Insulin-like Growth Factor-1 Bioactivity Research Articles

Association between IGF-1 and IGFBPs in Blood and Follicular Fluid in Dairy Cows Under Field Conditions.

Insulin-like growth factor 1 (IGF-1) regulates dairy cow reproduction, while the paracrine IGF system locally influences fertility. In both systems, IGF-1 bioactivity is regulated through binding proteins (IGFBPs) inhibiting IGF-1 binding to its receptor (IGF1R). This study aimed to investigate a possible transfer between this endocrine and paracrine system. Therefore, blood and follicular fluid (FF) from postpartum dairy cows were analysed for ß-hydroxybutyrate (BHB), IGF-1, IGFBP-2, -3, -4, -5, and an IGFBP fragment in two study parts. The mRNA expression of IGFBP-2, IGFBP-4, IGF1R, and the pregnancy-associated plasma protein A (PAPP-A) in granulosa cells was measured. The results showed correlations between plasma and FF for IGF-1 (r = 0.57, p < 0.001) and IGFBP-2 (r = -0.57, p < 0.05). Blood BHB negatively correlated with IGF-1 in blood and FF and IGFBP-3, -5 and total IGFBP in blood (IGF-1 plasma: r = -0.26, p < 0.05; FF: r = -0.35, p < 0.05; IGFBP-3: r = -0.64, p = 0.006; IGFBP-5: r = -0.49, p < 0.05; total IGFBP: r = -0.52, p < 0.05). A negative correlation was found between IGFBP-2 expression and IGF-1 concentration in FF (r = -0.97, p = 0.001), while an IGFBP fragment positively correlated with IGF1R-mRNA in FF (r = 0.82, p = 0.042). These findings suggest a transfer and local regulation between the somatotropic axis and the follicular IGF system, linking the metabolic status with local effects on dairy cow fertility.

Evaluation of Serum Levels of Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor-Binding Protein 3 in Patients With Colorectal Cancer: A Case-Control Study.

Background/aim: Limited information is available about the relationship between colorectal cancer (CRC) and serum concentration of insulin-like growth factor 1 (IGF1) and insulin-like growth factor-binding protein 3 (IGFBP3). This study aims to compare the serum levels of IGF1and IGFBP3 in colorectal cancer cases and controls and to assess the relationship between their level and the demographic and histopathological characteristics.Methods: A case-control study in which 50 patients with colorectal cancer and 50 controls matched by gender and age were compared regarding the demographic characteristics and the level of both IGF1 and IGFBP3. The correlation with different clinicopathological features was assessed.Results: Levels of IGF1 were significantly higher while levels of IGFBP3 were significantly lower among cases compared to control. IGF1 was significantly higher among patients with liver metastasis, lymph node (LN) spread, and lymphovenous invasions and did not show significant association with gender, smoking status, family history, or primary site of colorectal cancer. Lower IGFBP3 was significantly high among patients with liver and lymph node metastasis, lymphovenous invasion, and patients with positive family history. This significant negative correlation was also detected between IGFBP3 levels and the size of the tumor.Conclusions: High IGF1 levels and low concentrations of IGFBP3 are related to colorectal cancer and were significantly associated with liver metastasis, lymph node spread, and lymphovenous invasions. Further research is recommended to investigate if circulating IGF1 and IGFBP3 levels can be used to identify people at high risk of colorectal cancer and to investigate potential lifestyle or pharmaceutical ways to lower IGF1 bioactivity as a risk reduction strategy.

Sustained IGF-1 delivery ameliorates effects of chronic denervation and improves functional recovery after peripheral nerve injury and repair

Functional recovery following peripheral nerve injury is limited by progressive atrophy of denervated muscle and Schwann cells (SCs) that occurs during the long regenerative period prior to end-organ reinnervation. Insulin-like growth factor 1 (IGF-1) is a potent mitogen with well-described trophic and anti-apoptotic effects on neurons, myocytes, and SCs. Achieving sustained, targeted delivery of small protein therapeutics remains a challenge. We hypothesized that a novel nanoparticle (NP) delivery system can provide controlled release of bioactive IGF-1 targeted to denervated muscle and nerve tissue to achieve improved motor recovery through amelioration of denervation-induced muscle atrophy and SC senescence and enhanced axonal regeneration. Biodegradable NPs with encapsulated IGF-1/dextran sulfate polyelectrolyte complexes were formulated using a flash nanoprecipitation method to preserve IGF-1 bioactivity and maximize encapsulation efficiencies. Under optimized conditions, uniform PEG-b-PCL NPs were generated with an encapsulation efficiency of 88.4%, loading level of 14.2%, and a near-zero-order release of bioactive IGF-1 for more than 20 days in vitro. The effects of locally delivered IGF-1 NPs on denervated muscle and SCs were assessed in a rat median nerve transection-without- repair model. The effects of IGF-1 NPs on axonal regeneration, muscle atrophy, reinnervation, and recovery of motor function were assessed in a model in which chronic denervation is induced prior to nerve repair. IGF-1 NP treatment resulted in significantly greater recovery of forepaw grip strength, decreased denervation-induced muscle atrophy, decreased SC senescence, and improved neuromuscular reinnervation.

Controlled Delivery of Insulin-like Growth Factor-1 from Bioactive Glass-Incorporated Alginate-Poloxamer/Silk Fibroin Hydrogels.

Thermosensitive alginate–poloxamer (ALG–POL) copolymer with an optimal POL content was synthesized, and it was used to combine with silk fibroin (SF) for building ALG–POL/SF hydrogels with dual network structure. Mesoporous bioactive glass (BG) nanoparticles (NPs) with a high level of mesoporosity and large pore size were prepared and they were employed as a vehicle for loading insulin-like growth factor-1 (IGF-1). IGF-1-loaded BG NPs were embedded into ALG–POL/SF hydrogels to achieve the controlled delivery of IGF-1. The resulting IGF-1-loaded BG/ALG–POL/SF gels were found to be injectable with their sol-gel transition near physiological temperature and pH. Rheological measurements showed that BG/ALG–POL/SF gels had their elastic modulus higher than 5kPa with large ratio of elastic modulus to viscous modulus, indicative of their mechanically strong features. The dry BG/ALG–POL/SF gels were seen to be highly porous with well-interconnected pore characteristics. The gels loaded with varied amounts of IGF-1 showed abilities to administer IGF-1 release in approximately linear manners for a few weeks while effectively preserving the bioactivity of encapsulated IGF-1. Results suggest that such constructed BG/ALG–POL/SF gels can function as a promising injectable biomaterial for bone tissue engineering applications.

Cyclic‐glycine‐proline accelerates mammary involution by promoting apoptosis and inhibiting IGF‐1 function

In rodents, post-lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin-like growth factor-1 (IGF-1). Overexpression of IGF-1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic-glycine-proline (cGP), a metabolite of IGF-1, normalizes IGF-1 function under pathological conditions by regulating the bioavailability of IGF-1. The present study investigated the effect of cGP on the physiological decline in IGF-1 function during post-lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post-natal d8-22. Before collecting tissue on post-natal d23, a pair of mammary glands were sealed on d20 (72 hr-engorgement, thus representative of late-involution) and d22 (24 hr-engorgement, thus representative of mid-involution), while the remaining glands were allowed to involute naturally (early-involution). During early-involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up-regulation of the cell survival factors, Bcl-xl and IGF-1R, in the early-involution cGP glands compared with the control glands. During late-involution, cGP reduced the bioactivity of IGF-1, which was evident through decreased phosphorylation of IGF-1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early-, peak-, or late-stage of lactation. These data show that cGP accelerates post-lactational involution by promoting apoptosis and the physiological decline in IGF-1 function.

Glucagon decreases IGF-1 bioactivity in humans: A novel mechanism by which caloric restriction inhibits cancer development

Background: Caloric restriction is known to be one of the most potent dietary interventions in increasing life span and inhibiting cancer development, Moreover, accumulating evidence suggests the impact of insulin-like growth factor 1 (IGF-1) in tumorigenesis. In this study, we aimed to clarify the interaction between glucagon, a hormone secreted during fasting, and IGF-1 bioactivity.

Use of proton pump inhibitors in older subjects: Risk of adverse clinical outcomes and potential mechanisms

Background In the last 2 decades, it was observed a widely increased use of proton pump inhibitors (PPIs) especially in older populations. Despite the fact that PPIs are superior to histamine receptor antagonists in treating gastroesophageal reflux disease (GERD) and peptic ulcers, the chronic use of PPIs has been associated with adverse clinical outcomes including higher risk of fractures and Clostridium difficile infections. In vitro studies have shown that PPIs negatively modulate the bioactivity of insulin-like growth factor-1 (IGF-1), anabolic hormone and nutritional marker. However, whether or not PPIs use has negative influence on survival and independence of activities of daily living (ADL) and the mechanisms underlying these hypothesized associations are still poorly known. Aims of the study The aims of the study were to test the relationship between the use of PPIs and adverse clinical outcomes (mortality and rehospitalization, loss of ADL) and the association between use of PPIs and cortical and trabecular bone mineral density, IGF-1 bioactivity in older patients of 2 different populations. Methods In 491 patients (mean age 80.1 ± 5.9 years), categorized as PPI users and non users, discharged from 11 acute care medical wards and 3 long-term care/rehabilitation units, we tested the relationship between use of PPIs and 1- year mortality or combined end-point mortality and rehospitalization and incident dependency by using time-dependent Cox proportional hazard regression models and after propensity score matching. The association between use of PPIs, IGF-1 and bone mineral density was estimated by multivariate regression model adjusted for multiple confounders in 938 subjects (413 men and 525 women) aged ≥ 65 years, from the InCHIANTI Study, with complete information on tibial pQCT, IGF-1, IGF-binding protein-1 (IGFBP-1) and medications. Results In the hospitalized population the use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03–2.77]) but not with the combined end point (1.49 [0.98–2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22–7.16]). Use of PPIs was significantly associated with functional decline either before (OR = 1.75; 95% CI = 1.17–2.60) and after propensity score matching (OR = 2.44; 95% CI = 1.36–4.41). In the InCHIANTI population, PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5 ± 54.8 vs. 207.9 ± 59.4, P = 0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc between PPI users and nonusers. PPI users had lower IGF-1 levels (81,9 [61,1-113,8]) than non-users (110 [77,8–148,6]), P = 0.02. After further adjustment for BMI, liver function, number of medications, caloric intake and IGFBP-1, the relationship between use of PPI and IGF-1 remained statistically significant (β ± SE = –18,09 ± 9,38, P = 0,05). Conclusions In older persons discharged from acute care hospitals, the chronic use of PPIs is associated with increased 1-year mortality and functional decline. The lower trabecular bone mineral density and IGF-1 levels found in PPI users are potential mechanisms explaining this association.

Prenatal stress leads to changes in IGF-1 binding proteins network in the hippocampus and frontal cortex of adult male rat

Depression is a mental disorder of still unknown origin. Currently, much attention is paid to the potential influence of disturbances in the functioning of neurotrophic factors on the onset of this disease. Insulin-like growth factor 1 (IGF-1) is one of the most important growth agents affecting processes that are crucial for brain development. To date, there are no data showing the impact of prenatal stress on the family of six IGF binding proteins (IGFBP 1–6) that regulate IGF-1 bioactivity. The goal of this study was to investigate whether the decreased expression of IGF-1 in the frontal cortex (FCx) and hippocampus (Hp) of adult male rats following a prenatal stress procedure is related to changes in the IGFBP family. Our results show that rats exposed prenatally to stressful stimuli displayed depression-like behavior based on sucrose preference and elevated plus maze tests. In both cases, in the adult rat brain structures that were examined after the prenatal stress procedure, the IGF-1 protein level was reduced. Moreover, we observed changes of varying degrees in the levels of IGFBPs in stressed animals. A decrease in IGFBP-2 and IGFBP-3 accompanied by an increase in the IGFBP-4 concentration in the Hp and the FCx was detected. There were no differences in IGFBP-1 and IGFBP-6 brain levels between the stressed and control animals, whereas IGFBP-5 concentration was decreased in the Hp of prenatally stressed animals. This study demonstrated that stress during pregnancy may lead not only to behavioral disturbances but also to a decrease in IGF-1 level and the dysregulation of the IGF-1 binding protein network in adult rat offspring.

Diabetes and cancer: Associations, mechanisms, and implications for medical practice.

Both diabetes mellitus and cancer are prevalent diseases worldwide. It is evident that there is a substantial increase in cancer incidence in diabetic patients. Epidemiologic studies have indicated that diabetic patients are at significantly higher risk of common cancers including pancreatic, liver, breast, colorectal, urinary tract, gastric and female reproductive cancers. Mortality due to cancer is moderately increased among patients with diabetes compared with those without. There is increasing evidence that some cancers are associated with diabetes, but the underlying mechanisms of this potential association have not been fully elucidated. Insulin is a potent growth factor that promotes cell proliferation and carcinogenesis directly and/or through insulin-like growth factor 1 (IGF-1). Hyperinsulinemia leads to an increase in the bioactivity of IGF-1 by inhibiting IGF binding protein-1. Hyperglycemia serves as a subordinate plausible explanation of carcinogenesis. High glucose may exert direct and indirect effects upon cancer cells to promote proliferation. Also chronic inflammation is considered as a hallmark of carcinogenesis. The multiple drugs involved in the treatment of diabetes seem to modify the risk of cancer. Screening to detect cancer at an early stage and appropriate treatment of diabetic patients with cancer are important to improve their prognosis. This paper summarizes the associations between diabetes and common cancers, interprets possible mechanisms involved, and addresses implications for medical practice.

IGF-1, the Cross Road of the Nutritional, Inflammatory and Hormonal Pathways to Frailty

The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.

Unbound (bioavailable) IGF1 enhances somatic growth

SUMMARY Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

Magnesium and anabolic hormones in older men

Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. This observation suggests that magnesium can be a modulator of the anabolic/catabolic equilibrium disrupted in the elderly people. However, the relationship between magnesium and anabolic hormones in men has not been investigated. We evaluated 399 ≥65-year-old men of CHIANTI in a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels. Linear regression models were used to test the relationship between magnesium and testosterone and IGF-1. Mean age of the population was 74.18 ± 6.43 (years ± SD, age range 65.2-92.4). After adjusting for age, magnesium was positively associated with total testosterone (β ± SE, 34.9 ± 10.3; p = 0.001) and with total IGF-1 (β ± SE, 15.9 ± 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (β ± SE, 48.72 ± 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (β ± SE, 16.43 ± 4.90; p = 0.001) and remained significant after adjusting for total testosterone (β ± SE, 14.4 ± 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.

Unbound (bioavailable) IGF1 enhances somatic growth

SUMMARYUnderstanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or ‘free IGF1’. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

Controlled Release of IGF-1 and HGF from a Biodegradable Polyurethane Scaffold

Biodegradable elastomers, which can possess favorable mechanical properties and degradation rates for soft tissue engineering applications, are more recently being explored as depots for biomolecule delivery. The objective of this study was to synthesize and process biodegradable, elastomeric poly(ester urethane)urea (PEUU) scaffolds and to characterize their ability to incorporate and release bioactive insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF). Porous PEUU scaffolds made from either 5 or 8 wt% PEUU were prepared with direct growth-factor incorporation. Long-term in vitro IGF-1 release kinetics were investigated in saline or saline with 100 units/ml lipase to simulate in vivo degradation. Cellular assays were used to confirm released IGF-1 and HGF bioactivity. IGF-1 release into saline occurred in a complex multi-phasic manner for up to 440 days. Scaffolds generated from 5 wt% PEUU delivered protein faster than 8 wt% scaffolds. Lipase-accelerated scaffold degradation led to delivery of >90% protein over 9 weeks for both polymer concentrations. IGF-1 and HGF bioactivity in the first 3 weeks was confirmed. The capacity of a biodegradable elastomeric scaffold to provide long-term growth-factor delivery was demonstrated. Such a system might provide functional benefit in cardiovascular and other soft tissue engineering applications.

Growth hormone secretion and insulin-like growth factor-1 are related to hyperandrogenism in nonobese patients with polycystic ovary syndrome

Women of normal weight with polycystic ovary syndrome (PCOS) and hyperinsulinemia presented high growth hormone (GH) levels in response to the l-dopa test, suggesting that the action of GH and insulin-like growth factor-1 (IGF-1) might be responsible for the elevation in LH and the consequent hyperandrogenic anovulation observed in normal weight women with PCOS. Insulin resistance and obesity are related to a reduction in GH secretion in obese women with PCOS.

Effects of aging on expression of genes involved in regulation of proliferation and apoptosis in the colonic epithelium

The purpose of this study was to characterize the effects of aging on colonic messenger ribonucleic acid (mRNA) and protein levels of genes involved in the regulation of cell proliferation and apoptosis, and epithelial morphology in male Fischer 344 rats. Our study shows that, with aging, colonic expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) is significantly increased and decreased, respectively. Colonic Bax protein levels are increased significantly with aging. Immunohistochemical localization of Bax protein shows a greatly increased expression in colonic crypts, especially in the upper portion of crypts. p53 expression is unchanged with aging. No significant change in proliferation of colonic crypt cells is observed by bromodeoxyuridine (BrdU) labeling, although the increased colonic expression of IGF-1 and the decreased expression of IGFBP-3 with aging may result in an increased colonic IGF-1 bioactivity. The age-related changes in Bax and IGFBP-3 appear to be independent of p53. The finding of an unchanged colonic epithelium with aging in the face of a greatly increased Bax protein levels may suggest that the elevated Bax protein levels function to render colonic epithelial cells more sensitive to apoptotic stimuli.

Glucocorticoid-Associated Growth Failure

Through a variety of mechanisms, glucocorticoids exert potent growth-suppressing effects. Primarily through the use of inhaled corticosteroid preparations to treat asthma, the number of children exposed to exogenous glucocorticoids is rapidly increasing. Although growth failure is commonly experienced by children receiving long-term oral glucocorticoid therapy, the effect of inhaled corticosteroids on growth remains an unresolved and controversial issue. In situations where glucocorticoid therapy and its attendant adverse effects on growth are unavoidable, inhibitory effects of glucocorticoids on pulsatile growth hormone secretion, insulin-like growth factor-1 bioactivity, and collagen synthesis could theoretically be compensated for by exogenous growth hormone therapy. This article reviews the pathophysiology of growth suppression by glucocorticoids, the information currently available regarding the effects of chronic inhaled corticosteroids on growth, and the effectiveness of growth hormone therapy in reversing glucocorticoid-induced growth failure.

Expression of ovine insulin-like growth factor-1 (IGF-1) stimulates alveolar bud development in mammary glands of transgenic mice.

To determine whether murine mammary growth is modulated by local insulin-like growth factor-1 (IGF-1) production, expression of recombinant IGF-1 was directed to the mammary glands of transgenic mice using an ovine prepro IGF-1 cDNA under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter. Bioactivity of recombinant IGF-1 in transgenic mouse milk extracts was demonstrated by a concentration-dependent increase in [3H]thymidine incorporation in clonal bovine mammary epithelial cells (MAC-T) compared with control mouse milk extracts; moreover, addition of excess recombinant human insulin-like growth factor binding protein-3 (rhlGFBP-3) abolished the increase in [3H]thymidine incorporation attributed to recombinant IGF-1 in transgenic mouse milk. Recombinant IGF-1 was produced in mammary tissue of virgin and pregnant transgenic mice, and secreted into milk of lactating mice. However, recombinant IGF-1 was not detected in serum from transgenic mice; and ligand blot analysis of serum insulin-like growth factor binding proteins (IGFBPs) indicated no differences owing to transgene presence. In peripubertal virgin mice at 49 d of age, the frequency of appearance of mammary alveolar buds was significantly higher in MMTV-IGF-1 than in CD-1 mice, and was unaffected by ovariectomy or estradiol treatment. In conclusion, mammary synthesis of recombinant IGF-1 enhances the rate of development of alveolar buds in mammary glands of virgin transgenic mice.

Enhancement of the Anti-Neoplastic Effects of Tamoxifen by Somatostatin Analogues

Tamoxifen is useful in the treatment of breast cancer, but its effects in metastatic disease are rarely long term, and development of resistance to the drug is common. In vitro and in vivo data demonstrate anti-neoplastic (anti-proliferative) effects of somatostatin analogues, which may occur via binding to somatostatin receptors on the neoplastic cells, and/or via reductions in insulin-like growth factor-1 bioactivity. Moreover, several lines of evidence from in vitro and in vivo studies indicate that the long-acting somatostatin analogue octreotide enhances the anti-neoplastic effects of anti-oestrogenic agents such as tamoxifen. The anti-oestrogen-somatostatin approach appears to have a favourable long-term toxicity profile. Large-scale clinical trials are currently being planned to investigate the efficacy of combined tamoxifen plus octreotide therapy compared to tamoxifen alone in patients with breast cancer.

AP-1 and multiple response element binding sites are necessary for the stimulation of interleukin-6 by platelet-derived growth factor in osteoblasts

Depression is a mental disorder of still unknown origin. Currently, much attention is paid to the potential influence of disturbances in the functioning of neurotrophic factors on the onset of this disease. Insulin-like growth factor 1 (IGF-1) is one of the most important growth agents affecting processes that are crucial for brain development. To date, there are no data showing the impact of prenatal stress on the family of six IGF binding proteins (IGFBP 1–6) that regulate IGF-1 bioactivity. The goal of this study was to investigate whether the decreased expression of IGF-1 in the frontal cortex (FCx) and hippocampus (Hp) of adult male rats following a prenatal stress procedure is related to changes in the IGFBP family. Our results show that rats exposed prenatally to stressful stimuli displayed depression-like behavior based on sucrose preference and elevated plus maze tests. In both cases, in the adult rat brain structures that were examined after the prenatal stress procedure, the IGF-1 protein level was reduced. Moreover, we observed changes of varying degrees in the levels of IGFBPs in stressed animals. A decrease in IGFBP-2 and IGFBP-3 accompanied by an increase in the IGFBP-4 concentration in the Hp and the FCx was detected. There were no differences in IGFBP-1 and IGFBP-6 brain levels between the stressed and control animals, whereas IGFBP-5 concentration was decreased in the Hp of prenatally stressed animals. This study demonstrated that stress during pregnancy may lead not only to behavioral disturbances but also to a decrease in IGF-1 level and the dysregulation of the IGF-1 binding protein network in adult rat offspring.