (IGF-II) in the placental bed during human implantation.
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PMID:Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. 1199 88