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Aim: To explore the causative mechanism of gastric carcinoma and to investigate the roles of circulating IGF-I and IGFBP-3 in gastric cancer. Materials and methods: Serum IGF-I and IGFBP-3 concentrations were measured using a 2-site coated tube immunoradiometric assay. Results: Serum IGF-I and IGFBP-3 values in gastric cancer patients were significantly lower compared to those in the control group. The difference between serum IGF-I/IGFBP-3 in patients and the control group was not significant. Conclusion: The low serum IGF-I and IGFBP-3 levels detected in patients with gastric cancer could be due to decreased synthesis or increased catabolism of IGF-I or both. It could be suggested that these parameters may be important in the development and prognosis of gastric cancer. [ABSTRACT FROM AUTHOR]

Epidemiological studies indicate that poor growth before birth is associated with left ventricular hypertrophy and an increased risk of death from heart disease later in life., In fetal life, the insulin-like growth factor ( IGF) system has been implicated in physiological growth of the heart, whereas in postnatal life IGFs can be involved in both physiological and pathological cardiac hypertrophy., A reduction in substrate supply in fetal life, resulting in chronic hypoxaemia and intrauterine growth restriction, results in increased cardiac IGF-1R, IGF-2 and IGF-2R gene expression; and there is also evidence for a role of the IGF-2 receptor in the ensuing cardiac hypertrophy., The persistent high level of cardiac IGF-2R gene expression from fetal to postnatal life may be due to epigenetic changes in key cardiac hypertrophy regulatory pathways. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of this study was to evaluate the reactivity of steroid hormone receptors (SHRs), dystroglycans (DGs), matrix metalloproteinases (MMPs), insulin-like growth factor receptor (IGFR-1), and laminin (Lam) in both prostatic stromal and epithelial compartments showing different diseases in elderly men. METHODS: Sixty prostatic samples were obtained from 60- to 90-year-old patients (mean 63 years) with and without prostatic lesions from Hospital of the School of Medicine, State University of Campinas (UNICAMP). The Samples were divided into standard (no lesions); high grade prostatic intraepithelial neoplasia (HGPIN); prostatic cancer (PC); and benign prostatic hyperplasia (BPH) groups. The samples were submitted to immunohistochemistry and Western blotting analyses. Research Ethics Committee of the School of Medicine, University of Campinas/UNICAMP (number 0094.0.146.000-08). RESULTS: The results showed increased IGFR-1 and MMPs protein levels in the PC and HGPIN groups. Decreased αDG and βDG protein levels were verified in the PC and HGPIN groups. Androgen receptor (AR) reactivity was similar among all groups. Estrogen receptor α (Erα) immunoreactivity was more intense in the epithelium in the PC and HGPIN groups. Estrogen receptor β (ERβ) immunoreactivity was weak in the epithelium of the HGPIN and PC groups. CONCLUSIONS: To conclude, there was an association among IGFR-1, MMPs, and SHRs, indicating IGFR-1 as a target molecule in prostate therapy, considering the IGF proliferative properties. Also, the distinct SHRs reactivities in the lesions in both prostatic compartments indicated different paracrine signals and pointed out the importance of estrogenic pathways in the activation of these disorders. Microsc. Res. Tech. 75:1197-1205, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGFs), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and nuclear factor kappa-B (NF-κB) are known to play an important role in endometrial cancer pathogenesis. However, the proteolytic regulation of these factors is still poorly understood. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, VEGF, HIF-1, and NF-κB levels in endometrial cancer tissues. It was shown that the total activity of proteasomes and the activity of the 20S and 26S proteasomes in malignant tumors were significantly higher than those observed in the normal endometrium. Negative relationships between the proteasome activity and IGF-I, HIF-1, and NF-κB p50 expressions were found. High 20S proteasome activity was associated with increase of HIF-1 level. Positive relationships between IGF-I expression and two classic forms of NF-κB p50 and p65 in endometrial cancer were revealed. The data obtained indicate the possible proteasomal regulation of growth and transcription factors. The major pool of IGF-I is located in the extracellular space, and it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The present data show the evidence of proteasome regulation of growth and nuclear factors that can play an important role in cancer pathogenesis. [ABSTRACT FROM AUTHOR]

The type I insulin-like growth factor receptor (IGF1R) contributes to cancer cell biology. Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy. Our laboratory has shown that sequential treatment with doxorubicin (DOX) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy. In this study, we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response. Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF1R and insulin receptor (InsR) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells. PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner. PQIP did not induce apoptosis, but rather, PQIP treatment was associated with an increase in autophagy. We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition. PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone. In contrast, pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro. Furthermore, OSI-906, a PQIP derivative, inhibited IGF-I signaling in LCC6 xenograft tumors in vivo. When given once a week, simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX. In summary, these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials. Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy. [ABSTRACT FROM AUTHOR]

The importance of the insulin-like growth factor (IGF)-I axis in the regulation of bone size and bone mineral density, two important determinants of bone strength, has been well established from clinical studies involving patients with growth hormone deficiency and IGF-I gene disruption. Data from transgenic animal studies involving disruption and overexpression of components of the IGF-I axis also provide support for a key role for IGF-I in bone metabolism. IGF-I actions in bone are subject to regulation by systemic hormones, local growth factors, as well as mechanical stress. In this review we describe findings from various genetic mouse models that pertain to the role of endocrine and local sources of IGF-I in the regulation of skeletal growth. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D. Methods: At baseline, participants aged 35-56 years without known type 2 diabetes were examined using OGTTs, 25(OH)D and IGF peptide measurements, and anthropometric and lifestyle data. Participants who had prediabetes or type 2 diabetes at follow-up 8-10 years later were selected as cases; these were then age- and sex-matched to controls with normal glucose tolerance (NGT) at both baseline and follow-up, giving a total of 980 women and 1,398 men. Results: Men but not women in the highest quartile of 25(OH)D level had a decreased OR for developing type 2 diabetes after adjustment for confounders (OR 0.52, 95% CI 0.30, 0.90), an effect accounted for by individuals with prediabetes, but not with NGT, at baseline. In both sexes, progression from prediabetes to type 2 diabetes was reduced by about 25% per 10 nmol/l increase in 25(OH)D. A high IGFBP-1 value was a better predictor of a reduced risk of type 2 diabetes than high 25(OH)D for both sexes, whereas high IGF-1 concentrations predicted a decreased risk only in men. Conclusions/interpretation: High serum 25(OH)D concentrations predict a reduced risk of type 2 diabetes in individuals with prediabetes, but not NGT. There were no significant interactions between 25(OH)D and IGFBP-1 or IGF-1 in terms of risk of diabetes. Our data suggest that vitamin D supplementation should be evaluated for the prevention of type 2 diabetes in prediabetic individuals. [ABSTRACT FROM AUTHOR]

Abstract: Insulin-like growth factors (Igf) are known paracrine/autocrine regulators of ovarian development in teleosts. Initial studies investigated the hormonal and intracellular signalling cascades involved in regulating the expression of ovarian-derived Igfs in zebrafish (Danio rerio). Quantitative real-time PCR was used to quantify the expression of igf3, igf2a, and igf2b in full grown immature (FG; 0.57–0.65mm) and mid-vitellogenic (MV; 0.45–0.56mm) follicles. Addition of the gonadotropin analogue human chorionic gonadotropin (hCG) and the adenylate cyclase activator forskolin increased igf3 expression in FG and MV follicles, but had no effect on igf2a or igf2b expression. The effects of hCG on igf3 expression were blocked by the addition of the protein kinase A inhibitor H-89. Pituitary adenylate cyclase activating peptide also stimulated a small increase in igf3 expression in FG follicles, while growth hormone and salmon gonadotropin releasing hormone had no effect on igf3, igf2a, or igf2b expression. Secondary studies investigated the involvement of ovarian-derived Igfs in mediating the ovarian actions of gonadotropins on cell survival and steroidogenesis. Treatment of FG follicles with recombinant human IGF1, hCG, or forskolin inhibited the induction of caspase-3/7 activity, which was used as a measure of apoptosis. The effects of hCG and forskolin on caspase-3/7 were attenuated by co-treatment with NVP-AEW54, an IGF1 receptor antagonist. In other studies, hCG was shown to increase the production of the maturation-inducing steroid 17,20β-dihydroxy-4-pregnen-3-one, but this action was not affected by co-treatment with NVP-AEW54. These results suggest there is a high degree of hormonal specificity in regulating Igfs in the zebrafish ovary and the ovarian-derived Igfs, presumably Igf3, are downstream mediators of gonadotropin-dependent cell survival, but are not involved in gonadotropin-induced steroidogenesis. [Copyright &y& Elsevier]

Insulin-like growth factors (IGFs) and the nuclear factor κB (NF-κB) are known to play an important role in pathogenesis of endometrial cancer. However, there is still uncertainty about their proteolytic regulation. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, and NF-κB levels in endometrial cancer tissues. The total activity of proteasomes and the 20S and 26S proteasome activities were shown to be significantly higher in malignant tumors than in the unaltered endometrium. Negative correlations were found between the proteasome activity of 26S and the p50 level of NF-κB, as well as between the 26S and 20S proteasome activities and IGF-I level. The obtained data indicate the possible proteasome regulation of growth and transcription factors. As the major pool of IGF-I is considered to be located in the extracellular space, it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The positive correlation between the IGF-I level and PAPP-A metalloproteinase is evidence that this proteolytic enzyme is another important regulator of the level of growth factor, which ensures the proteolysis of IGF-I binding proteins and, thus, increases the concentration of IGF-I in tissues. The present data show the possibility of the proteolytic regulation of growth and nuclear factors that can play an important role in cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Ultraviolet (UV) A irradiation causes the degeneration of extracellular matrix in the skin dermis, mainly due to disrupted collagen homeostasis, resulting in the photo-aging of human skin. All-trans retinoic acid (ATRA) improves photo-aged human skin in vivo. Objectives: Although the effects of ATRA on collagen synthesis and MMP regulation are well known, the effects of ATRA on other collagen homeostasis-associated genes have not been elucidated. This study was aimed to study the factors that are pharmacologically associated with the effect of ATRA on collagen homeostasis. Methods: The gene transcription profile of collagen homeostasis-associated genes was systematically evaluated in three-dimensional human dermal equivalents (HDEs) following UVA-irradiation and/or ATRA treatment. Results: In addition to the expected changes in MMPs and collagen synthesis in HDEs in response to ATRA, prolidase, an important enzyme in the recycling of proline and hydroxyproline from degraded collagen molecules, was significantly decreased by UVA irradiation, and its down-regulation was antagonized by ATRA. Transfection with a prolidase-specific siRNA led to a significant decrease in procollagen synthesis in human fibroblasts. ATRA inhibited the UVA irradiation-induced decrease in prolidase activity through an insulin-like growth factor (IGF) receptor signaling pathway in HDEs. ARTA increased IGF1 and IGF2 production in HDEs, and neutralizing IGFs with anti-IGF antibodies abolished the effect of ATRA on proliase activity. Conclusions: These data demonstrate that ATRA regulates prolidase activity in HDEs via IGF receptor signaling, suggesting one of the pharmacological mechanisms by which improves photo-aged human skin. [Copyright &y& Elsevier]

Aims: We address the question of the expression and the role of the growth hormone/insulin-like growth factor (GH/IGF) axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. The effect of GH on T cell differentiation was explored via thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1 displayed distinct expression profiles depending on the developmental stage. The protein concentrations of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and the GH receptor (GHR) antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T cell differentiation could implicate a different local growth factor or cytokine. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: In this study, we have investigated the effect of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on endocrine signalling, growth and development in Atlantic salmon (Salmo salar) embryos and larvae. Expression of genes related to the hypothalamic–pituitary–thyroid (HPT) axis, growth-hormone/insulin-like growth factor (GH/IGF) axis and the steroid hormone axis were used as indicators of endocrine disruption. We also studied bone development in larvae, both by observing skeletal structure formation and by investigating expression of genes involved in ossification process. Atlantic salmon embryos, kept in plastic tanks at 5–7°C, were exposed to 100μg/L PFOA or PFOS from egg stage for a period of 52 days, followed by one-week recovery period. Sampling was performed at day 21, 35, 49 and 56 representing age 549, 597, 679 and 721 dd (dd or day degrees=number of days×temperature in degree Celsius:°C). Note that day 56 or 721 dd is the end of the 1-week recovery period. Larvae were divided into designated head and body regions for the purpose of gene expression analysis, except for genes that regulate ossification that were analyzed in whole larvae. Expression of thyroid receptor α and β (TRα and TRβ), thyroid-stimulating hormone β (TSHβ), T4 outer-ring deiodinase (T4ORD), growth hormone (GH), insulin-like growth factor-I and II (IGF-I and II), insulin-like growth factor I receptor (IGF-IR), and estrogen receptor α and β (ERα and ERβ) were investigated using quantitative PCR. Both PFOS and PFOA exposure produced non-significant alterations in larvae weight (except after the recovery period when a decrease was observed), while larvae length was unaffected. PFOS and PFOA exposure produced body- and head region-specific alterations in expression of all the investigated gene transcripts. Expression of IGF-I and IGF-IR paralleled that of GH, indicating that perturbation of GH expression is a possible end point for disruption of the GH–IGF axis. We did not observe developmental changes related to angiogenesis, ossification and chondrogenesis after exposure to PFOS and PFOA. Transcriptional abnormalities may serve as indicators of chronic exposure, although the concrete mechanisms causing the observed effects remain ambiguous. The implications of these findings for the complete lifecycle, including other developmental and/or reproductive damage, are areas of future study. [Copyright &y& Elsevier]

Context: Many studies have reported associations of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with prostate cancer development, but none have investigated their association with fatal progression of prostate cancer. Objective: We investigated associations of circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 with all-cause and prostate cancer mortality in men with clinically identified prostate cancer, stratified by whether localised (stage T1 or T2) or advanced (T3, T4, N1 or M1) at diagnosis. Design, setting and participants: UK hospital-based cohort study of 396 men with prostate cancer, diagnosed between 1990 and 2008, with mean follow-up of 3.7 years. Main outcome measures: All-cause and prostate cancer-specific mortality. Results: In men with advanced cancer, there was some evidence that IGF-I was positively associated (HR 1.20; 95% CI: 0.96, 1.49; p = 0.11) and IGFBP-3 was inversely associated (HR 0.84; 95% CI: 0.70, 1.01; p = 0.07) with all-cause mortality after controlling for age, treatment status, smoking, prostate-specific antigen and Gleason grade at diagnosis. There was some evidence that IGF-I was positively associated with prostate cancer mortality in advanced cases (HR 1.23; 95% CI: 0.94, 1.62; p = 0.13). In advanced cancers, associations of IGF-I with all-cause (HR 1.68; 95% CI: 1.28, 2.23; p < 0.001) and prostate cancer-specific (HR 1.59; 95% CI: 1.11, 2.28; p = 0.01) mortality strengthened (and were conventionally statistically significant) after further controlling for IGFBP-3. Conclusions: Measures of IGF-I and IGFBP-3 may have potential as prognostic markers in predicting risk of death in men with advanced prostate cancer. Large, prospective studies with repeat IGFs and IGFBPs are now required. [ABSTRACT FROM AUTHOR]

Environmental conditions during pregnancy determine birthweight, neonatal viability and adult phenotype in human and other animals. In part, these effects may be mediated by the placenta, the principal source of nutrients for fetal development. However, little is known about the environmental regulation of placental phenotype. Generally, placental weight is reduced during suboptimal conditions like maternal malnutrition or hypoxaemia but compensatory adaptations can occur in placental nutrient transport capacity to help maintain fetal growth. In vivo studies show that transplacental glucose and amino acid transfer adapt to the prevailing conditions induced by manipulating maternal calorie intake, dietary composition and hormone exposure. These adaptations are due to changes in placental morphology, metabolism and/or abundance of specific nutrient transporters. This review examines environmental programming of placental phenotype with particular emphasis on placental nutrient transport capacity and its implications for fetal growth, mainly in rodents. It also considers the systemic, cellular and molecular mechanisms involved in signalling environmental cues to the placenta. Ultimately, the ability of the placenta to balance the competing interests of mother and fetus in resource allocation may determine not only the success of pregnancy in producing viable neonates but also the long-term health of the offspring. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pregnancy-associated plasma protein A (PAPP-A) proteolyzes insulin-like growth factor (IGF)–binding proteins and thus increases IGF-1 bioactivity. PAPP-A has been reported to be involved in various pathophysiologic abnormalities; however, the clinical significance of PAPP-A has not been examined in cases of heart failure (HF). We hypothesized that PAPP-A levels might be correlated with the severity of HF. Methods and Results: PAPP-A and B-type natriuretic peptide (BNP) levels were measured in 262 subjects (182 HF patients and 80 control subjects). PAPP-A levels were higher in patients with HF than in control subjects and increased with advancing New York Heart Association functional class. There were 53 cardiac events during a mean follow-up period of 796 days. PAPP-A levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 3 groups on the basis of their PAPP-A and BNP levels. Kaplan-Meier analysis demonstrated that the group with both high BNP with high PAPP-A had a significantly higher cardiac event rate than other groups. Conclusions: Serum PAPP-A levels were related to the severity of HF and associated with a high risk for adverse cardiac events in HF patients, suggesting that PAPP-A might be involved in the pathogenesis of HF. [Copyright &y& Elsevier]

Placenta is a source of carbohydrate-binding proteins that function as molecular scavengers, but they could also be involved in interactions that assist in metabolic control. Mannose/N-acetyl-glucosamine (Man/GlcNAc)-binding proteins from placenta were isolated and their reactivity towards placental insulin and insulin-like growth factor receptors (IR and IGF-Rs) was analyzed. The lectins reduced the binding of insulin and IGF-I in a dose-dependent manner, while almost no effect was observed on the binding of IGF-II. The shape of the inhibition curves changed, suggesting altered binding specificity. The presence of sugar could not reverse completely the effect of the lectins, implicating both lectin-sugar and protein-protein conformational recognition. Since biological molecules in our experimental system were those that are in close relation in vivo, placental Man/GlcNAc-specific lectins may be regarded as potential allosteric modulators of lig- and-receptor interactions in a system of homologous ligands, selectively affecting only binding to tyrosine kinase type receptors (IR and IGF-1R). [ABSTRACT FROM AUTHOR]

Background: Insulin-like growth factor (IGF) binding protein (IGFBP)-3 is the main carrier of circulating IGFs and the main modulator of their activity. IGFBP-3 controls cellular availability of IGFs, which cannot exert their pro-proliferative activity while bound to IGFBP-3. Proteolysis of IGFBP-3 is one mechanism to control IGF release. A reduction of serum IGFBP-3 levels and the associated increased availability of IGFs may represent a strategy whereby melanoma increases its metastatic potential. Objective: The aim of our study was to evaluate the correlation between the IGFBP-3 serum level and melanoma stage. Methods: The study included 41 patients, 24 male and 17 female, with median age of 60 years (range 24-80), affected by cutaneous melanoma. Blood samples were taken from each patient and IGFBP-3 serum levels were measured using Western blot analysis with commercial antibodies. Values were normalized using commercial IGFBP-3. Results: The statistical analysis showed that full-size, glycosylated IGFBP-3 concentrations were significantly lower in the sera of patients with stage IV melanoma. Low serum levels of IGFBP-3 correlated with both disease progression and presence of disease at the time of sample collection. In patients who underwent follow-up visits with further collections of blood samples, the concentrations of glycosylated IGFBP-3 decreased only in those who showed progression of disease. Limitations: Our study shows only preliminary results on a limited number of patients. Conclusion: We demonstrate that there is a significant inverse correlation between the serum concentration of full-size, glycosylated IGFBP-3 and disease progression in patients with melanoma. [Copyright &y& Elsevier]

The article discusses a research study which investigated models applied to composite circulating biomarkers, for use in anticancer drug development. The predictive models used for colorectal cancer were logistic regression (LR), artificial neural networks (ANNs), fractional polynomial (FP) and support vector machines (SVMs). Serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2) and IGFBP-3 were measured to examine their potential dimensional relationships with sex, age, and body mass index (BMI).

Multiple advantages-including the short generation time, large numbers of fertilized eggs, low cost of cultivation and easy maintenance favor the use of fish as bioreactors for the production of pharmaceutical proteins. In the present study, zebrafish eggs were used as bioreactors to produce mature tilapia insulin-like growth factors (IGFs) proteins using the oocyte-specific zona pellucida ( zp3) promoter. The chimeric expression plasmids, pT2-ZP-tIGFs-IRES-hrGFP, in which hrGFP was used as reporter of tilapia IGFs expression, were designed to established Tg ( ZP:tIGFs:hrGFP) transgenic lines for the expression of tilapia IGF-1 and IGF-2. Recombinant tilapia IGF-1 and IGF-2 were expressed as soluble forms in cytoplasm of fertilized eggs. The content level of tilapia IGF-1 and IGF-2 were 6.5 and 5.0% of the soluble protein, respectively. Using a simple Ni-NTA affinity chromatography purification process, 0.58 and 0.49 mg of purified tilapia IGF-1 and IGF-2 were obtained, respectively, from 650 fertilized eggs. The biological activity of the purified tilapia IGF-1 and IGF-2 was confirmed via a colorimetric bioassay to monitor the growth stimulation of zebrafish embryonic cells (ZF4), tilapia ovary cells (TO-2) and human osteosarcoma epithelial cells (U2OS). These results demonstrate that the use of zebrafish eggs as bioreactors is a promising approach for the production of biological recombinant proteins. [ABSTRACT FROM AUTHOR]

The prevalence of overweight and obesity is increasing worldwide, and the evidence base for a link between obesity and cancer is growing. In the United States, approximately 85,000 new cancer cases per year are related to obesity. Recent research has found that as the body mass index increases by 5 kg/m, cancer mortality increases by 10%. Additionally, studies of patients who have had bariatric surgery for weight loss report reductions in cancer incidence and mortality, particularly for women. The goal of this review is to provide an update of recent research, with a focus on epidemiologic studies on the link between obesity and cancer. In addition, we will briefly review hypothesized mechanisms underlying the relationship between obesity and cancer. High priorities for future research involve additional work on the underlying mechanisms, and trials to examine the effect of lifestyle behavior change and weight loss interventions on cancer and intermediate biomarkers. [ABSTRACT FROM AUTHOR]

Objective: Adiposity is positively associated with advanced, metastatic, and fatal prostate cancer. Obesity-related variations in insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs) could underlie these associations.Methods: We investigated associations of adiposity throughout the life course (determined retrospectively) with serum levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in a population-based study of 1,106 healthy men.Results: IGF-I and IGF-II showed inverted U-shaped associations with adult body mass index (BMI) (p quadratic model = 0.04 and 0.06, respectively), although differences between quartiles with the highest and lowest IGF-I levels were small (no more than 5 ng/ml). IGFBP-2 was strongly inversely related to adult BMI (-22% change per SD increase in BMI; 95% confidence interval (CI) -24% to -19%) and waist circumference (-18% change per SD increase in waist circumference; 95% CI -20% to -15%) (p < 0.001). IGFBP-3 was positively related to BMI (63.5 ng/ml increase per SD increase in BMI; 95% CI -2.69 to 129.8, p = 0.06). IGFBP-2 and IGFBP-3 were strongly related to body shape change from childhood to adulthood, with men who gained the most weight having the lowest IGFBP-2 (9% lower per category body shape change; 95% CI -11% to -7%, p < 0.001) and the highest IGFBP-3 (50 ng/ml increase per category; 95% CI 8 to 92, p = 0.02).Conclusions: We provide evidence that adiposity and change in body shape through the life course are related to the IGF system, with the largest effect of adiposity being to lower IGFBP-2, a possible marker of insulin resistance. The results suggest that circulating IGF-I levels may not be important mediators of the association of adiposity with aggressive prostate cancer, but the role of IGFBP-2 deserves further investigation. [ABSTRACT FROM AUTHOR]

Abstract: The intrauterine environment may impact the conceptus (embryo/foetus and associated extra-embryonic membranes) during ‘critical periods’ of development, when rapid cell divisions occur in various tissues of the body, and may alter expression of the foetal genome, and this may have lifelong consequences; a phenomenon known as foetal programming. Among intrauterine environmental factors, nutrition appears to play the most critical role in influencing placental and foetal growth. Changes in maternal nutritional status during pregnancy often results in permanent structural and functional deficits in foetal, as well as, postnatal growth of animals. Maternal undernutrition or overnutrition during pregnancy can impair foetal growth. Alterations of the insulin-like growth factor cascade are speculated to play a significant role in intrauterine nutrition-associated compromised foetal growth and foetal programming. Insulin-like growth factors, IGF-1 and IGF-2 are nutritionally sensitive proteins that are believed to modulate foetal and placental growth. The role of these growth factors in nutrition-associated deficits in ovine foetal and placental growth is the subject of this review. [ABSTRACT FROM AUTHOR]

Abstract: Inappropriate activation of the IGF (insulin-like growth factor) system has been implicated in the growth and progression of a number of tumor types. Recent evidence indicates a possible role for the IGF system in modulating/mediating tumor cell response to hypoxia, a common occurrence in solid tumors, and particularly in malignant gliomas, causing tumor cells either to die, or to mount a pleiotropic adaptive response that is mainly orchestrated through activation of the hypoxia-inducible transcription factor HIF1. Experimental evidence suggests possible links between IGF- and HIF1-dependent signaling pathways, as well as a role for activated STAT3 in mediating their activities. Interestingly, igf2 is among the target genes transactivated by HIF1, thereby providing the missing link in a hypothetical autocrine self-amplifying circuit. The present study investigates the presence of the IGF-HIF1-VEGF axis in the human glioma cell line U-87 MG, and characterizes its molecular effectors. Our results show that exogenous IGF-I causes IGF1R and STAT3 activation, and increases HIF1α protein levels and HIF1 trascriptional activity, inducing VEGF release; a similar response, mediated by IGF-II release, is observed following HIF1α stabilization. The existence of an autocrine loop is confirmed by its down-regulation following inactivation of IGF1R (using the IGF1R-specific tyrosine kinase inhibitor NVP-AEW541), STAT3 (transfecting the cells with an expression vector encoding a dominant negative form of STAT3), or HIF1 (using the small molecule inhibitor YC-1). The ability of NVP-AEW541 to block this circuit could be beneficial in suppressing the growth and angiogenic potential of hypoxic glial tumors. [Copyright &y& Elsevier]

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Background: Our objective was to assess the relative bioavailability of the first somatropin produced in transgenic cloned cows that carry the human growth hormone (GH) gene (Biohormon®) and somatropin produced in Escherichia coli culture (HHT®), the procedure most frequently used for the commercial production of the hormone. Methods: Upon approval by an independent ethics committee and the National Regulatory Agency of Argentina, we compared the time-concentration profiles of somatropin in 24 healthy volunteers, in a randomized, 2-period, 2-sequence crossover design after inhibition of endogenous GH secretion with lanreotide, a long-acting somastostatin analogue. After the subcutaneous administration of 1.33 mg of each formulation, serum somatropin was analyzed by chemiluminescent immunoassay and IGF-I by immunoradiometric assay. Safety was assessed by clinical and laboratory parameters. Pharmacokinetic parameters were calculated with Win Nonlin® 5.2 using a non-compartmental model and bioequivalence was assessed. Results: The test/reference ratios of AUC, AUClast and Cmax were 106.4 (90% CI = 100.2-112.9), 105.3 (90% CI = 99.1-111.8) and 105.49 (90% CI = 92.6-120.1), respectively. No serious adverse events were reported and no GH antibodies were detected. Conclusion: This study demonstrates that a single dose of Biohormon, the first product with somatropin obtained from milk of transgenic mammals, is bioequivalent to the reference product HHT according to standard criteria. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Body mass index, as an approximation of body adiposity, is associated with increased risk of several common and less common malignancies in a sexand site-specific manner. These findings implicate sexand cancer site-specific biological mechanisms underpinning these associations, and it is unlikely that there is a "one system fits all" mechanism. Three main candidate systems have been proposed-insulin and the insulin-like growth factor-I axis, sex steroids, and adipokines-but there are shortfalls to these hypotheses. In this review, three novel candidate mechanisms are proposed: obesity-induced hypoxia, shared genetic susceptibility, and migrating adipose stromal cells. While public health policies aimed at curbing the underlying causes of the obesity epidemic are being implemented, there is a parallel need to better understand the biological processes linking obesity and cancer as a prerequisite to the development of new approaches to prevention and treatment. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor (HNF) families are composed of liver-enriched transcription factors and upstream regulators of many liver-specific genes. HNF are involved in liver-specific gene expression, metabolism, development, cell growth and many cellular functions in the body. HNF genes can be activated or influenced by several hormones and insulin-like growth factors (IGF), and different combinations of the four HNF factors form a network in controlling the expression of liver-specific or liver-enriched genes. The functions of these factors and their interactions within the gonads of bony fishes, however, are not well understood, and the related literature is scant. Recently, several members of the HNF families have been detected in teleost gonads together with their downstream genes (IGF-I and IGF-II), suggesting that these HNF could be upregulated in vitro by steroid hormones. Thus, the hormone–HNF–IGF–gonad interaction may be an alternative axis in the reproductive mechanism that acts in concert with the conventional hypothalamus–pituitary–gonad pathway. This may help the early development and maturation of the gonad or gamete, sexual maturity or reversion and spawning-regulating mechanisms among fishes to be understood. [ABSTRACT FROM AUTHOR]

Abstract: Maternal undernutrition causes fetal growth restriction. Protein is a vital dietary nutrient for fetal growth, and branched-chain amino acids (BCAA) are noted to have anabolic actions. In this study, we investigated the effects of maternal high-protein diet or BCAA-supplemented diet upon fetal growth under the condition of maternal calorie restriction. Pregnant mice were calorie-restricted (undernutrition: UN), using either a standard diet (S-UN group), high-protein diet (HP-UN group), or BCAA-supplemented diet (BCAA-UN group) to 70% of the control; dams fed ad libitum with a standard diet (S-NN group) from 10.5days post coitum (dpc) to 18.5dpc. The fetal weights of UN groups were significantly decreased compared to that of S-NN. However, the fetal weights of HP-UN and BCAA-UN were significantly higher by 5% and 4%, respectively, than those of S-UN, concomitant with augmentation of the gene and protein expressions of IGF-I and IGF-II in fetal liver. A high-protein diet as well as BCAA-supplemented diet partially improved fetal growth restriction caused by maternal calorie-restriction, suggesting a pivotal role of them in the amelioration of fetal growth restriction. [Copyright &y& Elsevier]

Fetal growth is determined by a complex interplay of genetic, nutritional, environmental, and hormonal factors. Greater than expected fetal growth has been positively associated with the risk of the development of some cancers in childhood, particularly acute lymphoblastic leukemia, and the biological mechanisms underlying such associations are thought to involve insulin-like growth factors (IGFs). Circulating IGF levels are highly correlated with fetal growth, and IGFs are believed to play an important role in carcinogenesis; however, these two bodies of evidence have not been well integrated and, as a result, the potential underlying biological mechanisms linking the IGF system with the development of specific childhood cancers have not been elucidated. This review aims to draw together and summarize the literature linking the IGF system, rapidity of fetal growth, and risk of some specific childhood cancers; suggest explanations for some of the inconsistencies observed in previous studies of these associations; and propose an integrated framework for the putative involvement of the IGF system in the development of at least some childhood cancers. If the challenges involved in studying the complex IGF system can be overcome, this field presents an exciting opportunity to elucidate etiological pathways to childhood malignancies. [ABSTRACT FROM AUTHOR]

The relationship between maternal plasma volume (PV) expansion and fetal growth is well established, but the underlying mechanisms remain unclear. Here, we examined the influence of maternal body weight and fetoplacental mass on gestational PV increment in the rat. Because IGF-l and IGF-II have growth-promoting and vasoactive properties, their relationship to PV expansion and fetoplacental growth was also studied. In normal rats, the gradual expansion of PV (+ 35% at day 22, i.e., term) was accompanied by a rise in circulating IGF-II (+45%) and a considerable drop in IGF-I (-73%). Increased maternal body weight induced by an obesogenic diet did not influence PV and circulating IGFs compared with rats on the standard diet. Combining the results from both diets, circulating IGF-II was the principal correlate of PV. A second experiment examined the effect of fetoplacental mass reduction by surgically removing half of the gestational sacs at day 16. This procedure reduced maternal PV and circulating IGF-II at term by 14% and 20%, respectively. We then investigated the effect of a constant infusion of IGF-II (1 mg·kg-1·day-1) from day 16, which raised circulating IGF-II by 38% and found increased PV (+ 19%) and a larger placental trophospongial area (+29%) at term. Our results indicate that the placenta, the primary source of IGF-II synthesis in pregnancy, drives PV expansion, and that IGF-II is among the regulatory factors of the gestational PV increment. Further studies should clarify whether IGF-II directly affects vascular function and/or indirectly promotes the secretion of placenta-derived vasoactive substances. [ABSTRACT FROM AUTHOR]

Hormones are both growth stimulatory and growth inhibitory in utero. They regulate tissue growth and development by controlling the rates of cell proliferation, apoptosis and differentiation in many fetal tissues. They also signal the level of resources available for intrauterine growth to the fe- tal tissues and relay back to the placenta the degree of mismatch between the actual fetal nutrient supply and the fetal nutrient demands for growth. They affect intrauterine growth by anabolic and catabolic actions on fetal metabolism and by altering the nutrient transfer capacity and endocrine function of the placenta. By modifying the fetal growth trajectory, hormones have a central role in programming development in utero and in determining the phenotypic outcome of changes in feto-placental growth during adverse intrauterine conditions. This review examines the role of hormones in feto-placental growth with particular emphasis on insulin, the insulin-like growth factors and glucocorticoids. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

To examine the association of insulin-like growth factors (IGFs) with metabolic syndrome in a nationally representative sample. We used data from the Third National Health and Nutrition Examination Survey. Analysis is based on participants who provided a fasting blood sample and were aged 20 years and older ( n = 5,903). Participants were classified by a number of risk factors for metabolic syndrome and stratified by diabetes status. Each of the components of metabolic syndrome (increased waist circumference, higher triglycerides, lower HDL cholesterol, higher blood pressure, higher fasting glucose and diabetes) was each associated with lower levels of IGF-I, IGF-BP3 and the Ratio IGF-I/IGF-BP3. Each of the metabolic syndrome components was also associated with higher levels of insulin. Participants with 3–5 components of metabolic syndrome had significantly lower IGF-I and higher IGF-BP3 levels compared to adults with 1–2 components or 0 components, after adjustment for potential confounders. Participants with diabetes had lower levels of IGF-I and IGF-BP3, and higher levels of insulin, regardless of the number of metabolic syndrome components. These findings may prove useful to an understanding of the role of IGF-I in human disease, in particular its relation to metabolic syndrome, diabetes and potentially some cancers. [ABSTRACT FROM AUTHOR]

The insulin/insulin-like growth factor (IGF) system regulates fetal and placental growth and development. In maternal diabetes, components of this system including insulin, IGF1, IGF2 and various IGF-binding proteins are deregulated in the maternal or fetal circulation, or in the placenta. The placenta expresses considerable amounts of insulin and IGF1 receptors at distinct locations on both placental surfaces. This makes the insulin and the IGF1 receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. Unlike the receptor for IGF1, the insulin receptor undergoes a gestational change in expression site from the trophoblast at the beginning of pregnancy to the endothelium at term. Insulin and IGFs are implicated in the receptor-mediated regulation of placental growth and transport, trophoblast invasion and placental angiogenesis. The dysregulation of the growth factors and their receptors may be involved in placental and fetal changes observed in diabetes, i.e. enhanced placental and fetal growth, placental hypervascularization and higher levels of fetal plasma amino acids. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We tested the hypothesis that lycopene supplementation reduces the expression of oxidant-responsive heme oxygenase-1 (HO-1) in basal conditions and in response to an oxidant challenge and determined whether this is temporally associated with increased cell viability. Methods: We determined basal and stimulated ex vivo expression of HO-1 and cell viability in lymphocytes from volunteers after lycopene supplementation. Twenty-four healthy young men on a low lycopene diet consumed 1) 170 g of passata sauce with butter or 2) butter alone for 3 wk in a randomized crossover design. Results: Plasma lycopene concentrations at the end of the tomato and control trials were 0.54 ± 0.20 versus 0.20 ± 0.15 μmol/L, respectively (P < 0.05). There was a significant increase in the proportion of live cells (91 ± 5% versus 87 ± 9%) and a corresponding reduction in apoptosis (6 ± 4% versus 11 ± 9%) in untreated lymphocytes after supplementation (P < 0.05), with no effect on cell viability in response to hydrogen peroxide treatment. HO-1 protein expression in basal conditions and induction of HO-1 after hydrogen peroxide treatment was not different between trials. Conclusion: Lycopene supplementation did not affect basal oxidative stress or susceptibility to oxidant-induced stress as indicated by the expression of the oxidant-responsive protein HO-1 and cell viability in response to hydrogen peroxide treatment. However, lycopene supplementation significantly reduced apoptosis in freshly harvested untreated lymphocytes. We conclude that this was not through an oxidant-mediated mechanism because of the lack of an effect on oxidant-responsive HO-1. [Copyright &y& Elsevier]

Abstract: During the last decade, involvement of growth hormone (GH), insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ovarian folliculogenesis has been extensively studied. This review provides an update on the GH, IGF system and their role in ovarian follicular development. In vitro studies and knockout experiments demonstrated an important role of GH in preantral follicle growth and differentiation through their binding with GH receptors, which are located both in the oocyte and follicular somatic tissues. Furthermore, GH stimulates the development of small antral follicles to gonadotrophin-dependent stages, as well as maturation of oocytes. With regard to the IGF system, IGF-I has no effects on primordial follicle development, but both IGF-I and IGF-II stimulate growth of secondary follicles. Depending on the species studies and method used, these proteins have been detected in oocytes and/or somatic cells. In antral follicles, these IGFs stimulate granulosa cell proliferation and steroidogenesis in most mammals. The bioavailability of IGFs is regulated by a family of intrafollicular expressed IGF binding proteins (IGFBPs). Facilitation of IGF can be increased through the activity of specific IGFBP proteases, which degrade the IGF/IGFBP complex, resulting in the production of IGFBP fragments and release of attached IGF. [Copyright &y& Elsevier]

Epidemiological studies assign a role to insulin signalling deregulation and diabetes mellitus in human hepatocarcinogenesis. The underlying mechanisms, however, remain largely unknown. To unravel the molecular pathogenesis of insulin-induced hepatocarcinogenesis, we generated an experimental animal model: after transplantation of only a low number of isologous pancreatic islets into the livers of diabetic rats, mild diabetes persists and the beta cells are maximally stimulated to permanently secrete insulin. As a consequence, liver acini, draining the hyperinsulinemic blood from islet grafts, show insulin-induced adaptive alterations simultaneously resembling preneoplastic foci of chemically-induced hepatocarcinogenesis models. These lesions progress to hepatocellular tumours within 6 and 24 months. Hepatocarcinogenesis is accompanied by alterations in hepatocytes metabolisms and changes in signal transduction pathways that, in the beginning, can be attributed solely to insulin action. In this review, we summarize our findings that may help understanding the oncogenic potential of diabetes mellitus in the human liver. [ABSTRACT FROM AUTHOR]

Decades of experience with growth hormone (GH) therapy have indicated considerable variability in responsiveness to therapy, even within single diagnostic categories, such as GH deficiency, Turner syndrome, intrauterine growth retardation and idiopathic short stature. It is likely that the major explanation for such variability lies in the genetic composition of the patient, including mutations of genes participating in the GH-insulin growth factor I cascade and genetic polymorphisms. Future studies of pharmacogenomic and pharmacoproteomic markers may allow us to better predict and categorize responsiveness to therapy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Irrespective of its primary etiology, chronic kidney disease (CKD) progresses. Glomerulosclerosis, interstitial fibrosis, and tubular atrophy are key features of CKD. The important roles of the transforming growth factor (TGF) and insulin-like growth factor (IGF) superfamilies have been indicated in recent studies. This review provides an update of the literature on these factors and their interactions in the pathophysiology of the progression of CKD as well as cachexia, which is an important complication. Specifically, the functions of key molecules, such as TGF-β, bone morphogenetic protein-7, myostatin, relaxin, and IGF-I in the pathobiology underlying CKD progression and CKD-associated cachexia are discussed. [ABSTRACT FROM AUTHOR]

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart. [ABSTRACT FROM AUTHOR]

Summary: The aim of the present study was to analyze the immunolocalization of insulin-like growth factor (IGF)-1 and IGF-2 and their receptors in the oviduct and uterus of control and diabetic mice. Sexually mature female ICR mice aged 6–8 weeks were rendered diabetic by streptozotocin (200mg/kg, administered intraperitoneally). Oviductal and uterine tissues were obtained from the superovulated control and diabetic mice at 48, 72 and 96h post-human chorionic gonadotropin (hCG) treatment. Localization of IGF-1, IGF-2, IGF-1R and IGF-2R was determined by immunohistochemistry and a semi-quantitative scoring of immunolabelling was performed using a standardized 5-point system. The immunohistochemical scorings for both IGF-1 and IGF-1R were significantly decreased in the oviducts of diabetic mice at 96h post-hCG treatment. The scores for IGF-2 were significantly increased in the oviducts of diabetic mice at 48 and 72h post-hCG treatment, and for IGF-2R at 72h post-hCG treatment. However, there was no significant difference in the scores of IGFs and their receptors in the uterus of control and diabetic mice. In conclusion, the oviductal immunolabelling for IGFs and their receptors was significantly altered by maternal diabetes, which may be of importance in the pathogenesis of preimplantation diabetic embryopathy. [Copyright &y& Elsevier]

Insulin and insulin-like growth factors (IGFs) bind to their cognate receptors with high affinities, but due to their homology they may cross-react with each other’s receptors. We performed a series of binding studies to reanalyze the cross-reactivity of insulin, IGF-I, and IGF-II to affinity-purified insulin (IR) and type 2 IGF receptors (IGF-2R) from human placental membranes. IR and IGF-2R were purified using insulin- and mannose-6-phosphate affinity chromatography (I-AC and M6P-AC). Binding studies were performed with 125I-labeled and unlabeled ligands. According to immunoblotting, the only receptor species isolated by I-AC was IR, whereas the only receptor isolated by M6P-AC was IGF-2R. Isolated IR reacted to similar extent with 125I-labeled insulin and 125I-labeled IGF-II and significantly less with 125I-labeled IGF-I, implicating predominance of IR-A. The affinity of IR towards heterologous ligands increased after its separation from other membrane proteins. Affinity-purified IGF-2R was almost unable to bind ligands under experimental conditions used in this work, but when incubated with 125I-labeled ligands prior to affinity chromatography, IGF-2R interacted not only with IGF-II, but to a certain extent with the other two ligands. In the competitive M6P-AC, the binding of labeled ligands was inhibited with either homologous or heterologous ligands, in a dose dependent manner. In competitive ligand-blotting, specific interactions between 125I-labeled insulin and IR, and 125I-labeled IGF-II and IGF-2R were also inhibited with all unlabeled ligands, although to a different extent. The results presented in this work imply that isolation of IR an IGF-2R from their membrane milieu increases their reactivity towards all members of the insulin/IGF ligand family. [ABSTRACT FROM AUTHOR]

In humans there is evidence that in utero exposure to cigarette smoke results in decreased fertility in female offspring. We have demonstrated in rats that fetal and neonatal exposure to nicotine alone results in impaired fertility and increased follicular atresia in the adult female offspring. In mammals, the insulin-like growth factor-I and -II (IGF-I and -II) and their binding proteins (IGFBPs) are considered stimulators and inhibitors of follicular growth and maturation. Therefore we hypothesized that dysregulation of the intra-ovarian IGF system could be implicated in the impaired fertility observed in nicotine-exposed offspring. Nulliparous female Wistar rats were exposed to nicotine (1 mg/kg/d) for 2 weeks prior to mating until weaning. Ovaries were collected on the morning of estrus from sexually mature saline- and nicotine-exposed offspring. Protein expression of IGF ligands and receptors (IGFR-I and IGFR-II) were quantifi ed by western blot and immunohistochemistry. The expression of IGF-I, IGF-II; IGFR-I, IGFR-II; and IGFBP1-6 mRNA in the ovary was determined by semi-quantitative reverse transcriptase-PCR. Results showed that nicotine exposure signifi cantly reduced IGF-I, IGF-II and IGFR-I protein expression (p < 0.01) relative to saline controls. Furthermore, nicotine-exposed offspring had signifi cantly reduced IGFR-II mRNA expression (p < 0.01) in the ovary. Data from this study suggest that the decreased fertility and increased follicular atresia in nicotine-exposed animals may be due, in part, to disruption of IGF regulation in the ovary. [ABSTRACT FROM AUTHOR]

Summary: The sole structural determinant for the differential ability of the insulin-like growth factors (IGF-I and IGF-II) to induce autophosphorylation of specific insulin receptor (IR) tyrosine residues and activate downstream signaling molecules is the C domain. The IR is structurally related to the type I insulin-like growth factor receptor (IGF–IR). This study aimed to identify the presence of IGF receptors by which the IGF-II C-peptide could mediate its effects in the frog (Rana ridibunda) adrenal glands and to observe whether injection of IGF-II C-peptide affects the function of adrenal steroidogenic cells using light and transmission electron microscopy and by the evaluation of the immunoreactivity of steroidogenic acute regulatory protein (StAR). After IGF-II C-peptide injection, there was a reduction of StAR protein immunoreactivity levels, an accumulation of large lipid droplets in close contact with each other, and an induction of proliferation of the steroidogenic cells. These results indicate a possible role of IGF-II C-peptide in steroidogenic cell function and in induction of steroidogenesis. The detection in this study of IGF-I receptor (IGF–IR) immunoreactivity in frog adrenal glands also indicates that the metabolic and mitogenic effects of IGF-II C-peptide in these glands may occur via the IGF–IR. [Copyright &y& Elsevier]