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Sample records for igf-i stimulates neurogenesis

  1. Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans

    DEFF Research Database (Denmark)

    Hansen, Mette; Boesen, A; Holm, L

    2012-01-01

    Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin-like growth factor I (IGF-I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing......, but the effect of local IGF-I administration on tendon collagen synthesis in human has not been studied. The purpose of this study was to study whether local injections of IGF-I would have a stimulating effect on tendon collagen synthesis. Twelve healthy nonsmoking men [age 62 ± 1 years (mean ± SEM), BMI 27 ± 1......] participated. Two injections of either human recombinant IGF-I (0.1 mL Increlex©) or saline (control) into each patellar tendon were performed 24-h apart, respectively. Tendon collagen fractional synthesis rate (FSR) was measured by stable isotope technique in the hours after the second injection...

  2. PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis.

    Science.gov (United States)

    Riedel, H; Yousaf, N; Zhao, Y; Dai, H; Deng, Y; Wang, J

    2000-01-06

    PSM/SH2-B has been described as a cellular partner of the FcepsilonRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve growth factor receptor (TrkA). A function has been proposed in neuronal differentiation and development but its role in other signaling pathways is still unclear. To further elucidate the physiologic role of PSM we have identified additional mitogenic receptor tyrosine kinases as putative PSM partners including platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth factor receptor (Met), and fibroblast growth factor receptor. We have mapped Y740 as a site of PDGFR beta that is involved in the association with PSM. We have further investigated the putative role of PSM in mitogenesis with three independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby hamster kidney fibroblasts. (1) PSM expression from cDNA using an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin- but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2) Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB- and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Pro-rich putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin- but not with EGF-induced DNA synthesis in NIH3T3 fibroblasts. This experiment was based on cell-permeable fusion peptides with the Drosophila antennapedia homeodomain which effectively traverse the plasma membrane of cultured cells. These experimental strategies independently suggest that PSM functions as a positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and insulin but not in EGF action. This function appears to involve the PSM SH2 domain as well as the Pro-rich putative SH3 domain binding region. Our findings support the model that PSM

  3. Do IGF-I concentrations better reflect growth hormone (GH action in children with short stature than the results of GH stimulating tests? Evidence from the simultaneous assessment of thyroid function

    Directory of Open Access Journals (Sweden)

    Smyczyńska Joanna

    2011-01-01

    Full Text Available Abstract Background The diagnosis of growth hormone (GH deficiency (GHD in short children seems unquestionable when both GH peak in stimulating tests (GHST and IGF-I concentration are decreased. However, the discrepancies between the results of GHST and IGF-I secretion are observed. It seems purposeful to determine the significance of GHST and IGF-I assessment in diagnosing GHD. The relationship between GH secretion and thyroid function, as well as GH influence on the peripheral thyroxine (T4 to triiodothyronine (T3 deiodination, mediated by IGF-I, were identified. Thus, clear differences in thyroid function between GH-deficient and non-GH-deficient subjects should exist. Methods Analysis comprised 800 children (541 boys, age 11.6 ± 3.1 years (mean ± SD, with short stature, in whom two (2 standard GHST (with clonidine and with glucagon were performed and IGF-I, free T4 (FT4, free T3 (FT3 and TSH serum concentrations were assessed. The patients were qualified to the following groups: GHD - decreased GH peak in GHST and IGF-I SDS (n = 81, ISS - normal GH peak and IGF-I SDS (n = 347, low GH - normal IGF-I SDS, and decreased GH peak (n = 212, low IGF - decreased IGF-I SDS, and normal GH peak (n = 160. The relationships among the results of particular tests were evaluated. Results In the groups with decreased IGF-I concentrations (GHD Group and low IGF Group, the more severe deficit of height was observed, together with higher TSH and FT4 but lower FT3 levels than in groups with normal IGF-I concentrations (ISS Group and low GH Group, independently of the results of GHST. TSH, FT4 and FT3 concentrations were - respectively - similar in two groups with decreased IGF-I secretion, as well as in two groups with normal IGF-I levels. Significant correlations were found between patients' height SDS and IGF-I SDS, between FT3 and IGF-I SDS (positive, and between FT4 and IGF-I SDS (negative, with no correlation between GH peak and any of the parameters

  4. Usefulness of growth hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency diagnosis.

    Science.gov (United States)

    Obara-Moszyńska, Monika; Kedzia, Andrzej; Korman, Eugeniusz; Niedziela, Marek

    2008-06-01

    The diagnosis of growth hormone (GH) deficiency (GHD) is still problematic for the clinician. There is no gold standard for estimating GH secretion. The aim of this study was to compare the diagnostic usefulness of spontaneous GH secretion test, pharmacological tests with insulin, clonidine, L-dopa, and glucagon, and IGF-I measurement in GHD. We studied 180 prepubertal, short children. Predictive values were calculated for different GH cutoff levels for each diagnostic test. ROC curves were used to estimate the diagnostic usefulness of the tests. The results show that sleep is the strongest stimulatory agent for GH secretion. The estimation of GH secretion after onset of sleep can be used as a screening test in GHD diagnosis. The insulin test has the highest discrimination. A combination of insulin test with another provocative test allows high discrimination and accuracy for standard cut-off GH level. Measurement of IGF-I is characterized by low predictive values. IGF-I level below the mean according to age indicates high probability of GHD. Auxological parameters should be the most important factor in diagnosing GHD.

  5. Cartilage formation measured by a novel PIINP assay suggests that IGF-I does not stimulate but maintains cartilage formation ex vivo

    DEFF Research Database (Denmark)

    Madsen, S H; Sondergaard, B C; Jensen, Anne-Christine Bay;

    2009-01-01

    . Proteoglycan levels retained in the explants after 22 days of culture were extracted and measured by the sulfated glycosaminoglycan (sGAG) assay. RESULTS: In the absence of stimulation, PIINP markedly decreased as a function of time (99.4%, p collagen formation...... explants were cultured in Dulbecco's modified Eagle's medium (DMEM):F12 in the presence of 0, 0.01, 0.1, 1, 10, or 100 ng/mL of IGF-I. The viability of the chondrocytes was measured by the colorimetric Alamar blue assay. Collagen formation was assessed from the conditioned medium by the PIINP assay...

  6. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

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    Lorena Varela-Nallar

    2015-01-01

    Full Text Available Andrographolide (ANDRO is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β, a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.

  7. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus.

    Science.gov (United States)

    Varela-Nallar, Lorena; Arredondo, Sebastian B; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.

  8. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

    Science.gov (United States)

    Varela-Nallar, Lorena; Arredondo, Sebastian B.; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C.

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected. PMID:26798521

  9. Acupuncture stimulation induces neurogenesis in adult brain.

    Science.gov (United States)

    Nam, Min-Ho; Ahn, Kwang Seok; Choi, Seung-Hoon

    2013-01-01

    The discovery of adult neurogenesis was a turning point in the field of neuroscience. Adult neurogenesis offers an enormous possibility to open a new therapeutic paradigm of neurodegenerative diseases and stroke. Recently, several studies suggested that acupuncture may enhance adult neurogenesis. Acupuncture has long been an important treatment for brain diseases in the East Asia. The scientific mechanisms of acupuncture treatment for the diseases, such as Alzheimer's disease, Parkinson's disease, and stroke, have not been clarified yet; however, the neurogenic effect of acupuncture can be a possible reason. Here, we have reviewed the studies on the effect of stimulation at various acupoints for neurogenesis, such as ST36 and GV20. The suggested mechanisms are also discussed including upregulation of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, basic fibroblast growth factor and neuropeptide Y, and activation of the function of primo vascular system.

  10. Insulin and IGF-II, but not IGF-I, stimulate the in vitro regeneration of adult frog sciatic sensory axons

    DEFF Research Database (Denmark)

    Edbladh, M; Svenningsen, Åsa Fex; Ekström, P A

    1994-01-01

    We used the in vitro regenerating frog sciatic nerve to look for effects of insulin and insulin-like growth factors I and II (IGF-I, IGF-II) on regeneration of sensory axons and on injury induced support cell proliferation in the outgrowth region. In nerves cultured for 11 days, a physiological...

  11. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy

    Science.gov (United States)

    Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-01-01

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. PMID:26219865

  12. Insulin and IGF-II, but not IGF-I, stimulate the in vitro regeneration of adult frog sciatic sensory axons

    DEFF Research Database (Denmark)

    Edbladh, M; Svenningsen, Åsa Fex; Ekström, P A

    1994-01-01

    We used the in vitro regenerating frog sciatic nerve to look for effects of insulin and insulin-like growth factors I and II (IGF-I, IGF-II) on regeneration of sensory axons and on injury induced support cell proliferation in the outgrowth region. In nerves cultured for 11 days, a physiological...... dose (10 ng/ml, approximately 2 nM) of insulin or IGF-II increased ganglionic protein synthesis (by 20% and 50%, respectively) as well as the level of newly formed, radiolabelled axonal material distal to a crush injury (both by 80%), compared to untreated, paired controls. In addition, insulin...... increased the outgrowth distance of the furthest regenerating sensory axons by 10%. The preparation was particularly sensitive to insulin during the first 5 days of culturing. Furthermore, both insulin and IGF-II were found to inhibit proliferation of support cells in the outgrowth region in a manner...

  13. IGF-I abuse in sport: current knowledge and future prospects for detection.

    Science.gov (United States)

    Guha, Nishan; Sönksen, Peter H; Holt, Richard I G

    2009-08-01

    As the tests for detecting growth hormone (GH) abuse develop further, it is likely that athletes will turn to doping with insulin-like growth factor-I (IGF-I). IGF-I mediates many of the anabolic actions of growth hormone. It stimulates muscle protein synthesis, promotes glycogen storage and enhances lipolysis, all of which make IGF-I attractive as a potential performance-enhancing agent. Pharmaceutical companies have developed commercial preparations of recombinant human IGF-I (rhIGF-I) for use in disorders of growth. The increased availability of rhIGF-I increases the opportunity for athletes to acquire supplies of the drug on the black market. The long-term effects of IGF-I administration are currently unknown but it is likely that these will be similar to the adverse effects of chronic GH abuse. The detection of IGF-I abuse is a challenge for anti-doping organisations. Research has commenced into the development of a test for IGF-I abuse based on the measurement of markers of GH action. Simultaneously, the effects of rhIGF-I on physical fitness, body composition and substrate utilisation in healthy volunteers are being investigated.

  14. IGF-I abuse in sport.

    Science.gov (United States)

    Guha, Nishan; Dashwood, Alexander; Thomas, Nicholas J; Skingle, Alexander J; Sönksen, Peter H; Holt, Richard I G

    2009-09-01

    It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse.

  15. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

    Science.gov (United States)

    Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-09-15

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. Copyright © 2015 the American Physiological Society.

  16. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

    Science.gov (United States)

    Adams, G. R.; McCue, S. A.

    1998-01-01

    Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles (P hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

  17. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

    Science.gov (United States)

    Adams, G. R.; McCue, S. A.

    1998-01-01

    Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles (P hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

  18. Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

    Science.gov (United States)

    Taupin, Philippe

    2009-05-01

    The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

  19. Endocrine and Local IGF-I in the Bony Fish Immune System

    Directory of Open Access Journals (Sweden)

    Anne-Constance Franz

    2016-01-01

    Full Text Available A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived, which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health.

  20. IGF-I induced genes in stromal fibroblasts predict the clinical outcome of breast and lung cancer patients

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    Herrmann Richard

    2010-01-01

    Full Text Available Abstract Background Insulin-like growth factor-1 (IGF-I signalling is important for cancer initiation and progression. Given the emerging evidence for the role of the stroma in these processes, we aimed to characterize the effects of IGF-I on cancer cells and stromal cells separately. Methods We used an ex vivo culture model and measured gene expression changes after IGF-I stimulation with cDNA microarrays. In vitro data were correlated with in vivo findings by comparing the results with published expression datasets on human cancer biopsies. Results Upon stimulation with IGF-I, breast cancer cells and stromal fibroblasts show some common and other distinct response patterns. Among the up-regulated genes in the stromal fibroblasts we observed a significant enrichment in proliferation associated genes. The expression of the IGF-I induced genes was coherent and it provided a basis for the segregation of the patients into two groups. Patients with tumours with highly expressed IGF-I induced genes had a significantly lower survival rate than patients whose tumours showed lower levels of IGF-I induced gene expression (P = 0.029 - Norway/Stanford and P = 7.96e-09 - NKI dataset. Furthermore, based on an IGF-I induced gene expression signature derived from primary lung fibroblasts, a separation of prognostically different lung cancers was possible (P = 0.007 - Bhattacharjee and P = 0.008 - Garber dataset. Conclusion Expression patterns of genes induced by IGF-I in primary breast and lung fibroblasts accurately predict outcomes in breast and lung cancer patients. Furthermore, these IGF-I induced gene signatures derived from stromal fibroblasts might be promising predictors for the response to IGF-I targeted therapies. See the related commentary by Werner and Bruchim: http://www.biomedcentral.com/1741-7015/8/2

  1. Ovarian receptors for insulin and insulin-like growth factor I (IGF-I) and effects of IGF-I on steroid production by isolated follicular layers of the preovulatory coho salmon ovarian follicle.

    Science.gov (United States)

    Maestro, M A; Planas, J V; Moriyama, S; Gutiérrez, J; Planas, J; Swanson, P

    1997-05-01

    In this study, receptors for insulin and insulin-like growth factor I (IGF-I) in isolated theca-interstitial layers and granulosa cells of the coho salmon preovulatory ovary were characterized, and the effects of IGF-I on ovarian steroidogenesis were examined. Specific receptors for insulin and IGF-I were found in granulosa and theca-interstitial layers. In both follicular layers, IGF-I receptors were greater in number and higher in affinity than insulin receptors. The effects of IGF-I on in vitro production of testosterone (T) and 17 alpha-hydroxyprogesterone (17OH-P) by theca-interstitial layers and of 17 beta-estradiol (E2) and 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P) by granulosa cell layers were evaluated during the preovulatory period. Both human and salmon recombinant IGF-I inhibited the basal and GTH II-stimulated T and 17OH-P production by theca-interstitial layers throughout the preovulatory period. In contrast, IGF-I stimulated the production of both E2 and 17,20 beta-P by granulosa cell layers prior to germinal vesicle breakdown (GVBD) but only stimulated the production of 17,20 beta-P by granulosa cell layers after GVBD. The inhibitory effects of IGF-I on steroid production by the theca-interstitial layer and the opposite stimulatory effects on steroid production by the granulosa cell layer, coupled by the presence of specific IGF-I receptors in both follicular layers, suggest that IGF-I may play a role in the regulation of steroidogenesis in the preovulatory coho salmon ovary.

  2. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

    Science.gov (United States)

    Adams, G. R.; McCue, S. A.

    1998-01-01

    Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

  3. IGF-I augments resection-induced mucosal hyperplasia by altering enterocyte kinetics.

    Science.gov (United States)

    Dahly, Elizabeth M; Guo, Ziwen; Ney, Denise M

    2003-10-01

    Our objective was to determine if exogenous insulin-like growth factor-I (IGF-I) augments the adaptive growth response to mid small bowel resection in association with changes in enterocyte kinetics. We determined structural adaptation and concomitant changes in enterocyte proliferation, apoptosis, and migration of the jejunum in growing, parenterally fed rats after mid small bowel resection or small bowel transection, and treatment with IGF-I or vehicle. IGF-I treatment in resected rats significantly increased jejunal mucosal mass by 20% and mucosal concentrations of protein and DNA by 36 and 33%, respectively, above the response to resection alone. The enhancement of resection-induced adaptive growth and cellularity by IGF-I reflected an increase in enterocyte proliferation, an expansion of the proliferative compartment in the crypt, and no further decrease in enterocyte apoptosis or increase in enterocyte migration beyond the effects of resection. The ability of IGF-I to augment the mucosal hyperplasia stimulated by the endogenous response to resection substantiates the role of IGF-I as an intestinal mitogen that promotes tissue regeneration.

  4. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

    Science.gov (United States)

    Adams, G. R.; McCue, S. A.

    1998-01-01

    Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P protein and DNA content of TA muscles (P DNA-to-protein ratio of the hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

  5. Early programming of the IGF-I axis

    DEFF Research Database (Denmark)

    Larnkjær, Anni; Ingstrup, Helga Kristensen; Schack-Nielsen, Lene

    2009-01-01

    -I production. Conversely, studies suggest that later in childhood, those breastfed are taller and have higher IGF-I levels. Therefore, it has been suggested that the IGF-I axis may be programmed by diet during infancy. The association between IGF-I in infancy and later life is not known. OBJECTIVE: To examine......=-0.26, P=0.043, and n=109). CONCLUSION: The results support the hypothesis that the IGF-I axis can be programmed early in life....

  6. Compensatory growth assessment by plasma IGF-I hormone ...

    African Journals Online (AJOL)

    USER

    2010-06-21

    Jun 21, 2010 ... metabolism (Banos et al., 1999). IGF-I has been reported ... 37% protein, 14% fat, 20% carbohydrate, 12% ash, 9% humidity according to the ... recombinant IGF-I as standard and rabbit anti-human. IGF-I antibodies as ...

  7. Effects of dietary genistein on GH/IGF-I axis of Nile tilapia Oreochromis niloticus

    Science.gov (United States)

    Chen, Dong; Wang, Wei; Ru, Shaoguo

    2016-09-01

    There is considerable concern that isoflavones, such as genistein in fish feed composed of soybean protein, aff ects somatic growth in fish. Our previous works demonstrated that 30 and 300 μg/g dietary genistein had no significant eff ect on growth performance in Nile tilapia ( Oreochromis niloticus), but the higher level of genistein (3 000 μg/g) significantly depressed growth. This study was conducted to further examine the eff ects of dietary genistein on the endocrine disruption on growth hormone/insulin-like growth factor-I (GH/IGF-I) axis in Nile tilapia ( O. niloticus). Juvenile fish were fed by hand twice daily to satiation with one of four isonitrogenous and isoenergetic diets, each containing either 0, 30, 300 or 3 000 μg/g genistein. Following an 8-week feeding period, plasma GH and IGF-I levels were investigated by radioimmunoassay and gene expression levels of gh, ghrelin, gnrhs, ghr, npy, npyrs, pacap, ghrs, i gf-I, igf-Ir, and igfbp3 were examined by real-time PCR. The results show that no significant change in plasma GH and IGF-I levels in fish fed with diets containing 30 μg/g and 300 μg/g genistein. mRNA expression of genes along the GH/IGF-I axis remained unaff ected, except for igf-Ir, which was stimulated by the 300 μg/g genistein diet. While in fish fed the 3 000 μg/g genistein diet, the plasma GH and IGF-I levels decreased, and mRNA expression of gh, ghr2, npyr1, igf-I, and igf-Ir were also significantly depressed. In contrast, npy and igfbp3 mRNA expression were enhanced. This study provides convincing evidence for growth impediment by genistein by disturbing the GH/IGF-I axis in Nile tilapia O. niloticus.

  8. IGF-I and IGF-binding proteins in articular exudates of children with post-traumatic knee damage and juvenile idiopathic arthritis.

    Science.gov (United States)

    Guszczyn, Tomasz; Rzeczycka, Justyna; Popko, Janusz

    2009-01-01

    IGF-I stimulates multiple functions of connective tissue cells and its activity is modulated by IGF-binding proteins (BPs). Some metalloproteinases are expected to modify IGF-I activity by digestion of IGF-BPs. It was decided to evaluate the concentration of IGF-I, IGF-BPs and the activity of gelatinases A and B in knee exudates of children with post-traumatic damage (PTD) and children with juvenile idiopathic arthritis (JIA) in comparison with those in the sera of the same patients. ELISA (for IGF-I assay), polyacrylamine gel electrophoresis following Western immunoblotting (for IGF-I and IGF-BPs expression), and zymography (for gelatinase detection) were used. The knee exudates, especially those taken from patients with JIA, contained large amounts of IGF-I. The exudates of PTD and JIA patients contained some forms of IGF-BP-1 of molecular weight lower than those occurring in serum. Low expression BP-3 and high activity of gelatinase B were detected in the JIA exudates. The high gelatinase activities in exudates imply joint tissue damage. The cellular response to damage of this kind is an increase in IGF-I production, which stimulates repair processes. High proteolytic activities of gelatinase B in JIA patients may lower the amount of BP-3, possibly causing a relative decrease of IGF-I concentration and impairing the reparation processes stimulated by IGF-I. Copyright 2009 S. Karger AG, Basel.

  9. Brief, high intensity exercise alters serum ghrelin and growth hormone concentrations but not IGF-I, IGF-II or IGF-I bioactivity.

    Science.gov (United States)

    Stokes, Keith A; Sykes, Dave; Gilbert, Kate L; Chen, Jian-Wen; Frystyk, Jan

    2010-08-01

    Exercise stimulates growth hormone (GH) release, but there are conflicting reports regarding the acute effects of exercise on circulating ghrelin and insulin-like growth factor (IGF) concentrations. This investigation examined (1) the effect of a single sprint on circulating GH, ghrelin and IGF concentrations as well as a marker of IGF-I bioactivity, and (2) whether the number of muscle actions performed during a sprint influences these responses. Seven healthy men completed 3 trials in a random order. In two exercise trials they performed a single 30-s sprint on a cycle ergometer against a resistance equivalent to either 7% (FAST) or 9% (SLOW) of their body mass. In the other they rested in the laboratory (CON). Blood samples were taken pre-, immediately post-, 10 and 30 min post-exercise, and at equivalent times in the CON trial. Total ghrelin concentrations declined after the sprint and were significantly lower after 30 min of recovery than they were pre-exercise (pre-exercise vs. 30 min; FAST, 0.62 (0.19) vs. 0.49 (0.16) microg/L, Pexercise trials and were greater in the FAST than the SLOW trial. Serum concentrations of total IGF-I, free IGF-I, total IGF-II, and IGF-I bioactivity did not change after sprinting. In conclusion, sprint exercise suppresses total ghrelin concentrations and stimulates GH release but does not alter IGF concentrations or bioactivity.

  10. Coordinated increase in skeletal muscle fiber area and expression of IGF-I with resistance exercise in elderly post-operative patients

    DEFF Research Database (Denmark)

    Suetta, Charlotte; Suetta, Charlotte Arneboe; Clemmensen, Christoffer

    2010-01-01

    Hypertrophy of developing skeletal muscle involves stimulation by insulin-like growth factor-I (IGF-I), however, the role of IGF-I in adult muscle is less clarified. In the present study, the mRNA splice variants of IGF-I (IGF-IEa and MGF) and the changes in muscle fiber cross sectional area after...... and in addition induces marked increases in the expression of IGF-I splice variants, supporting the idea that IGF-I is involved in regulating muscle hypertrophy.......-operated-side served as a within subject control. Muscle biopsies were obtained from the vastus lateralis of both limbs at +2d post-operative (baseline), at 5weeks and 12weeks post-surgery to analyze for changes in type 1 and type 2 muscle fiber area. Changes in expression levels of IGF-I mRNA isoforms were determined...

  11. Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids.

    Science.gov (United States)

    Leuner, Benedetta; Caponiti, Julia M; Gould, Elizabeth

    2012-04-01

    Oxytocin has been linked to social behavior, including social recognition, pair bonding and parenting, but its potential role in promoting neuronal growth has not been investigated. We show here that oxytocin, but not vasopressin, stimulates both cell proliferation and adult neurogenesis in the hippocampus of rats. Oxytocin is also capable of stimulating adult neurogenesis in rats subjected to glucocorticoid administration or cold water swim stress. These findings suggest that oxytocin stimulates neuronal growth and may protect against the suppressive effects of stress hormones on hippocampal plasticity.

  12. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    Science.gov (United States)

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

  13. Identification of Compounds That Inhibit IGF-I Signaling in Hyperglycemia

    Directory of Open Access Journals (Sweden)

    Laura A. Maile

    2009-01-01

    Full Text Available Increased responsiveness of vascular cells to the growth factor IGF-I has been implicated in complications associated with diabetes. Here we describe the development of an assay and screening of a library of compounds for their ability to accelerate cleavage of the transmembrane protein integrin-associated protein (IAP thereby disrupting the association between IAP and SHPS-1 which we have shown as critical for the enhanced response of vascular cells to IGF-I. The cell-based ELISA utilizes an antibody that specifically detects cleaved, but not intact, IAP. Of the 1040 compounds tested, 14 were considered active by virtue of their ability to stimulate an increase in antibody-binding indicative of IAP cleavage. In experiments with smooth muscle and retinal endothelial cell cultures in hyperglycemic conditions, each active compound was shown to accelerate the cleavage of IAP, and this was associated with a decrease in IAP association with SHPS-1 as determined by coimmunoprecipitation of the proteins from cell lysates. As a consequence of the acceleration in IAP cleavage, the compounds were shown to inhibit IGF-I-stimulated phosphorylation of key signaling molecules including Shc and ERK1/2, and this in turn was associated with a decrease in IGF-I-stimulated cell proliferation. Identification of these compounds that utilize this mechanism has the potential to yield novel therapeutic approaches for the prevention and treatment of vascular complications associated with diabetes.

  14. The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle.

    Science.gov (United States)

    Serra, Carlo; Bhasin, Shalender; Tangherlini, Frances; Barton, Elisabeth R; Ganno, Michelle; Zhang, Anqi; Shansky, Janet; Vandenburgh, Herman H; Travison, Thomas G; Jasuja, Ravi; Morris, Carl

    2011-01-01

    Testosterone (T) supplementation increases skeletal muscle mass, circulating GH, IGF-I, and im IGF-I expression, but the role of GH and IGF-I in mediating T's effects on the skeletal muscle remains poorly understood. Here, we show that T administration increased body weight and the mass of the androgen-dependent levator ani muscle in hypophysectomized as well as castrated plus hypophysectomized adult male rats. T stimulated the proliferation of primary human skeletal muscle cells (hSKMCs) in vitro, an effect blocked by transfecting hSKMCs with small interference RNA targeting human IGF-I receptor (IGF-IR). In differentiation conditions, T promoted the fusion of hSKMCs into larger myotubes, an effect attenuated by small interference RNA targeting human IGF-IR. Notably, MKR mice, which express a dominant negative form of the IGF-IR in skeletal muscle fibers, treated with a GnRH antagonist (acyline) to suppress endogenous T, responded to T administration by an attenuated increase in the levator ani muscle mass. In conclusion, circulating GH and IGF-I are not essential for mediating T's effects on an androgen-responsive skeletal muscle. IGF-I signaling plays an important role in mediating T's effects on skeletal muscle progenitor cell growth and differentiation in vitro. However, IGF-IR signaling in skeletal muscle fibers does not appear to be obligatory for mediating the anabolic effects of T on the mass of androgen-responsive skeletal muscles in mice.

  15. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I

    Directory of Open Access Journals (Sweden)

    Alexander V. Sirotkin

    2016-02-01

    Full Text Available The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings and old (3-5 years of age minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml. We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a reduction in basal progesterone release and (b alterations in the response of estradiol but not of progesterone to leptin and IGF-I.

  16. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I.

    Science.gov (United States)

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-21

    The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.

  17. Serum total IGF-I, free IGF-I, and IGFBP-1 levels in an elderly population - Relation to cardiovascular risk factors and disease

    NARCIS (Netherlands)

    Janssen, JAMJL; Stolk, RP; Pols, HAP; Grobbee, DE; Lamberts, SWJ

    Recently, a method to measure free insulin-like growth factor-I (IGF-I) levels has been developed. Free IGF-I levels may have greater physiological and clinical relevance than total (bound and free) IGF-I. The associations between the circulating IGF-I/IGF binding protein (IGFBP) system and

  18. Effects of type IV collagen on myogenic characteristics of IGF-I gene-engineered myoblasts.

    Science.gov (United States)

    Ito, Akira; Yamamoto, Masahiro; Ikeda, Kazushi; Sato, Masanori; Kawabe, Yoshinori; Kamihira, Masamichi

    2015-05-01

    Skeletal muscle regeneration requires migration, proliferation and fusion of myoblasts to form multinucleated myotubes. In our previous study, we showed that insulin-like growth factor (IGF)-I gene delivery stimulates the proliferation and differentiation of mouse myoblast C2C12 cells and promotes the contractile force generated by tissue-engineered skeletal muscles. The aim of this study was to investigate the effects of the extracellular matrix on IGF-I gene-engineered C2C12 cells in vitro. Retroviral vectors for doxycycline (Dox)-inducible expression of the IGF-I gene were transduced into C2C12 cells. When cultured on a type IV collagen-coated surface, we observed significant increases in the migration speed and number of IGF-I gene-engineered C2C12 cells with Dox addition, designated as C2C12/IGF (+) cells. Co-culture of C2C12/IGF (+) cells and parental C2C12 cells, which had been cultured in differentiation medium for 3 days, greatly enhanced myotube formation. Moreover, type IV collagen supplementation promoted the fusion of C2C12/IGF (+) cells with differentiated C2C12 cells and increased the number of myotubes with striations. Myotubes formed by C2C12/IGF (+) cells cultured on type IV collagen showed a dynamic contractile activity in response to electrical pulse stimulation. These findings indicate that type IV collagen promotes skeletal muscle regeneration mediated by IGF-I-expressing myoblasts, which may have important clinical implications in the design of myoblast-based therapies.

  19. Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells.

    Science.gov (United States)

    Liu, Xunxian; Allen, Jeffrey D; Arnold, Julia T; Blackman, Marc R

    2008-04-01

    Prostate stromal and epithelial cell communication is important in prostate functioning and cancer development. Primary human stromal cells from normal prostate stromal cells (PRSC) maintain a smooth muscle phenotype, whereas those from prostate cancer (6S) display reactive and fibroblastic characteristics. Dihydrotestosterone (DHT) stimulates insulin-like growth factor-I (IGF-I) production by 6S but not PSRC cells. Effects of reactive versus normal stroma on normal human prostate epithelial (NPE or PREC) cells are poorly understood. We co-cultured NPE plus 6S or PRSC cells to compare influences of different stromal cells on normal epithelium. Because NPE and PREC cells lose androgen receptor (AR) expression in culture, DHT effects must be modulated by associated stromal cells. When treated with camptothecin (CM), NPE cells, alone and in stromal co-cultures, displayed a dose-dependent increase in DNA fragmentation. NPE/6S co-cultures exhibited reduced CM-induced cell death with exposure to DHT, whereas NPE/PRSC co-cultures exhibited CM-induced cell death regardless of DHT treatment. DHT blocked CM-induced, IGF-I-mediated, NPE death in co-cultured NPE/6S cells without, but not with, added anti-IGF-I and anti-IGF-R antibodies. Lycopene consumption is inversely related to human prostate cancer risk and inhibits IGF-I and androgen signaling in rat prostate cancer. In this study, lycopene, in dietary concentrations, reversed DHT effects of 6S cells on NPE cell death, decreased 6S cell IGF-I production by reducing AR and beta-catenin nuclear localization and inhibited IGF-I-stimulated NPE and PREC growth, perhaps by attenuating IGF-I's effects on serine phosphorylation of Akt and GSK3beta and tyrosine phosphorylation of GSK3. This study expands the understanding of the preventive mechanisms of lycopene in prostate cancer.

  20. Antidepressants stimulate hippocampal neurogenesis by inhibiting p21 expression in the subgranular zone of the hipppocampus.

    Directory of Open Access Journals (Sweden)

    Robert N Pechnick

    Full Text Available The relationships among hippocampal neurogenesis, depression and the mechanism of action of antidepressant drugs have generated a considerable amount of controversy. The cyclin-dependent kinase (Cdk inhibitor p21(Cip1 (p21 plays a crucial role in restraining cellular proliferation and maintaining cellular quiescence. Using in vivo and in vitro approaches the present study shows that p21 is expressed in the subgranular zone of the dentate gyrus of the hippocampus in early neuronal progenitors and in immature neurons, but not in mature neurons or astroglia. In vitro, proliferation is higher in neuronal progenitor cells derived from p21-/- mice compared to cells derived from wild-type mice. Proliferation is increased in neuronal progenitor cells after suppression of p21 using lentivirus expressing short hairpin RNA against p21. In vivo, chronic treatment with the non-selective antidepressant imipramine as well as the norepinephrine-selective reuptake inhibitor desipramine or the serotonin-selective reuptake inhibitor fluoxetine all decrease p21 expression, and this was associated with increased neurogenesis. Chronic antidepressant treatment did not affect the expression of other Cdk inhibitors. Untreated p21-/- mice exhibit a higher degree of baseline neurogenesis and decreased immobility in the forced swim test. Although chronic imipramine treatment increased neurogenesis and reduced immobility in the forced swim test in wild-type mice, it reduced neurogenesis and increased immobility in p21-/- mice. These results demonstrate the unique role of p21 in the control of neurogenesis, and support the hypothesis that different classes of reuptake inhibitor-type antidepressant drugs all stimulate hippocampal neurogenesis by inhibiting p21 expression.

  1. IGF-I and IGFBP2 in peripheral artery disease

    DEFF Research Database (Denmark)

    Urbonaviciene, Grazina; Frystyk, Jan; Urbonavicius, Sigitas

    2014-01-01

    -2) in the pathogenesis of CVD disorders. The aim of this study was to examine the relationship between levels of IGF-I and IGFBP-2 with all-cause and CVD mortality in a prospective study of patients with lower-extremity peripheral artery disease (PAD). METHODS AND MATERIAL: Serum IGF-I and IGFBP-2......BACKGROUND AND OBJECTIVES: The search for novel risk factors of cardiovascular disease (CVD) has provided valuable clinical data concerning underlying mechanism of disease. Increasing evidence indicates a possible involvement of insulin-like growth factor-I (IGF-I) and its binding protein 2 (IGFBP...

  2. Maternal cortisol stimulates neurogenesis and affects larval behaviour in zebrafish

    Science.gov (United States)

    Best, Carol; Kurrasch, Deborah M.; Vijayan, Mathilakath M.

    2017-01-01

    Excess glucocorticoid transferred from stressed mother to the embryo affects developing vertebrate offspring, but the underlying programming events are unclear. In this study, we tested the hypothesis that increased zygotic glucocorticoid deposition, mimicking a maternal stress scenario, modifies early brain development and larval behaviour in zebrafish (Danio rerio). Cortisol was microinjected into the yolk at one cell-stage, to mimic maternal transfer, and the larvae [96 hours post-fertilization (hpf)] displayed increased activity in light and a reduction in thigmotaxis, a behavioural model for anxiety, suggesting an increased propensity for boldness. This cortisol-mediated behavioural phenotype corresponded with an increase in primary neurogenesis, as measured by incorporation of EdU at 24 hpf, in a region-specific manner in the preoptic region and the pallium, the teleostean homolog of the hippocampus. Also, cortisol increased the expression of the proneural gene neurod4, a marker of neurogenesis, in a region- and development-specific manner in the embryos. Altogether, excess zygotic cortisol, mimicking maternal stress, affects early brain development and behavioural phenotype in larval zebrafish. We propose a key role for cortisol in altering brain development leading to enhanced boldness, which may be beneficial in preparing the offspring to a stressful environment and enhancing fitness. PMID:28098234

  3. Maternal cortisol stimulates neurogenesis and affects larval behaviour in zebrafish.

    Science.gov (United States)

    Best, Carol; Kurrasch, Deborah M; Vijayan, Mathilakath M

    2017-01-18

    Excess glucocorticoid transferred from stressed mother to the embryo affects developing vertebrate offspring, but the underlying programming events are unclear. In this study, we tested the hypothesis that increased zygotic glucocorticoid deposition, mimicking a maternal stress scenario, modifies early brain development and larval behaviour in zebrafish (Danio rerio). Cortisol was microinjected into the yolk at one cell-stage, to mimic maternal transfer, and the larvae [96 hours post-fertilization (hpf)] displayed increased activity in light and a reduction in thigmotaxis, a behavioural model for anxiety, suggesting an increased propensity for boldness. This cortisol-mediated behavioural phenotype corresponded with an increase in primary neurogenesis, as measured by incorporation of EdU at 24 hpf, in a region-specific manner in the preoptic region and the pallium, the teleostean homolog of the hippocampus. Also, cortisol increased the expression of the proneural gene neurod4, a marker of neurogenesis, in a region- and development-specific manner in the embryos. Altogether, excess zygotic cortisol, mimicking maternal stress, affects early brain development and behavioural phenotype in larval zebrafish. We propose a key role for cortisol in altering brain development leading to enhanced boldness, which may be beneficial in preparing the offspring to a stressful environment and enhancing fitness.

  4. Discovery of efficient stimulators for adult hippocampal neurogenesis based on scaffolds in dragon's blood.

    Science.gov (United States)

    Liang, Jian-Hua; Yang, Liang; Wu, Si; Liu, Si-Si; Cushman, Mark; Tian, Jing; Li, Nuo-Min; Yang, Qing-Hu; Zhang, He-Ao; Qiu, Yun-Jie; Xiang, Lin; Ma, Cong-Xuan; Li, Xue-Meng; Qing, Hong

    2017-08-18

    Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling.

    Science.gov (United States)

    Wadosky, Kristine M; Rodríguez, Jessica E; Hite, Rebecca L; Min, Jin-na; Walton, Bethany L; Willis, Monte S

    2014-04-01

    Recent studies implicate the muscle-specific ubiquitin ligase muscle RING finger-1 (MuRF1) in inhibiting pathological cardiomyocyte growth in vivo by inhibiting the transcription factor SRF. These studies led us to hypothesize that MuRF1 similarly inhibits insulin-like growth factor-I (IGF-I)-mediated physiological cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: IGF-I stimulation of cardiac-derived cells with MuRF1 knockdown 1) exhibited an exaggerated hypertrophy and, 2) conversely, increased MuRF1 expression-abolished IGF-I-dependent cardiomyocyte growth. Enhanced hypertrophy with MuRF1 knockdown was accompanied by increases in Akt-regulated gene expression. Unexpectedly, MuRF1 inhibition of this gene expression profile was not a result of differences in p-Akt. Instead, we found that MuRF1 inhibits total protein levels of Akt, GSK-3β (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-I signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia-reperfusion injury. Since IGF-I regulates exercise-mediated physiological cardiac growth, we challenged MuRF1(-/-) and MuRF1-Tg+ mice and their wild-type sibling controls to 5 wk of voluntary wheel running. MuRF1(-/-) cardiac growth was increased significantly over wild-type control; conversely, the enhanced exercise-induced cardiac growth was lost in MuRF1-Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-I signaling via c-Jun is applicable in vivo and establish that further understanding of this novel mechanism may be crucial in the development of therapies targeting IGF-I signaling.

  6. PKC{eta} is a negative regulator of AKT inhibiting the IGF-I induced proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Shahaf, Galit; Rotem-Dai, Noa; Koifman, Gabriela; Raveh-Amit, Hadas; Frost, Sigal A.; Livneh, Etta, E-mail: etta@bgu.ac.il

    2012-04-15

    The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKC{eta} isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC{eta}-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC{eta}-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKC{eta} exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKC{eta} and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKC{eta} expression, suggesting that PKC{eta} acts through a different route to increase cell survival. Hence, our studies show that PKC{eta} provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value.

  7. The Association Between IGF-I and Insulin Resistance

    DEFF Research Database (Denmark)

    Friedrich, Nele; Thuesen, Betina; Jørgensen, Torben

    2012-01-01

    OBJECTIVEIGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate...... the association between IGF-I level and insulin resistance in a Danish general population.RESEARCH DESIGN AND METHODSIncluded were 3,354 adults, aged 19-72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin...... with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model.CONCLUSIONSLow- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism...

  8. Free dissociable insulin-like growth factor I (IGF-I), total IGF-I and their binding proteins in girls with Turner syndrome during long-term growth hormone treatment

    NARCIS (Netherlands)

    Bannink, Ellen M. N.; Van Doorn, Jaap; Stijnen, Theo; Drop, Stenvert L. S.; Keizer-Schrama, Sabine M. P. F. de Muinck

    2006-01-01

    Objective To investigate the effect of GH treatment on free IGF-I levels in girls with Turner syndrome (TS) and to verify relationships between free IGF-I levels and total IGF-I, IGFBP-1, 2 and 3. Additionally, to analyse whether free IGF-I, total IGF-I, IGFBP-3 or its ratio were related to IGF-I bi

  9. SERUM IGF-I AND HORMONAL RESPONSES TO INCREMENTAL EXERCISE IN ATHLETES WITH AND WITHOUT LEFT VENTRICULAR HYPERTROPHY

    Directory of Open Access Journals (Sweden)

    Aleksandra Zebrowska

    2009-03-01

    Full Text Available We investigated the response of insulin-like growth factor (IGF- I, insulin-like growth factor binding protein-3 (IGFBP-3 and some hormones, i.e., testosterone (T, growth hormone (GH, cortisol (C, and insulin (I, to maximal exercise in road cyclists with and without diagnosed left ventricular hypertrophy. M-mode and two-dimensional Doppler echocardiography was performed in 30 professional male endurance athletes and a group of 14 healthy untrained subjects using a Hewlett-Packard Image Point HX ultrasound system with standard imaging transducers. Echocardiography and an incremental physical exercise test were performed during the competitive season. Venous blood samples were drawn before and immediately after the maximal cycling exercise test for determination of somatomedin and hormonal concentrations. The basal concentration of IGF-I was statistically higher (p < 0.05 in athletes with left ventricular muscle hypertrophy (LVH when compared to athletes with a normal upper limit of the left ventricular wall (LVN (p < 0.05 and to the control group (CG (p < 0.01. The IGF-I level increased significantly at maximal intensity of incremental exercise in CG (p < 0.01, LVN (p < 0.05 and LVH (p < 0.05 compared to respective values at rest. Long-term endurance training induced an increase in resting (p < 0.01 and post-exercise (p < 0.05 IGF-I/IGFBP-3 ratio in athletes with LVH compared to LVN. The testosterone (T level was lower in LVH at rest compared to LVN and CG groups (p < 0.05. These results indicate that resting serum IGF-I concentration were higher in trained subjects with LVH compared to athletes without LVH. Serum IGF- I/IGFBP-3 elevation at rest and after exercise might suggest that IGF-I act as a potent stimulant of left ventricular hypertrophy in chronically trained endurance athletes

  10. Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis.

    Science.gov (United States)

    Hescham, Sarah; Temel, Yasin; Schipper, Sandra; Lagiere, Mélanie; Schönfeld, Lisa-Maria; Blokland, Arjan; Jahanshahi, Ali

    2017-03-01

    Deep brain stimulation (DBS) is an established symptomatic treatment modality for movement disorders and constitutes an emerging therapeutic approach for the treatment of memory impairment. In line with this, fornix DBS has shown to ameliorate cognitive decline associated with dementia. Nonetheless, mechanisms mediating clinical effects in demented patients or patients with other neurological disorders are largely unknown. There is evidence that DBS is able to modulate neurophysiological activity in targeted brain regions. We therefore hypothesized that DBS might be able to influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters, which were validated to restore memory loss in a previous behavioral study, we here assessed long-term effects of fornix DBS. To do so, we injected the thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), after DBS and perfused the animals 6.5 weeks later. A week prior to perfusion, memory performance was assessed in the water maze. We found that acute stimulation of the fornix improved spatial memory performance in the water maze when the probe trial was performed 1 h after the last training session. However, no evidence for stimulation-induced neurogenesis was found in fornix DBS rats when compared to sham. Our results suggest that fornix DBS improves memory functions independent of hippocampal neurogenesis, possibly through other mechanisms such as synaptic plasticity and acute neurotransmitter release.

  11. Serum tree IGF-I, total IGF-I, IGFBP-1 and IGFBP-3 levels in an elderly population : relation to age and sex steroid levels

    NARCIS (Netherlands)

    Janssen, JAMJL; Stolk, RP; Pols, HAP; Grobbee, DE; de Jong, FH; Lamberts, SWJ

    1998-01-01

    BACKGROUND Most previous studies concerning the relationship between IGF-I and age used assays measuring total IGF-I, Although free IGF-I is considered of greater biological relevance, little is known about its relationship with sex steroids levels in elderly healthy subjects, MEASUREMENTS In a cros

  12. Transcranial Direct Current Stimulation Modulates Neurogenesis and Microglia Activation in the Mouse Brain

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    Anton Pikhovych

    2016-01-01

    Full Text Available Transcranial direct current stimulation (tDCS has been suggested as an adjuvant tool to promote recovery of function after stroke, but the mechanisms of its action to date remain poorly understood. Moreover, studies aimed at unraveling those mechanisms have essentially been limited to the rat, where tDCS activates resident microglia as well as endogenous neural stem cells. Here we studied the effects of tDCS on microglia activation and neurogenesis in the mouse brain. Male wild-type mice were subjected to multisession tDCS of either anodal or cathodal polarity; sham-stimulated mice served as control. Activated microglia in the cerebral cortex and neuroblasts generated in the subventricular zone as the major neural stem cell niche were assessed immunohistochemically. Multisession tDCS at a sublesional charge density led to a polarity-dependent downregulation of the constitutive expression of Iba1 by microglia in the mouse cortex. In contrast, both anodal and, to an even greater extent, cathodal tDCS induced neurogenesis from the subventricular zone. Data suggest that tDCS elicits its action through multifacetted mechanisms, including immunomodulation and neurogenesis, and thus support the idea of using tDCS to induce regeneration and to promote recovery of function. Furthermore, data suggest that the effects of tDCS may be animal- and polarity-specific.

  13. Neurogenesis in the dentate gyrus of the rat hippocampus enhanced by tickling stimulation with positive emotion.

    Science.gov (United States)

    Yamamuro, Takuya; Senzaki, Kouji; Iwamoto, Satomi; Nakagawa, Yoshimi; Hayashi, Takashi; Hori, Miyo; Sakamoto, Shigeko; Murakami, Kazuo; Shiga, Takashi; Urayama, Osamu

    2010-12-01

    Hippocampal neurogenesis is influenced by many factors. In this study, we examined the effect of tactile stimulation (tickling), which induced positive emotion, on neurogenesis in the dentate gyrus (DG) of the hippocampus. Four week-old rats were tickled for 5 min/day on 5 consecutive days and received 5-bromo-2'-deoxyuridine (BrdU) administration for 4 days from the second tickling day. Then they were allowed to survive for 18 h or 3 weeks after the end of BrdU treatment. Neurogenesis in the DG was compared between the tickled and untickled rats by using immunohistochemistry with anti-BrdU antibody. The result showed that the number of BrdU- and NeuN (neural cell marker)-double positive neurons on 18h as well as 3 weeks of the survival periods was significantly increased in the tickled group as compared with the untickled group. The expression of mRNA of brain-derived neurotrophic factor (BDNF) in the hippocampus of the tickled rats was not altered when compared with the control rats. In conclusion, tickling stimulation which induces positive emotion may affect the generation and survival of new neurons of the DG through the BDNF-independent pathway.

  14. Polymorphism of the IGF-I System and Sports Performance.

    Science.gov (United States)

    Ben-Zaken, Sigal; Meckel, Yoav; Nemet, Dan; Dror, Nitzan; Eliakim, Alon

    2016-06-01

    The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism.

  15. Therapeutic Intervention of Learning and Memory Decays by Salidroside Stimulation of Neurogenesis in Aging.

    Science.gov (United States)

    Jin, Huijuan; Pei, Lei; Shu, Xiaogang; Yang, Xin; Yan, Tianhua; Wu, Yan; Wei, Na; Yan, Honglin; Wang, Shan; Yao, Chengye; Liu, Dan; Tian, Qing; Wang, Lin; Lu, Youming

    2016-03-01

    Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging.

  16. Galvanic vestibular stimulation impairs cell proliferation and neurogenesis in the rat hippocampus but not spatial memory.

    Science.gov (United States)

    Zheng, Yiwen; Geddes, Lisa; Sato, Go; Stiles, Lucy; Darlington, Cynthia L; Smith, Paul F

    2014-05-01

    Galvanic vestibular stimulation (GVS) is a method of activating the peripheral vestibular system using direct current that is widely employed in clinical neurological testing. Since movement is recognized to stimulate hippocampal neurogenesis and movement is impossible without activation of the vestibular system, we speculated that activating the vestibular system in rats while minimizing movement, by delivering GVS under anesthesia, would affect hippocampal cell proliferation and neurogenesis, and spatial memory. Compared with the sham control group, the number of cells incorporating the DNA replication marker, bromodeoxyuridine (BrdU), was significantly reduced in the bilateral hippocampi in both the cathode left-anode right and cathode right-anode left stimulation groups (P ≤ 0.0001). The majority of the BrdU(+ve) cells co-expressed Ki-67, a marker for the S phase of the cell cycle, suggesting that these BrdU(+ve) cells were still in the cell cycle; however, there was no significant difference in the degree of co-labeling between the two stimulation groups. Single labeling for doublecortin (DCX), a marker of immature neurons, showed that while there was no significant difference between the different groups in the number of DCX(+ve) cells in the right dentate gryus, in the left dentate gyrus there was a significant decrease in the cathode left-anode right group compared with the sham controls (P ≤ 0.03). Nonetheless, when animals were tested in place recognition, object exploration and Morris water maze tasks, there were no significant differences between the GVS groups and the sham controls. These results suggest that GVS can have striking effects on cell proliferation and possibly neurogenesis in the hippocampus, without affecting spatial memory.

  17. Long Course Hyperbaric Oxygen Stimulates Neurogenesis and Attenuates Inflammation after Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Ying-Sheng Lee

    2013-01-01

    Full Text Available Several studies have provided evidence with regard to the neuroprotection benefits of hyperbaric oxygen (HBO therapy in cases of stroke, and HBO also promotes bone marrow stem cells (BMSCs proliferation and mobilization. This study investigates the influence of HBO therapy on the migration of BMSCs, neurogenesis, gliosis, and inflammation after stroke. Rats that sustained transient middle cerebral artery occlusion (MCAO were treated with HBO three weeks or two days. The results were examined using a behavior test (modified neurological severity score, mNSS and immunostaining to evaluate the effects of HBO therapy on migration of BMSCs, neurogenesis, and gliosis, and expression of neurotrophic factors was also evaluated. There was a lower mNSS score in the three-week HBO group when compared with the two-day HBO group. Mobilization of BMSCs to an ischemic area was more improved in long course HBO treatments, suggesting the duration of therapy is crucial for promoting the homing of BMSCs to ischemic brain by HBO therapies. HBO also can stimulate expression of trophic factors and improve neurogenesis and gliosis. These effects may help in neuronal repair after ischemic stroke, and increasing the course of HBO therapy might enhance therapeutic effects on ischemic stroke.

  18. Genetic disorders in the growth hormone - IGF-I Axis

    NARCIS (Netherlands)

    Walenkamp, Maria Josephina Elisabeth

    2007-01-01

    Growth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder, disrupting the normal growth process. The growth hormone – IGF-I axis plays a key role in regulating this growt

  19. Pre-infection physical exercise decreases mortality and stimulates neurogenesis in bacterial meningitis

    Directory of Open Access Journals (Sweden)

    Liebetanz David

    2012-07-01

    Full Text Available Abstract Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily. Experiments were terminated either 30 hours or 4 days (short-term or 7 weeks (long-term after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test. At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher’s Exact test. Hippocampal neurogenesis – assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells - was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.

  20. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

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    Rachele eSalvi

    2016-03-01

    Full Text Available While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG and the subventricular zone (SVZ, recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g. the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX and Ropinirole (ROP, on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU a proliferation paradigm was performed in which two BrdU injections (100 mg/kg were applied intraperitoneally within 12 hours after a 14-day-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and NeuN 32 days after the last of five BrdU injections (50 mg/kg applied at the beginning of 14-day DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and

  1. Involvement of PI3 kinase and MAP kinase in IGF-I and insulin-induced ovarian steroidogenesis in common carp Cyprinus carpio.

    Science.gov (United States)

    Paul, Sudipta; Pramanick, Kousik; Kundu, Sourav; Roy Moulik, Sujata; Pal, Puja; Mukherjee, Dilip

    2013-01-15

    Previously, we observed that in vitro steroidogenesis in intact ovarian follicles of common carp Cyprinus carpio can alone be induced by recombinant human insulin-like growth factor (IGF-I) and bovine insulin (b-insulin) and this induction was gonadotropin-independent. To investigate early signal transduction components involved in this process, the possible role of phosphatidylinositol 3-kinase (PI3 kinase) during ovarian steroidogenesis was examined. IGF-I and b-insulin induced testosterone and 17β-estradiol production in carp ovarian theca and granulosa cells in short-term coincubation and this induction was significantly inhibited by Wortmannin and LY294002, two mechanistically different specific inhibitors of PI3 kinase. IGF-I and b-insulin were shown to activate PI3 kinase from 30 min onwards with a maximum at 90 min. In this study, we found the involvement of mitogen-activated protein kinase (MAP kinase) in the regulation of IGF-I- and b-insulin-induced steroidogenesis in carp ovary. An antagonist of mitogen-activated protein kinase kinase1/2 (MEK1/2) markedly attenuated IGF-I- and b-insulin-induced steroid production. Cells treated with IGF-I and b-insulin stimulated ERK1/2-dependent phosphorylation of extracellular signal regulated protein kinase1/2 (ERKs1/2) in a time-dependent manner, which was significantly attenuated in presence of MEK1/2 inhibitor. PI3 kinase inhibitors strongly attenuated phosphorylation and activation of MAP kinase, which was increased during IGF-I and b-insulin-induced steroidogenesis. Taken together, these results suggest that PI3 kinase is an initial component of the signal transduction pathway which precedes the MAP kinase during IGF-I- and b-insulin-induced steroidogenesis in C. carpio ovarian follicles.

  2. Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro.

    Science.gov (United States)

    Makrantonaki, Evgenia; Vogel, Kim; Fimmel, Sabine; Oeff, Marina; Seltmann, Holger; Zouboulis, Christos C

    2008-10-01

    In order to obtain greater insights into the molecular mechanisms accompanying hormonal aging the effects of growth hormone (GH), insulin-like growth factor-I (IGF-I), 17beta-estradiol, progesterone and dehydroepiandrosterone were tested as single agents in concentrations corresponding to 20- and 60-year-old females on human SZ95 sebocytes and fibroblasts. Cell proliferation and viability were measured by 4-methylumbelliferyl heptanoate and lactate dehydrogenase microassays, respectively, whereas lipid accumulation was documented via nile red microassay and fluorescence microscopy. mRNA and protein expression were evaluated via real-time RT-PCR and Western blotting or ELISA, accordingly. Our results depict the importance of IGF-I for lipid synthesis in SZ95 sebocyte and demonstrate the lack of 17beta-estradiol, dehydroepiandrosterone and progesterone activity on lipid synthesis and SZ95 sebocyte proliferation suggesting that the action of these hormones in vivo may be implemented through indirect pathways. Fibroblast showed to be more susceptible to 17beta-estradiol treatment, while IGF-I could significantly stimulate fibroblast proliferation in a dose-dependent manner. Furthermore, an interplay between the 17beta-estradiol and IGF-I signaling pathway was documented in both cell types. In conclusion, IGF-I is a key regulator of human skin aging and declining IGF-I levels with age may play a significant role in the reduction of skin surface lipids and thickness.

  3. Role of ghrelin in regulating rabbit ovarian function and the response to LH and IGF-I.

    Science.gov (United States)

    Sirotkin, Alexander V; Rafay, Ján; Kotwica, Ján; Darlak, Krzysztof; Valenzuela, Francisco

    2009-04-01

    The aim of these in vivo and in vitro studies was to examine the role of ghrelin in the control of plasma hormone concentrations, the proliferation, apoptosis and secretory activity of ovarian granulosa cells and the response of these cells to hormonal treatments. Female rabbits were injected with ghrelin (10 microg/animal/day for one week before ovulation induced by 25IU PMSG and 0.25IU LHRH). On the day of ovulation, blood samples were collected and analyzed for concentrations of progesterone (P(4)), testosterone (T), estradiol (E(2)), estrone-sulphate (ES), insulin-like growth factor I (IGF-I) and leptin (L) by RIA. Some control and ghrelin-treated animals were killed in the periovulatory period, their ovaries were weighed and granulosa cells were isolated and cultured for 2d. Cell proliferation (expression of PCNA) and apoptosis (expression of TdT) were evaluated by immunocytochemistry and TUNEL respectively. Secretion of P(4), T, E(2), IGF-I, and prostaglandin F (PGF) by granulosa cells cultured with and without LH or IGF-I (1, 10 or 100 ng/ml medium) was assessed by RIA. The remaining control and treated animals were kept until parturition, while the number, viability and body weight of pups were recorded. Ghrelin treatment increased rabbit plasma T and decreased ES concentrations but did not influence P(4), E(2), IGF-I or L. Granulosa cells from ghrelin-treated animals showed higher expression of PCNA and lower expression of TdT, than those from control animals. They also secreted less P(4), T, E(2), IGF-I and PGF than granulosa cells from untreated animals. Treatment of cultured granulosa cells with ghrelin (1, 10 or 100 ng/ml medium) either increased (at 1 ng/ml) or decreased (at 10 ng/ml) P(4) secretion, increased (at 100 ng/ml) or decreased (at 10 ng/ml) IGF-I secretion, decreased T (at 1 and 10 ng/ml) and OT (at 1 ng/ml) secretion, and increased (at 100 ng/ml) PGF secretion. LH treatment of cells from control animals stimulated P(4) (at 1 and 10 ng

  4. Low circulating IGF-I bioactivity is associated with human longevity: Findings in centenarians’ offspring

    Science.gov (United States)

    Vitale, Giovanni; Brugts, Michael P; Ogliari, Giulia; Castaldi, Davide; Fatti, Letizia M.; Varewijck, Aimee J.; Lamberts, Steven W.; Monti, Daniela; Bucci, Laura; Cevenini, Elisa; Cavagnini, Francesco; Franceschi, Claudio; Hofland, Leo J; Mari, Daniela; Janssen, Joseph A.M.J.L.

    2012-01-01

    Centenarians’ offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians’ offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians’ offspring. IGF-I bioactivity (p<0.01), total IGF-I (p<0.01) and the IGF-I/IGFBP-3 molar ratio (p<0.001) were significantly lower in centenarians’ offspring compared to offspring matched-controls. Serum insulin, glucose, HOMA2-B% and HOMA2-S% values were similar between both groups. In centenarians’ offspring IGF-I bioactivity was inversely associated to insulin sensitivity. In conclusion: 1) centenarians’ offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians’ offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process. PMID:22983440

  5. GH/IGF-I Transgene Expression on Muscle Homeostasis

    Science.gov (United States)

    Schwartz, Robert J.

    1999-01-01

    We propose to test the hypothesis that the growth hormone/ insulin like growth factor-I axis through autocrine/paracrine mechanisms may provide long term muscle homeostasis under conditions of prolonged weightlessness. As a key alternative to hormone replacement therapy, ectopic production of hGH, growth hormone releasing hormone (GHRH), and IGF-I will be studied for its potential on muscle mass impact in transgenic mice under simulated microgravity. Expression of either hGH or IGF-I would provide a chronic source of a growth-promoting protein whose biosynthesis or secretion is shut down in space. Muscle expression of the IGF-I transgene has demonstrated about a 20% increase in hind limb muscle mass over control nontransgenic litter mates. These recent experiments, also establish the utility of hind-limb suspension in mice as a workable model to study atrophy in weight bearing muscles. Thus, transgenic mice will be used in hind-limb suspension models to determine the role of GH/IGF-I on maintenance of muscle mass and whether concentric exercises might act in synergy with hormone treatment. As a means to engineer and ensure long-term protein production that would be workable in humans, gene therapy technology will be used by to monitor muscle mass preservation during hind-limb suspension, after direct intramuscular injection of a genetically engineered muscle-specific vector expressing GHRH. Effects of this gene-based therapy will be assessed in both fast twitch (medial gastrocnemius) and slow twitch muscle (soleus). End-points include muscle size, ultrastructure, fiber type, and contractile function, in normal animals, hind limb suspension, and reambutation.

  6. GH/IGF-I Transgene Expression on Muscle Homeostasis

    Science.gov (United States)

    Schwartz, Robert J.

    1999-01-01

    We propose to test the hypothesis that the growth hormone/ insulin like growth factor-I axis through autocrine/paracrine mechanisms may provide long term muscle homeostasis under conditions of prolonged weightlessness. As a key alternative to hormone replacement therapy, ectopic production of hGH, growth hormone releasing hormone (GHRH), and IGF-I will be studied for its potential on muscle mass impact in transgenic mice under simulated microgravity. Expression of either hGH or IGF-I would provide a chronic source of a growth-promoting protein whose biosynthesis or secretion is shut down in space. Muscle expression of the IGF-I transgene has demonstrated about a 20% increase in hind limb muscle mass over control nontransgenic litter mates. These recent experiments, also establish the utility of hind-limb suspension in mice as a workable model to study atrophy in weight bearing muscles. Thus, transgenic mice will be used in hind-limb suspension models to determine the role of GH/IGF-I on maintenance of muscle mass and whether concentric exercises might act in synergy with hormone treatment. As a means to engineer and ensure long-term protein production that would be workable in humans, gene therapy technology will be used by to monitor muscle mass preservation during hind-limb suspension, after direct intramuscular injection of a genetically engineered muscle-specific vector expressing GHRH. Effects of this gene-based therapy will be assessed in both fast twitch (medial gastrocnemius) and slow twitch muscle (soleus). End-points include muscle size, ultrastructure, fiber type, and contractile function, in normal animals, hind limb suspension, and reambutation.

  7. Influence of environmental stimulation on neurogenesis in the adult insect brain.

    Science.gov (United States)

    Scotto Lomassese, S; Strambi, C; Strambi, A; Charpin, P; Augier, R; Aouane, A; Cayre, M

    2000-11-15

    Mushroom bodies are the main integrative structures of insect brain. They receive sensory information from the eyes, the palps, and the antennae. In the house cricket, Acheta domesticus, a cluster of mushroom body neuroblasts keeps producing new interneurons during an insect's life span. The aim of the present work is to study the impact of environmental stimuli on mushroom body neurogenesis during adulthood. Crickets were reared either in an enriched environment, where they received complex environmental and congeneric stimulations or isolated in small cages and deprived of most visual, auditory, and olfactory stimuli. They then were injected with a S-phase marker, 5-bromo, 2'-deoxyuridine (BrdU) and sacrificed at different periods of their life. Neurogenesis and cell survival were estimated by counting the number of BrdU-labeled cells in the mushroom bodies. Environmentally enriched crickets were found to have an increased number of newborn cells in their mushroom bodies compared with crickets housed in cages with an impoverished environment. This effect of external factors on neurogenesis seems to be limited to the beginning of imaginal life. Furthermore, no cell loss could be detected among the newborn neurons in either environmental situation, suggesting that cell survival was not affected by the quality of the environment. Considering vertebrate studies which showed that enriched environment increases hippocampal cell survival and improves animal performances in spatial learning tests, we suggest that the increased number of interneurons produced in an integrative brain structure after exposure to enriched environment could contribute to adaptive behavioral performances in adult insects.

  8. Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis.

    Science.gov (United States)

    Hazelgrove, Krystina B; Flynn, Robert S; Qiao, Li-Ya; Grider, John R; Kuemmerle, John F

    2009-06-01

    Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the alpha(v)beta(3) integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although alpha(v)beta(3) integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 +/- 10% and 90 +/- 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 +/- 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3beta phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 +/- 15% and decreased apoptosis by 20 +/- 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an alpha(v)beta(3) integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of alpha(v)beta(3) integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

  9. IGF-I and branchial IGF receptor expression and localization during salinity acclimation in striped bass

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbaek; Luckenbach, John Adam; Madsen, Steffen

    2007-01-01

    The initial response of the IGF-I system and the expression and cellular localization of IGF type-I receptor (IGF-IR) were studied in the gill of a euryhaline teleost during salinity acclimation. Exposure of striped bass (Morone saxatilis) to hyperosmotic and hypoosmotic challenges induced small...... in either plasma IGF-I, liver, or gill IGF-I mRNA, or gill IGF-IR mRNA levels. In a separate experiment, FW-acclimated fish were injected with saline or IGF-I prior to a 24-h SW challenge. Rapid regain of osmotic balance following SW transfer was hindered by IGF-I. Immunohistochemistry revealed...

  10. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T

    1995-01-01

    Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn......, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term...

  11. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling.

    Science.gov (United States)

    Beitner-Johnson, D; Blakesley, V A; Shen-Orr, Z; Jimenez, M; Stannard, B; Wang, L M; Pierce, J; LeRoith, D

    1996-04-19

    The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. In order to further characterize the role of Crk in the IGF-I signaling pathway, NIH-3T3 and 293 cells were stably transfected with an expression vector containing the Crk cDNA. The various resultant 3T3-Crk clones expressed Crk at approximately 2-15-fold higher levels than parental 3T3 cells. In 3T3-Crk cells, Crk immunoreactivity was detected in insulin receptor substrate-1 (IRS-1) immunoprecipitates. Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. Similar results were obtained in stably transfected 293-Crk cells, which express both IRS-1 and the IRS-1-related signaling protein 4PS. In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. Overexpression of Crk also enhanced IGF-I-induced mitogenesis of NIH-3T3 cells, as measured by [3H]thymidine incorporation. The levels of IGF-I-induced mitogenesis were proportional to the level of Crk expression. These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS.

  12. Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

    Directory of Open Access Journals (Sweden)

    Oumei Cheng

    Full Text Available Sleep deprivation (SD plays a complex role in central nervous system (CNS diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR.One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU and neuron-specific enolase (NSE, respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.

  13. Effect of voluntary exercise on the expression of IGF-I and androgen receptor in three rat skeletal muscles and on serum IGF-I and testosterone levels.

    Science.gov (United States)

    Matsakas, A; Nikolaidis, M G; Kokalas, N; Mougios, V; Diel, P

    2004-10-01

    The effects of anabolic agents and training on skeletal muscle are believed to be mediated by a variety of growth and transcription factors. Among these regulatory proteins, insulin-like growth factor-I (IGF-I) and androgen receptor (AR) play a crucial role. The purpose of this study was to investigate the effects of wheel running on IGF-I and AR mRNA expression in three distinct rat skeletal muscles (i.e., gastrocnemius, vastus lateralis, and soleus), as well as on the serum levels of IGF-I and testosterone. Twenty male Wistar rats were housed in cages with free access to running wheels for 12 weeks, while nine rats served as controls. Analysis of the mRNA expression of IGF-I and AR using real time RT-PCR revealed no significant differences between the trained and untrained rats in any of the muscles studied. Enzyme immunoassay showed significantly lower serum levels of IGF-I and testosterone in the trained compared to the untrained animals. These results suggest that chronic exercise in wheels does not affect IGF-I and AR mRNA levels in rat skeletal muscle, while decreasing the circulating levels of two anabolic factors, i.e., IGF-I and testosterone. It is concluded that IGF-I, AR and testosterone seem to play a marginal role during the adaptation process of rat skeletal muscle to long-term wheel running.

  14. IGF-I bioactivity might reflect different aspects of quality of life than total IGF-I in gh-deficient patients during GH treatment

    NARCIS (Netherlands)

    A.J. Varewijck (Aimee); S.W.J. Lamberts (Steven); S.J.C.M.M. Neggers (Bas); L.J. Hofland (Leo); J.A.M.J.L. Janssen (Joseph)

    2013-01-01

    textabstractContext: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy. Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months. Methods: Of 106 GHD patien

  15. IGF-I biomarker testing in an ethical context

    Directory of Open Access Journals (Sweden)

    Annabelle Trojan

    2016-08-01

    Full Text Available As we have come to know, there is a connection between cancer biomarkers and genes, along with their susceptibility to a particular disease, all of which have an obvious impact on the clinical practice and development of genetic testing. In any cancer disease, the diagnosis and treatment should be related to the investigation of specific biomarkers (generally antigens and proteins and their corresponding genes. The study of different antigens such as alpha-fetoprotein, insulin-like growth factor I (IGF-I, insulin-like growth factor II, vascular endothelial growth factor, and epidermal growth factor, as well as their presence in neoplastic cells have demonstrated that IGF-I is an essential target for gene testing and therapeutic purpose. An over-expression of the IGF-I gene in mature tissues is a sign of neoplastic processes e.g. brain or breast malignancy. A lot of questions have arisen regarding the ethics of gene testing, particularly concerns on the selection of patients for specific growth hormone/insulin-like growth factor I (GHIIGF-I testing. Evidently, our current society is involved in a process of geneticization – the redefinition of individuals in terms of genetic codes. As such, we should take extreme care when making ethical judgments based on “scientific evidence” derived from genetic testing (typically those involving different biomarkers such as DNA, RNA, chromosomes, and proteins in relation to genetic abnormalities that could predict current or future diseases. In this situation, the understanding of bioethics is of utmost importance.

  16. FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment

    Directory of Open Access Journals (Sweden)

    Arianna Smerieri

    2014-10-01

    Full Text Available Cystic fibrosis-related diabetes is to date the most frequent complication in cystic fibrosis (CF. The mechanisms underlying this condition are not well understood, and a possible role of insulin resistance is debated. We investigated insulin signal transduction in CF. Total insulin receptor, IRS1, p85 PI3K, and AKT contents were substantially normal in CF cells (CFBE41o-, whereas winged helix forkhead (FOXO1 contents were reduced both in baseline conditions and after insulin stimulation. In addition, CF cells showed increased ERK1/2, and reduced β2 arrestin contents. No significant change in SOCS2 was observed. By using a CFTR inhibitor and siRNA, changes in FOXO1 were related to CFTR loss of function. In a CF-affected mouse model, FOXO1 content was reduced in the muscle while no significant difference was observed in liver and adipose tissue compared with wild-type. Insulin-like growth factor 1 (IGF-I increased FOXO1 content in vitro and in vivo in muscle and adipose tissue. In conclusion; we present the first description of reduced FOXO1 content in CF, which is compatible with reduced gluconeogenesis and increased adipogenesis, both features of insulin insensitivity. IGF-I treatment was effective in increasing FOXO1, thereby suggesting that it could be considered as a potential treatment in CF patients possibly to prevent and treat cystic fibrosis-related diabetes.

  17. The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.

    Science.gov (United States)

    Morales-García, Jose A; de la Fuente Revenga, Mario; Alonso-Gil, Sandra; Rodríguez-Franco, María Isabel; Feilding, Amanda; Perez-Castillo, Ana; Riba, Jordi

    2017-07-13

    Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

  18. Exercise-dependent IGF-I, IGFBPs, and type I collagen changes in human peritendinous connective tissue determined by microdialysis

    DEFF Research Database (Denmark)

    Olesen, Jens L; Heinemeier, Katja M; Gemmer, Carsten

    2007-01-01

    -like growth factor I (IGF-I) and its binding proteins (IGFBPs), which are known to stimulate collagen production in animal tendons, may regulate the translation of mechanical loading to collagen synthesis. Systemic and tissue levels of IGF-I, IGFBP, and type I collagen metabolism markers [procollagen I COOH......-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen] were measured by microdialysis in peritendinous tissue of the human Achilles tendon in an exercise group (performing a 36-km run, n = 6) and a control group (no intervention, n = 6). An increase in local PICP concentration was seen in both...... and exercise groups after 48 h (P tissue in response to prolonged mechanical loading with part of the increase due to trauma from the sampling...

  19. Sublethal transient global ischemia stimulates migration of neuroblasts and neurogenesis in mice.

    Science.gov (United States)

    Li, Ying; Yu, Shan Ping; Mohamad, Osama; Genetta, Thomas; Wei, Ling

    2010-09-01

    Increasing evidence has shown the potential of neuronal plasticity in adult brain after injury. Neural proliferation can be triggered by a focal sublethal ischemic preconditioning event; whether mild global ischemia could cause neurogenesis has been not clear. The present study investigated stimulating effects of sublethal transient global ischemia (TGI) on endogenous neurogenesis and neuroblast migration in the subventricular zone (SVZ), dentate gyrus, and peri-infarct areas of the adult cortex. Adult mice of 129S2/Sv strain were subjected to 8-min bilateral common carotid artery ligation followed by 5-bromo-2'-deoxyuridine (BrdU; 50 mg/kg, intraperitoneal) administration every day until being sacrificed at 1-21 days after reperfusion. The mild TGI did not induce neuronal cell death for up to 7 days after TGI, as evidenced by negative terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining among NeuN-positive cells in the hippocampus and neocortex. In TGI animals, BrdU staining revealed enhanced proliferation of neuroblasts and their migration track from the SVZ into the striatum and neocortex. In the corpus callosum, there were more BrdU-positive cells in the TGI group in the first 2 days. Increasing numbers of BrdU-positive cells were seen 7-21 days later in the striatum and cortex of TGI mice. The cortex of TGI animals showed increased expression of erythropoietin, erythropoietin receptor, fibroblast growth factor 2, vascular endothelial growth factor, and phosphorylated Jun N-terminal kinase; the expression was peaked 2 to 3 days after reperfusion. BrdU and NeuN double staining in the dentate gyrus, striatum, and cortex implied increased neurogenesis induced by the TGI preconditioning. Doublecortin (DCX)-positive cells increased in the cortex of TGI mice, localized to cortical layers II, III, and V, and many stained positive for the mature neuronal markers NeuN, neurofilament, N-methyl-d-aspartic acid receptor subunit gene NR1, or the

  20. IGF-I bioactivity in an elderly population: Relation to insulin sensitivity, insulin levels, and the metabolic syndrome

    NARCIS (Netherlands)

    M.P. Brugts (Michael); C.M. van Duijn (Cock); L.J. Hofland (Leo); J.C.M. Witteman (Jacqueline); S.W.J. Lamberts (Steven); J.A.M.J.L. Janssen (Joseph)

    2010-01-01

    textabstractOBJECTIVE - There is a complex relationship between IGF-I, IGF binding proteins, growth hormone, and insulin. The IGF-I kinase receptor activation assay (KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of IGF-I bioactivity might br

  1. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan); Takahashi, Yutaka, E-mail: takahash@med.kobe-u.ac.jp [Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe (Japan)

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  2. GH/IGF-I axis and matrix adaptation of the musculotendinous tissue to exercise in humans

    DEFF Research Database (Denmark)

    Heinemeier, K M; Mackey, Abigail; Doessing, S

    2012-01-01

    Exercise is not only associated with adaptive responses within skeletal muscle fibers but also with induction of collagen synthesis both in muscle and adjacent connective tissue. Additionally, exercise and training leads to activation of the systemic growth hormone/insulin-like growth factor I axis...... (GH/IGF-I), as well as increased local IGF-I expression. Studies in humans with pathologically high levels of GH/IGF-I, and in healthy humans who receive either weeks of GH administration or acute injection of IGF-I into connective tissue, demonstrate increased expression and synthesis of collagen...

  3. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC-.

    Science.gov (United States)

    Yang, Yuzhe; Yee, Douglas

    2014-04-15

    Insulin-like growth factors (IGF) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC(-), which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER(+)) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacologic inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the type I IGF receptor (IGF-IR) in a manner reversed by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER(+) breast cancer cells by regulating xC(-) transporter function to protect cancer cells from ROS in an IRS-1-dependent manner. Our findings suggest that inhibiting xC(-) transporter function may synergize with modalities that target the IGF-IR to heighten their therapeutic effects.

  4. Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory.

    Science.gov (United States)

    Li, Endan; Chung, Hyunju; Kim, Yumi; Kim, Dong Hyun; Ryu, Jong Hoon; Sato, Takahiro; Kojima, Masayasu; Park, Seungjoon

    2013-01-01

    Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of bromodeoxyuridine (BrdU)-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.

  5. RELEASE OF PROGESTERONE AND TESTOSTERONE BY OVARIAN GRANULOSA CELLS AFTER ADDITION OF T-2 TOXIN AND ITS COMBINATION WITH GROWTH FACTOR IGF-I

    Directory of Open Access Journals (Sweden)

    Nora Maruniaková

    2013-02-01

    Full Text Available The aim of the present study was to examine the effect of T-2 toxin and combination of this toxin with growth factor IGF-I on secretion of ovarian hormones progesterone P4 and testosterone by ovarian granulosa cells (GCs of gilts. Ovarian granulosa cells were incubated withouth (control or with treatments at various doses for 48h: T-2 toxin (10, 100 and 1000 ng.ml-1 / T-2 toxin (10,100 and 1000 ng.ml-1 plus IGF-I (100 ng.ml-1. Progesterone and testosterone were determined by RIA. Progesterone release by GCs was significantly (P<0.05 inhibited after addition of T-2 toxin at all doses 10, 100, 1000 ng.ml-1. Release of testosterone was inhibited after addition of T-2 toxin at 10 and 100 ng.ml-1. On the other hand significant (P<0.05 stimulation of testosterone release at the highest dose 1000 ng.ml-1 was observed. T-2 toxin in combination with growth factor IGF-I inhibited significantly (P<0.05 progesterone release by GCs at all used doses 10, 100, 1000 ng.ml-1of T-2 toxin with 100 ng.ml-1 of IGF-I. Testosterone release was significantly (P<0.05 inhibited after addition of doses 100, 1000 ng.ml-1 of T-2 toxin with 100 ng.ml-1of IGF-I. Our in vitro results examined the dose-dependent effect of T-2 toxin and its combination with growth factor IGF-I on release of progesterone and testosterone by ovarian granulosa cells.

  6. DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells.

    Science.gov (United States)

    Le, Hanh; Arnold, Julia T; McFann, Kimberly K; Blackman, Marc R

    2006-05-01

    Prostate cancer is one of the four most common cancers in the United States, affecting one of six men. Increased serum levels of androgens and IGF-I are associated with an augmented risk of prostate cancer. Dihydrotestosterone (DHT) and testosterone (T) stimulate prostate cancer cell growth, development, and function, whereas the effects of DHT and T in prostate stromal cells, and of dehydroepiandrosterone (DHEA) in prostate cancer or stromal cells, are uncertain. We investigated the actions of DHT, T, DHEA, and estradiol (E2) on insulin-like growth factor (IGF)-I, IGF-II, IGF-I receptor (R), IGF-binding protein (IGFBP)-2, IGFBP-3, and IGFBP-5 in primary cultures of human prostatic stromal cells by assessing cell proliferation, mRNA expression, and protein secretion by MTT growth assay, quantitative real-time PCR, and ELISA, respectively. DHT and T each increased IGF-I (7-fold) and decreased IGFBP-3 (2-fold) mRNA expression and protein secretion in a dose- and time-dependent manner and increased IGFBP-2 (2-fold) mRNA in a dose- and time-dependent manner. DHEA and E2 did not significantly alter these measures. Flutamide abolished the DHT-modulated increases in IGF-I and IGFBP-2, suggesting that the influences of DHT and T on these measures were androgen receptor mediated. None of the four steroids significantly affected IGF-IR, IGF-II, or IGFBP-5 mRNA levels or stromal cell proliferation. The effects of DHT on IGF-I, IGFBP-2, and IGFBP-3 were more pronounced in stromal cultures that did not express desmin. These data suggest that DHT and T promote prostate growth partly via modulation of the stromal cell IGF axis, with potential paracrine effects on prostate epithelial cells.

  7. Improvements in Memory after Medial Septum Stimulation Are Associated with Changes in Hippocampal Cholinergic Activity and Neurogenesis

    Directory of Open Access Journals (Sweden)

    Da Un Jeong

    2014-01-01

    Full Text Available Deep brain stimulation (DBS has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS electrode implantation (sham stimulation; group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.

  8. Optogenetic stimulation of glutamatergic neuronal activity in the striatum enhances neurogenesis in the subventricular zone of normal and stroke mice.

    Science.gov (United States)

    Song, Mingke; Yu, Shan Ping; Mohamad, Osama; Cao, Wenyuan; Wei, Zheng Zachory; Gu, Xiaohuan; Jiang, Michael Qize; Wei, Ling

    2017-02-01

    Neurogenesis in the subventricular zone (SVZ) of the adult brain may contribute to tissue repair after brain injuries. Whether SVZ neurogenesis can be upregulated by specific neuronal activity in vivo and promote functional recovery after stroke is largely unknown. Using the spatial and cell type specific optogenetic technique combined with multiple approaches of in vitro, ex vivo and in vivo examinations, we tested the hypothesis that glutamatergic activation in the striatum could upregulate SVZ neurogenesis in the normal and ischemic brain. In transgenic mice expressing the light-gated channelrhodopsin-2 (ChR2) channel in glutamatergic neurons, optogenetic stimulation of the glutamatergic activity in the striatum triggered glutamate release into SVZ region, evoked membrane currents, Ca(2+) influx and increased proliferation of SVZ neuroblasts, mediated by AMPA receptor activation. In ChR2 transgenic mice subjected to focal ischemic stroke, optogenetic stimuli to the striatum started 5days after stroke for 8days not only promoted cell proliferation but also the migration of SVZ neuroblasts into the peri-infarct cortex with increased neuronal differentiation and improved long-term functional recovery. These data provide the first morphological and functional evidence showing a unique striatum-SVZ neuronal regulation via a semi-phasic synaptic mechanism that can boost neurogenic cascades and stroke recovery. The benefits from stimulating endogenous glutamatergic activity suggest a novel regenerative strategy after ischemic stroke and other brain injuries.

  9. Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

    Science.gov (United States)

    Klein, C.; Schreyer, S.; Kohrs, F. E.; Elhamoury, P.; Pfeffer, A.; Munder, T.; Steiner, B.

    2017-01-01

    In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3-dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL. PMID:28345617

  10. Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development

    Institute of Scientific and Technical Information of China (English)

    Yongmei Wang; Daniel D. Bikle; Wenhan Chang

    2013-01-01

    Insulin-like growth factor-I (IGF-I) regulates cell growth, survival, and differentiation by acting on the IGF-I receptor, (IGF-IR)-a tyrosine kinase receptor, which elicits diverse intracellular signaling responses. All skeletal cells express IGF-I and IGF-IR. Recent studies using tissue/cell-specific gene knockout mouse models and cell culture techniques have clearly demonstrated that locally produced IGF-I is more critical than the systemic IGF-I in supporting embryonic and postnatal skeletal development and bone remodeling. Local IGF-I/IGF-IR signaling promotes the growth, survival and differentiation of chondrocytes and osteo-blasts, directly and indirectly, by altering other autocrine/paracrine signaling pathways in cartilage and bone, and by enhancing interactions among these skeletal cells through hormonal and physical means. Moreover, local IGF-I/IGF-IR signaling is critical for the anabolic bone actions of growth hormone and parathyroid hormone. Herein, we review evidence supporting the actions of local IGF-I/IGF-IR in the above aspects of skeletal development and remodeling.

  11. Rescue of ligand binding of a mutant IGF-I receptor by complementation

    DEFF Research Database (Denmark)

    Chakravarty, Arjun Anders; Hinrichsen, Jane; Whittaker, Linda;

    2005-01-01

    The IGF-I receptor binds IGF-I with complex kinetics characterized by a curvilinear Scatchard plot, suggesting receptor heterogeneity and apparent negative cooperativity. To explore the molecular mechanisms underlying these properties, we have characterized the binding of a hybrid receptor formed...

  12. Human conditions of insulin-like growth factor-I (IGF-I deficiency

    Directory of Open Access Journals (Sweden)

    Puche Juan E

    2012-11-01

    Full Text Available Abstract Insulin-like growth factor I (IGF-I is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions. IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.

  13. Maternal BMI, IGF-I Levels, and Birth Weight in African American and White Infants

    Directory of Open Access Journals (Sweden)

    Adriana C. Vidal

    2013-01-01

    Full Text Available At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile, those with higher IGF-I levels (>3rd tertile were 130 g heavier at birth, (β-coefficient=230, se=58.0, P=0.0001, after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30 kg/m2; the cross product term for IGF-I and maternal BMI was statistically significant (P≤0.0004. Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity.

  14. Conditionally immortalized human pancreatic stellate cell lines demonstrate enhanced proliferation and migration in response to IGF-I

    Energy Technology Data Exchange (ETDEWEB)

    Rosendahl, Ann H., E-mail: ann.rosendahl@med.lu.se [Lund University, Department of Clinical Sciences Lund, Division of Surgery, Lund (Sweden); Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund (Sweden); Gundewar, Chinmay; Said Hilmersson, Katarzyna [Lund University, Department of Clinical Sciences Lund, Division of Surgery, Lund (Sweden); Ni, Lan; Saleem, Moin A. [University of Bristol, School of Clinical Sciences, Children' s Renal Unit and Academic Renal Unit, Bristol (United Kingdom); Andersson, Roland [Lund University, Department of Clinical Sciences Lund, Division of Surgery, Lund (Sweden)

    2015-01-15

    Pancreatic stellate cells (PSCs) play a key role in the dense desmoplastic stroma associated with pancreatic ductal adenocarcinoma. Studies on human PSCs have been minimal due to difficulty in maintaining primary PSC in culture. We have generated the first conditionally immortalized human non-tumor (NPSC) and tumor-derived (TPSC) pancreatic stellate cells via transformation with the temperature-sensitive SV40 large T antigen and human telomerase (hTERT). These cells proliferate at 33°C. After transfer to 37°C, the SV40LT is switched off and the cells regain their primary PSC phenotype and growth characteristics. NPSC contained cytoplasmic vitamin A-storing lipid droplets, while both NPSC and TPSC expressed the characteristic markers αSMA, vimentin, desmin and GFAP. Proteome array analysis revealed that of the 55 evaluated proteins, 27 (49%) were upregulated ≥3-fold in TPSC compared to NPSC, including uPA, pentraxin-3, endoglin and endothelin-1. Two insulin-like growth factor binding proteins (IGFBPs) were inversely expressed. Although discordant IGFBP-2 and IGFBP-3 levels, IGF-I was found to stimulate proliferation of both NPSC and TPSC. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. In conclusion, these cells provide a unique resource that will facilitate further study of the active stroma compartment associated with pancreatic cancer. - Highlights: • Generation of human conditionally immortalized human pancreatic stellate cell lines. • Temperature-sensitive SV40LT allows switch to primary PSC phenotype characteristics. • Proteome profiling revealed distinct expression patterns between TPSC and NPSC. • Enhanced IGF-I-stimulated proliferation and motility by TPSC compared to NPSC.

  15. Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways

    DEFF Research Database (Denmark)

    Cypess, Aaron M; Zhang, Hongbin; Schulz, Tim J

    2011-01-01

    Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from brown preadipocytes to mature adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study...... with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of brown preadipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase...

  16. The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome.

    Science.gov (United States)

    Laron, Z

    1999-12-01

    Fifty patients with primary GH resistance (Laron syndrome) due to molecular defects of the GH receptor or post-receptor pathways were followed from infancy through adulthood. This condition leading to long-term insulin-like growth factor-I (IGF-I) deprivation caused marked growth retardation (-4 to 8 height SD), acromicia, organomicria, retarded development of the skeletal and muscular systems, a small cranium, slow motor development, and impairment of intellectual development in some of the patients. In addition, there was progressive obesity, insulin resistance, a tendency for hypoglycemia, followed later in life by hypercholesterolemia and by glucose intolerance and even diabetes. IGF-I treatment of children with Laron syndrome, by our and other groups (150-240 microg/day sc), stimulated growth (8 cm in the first year and 4-5 cm in the following years) and normalized the biochemical abnormalities. Overdosage led to adverse effects such as hypoglycemia, edema, swelling of soft tissues, and hyperandrogenism. It is concluded that primary IGF-I deprivation induces severe auxological, biochemical, and hormonal changes, the only treatment being biosynthetic IGF-I administration.

  17. Large scale, in situ isolation of periplasmic IGF-I from E. coli.

    Science.gov (United States)

    Hart, R A; Lester, P M; Reifsnyder, D H; Ogez, J R; Builder, S E

    1994-11-01

    Human insulin-like growth factor I (IGF-I) accumulates in both folded and aggregated forms in the fermentation medium and cellular periplasmic space when expressed in E. coli with an endogenous secretory signal sequence. Due to its heterogeneity in form and location, low yield of IGF-I was obtained using a typical refractile body recovery strategy. To enhance recovery yield, a new procedure was developed to solubilize and extract IGF-I from cells while in fermentation broth. This method, called in situ solubilization, involves addition of chaotrope and reductant to alkaline fermentation broth and provides recovery of about 90% of all IGF-I in an isolated supernatant. To further enhance recovery, a new aqueous two-phase extraction procedure was developed which partitions soluble non-native IGF-I and biomass solids into separate liquid phases. This two-phase extraction procedure involves addition of polymer and salt to the solubilization mixture and provides about 90% recovery of solubilized IGF-I in the light phase. The performance of the solubilization and aqueous extraction procedures is reproducible at scales ranging from 10 to 1000 liters and provides a 70% cumulative recovery yield of IGF-I in the isolated light phase. The procedure provides significant initial IGF-I purification since most host proteins remain cell associated during solubilization and are enriched in heavy phase. ELISA analysis for E. coli proteins indicates that 97% of the protein in the light phase is IGF-I. Together, the techniques of in situ solubilization and aqueous two-phase extraction provide a new, high yield approach for isolating recombinant protein which is accumulated in more than one form during fermentation.

  18. Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy.

    Science.gov (United States)

    Wang, S N; Lapage, J; Hirschberg, R

    1999-08-01

    Insulin-like growth factor-I (IGF-I) is found in plasma at relatively high levels (approximately 40 nmol/L) but 99% is bound to specific binding proteins to form high-molecular-weight complexes of approximately 50 and approximately 150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-I-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-I receptors in apical tubular membranes. By this route, ultrafiltered IGF-I may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-I levels (227 +/- 34 ng/mL) were reduced as compared with control levels (319 +/- 33 ng/mL, P = .05), and IGF-binding protein-2 (IGFBP-2) is increased about 2-fold. In diabetic rats, IGF-I undergoes glomerular ultrafiltration and is present in proximal tubular fluid that was collected by nephron micropuncture at 2.54 +/- 0.54 nmol/L but is below the detection limit in tubular fluid from normal rats. IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 are all present in diabetic rat glomerular ultrafiltrate, but IGFBP-2 levels are greater than those of each of the other three IGFBPs. Neither recombinant human IGF-I (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-I and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of 22Na+ in distal tubule-like A6 cells through mechanisms involving apical IGF-I receptors. In normal rats, luminal infusion with rhIGF-I or with diabetic rat glomerular ultrafiltrate into late proximal tubules increases distal tubular Na+ absorption. These findings indicate that diabetic glomerular sclerosis causes glomerular ultrafiltration of IGF-I, and they suggest that tubular fluid IGF-I may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.

  19. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Directory of Open Access Journals (Sweden)

    Sanberg Paul R

    2008-02-01

    Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

  20. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Science.gov (United States)

    Bachstetter, Adam D; Pabon, Mibel M; Cole, Michael J; Hudson, Charles E; Sanberg, Paul R; Willing, Alison E; Bickford, Paula C; Gemma, Carmelina

    2008-01-01

    Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain. PMID:18275610

  1. IGF-IR signal transduction protein content and its activation by IGF-I in human placentas: relationship with gestational age and birth weight.

    Science.gov (United States)

    Iñiguez, Germán; Castro, Juan José; Garcia, Mirna; Kakarieka, Elena; Johnson, M Cecilia; Cassorla, Fernando; Mericq, Verónica

    2014-01-01

    The human placenta expresses the IGF-I and IGF-IR proteins and their intracellular signal components (IRS-1, AKT and mTOR). The aim of this study was to assess the IGF-IR content and activation of downstream signaling molecules in placentas from newborns who were classified by gestational age and birth weight. We studied placentas from 25 term appropriate (T-AGA), 26 term small (T-SGA), 22 preterm AGA (PT-AGA), and 20 preterm SGA (PT-SGA) newborns. The total and phosphorylated IGF-IR, IRS-1, AKT, and mTOR contents were determined by Western Blot and normalized by actin or with their respective total content. The effect of IGF-I was determined by stimulating placental explants with recombinant IGF-I 10-8 mol/L for 15, 30, and 60 minutes. The IGF-IR content was higher in T-SGA compared to T-AGA placentas, and the IRS-1 content was higher in PT-placentas compared with their respective T-placentas. The effect of IGF-I on the phosphorylated forms of IGF-IR was increased in T-SGA (150%) and PT-SGA (300%) compared with their respective AGA placentas. In addition, AKT serine phosphorylation was higher in PT-SGA compared to PT-AGA and T-SGA placentas (90% and 390% respectively). The higher protein content and response to IGF-I of IGF-IR, IRS-1, and AKT observed in SGA placentas may represent a compensatory mechanism in response to fetal growth restriction.

  2. IGF-IR signal transduction protein content and its activation by IGF-I in human placentas: relationship with gestational age and birth weight.

    Directory of Open Access Journals (Sweden)

    Germán Iñiguez

    Full Text Available The human placenta expresses the IGF-I and IGF-IR proteins and their intracellular signal components (IRS-1, AKT and mTOR. The aim of this study was to assess the IGF-IR content and activation of downstream signaling molecules in placentas from newborns who were classified by gestational age and birth weight. We studied placentas from 25 term appropriate (T-AGA, 26 term small (T-SGA, 22 preterm AGA (PT-AGA, and 20 preterm SGA (PT-SGA newborns. The total and phosphorylated IGF-IR, IRS-1, AKT, and mTOR contents were determined by Western Blot and normalized by actin or with their respective total content. The effect of IGF-I was determined by stimulating placental explants with recombinant IGF-I 10-8 mol/L for 15, 30, and 60 minutes.The IGF-IR content was higher in T-SGA compared to T-AGA placentas, and the IRS-1 content was higher in PT-placentas compared with their respective T-placentas. The effect of IGF-I on the phosphorylated forms of IGF-IR was increased in T-SGA (150% and PT-SGA (300% compared with their respective AGA placentas. In addition, AKT serine phosphorylation was higher in PT-SGA compared to PT-AGA and T-SGA placentas (90% and 390% respectively.The higher protein content and response to IGF-I of IGF-IR, IRS-1, and AKT observed in SGA placentas may represent a compensatory mechanism in response to fetal growth restriction.

  3. ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs.

    Science.gov (United States)

    Andres-Mach, Marta; Haratym-Maj, Agnieszka; Zagaja, Miroslaw; Rola, Radoslaw; Maj, Maciej; Chrościńska-Krawczyk, Magdalena; Luszczki, Jarogniew J

    2015-10-22

    Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2'-chloroethylamide--a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells' proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10mg/kg), ACEA (10mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride--a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells' population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to

  4. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats.

    Science.gov (United States)

    Speisman, Rachel B; Kumar, Ashok; Rani, Asha; Foster, Thomas C; Ormerod, Brandi K

    2013-02-01

    We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18mo upon arrival). Twelve weeks after conditioned running or control group assignment, the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12days after behavioral testing and killed 3weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24h water maze discrimination index (DI) scores and 24h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found novel positive correlations between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. Our correlational data begin to provide a framework for systematically manipulating these immune and neuroimmune signaling molecules to test their effects on cognition and neurogenesis across lifespan in future experiments. Published by Elsevier Inc.

  5. Long-term IGF-I treatment of children with Laron syndrome increases adiposity.

    Science.gov (United States)

    Laron, Zvi; Ginsberg, Shira; Lilos, Pnina; Arbiv, Mira; Vaisman, Nahum

    2006-02-01

    Laron syndrome (LS) is an autosomal recessive disease caused by deletions or mutations in the GH receptor gene leading to an inability of insulin-like growth factor I (IGF-I) generation. Among the major resulting body changes are dwarfism and obesity. The only effective treatment is daily administration of biosynthetic IGF-I. Body composition determination by DEXA (dual energy X-ray absorptiometry) of three girls with LS treated by IGF-I for 1, 3 and 11 1/2 years, respectively, revealed that concomitantly with the increase in growth there was a significant increase in body adipose tissue to double or triple the normal values. Due to the underdevelopment of the muscular and skeletal systems body mass index (BMI) did not accurately reflect the degree of obesity. In conclusion, IGF-I similar to insulin, exerts an adipogenic effect.

  6. Reference Values for IGF-I Serum Concentrations: Comparison of Six Immunoassays.

    Science.gov (United States)

    Chanson, Philippe; Arnoux, Armelle; Mavromati, Maria; Brailly-Tabard, Sylvie; Massart, Catherine; Young, Jacques; Piketty, Marie-Liesse; Souberbielle, Jean-Claude

    2016-09-01

    Measurement of IGF-I is essential for diagnosis and management of patients with disorders affecting the somatotropic axis. However, even when IGF-I kit manufacturers follow recent consensus guidelines, different kits can give very different results for a given sample. We sought to establish normative data for six IGF-I assay kits based on a large random sample of the French general adult population. In a cross-sectional multicenter cohort study, we measured IGF-I in 911 healthy adults (18-90 years) with six immunoassays (iSYS, LIAISON XL, IMMULITE, IGFI RIACT, Mediagnost ELISA, and Mediagnost RIA). Pairwise concordance between assays was assessed with Bland-Altman plots for both IGF-1 raw data and standard deviation scores (SDS), as well as with the percentage of observed agreement and the weighted Kappa coefficient for categorized IGF-I SDS. Normative data included the range of values (2.5-97.5 percentiles) given by the six IGF-I assays according to age group and sex. A formula for SDS calculation is provided. Although the lower limits of the reference intervals of the six assays were similar, the upper limits varied markedly. Pairwise concordances were moderate to good (0.38-0.70). Despite being obtained in the same healthy population, the reference intervals of the six commercial IGF-1 assay kits showed noteworthy differences. Agreement between methods was moderate to good.

  7. Association between DLK1 and IGF-I gene expression and meat quality in sheep.

    Science.gov (United States)

    Su, R; Sun, W; Li, D; Wang, Q Z; Lv, X Y; Musa, H H; Chen, L; Zhang, Y F; Wu, W Z

    2014-12-04

    The aim of the present study was to detect delta-like 1 ho-molog (DLK1) and insulin-like growth factor-I (IGF-I) gene expression in the longissimus dorsi of Hu sheep at different growth stages and study the association between these genes and meat quality. The diameter and density of muscle fibers and tenderness of the longissimus dorsi were measured. Growth stage, but not sex, significantly affected DLK1 and IGF-I expression. DLK1 and IGF-I expression in the sheep longissimus dorsi gradually increased with growth, but also decreased during some periods. These results suggest that different growth stages significantly affect DLK1 and IGF-I gene expression in sheep muscle tissue. The ex-pression of DLK1 and IGF-I genes were positively and significantly (P < 0.01) correlated with muscle fiber diameter and muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. Muscle fiber diameter was positively and significantly (P < 0.01) correlated with muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. In addition, DLK-1 expression was significantly (P < 0.01) and positively correlated with IGF-I expression.

  8. IGF-I Polymorphism is Associated with Lean Mass, Exercise Economy and Performance Among Premenopausal Women

    Science.gov (United States)

    López-Alarcón, Mardya; Hunter, Gary R.; Gower, Barba A.; Fernández, José R.

    2007-01-01

    Background We undertook this study to investigate the association of a genetic polymorphism of the insulin-like growth factor, IGF-I189, on body composition, exercise performance and exercise economy, after controlling for the independent effect of race as assessed by African genetic admixture (AFADM). Methods A total of 114 premenopausal sedentary women were genotyped for IGF-I189, obtaining measures of fat mass, lean body mass, VO2 during cycling and stairclimbing, time on treadmill and leg strength. A quantitative value for AFADM was derived from genotypic information of approximately 40 ancestry informative markers and used as covariate in statistical models. Results After adjusting for AFADM, IGF-I189 was negatively associated with lean body mass (p = 0.029) and lean leg mass (p = 0.050). Leg strength was not associated with the presence/absence of IGF-I189 (p = 0.380), but carriers of the allele demonstrated a longer time on the treadmill (p = 0.015) after adjusting for AFADM. There was also a negative relationship between oxygen uptake during cycling and presence of the IGF-I189 independent of AFADM (p = 0.010). Conclusion Independent of AFADM, individuals with IGF-I189 are more likely to have low leg lean mass and to perform better in activities requiring exercise economy and endurance performance. PMID:17174724

  9. High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats.

    Science.gov (United States)

    Luo, Jing; Zheng, Haiqing; Zhang, Liying; Zhang, Qingjie; Li, Lili; Pei, Zhong; Hu, Xiquan

    2017-02-20

    Repetitive transcranial magnetic stimulation (rTMS) has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS) on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO), following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX), NeuN and glial fibrillary acidic protein (GFAP), and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.

  10. High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats

    Directory of Open Access Journals (Sweden)

    Jing Luo

    2017-02-01

    Full Text Available Repetitive transcranial magnetic stimulation (rTMS has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF/tropomyosin-related kinase B (TrkB pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO, following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX, NeuN and glial fibrillary acidic protein (GFAP, and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats.

  11. High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Functional Recovery by Enhancing Neurogenesis and Activating BDNF/TrkB Signaling in Ischemic Rats

    Science.gov (United States)

    Luo, Jing; Zheng, Haiqing; Zhang, Liying; Zhang, Qingjie; Li, Lili; Pei, Zhong; Hu, Xiquan

    2017-01-01

    Repetitive transcranial magnetic stimulation (rTMS) has rapidly become an attractive therapeutic approach for stroke. However, the mechanisms underlying this remain elusive. This study aimed to investigate whether high-frequency rTMS improves functional recovery mediated by enhanced neurogenesis and activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway and to compare the effect of conventional 20 Hz rTMS and intermittent theta burst stimulation (iTBS) on ischemic rats. Rats after rTMS were sacrificed seven and 14 days after middle cerebral artery occlusion (MCAO), following evaluation of neurological function. Neurogenesis was measured using specific markers: Ki67, Nestin, doublecortin (DCX), NeuN and glial fibrillary acidic protein (GFAP), and the expression levels of BDNF were visualized by Western blotting and RT-PCR analysis. Both high-frequency rTMS methods significantly improved neurological function and reduced infarct volume. Moreover, 20 Hz rTMS and iTBS significantly promoted neurogenesis, shown by an increase of Ki67/DCX, Ki67/Nestin, and Ki67/NeuN-positive cells in the peri-infarct striatum. These beneficial effects were accompanied by elevated protein levels of BDNF and phosphorylated-TrkB. In conclusion, high-frequency rTMS improves functional recovery possibly by enhancing neurogenesis and activating BDNF/TrkB signaling pathway and conventional 20 Hz rTMS is better than iTBS at enhancing neurogenesis in ischemic rats. PMID:28230741

  12. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

    Science.gov (United States)

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I. PMID:26448623

  13. Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection.

    Science.gov (United States)

    Guha, Nishan; Cowan, David A; Sönksen, Peter H; Holt, Richard I G

    2013-12-01

    To athletes, insulin-like growth factor-I (IGF-I) is an attractive performance-enhancing drug, particularly as an alternative to growth hormone (GH) because IGF-I mediates many of the anabolic actions of GH. IGF-I has beneficial effects on muscle protein synthesis and glycogen storage that could enhance performance in several sporting disciplines. Recombinant human IGF-I (rhIGF-I) is used in clinical practice, but a variety of IGF-I compounds and IGF-I analogues are also advertised on the internet and many have been available on the black market for several years. Although methods for detecting GH misuse are now well established and there have been several cases in which athletes have tested positive for GH, no test is yet in place for detecting IGF-I misuse. The GH-2004 research group has been investigating methods for detection of IGF-I misuse and a test is being developed on the basis of the principles of the successful GH-2000 marker method, in which markers from the IGF axis and markers of collagen and bone turnover are used to detect GH misuse. Commercial immunoassays for these markers have been validated for anti-doping purposes but new methods, including IGF-I measurement by use of mass spectrometry, should improve the performance of the tests and help in the detection of athletes who are doping with these peptide hormones.

  14. Favorable prognostic value of SOCS2 and IGF-I in breast cancer

    Directory of Open Access Journals (Sweden)

    Daxenbichler Günter

    2007-07-01

    Full Text Available Abstract Background Suppressor of cytokine signaling (SOCS proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer. Methods We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry. Results SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015 and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026. In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002. Conclusion This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I

  15. Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays; Improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand

    Energy Technology Data Exchange (ETDEWEB)

    Bang, P.; Eriksson, U.; Wivall, I.-L.; Hall, K. (Department of Endocrinology, Karolinska Institute, Stockholm (Sweden)); Sara, V. (Department of Pathology, Karolinska Institute, Stockholm (Sweden))

    1991-01-01

    Insulin-like growth factor binding proteins interfere in the IGF-I and -II radioimmunoassays. In an attempt to overcome this problem, we have compared the use of truncated IGF-I, with reduced IGFBP affinity, and IGF-I as radioligands for IGF-I RIA measurements in serum separated by acid gel filtration or acid ethanol extraction followed by cryo-precipitation. With truncated IGF-I as radioligand the IGF-I measurements in acid gel filtrates and acid ethanol extracts were significantly correlated in healthy subjects (N=42, r=0.91, p<0.001) and in patients with acromegaly (N=10, r=0.85, p<0.01), GH deficiency (N=10, r=0.88, p<0.001) or Type I diabetes mellitus (N=10, r=0.90, p<0.001). In contrast, the IGF-I concentrations in acid ethanol extracts determined with IGF-I as radioligand did not correlate with those in acid gel filtrates using truncated IGF-I radioligand in patients with acromegaly (r=0.61, NS) or GH deficiency (r=0.46, NS). In the latter group the mean IGF-I concentrations measured in acid ethanol extracts were erroneously elevated by 112%. Low-affinity antibodies used for IGF-II RIA determinations failed to give reliable results in acid ethanol extracts from patients with Type I diabetes mellitus or GH deficiency. In conclusion, erroneously high IGF-I concentrations owing to binding of the radioligand to IGFBPs not completely removed by acid ethanol extraction can be avoided by the use of truncated IGF-I as radioligand. (author).

  16. Coordinate expression of IGF-I and its receptor during limb outgrowth.

    Science.gov (United States)

    Geduspan, J S; Padanilam, B J; Solursh, M

    1992-09-01

    The morphogenetic mechanisms involved in shaping the embyro are largely unknown. Previous studies from this laboratory suggest that the mesonephros promotes limb outgrowth in ovo in the chicken embryo and might be involved in early limb morphogenesis, since damage to the mesonephros results in truncated limbs. In limb bud organ cultures, the presence of the mesonephros promotes cartilage formation. This effect can be reproduced by exogenous IGF-I or prevented by blocking antibody to IGF-I. In order to examine the hypothesis that mesonephros-derived IGF-I is involved in the early morphogenesis of the limb, we examined the spatial and temporal expression of IGF-I and type I receptor for IGF by in situ hybridization at stages when the onset of limb development occurs. The results show that neither transcript is detected at stage 13, prior to the appearance of the limb bud; but both transcripts are detected in the mesonephros at stage 14, an early stage in limb outgrowth. The hybridization signal in the mesonephros for both transcripts increases with development and signal was codistributed as well. At stage 18 the level of receptor transcripts detected in the flank relative to the limb decreased. Thus, the temporal and spatial patterns of expression of IGF-I and its receptor are consistent with their involvement in the initiation of limb outgrowth and support the model that localized expression of a growth factor and its receptor can be involved in shaping the embryo.

  17. Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critically ill patients.

    Science.gov (United States)

    Jackson, N C; Carroll, P V; Russell-Jones, D L; Sönksen, P H; Treacher, D F; Umpleby, A M

    2000-02-01

    During critical illness glutamine deficiency may develop. Glutamine supplementation can restore plasma concentration to normal, but the effect on glutamine metabolism is unknown. The use of growth hormone (GH) and insulin-like growth factor I (IGF-I) to prevent protein catabolism in these patients may exacerbate the glutamine deficiency. We have investigated, in critically ill patients, the effects of 72 h of treatment with standard parenteral nutrition (TPN; n = 6), TPN supplemented with glutamine (TPNGLN; 0.4 g x kg(-1) x day(-1), n = 6), or TPNGLN with combined GH (0.2 IU. kg(-1). day(-1)) and IGF-I (160 microg x kg (-1) x day(-1)) (TPNGLN+GH/IGF-I; n = 5) on glutamine metabolism using [2-(15)N]glutamine. In patients receiving TPNGLN and TPNGLN+GH/IGF-I, plasma glutamine concentration was increased (338 +/- 22 vs. 461 +/- 24 micromol/l, P requirement for glutamine in critically ill patients. Combined GH/IGF-I treatment with TPNGLN did not have adverse effects on glutamine metabolism.

  18. Free insulin-like growth factors (IGF-I and IGF-II) in human serum.

    Science.gov (United States)

    Frystyk, J; Skjaerbaek, C; Dinesen, B; Orskov, H

    1994-07-11

    Using ultrafiltration by centrifugation we have isolated the free, unbound fractions of insulin-like growth factor I and II (free IGF-I and IGF-II) in human serum. In this way near in vivo conditions could be maintained before and during isolation. The recovery was 80 to 100% in the ultrafiltrates, which contained no detectable amounts of IGF-binding proteins (IGFBPs) as measured by Western ligand blotting and IGFBP-1 and IGFBP-3 immunoassays. The concentration of free peptides was measured in two ultrasensitive non-competitive IGF-I and IGF-II time-resolved fluoroimmunoassays. We found that (i) equilibrium between free and protein-complexed IGF was strongly dependent on re-establishment of in vivo conditions (temperature, pH, ionic milieu and dilution); (ii) metabolic events (glucose load and fasting) caused significant changes in free IGF-I and IGF-II levels without concomitant changes in total circulating levels of IGFs; (iii) in 49 healthy adult subjects (20 to above 60 years) free IGF-I was inversely related to age and ranged from 950 +/- 150 ng/l (mean +/- S.E.M.) (20-30 years) to 410 +/- 70 ng/l (> 60 years). The relative percentage was, however, unchanged, being 0.38 +/- 0.02% of total IGF-I. In contrast, free IGF-II was independent of age, being 1,480 +/- 80 ng/l (approximately 0.20 +/- 0.01% of total IGF-II).

  19. Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

    Science.gov (United States)

    Laron, Z; Klinger, B; Silbergeld, A

    1999-01-01

    Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

  20. [Growth Hormone-Insulin Growth Factor I (GH-IGF-I) axis and growth].

    Science.gov (United States)

    Castell, A-L; Sadoul, J-L; Bouvattier, C

    2013-10-01

    Normal human linear growth results from an evolutionary process expressing the sum effect of multiple genes. The growth hormone (GH) - insulin like growth factor (IGF)-I axis is one of the main actors in the growth process. Defects in this axis can be responsible for short or tall stature. Short stature is defined as smaller than - 2 standard deviations (SD). It is a very common reason for consultation in pediatrics; indeed, 2.5 % of children are concerned. Multiple causes make diagnosis difficult. In this article, we detail the most common constitutional causes of small size, including those related to a defect in the GH-IGF-I axis. Then, we report, the first results of the clinical and genetic study conducted on 213 patients with gigantism. Tall stature is defined by a height superior to 2 SD. Finally, recent work linking epigenetics and growth - via signaling pathways of GH-IGF-I axis - will be presented.

  1. Detection of exogenous gene doping of IGF-I by a real-time quantitative PCR assay.

    Science.gov (United States)

    Zhang, Jin-Ju; Xu, Jing-Feng; Shen, Yong-Wei; Ma, Shi-Jiao; Zhang, Ting-Ting; Meng, Qing-Lin; Lan, Wen-Jun; Zhang, Chun; Liu, Xiao-Mei

    2017-07-01

    Gene doping can be easily concealed since its product is similar to endogenous protein, making its effective detection very challenging. In this study, we selected insulin-like growth factor I (IGF-I) exogenous gene for gene doping detection. First, the synthetic IGF-I gene was subcloned to recombinant adeno-associated virus (rAAV) plasmid to produce recombinant rAAV2/IGF-I-GFP vectors. Second, in an animal model, rAAV2/IGF-I-GFP vectors were injected into the thigh muscle tissue of mice, and then muscle and blood specimens were sampled at different time points for total DNA isolation. Finally, real-time quantitative PCR was employed to detect the exogenous gene doping of IGF-I. In view of the characteristics of endogenous IGF-I gene sequences, a TaqMan probe was designed at the junction of exons 2 and 3 of IGF-I gene to distinguish it from the exogenous IGF-I gene. In addition, an internal reference control plasmid and its probe were used in PCR to rule out false-positive results through comparison of their threshold cycle (Ct) values. Thus, an accurate exogenous IGF-I gene detection approach was developed in this study. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

  2. Cysteine induces longitudinal bone growth in mice by upregulating IGF-I.

    Science.gov (United States)

    Moon, Phil-Dong; Kim, Min-Ho; Oh, Hyun-A; Nam, Sun-Young; Han, Na-Ra; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-08-01

    Cysteine (Cys) is known to exert various effects, such as antioxidant, antipancreatitic and antidiabetic effects. However, the effects of Cys on longitudinal bone growth have not been elucidate to date. Thus, the aim of the present study was to evaluate the effects of Cys on bone growth. Growth-plate thickness and bone parameters, such as bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), connectivity density (Conn.D) and total porosity were analyzed by means of micro-computed tomography (μCT). The levels of serum insulin-like growth factor-I (IGF-I) were measured by enzyme-linked immunosorbent assay (ELISA). Hepatic IGF-I mRNA expression was analyzed by quantitative polymerase chain reaction (qPCR). The phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) was investigated by western blot analysis. Our results revealed that Cys increased IGF-I mRNA expression in HepG2 cells. The thickness of the growth plates was increased following treatment with Cys. Moreover, BV/TV, Tb.Th, TbN, Conn.D and total porosity were improved following treatment with Cys. Hepatic IGF-I mRNA expression and serum IGF-I levels were increased by Cys. The levels of phosphorylated JAK2 and STAT5 were elevated by Cys. The findings of our study indicate that Cys increases the thickness of growth plates through the upregulation of IGF-I, which results from the phosphorylation of JAK2-STAT5. Thus, our data suggest that Cys may have potential for use as a growth-promoting agent.

  3. Characterization and polymorphism screening of IGF-I and prolactin genes in Nelore heifers

    Directory of Open Access Journals (Sweden)

    Janete Apparecida Desidério Sena

    2010-01-01

    Full Text Available Insulin growth factor I (IGF-I and prolactin (PRL are peptide hormones that exert complementary effects on reproductive traits by acting on folliculogenesis. In view of the lack of information about the IGF-I and PRL genes in Bos indicus, the objective of this study was to partially characterize the promoter regions of these genes and to screen animals of different ages at first pregnancy for the presence of polymorphisms in these regions. In addition, we determined whether polymorphisms influence the regulation of the two hormone genes, evaluating their association with sexual precocity. The animals were divided into three groups according to age at first pregnancy: 1 100 heifers considered to be sexually precocious that became pregnant at 15-16 months of age, 2 100 heifers that became pregnant during the normal breeding season at 24 months of age, and 3 100 heifers that did not become pregnant until 24 months of age. For the IGF-I gene, PCR-RFLP-SnaBI analysis showed the presence of genotypes AB and BB at frequencies of 0.02 and 0.98, respectively. Sequencing of the IGF-I gene fragment revealed a single nitrogen base change from cytosine to thymine, corresponding to the restriction site of SnaBI. The polymorphisms identified in the 5’-flanking region of the IGF-I gene may serve as a basis for future studies of molecular markers in cattle. For the PRL gene, PCR-RFLP-HaeIII analysis showed the presence of only one migration pattern, a finding characterizing the region studied as monomorphic. The study of other regions in the IGF-I and PRL genes might provide molecular data that can be used in the future for the selection of sexually precocious animals.

  4. Interaction of Mechanical Load with Growth Hormone (GH) and Insulin-Like Growth Factor I (IGF-I) on Slow-Twitch Skeletal Muscle and Bone

    Science.gov (United States)

    Linderman, Jon K.; Gosselink, Kristin L.; Wang, Tommy J.; Mukku, Venkat R.; Grindeland, Richard E.

    1994-01-01

    Exogenous humoral growth factors, combined with increased mechanical loading, reportedly induce hypertrophy of fast-, but not slow-twitch skeletal muscles, and have little effect in attenuating atrophy of slow-twitch muscle associated with exposure to microgravity in animals with intact neuroendocrine systems. These observations suggest that anabolic adjuvants and muscle tension do not interact to stimulate growth or maintenance of slow-twitch skeletal muscle. The purpose of the present study was to determine whether a chronic increase in mechanical loading (synergistic ablation) or hindlimb unweighting (hindlimb suspension) interact with exogenous GH and IGF-I (Genentech, So San Francisco, CA) in the slow-twitch soleus muscles of female rats (approx. 250 g). Bilateral ablation of the plantaris and gastrocnemius muscles induced 38% and 40% increases in the absolute (mg/pair) and relative (mg/100 g body weight) weights of the soleus, respectively (p less than or = 0.05), in ambulatory rats. GH and IGF-I interacted with chronic loading to increase absolute soleus mass an additional 20% (p less than or = 0.05), and mixed and myofibrillar protein contents an additional 12% and 7%, respectively (NS). In contrast, hindlimb suspension (HLS) resulted in 20% and 18% decreases in the absolute and relative weights of the soleus, respectively (p less than or = 0.05); GH and IGF-I did not spare loss of soleus mass or protein content in HLS rats. HLS decreased tibial plate thickness approx. 11% (p less than or = 0.05), but not weights of the tibia or femus. GH and IGF-I increased tibial plate thickness approx. 30% (p less than or = 0.05), in ambulatory and HLS rats, and increased femur and tibial weights 12% (p less than or = 0.05) and 8% (NS), respectively, in ambulatory rats, but had no effect in HLS rats. Results of the present investigation suggest that GH and IGF-I can stimulate hypertrophy of slow-twitch skeletal muscle when chronically overloaded, but can also stimulate

  5. Interaction of Mechanical Load with Growth Hormone (GH) and Insulin-Like Growth Factor I (IGF-I) on Slow-Twitch Skeletal Muscle and Bone

    Science.gov (United States)

    Linderman, Jon K.; Gosselink, Kristin L.; Wang, Tommy J.; Mukku, Venkat R.; Grindeland, Richard E.

    1994-01-01

    Exogenous humoral growth factors, combined with increased mechanical loading, reportedly induce hypertrophy of fast-, but not slow-twitch skeletal muscles, and have little effect in attenuating atrophy of slow-twitch muscle associated with exposure to microgravity in animals with intact neuroendocrine systems. These observations suggest that anabolic adjuvants and muscle tension do not interact to stimulate growth or maintenance of slow-twitch skeletal muscle. The purpose of the present study was to determine whether a chronic increase in mechanical loading (synergistic ablation) or hindlimb unweighting (hindlimb suspension) interact with exogenous GH and IGF-I (Genentech, So San Francisco, CA) in the slow-twitch soleus muscles of female rats (approx. 250 g). Bilateral ablation of the plantaris and gastrocnemius muscles induced 38% and 40% increases in the absolute (mg/pair) and relative (mg/100 g body weight) weights of the soleus, respectively (p less than or = 0.05), in ambulatory rats. GH and IGF-I interacted with chronic loading to increase absolute soleus mass an additional 20% (p less than or = 0.05), and mixed and myofibrillar protein contents an additional 12% and 7%, respectively (NS). In contrast, hindlimb suspension (HLS) resulted in 20% and 18% decreases in the absolute and relative weights of the soleus, respectively (p less than or = 0.05); GH and IGF-I did not spare loss of soleus mass or protein content in HLS rats. HLS decreased tibial plate thickness approx. 11% (p less than or = 0.05), but not weights of the tibia or femus. GH and IGF-I increased tibial plate thickness approx. 30% (p less than or = 0.05), in ambulatory and HLS rats, and increased femur and tibial weights 12% (p less than or = 0.05) and 8% (NS), respectively, in ambulatory rats, but had no effect in HLS rats. Results of the present investigation suggest that GH and IGF-I can stimulate hypertrophy of slow-twitch skeletal muscle when chronically overloaded, but can also stimulate

  6. Linear growth, growth-hormone secretion and IGF-I generation in children with neglected hypothyroidism before and after thyroxine replacement.

    Science.gov (United States)

    Soliman, Ashraf T; Omar, Magdy; El Awwa, Ahmad; Rizk, Mostafa M; El Alaily, Rania K; Bedair, Elsaid M A

    2008-10-01

    We studied growth hormone (GH) stimulation and insulin-like growth factor -I (IGF-I) generation tests in 15 children with neglected congenital hypothyroidism (CH) (age = 6.4 +/- 4.2 years) and measured their growth parameters for >1 years after starting thyroxine (T4) replacement. One year after treatment, height SDS (HtSDS) increased from -4.3 +/- 2.5 to -2.7 +/- 2.3. Peak GH response to clonidine increased from 3.2 +/- 1.2 ng ml(-1) to 7.62 +/- 1.38 ng ml(-1) after treatments. Basal and peak IGF-I response to GH increased from (34.66 +/- 17.3 ng ml(-1) and 58.4 +/- 36.99 ng ml(-1), respectively) before treatment to (130.6 +/- 97.8 ng ml(-1) and 193.75 +/- 122.5 ng ml(-1), respectively). HtSDS increments were correlated significantly with basal free T4 concentrations (r = 0.622, P < 0.01). In summary, after long period of hypothyroidism, T4 replacement produced significant, although incomplete, catch-up growth through a partial recovery of GH- IGF-I axis.

  7. Improved Insulin Sensitivity during Pioglitazone Treatment Is Associated with Changes in IGF-I and Cortisol Secretion in Type 2 Diabetes and Impaired Glucose Tolerance.

    Science.gov (United States)

    Arnetz, Lisa; Rajamand Ekberg, Neda; Höybye, Charlotte; Brismar, Kerstin; Alvarsson, Michael

    2013-01-01

    Background. Hypercortisolism and type 2 diabetes (T2D) share clinical characteristics. We examined pioglitazone's effects on the GH-IGF-I and HPA axes in men with varying glucose intolerance. Methods. 10 men with T2D and 10 with IGT received pioglitazone 30-45 mg for 12 weeks. OGTT with microdialysis in subcutaneous adipose tissue and 1 μg ACTH-stimulation test were performed before and after. Glucose, insulin, IGF-I, IGFBP1, and interstitial measurements were analyzed during the OGTT. Insulin sensitivity was estimated using HOMA-IR. Results. HOMA-IR improved in both groups. IGF-I was initially lower in T2D subjects (P = 0.004) and increased during treatment (-1.4 ± 0.5 to -0.5 ± 0.4 SD; P = 0.007); no change was seen in IGT (0.4 ± 39 SD before and during treatment). Fasting glycerol decreased in T2D (P = 0.038), indicating reduced lipolysis. Fasting cortisol decreased in T2D (400 ± 30 to 312 ± 25 nmol/L; P = 0.041) but increased in IGT (402 ± 21 to 461 ± 35 nmol/L; P = 0.044). Peak cortisol was lower in T2D during treatment (599 ± 32 to 511 ± 43, versus 643 ± 0.3 to 713 ± 37 nmol/L in IGT; P = 0.007). Conclusions. Pioglitazone improved adipose tissue and liver insulin sensitivity in both groups. This may explain increased IGF-I in T2D. Pioglitazone affected cortisol levels in both groups but differently, suggesting different mechanisms for improving insulin sensitivity between T2D and IGT.

  8. Functional electrical stimulation increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of rats with stroke

    Institute of Scientific and Technical Information of China (English)

    LIU Hui-hua; XIANG Yun; YAN Tie-bin; TAN Zhi-mei; LI Sheng-huo; HE Xiao-kuo

    2013-01-01

    Background Functional electrical stimulation (FES) is known to promote the recovery of motor function in rats with ischemia and to upregulate the expression of growth factors which support brain neurogenesis.In this study,we investigated whether postischemic FES could improve functional outcomes and modulate neurogenesis in the subventricular zone (SVZ) after focal cerebral ischemia.Methods Adult male Sprague-Dawley rats with permanent middle cerebral artery occlusion (MCAO) were randomly assigned to the control group,the placebo stimulation group,and the FES group.The rats in each group were further assigned to one of four therapeutic periods (1,3,7,or 14 days).FES was delivered 48 hours after the MCAO procedure and divided into two 10-minute sessions on each day of treatment with a 10-minute rest between them.Two intraperitoneal injections of bromodeoxyuridine (BrdU) were given 4 hours apart every day beginning 48 hours after the MCAO.Neurogenesis was evaluated by immunofluorescence staining.Wnt-3 which is strongly implicated in the proliferation and differentiation of neural stem cells (NSCs) was investigated by Western blotting analysis.The data wera subjected to oneway analysis of variance (ANOVA),followed by a Tukey/Kramer or Dunnett post hoc test.Results FES significantly increased the number of BrdU-positive cells and BrdU/glial flbrillary acidic protein doublepositive neural progenitor cells in the SVZ on days 7 and 14 of the treatment (P <0.05).The number of BrdU/doublecortin (DCX) double-positive migrating neuroblast cells in the ipsilateral SVZ on day 14 of the FES treatment group ((522.77±33.32) cells/mm2) was significantly increased compared with the control group ((262.58±35.11) cells/mm2,P <0.05) and the placebo group ((266.17±47.98) cells/mm2,P <0.05).However,only a few BrdU/neuron-specific nuclear protein-positive cells were observed by day 14 of the treatment.At day 7,Wnt-3 was upregulated in the ipsilateral SVZs of the rats receiving

  9. Direct Stimulation of Adult Neural Stem/Progenitor Cells In Vitro and Neurogenesis In Vivo by Salvianolic Acid B

    Science.gov (United States)

    Zhuang, Pengwei; Zhang, Yanjun; Cui, Guangzhi; Bian, Yuhong; Zhang, Mixia; Zhang, Jinbao; Liu, Yang; Yang, Xinpeng; Isaiah, Adejobi Oluwaniyi; Lin, Yingxue; Jiang, Yongbo

    2012-01-01

    Background Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. Methodology and Principal Findings We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor), but neither U0126 (ERK inhibitor) nor DAPT (Notch inhibitor) inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. Significance Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases. PMID:22545124

  10. Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B.

    Directory of Open Access Journals (Sweden)

    Pengwei Zhuang

    Full Text Available BACKGROUND: Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. METHODOLOGY AND PRINCIPAL FINDINGS: We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs. The screening results showed that salvianolic acid B (Sal B displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor, but neither U0126 (ERK inhibitor nor DAPT (Notch inhibitor inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. SIGNIFICANCE: Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases.

  11. Acute regulation of IGF-I by alterations in post-exercise macronutrients

    Science.gov (United States)

    This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training (HIIT) protocols followed by three post-exercise ...

  12. Sleep extension increases IGF-I concentrations before and during sleep deprivation in healthy young men.

    Science.gov (United States)

    Chennaoui, Mounir; Arnal, Pierrick J; Drogou, Catherine; Sauvet, Fabien; Gomez-Merino, Danielle

    2016-09-01

    Sleep deprivation is known to suppress circulating trophic factors such as insulin-like growth factor (IGF)-I and brain-derived neurotrophic factor (BDNF). This experiment examined the effect of an intervention involving 6 nights of extended sleep before total sleep deprivation on this catabolic profile. In a randomized crossover design, 14 young men (age range: 26-37 years) were either in an extended (EXT; time in bed: 2100-0700 h) or habitual (HAB: 2230-0700 h) sleep condition, followed by 3 days in the laboratory with blood sampling at baseline (B), after 24 h of sleep deprivation (24h-SD), and after 1 night of recovery sleep (R). In the EXT condition compared with the HAB condition, free IGF-I levels were significantly higher at B, 24h-SD, and R (P sleep deprivation was for insulin levels, which were significantly higher after R compared with B. In a healthy adult, additional sleep over 1 week increased blood concentrations of the anabolic factor IGF-I before and during 24 h of sleep deprivation and after the subsequent recovery night without effects on BDNF. With further research, these findings may prove to be important in guiding effective lifestyle modifications to limit physical or cognitive deficits associated with IGF-I decrease with age.

  13. IGF-I en la homeostasia cerebral: implicaciones patológicas

    Directory of Open Access Journals (Sweden)

    Ignacio Torres

    2005-03-01

    Full Text Available El factor de crecimiento de la familia de la insulina tipo I (IGF-I es una proteína sérica especialmente abundante fabricada principalmente en el hígado; su producción está regulada por la hormona de crecimiento (GH hipofisario.

  14. Effect of Insulin Infusion on insulin-like growth factor I (IGF-I) during Hemodialysis

    DEFF Research Database (Denmark)

    Reinhard, Mark; Frystyk, Jan; Bjerre, Mette

    2012-01-01

    Background: Hemodialysis (HD) is a catabolic procedure probably contributing to the high frequency of protein-energy wasting among patients on maintenance HD. The aim was to investigate the effect of insulin infusion on insulin-like growth factor I (IGF-I) during HD compared with a meal alone...... infusion and followed by the only meal allowed during the study. Results: Data are presented as mean±SD. From baseline to end of HD session we observed an overall increase in both serum bioactive IGF-I (from 0.83±0.27 to 1.01±0.34 µg/L, p... in the change between the groups (p=0.43). Conclusion: A meal at the beginning of a HD session leads to an increase in bioactive IGF-I thereby assumingly counteracting the catabolic effects of HD. However, according to changes in bioactive IGF-I neither glucose nor glucose-insulin infusion during HD appear...

  15. IGF-I AND FGF-2 RESPONSES TO WINGATE ANAEROBIC TEST IN OLDER MEN

    Directory of Open Access Journals (Sweden)

    Ruthie Amir

    2007-06-01

    Full Text Available Reduced activity of the potent anabolic effectors: insulin-like growth factor-I (IGF-I and fibroblast growth factor-2 (FGF-2, play a role in aging associated muscle loss. The effect of fitness level on IGF-I and FGF-2 responses to all-out anaerobic exercise in older men was studied. Twenty four healthy older males: 12 higher fit (58 ± 1y and 12 lower fit (59 ± 1y underwent the Wingate anaerobic test. Serum levels of IGF-I and FGF-2 were measured before, immediately after exercise, and 50 min into recovery. Immediately post exercise, the average peak power output and serum lactate were higher (p < 0.05 in the higher fit (446.0 ± 14. 9 kgm·min-1 for mean (± SD peak power and 12.6 ± 1.1 mml·l-1 for lactate compared with the lower fit individuals (284.0 ± 6.5 kgm·min-1 and 8.5 ± 0.7 mml·l-1, respectively. Pre-exercise IGF-I was lower and FGF-2 was higher in the higher fit (335.0 ± 54.0 ng·ml-1 and 1.6 ± 0.1 ng·ml-1, respectively compared with lower fit individuals (402.0 ± 50.0 ng·ml-1 and 1.4 ± 0.2 ng·ml-1, respectively. Following the anaerobic exercise, in both groups, FGF-2 decreased dramatically (p < 0.05; in the higher fit individuals FGF-2 level was 0.4 ± 0.1 pg·ml-1 compared to 0.1 ± 0.02 pg·ml-1 in the lower fit individuals. In contrast to FGF-2, IGF-I increased transiently to levels of 405.0 ± 62.0 ng·ml-1 in the higher fit individuals and to levels of 436 ± 57.0 ng·ml-1 in the lower fit individuals. However, the IGF-I elevation was significant (p < 0. 05 only in the higher fit individuals. In conclusion, the present study demonstrates that during aging, fitness level can alter circulating levels of IGF-I and FGF-2. Furthermore, fitness level can affect the response of both mediators to all-out anaerobic exercise.

  16. Bioactive insulin-like growth factor (IGF) I and IGF-binding protein-1 in anorexia nervosa

    DEFF Research Database (Denmark)

    Støving, René; Chen, Jian-Wen; Glintborg, Dorte

    2007-01-01

    CONTEXT: Regulation of IGF-I activity appears crucial in anorexia nervosa (AN) during adaptation to chronic starvation as well as during the regenerative processes on nutritional restoration. OBJECTIVE: The objective of this study was to examine the relationship between IGF-I bioactivity and IGF...

  17. The insulin-like growth factor (IGF)-I E-peptides are required for isoform-specific gene expression and muscle hypertrophy after local IGF-I production

    Science.gov (United States)

    DeMeo, J; Lei, Hanqin

    2010-01-01

    Insulin-like growth factor I (IGF-I) coordinates proliferation and differentiation in a wide variety of cell types. The igf1 gene not only produces IGF-I, but also generates multiple carboxy-terminal extensions, the E-peptides, through alternative splicing leading to different isoforms. It is not known if the IGF-I isoforms share a common pathway for their actions, or if there are specific actions of each protein. Viral administration of murine IGF-IA, IGF-IB, and mature IGF, which lacked an E-peptide extension, was utilized to identify IGF-I isoform-specific responsive genes in muscles of young growing mice. Microarray analysis revealed responses that were driven by increased IGF-I regardless of the presence of E-peptide, such as Bcl-XL. In contrast, distinct expression patterns were observed after viral delivery of IGF-IA or IGF-IB, which included matrix metalloproteinase 13 (MMP13). Expression of Bcl-XL was prevented when viral administration of the IGF-I isoforms was performed into muscles of MKR mice, which lack functional IGF-I receptors on the muscle fibers. However, MMP13 expression persisted under the same conditions after viral injection of IGF-IB. At 4 mo after viral delivery, expression of IGF-IA or IGF-IB promoted muscle hypertrophy, but viral delivery of mature IGF-I failed to increase muscle mass. These studies provide evidence that local production of IGF-I requires the E-peptides to drive hypertrophy in growing muscle and that both common and unique pathways exist for the IGF-I isoforms to promote biological effects. PMID:20133429

  18. Papel emergente do eixo GH/IGF-I no controle cardiometabólico

    Directory of Open Access Journals (Sweden)

    Carla R.P Oliveira

    2011-11-01

    Full Text Available O hormônio de crescimento (GH, principal regulador do crescimento pós-natal, tem importantes ações metabólicas em diferentes tecidos, sinérgicas ou até antagônicas às do fator de crescimento semelhante à insulina tipo I (IGF-I, produzido sobretudo no fígado após ligação do GH ao seu receptor. Experimentos em modelos animais indicam um papel importante do GH na resistência a insulina, enquanto o papel do IGF-I nessa condição ainda não está completamente elucidado. Em humanos, o GH promove aumento da lipólise e da oxidação lipídica, enquanto o IGF-I desencadeia o aumento da oxidação lipídica apenas cronicamente. Enquanto as ações sobre o crescimento são tempo limitado, as ações metabólicas e cardiovasculares do eixo GH/IGF-I perduram durante toda a vida. Os potenciais efeitos anabólicos do GH têm sido utilizados em condições crônicas e hipercatabólicas, embora as investigações sobre os desfechos clínicos ainda sejam escassas. Neste artigo, pretendemos revisar as ações metabólicas do GH oriundas de modelos animais, os estudos em humanos normais e indivíduos com deficiência de GH, diabete melito tipo 1, síndrome metabólica, estados hipercatabólicos e a relação do eixo GH/IGF-I com as adipocinas, disfunção endotelial e aterogênese

  19. AKT signaling mediates IGF-I survival actions on otic neural progenitors.

    Directory of Open Access Journals (Sweden)

    Maria R Aburto

    Full Text Available BACKGROUND: Otic neurons and sensory cells derive from common progenitors whose transition into mature cells requires the coordination of cell survival, proliferation and differentiation programmes. Neurotrophic support and survival of post-mitotic otic neurons have been intensively studied, but the bases underlying the regulation of programmed cell death in immature proliferative otic neuroblasts remains poorly understood. The protein kinase AKT acts as a node, playing a critical role in controlling cell survival and cell cycle progression. AKT is activated by trophic factors, including insulin-like growth factor I (IGF-I, through the generation of the lipidic second messenger phosphatidylinositol 3-phosphate by phosphatidylinositol 3-kinase (PI3K. Here we have investigated the role of IGF-dependent activation of the PI3K-AKT pathway in maintenance of otic neuroblasts. METHODOLOGY/PRINCIPAL FINDINGS: By using a combination of organotypic cultures of chicken (Gallus gallus otic vesicles and acoustic-vestibular ganglia, Western blotting, immunohistochemistry and in situ hybridization, we show that IGF-I-activation of AKT protects neural progenitors from programmed cell death. IGF-I maintains otic neuroblasts in an undifferentiated and proliferative state, which is characterised by the upregulation of the forkhead box M1 (FoxM1 transcription factor. By contrast, our results indicate that post-mitotic p27(Kip-positive neurons become IGF-I independent as they extend their neuronal processes. Neurons gradually reduce their expression of the Igf1r, while they increase that of the neurotrophin receptor, TrkC. CONCLUSIONS/SIGNIFICANCE: Proliferative otic neuroblasts are dependent on the activation of the PI3K-AKT pathway by IGF-I for survival during the otic neuronal progenitor phase of early inner ear development.

  20. Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells

    National Research Council Canada - National Science Library

    Qin Shen; Susan K. Goderie; Li Jin; Nithin Karanth; Yu Sun; Natalia Abramova; Peter Vincent; Kevin Pumiglia; Sally Temple

    2004-01-01

    .... We show that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production...

  1. Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I.

    Directory of Open Access Journals (Sweden)

    Marc U Baumann

    Full Text Available Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

  2. Association between Serum IGF-I levels and Postoperative Delirium in Elderly Subjects Undergoing Elective Knee Arthroplasty.

    Science.gov (United States)

    Yen, Timothy E; Allen, John C; Rivelli, Sarah K; Patterson, Stephanie C; Metcalf, Meredith R; Flink, Benjamin J; Mirrakhimov, Aibek E; Lagoo, Sandhya A; Vail, Thomas P; Young, Christopher C; Moon, Richard E; Trzepacz, Paula T; Kwatra, Madan M

    2016-02-05

    Evidence is mixed for an association between serum insulin-like growth factor-I (IGF-I) levels and postoperative delirium (POD). The current study assessed preoperative serum IGF-I levels as a predictor of incident delirium in non-demented elderly elective knee arthroplasty patients. Preoperative serum levels of total IGF-I were measured using a commercially available Human IGF-I ELISA kit. POD incidence and severity were determined using DSM-IV criteria and the Delirium Rating Scale-Revised-98 (DRS-R98), respectively. Median IGF-I levels in delirious (62.6 ng/ml) and non-delirious groups (65.9 ng/ml) were not significantly different (p = 0.141). The ratio (95% CI) of geometric means, D/ND, was 0.86 (0.70, 1.06). The Hodges-Lehmann median difference estimate was 7.23 ng/mL with 95% confidence interval (-2.32, 19.9). In multivariate logistic regression analysis IGF-I level was not a significant predictor of incident POD after correcting for medical comorbidities. IGF-I levels did not correlate with DRS-R98 scores for delirium severity. In conclusion, we report no evidence of association between serum IGF-I levels and incidence of POD, although the sample size was inadequate for a conclusive study. Further efforts to investigate IGF-I as a delirium risk factor in elderly should address comorbidities and confounders that influence IGF-I levels.

  3. Development and validation of a radioimmunoassay for fish insulin-like growth factor I (IGF-I) and the effect of aquaculture related stressors on circulating IGF-I levels.

    Science.gov (United States)

    Dyer, Anthony R; Upton, Zee; Stone, David; Thomas, Philip M; Soole, Kathleen L; Higgs, Naomi; Quinn, Kirsty; Carragher, John F

    2004-02-01

    This paper describes the development and validation of a commercially available radioimmunoassay (RIA) for the detection of fish insulin-like growth factor-I (IGF-I). The assay was developed using recombinant barramundi IGF-I as antigen and recombinant tuna IGF-I as radiolabelled tracer and standard. Assay sensitivity was 0.15 ng/ml, inter-assay variation was 16% (n = 9) and intra-assay variation was 3% (n = 10). Cross reactivity of less than 0.01% was found with salmon insulin, salmon IGF-II and barramundi IGF-II, less than 0.5% with human IGF-I and less than 1% with human IGF-II. Parallel dose-response inhibition curves were shown for barramundi (Lates calcarifer), coho salmon (Oncorhynchus kisutch), Southern Bluefin tuna (Thunnus maccoyii), tilapia (Oreochromis mossambicus), and seabream (Pagrus auratus) IGF-I. The assay was then used to measure stress related changes in different aquacultured fish species. Salt water acclimated Atlantic salmon smolts (Salmo salar) bathed for 2 h in fresh water showed significantly lower IGF-I concentrations than control smolts two days after the bath (53.1 compared to 32.1 ng/ml), with levels of IGF-I also lower in smolts exhibiting stunted growth (stunts). Capture and confinement of wild tuna in sea-cages resulted in a significant decrease in IGF-I levels (28 ng/ml) when compared to tuna captured and sampled immediately (48 ng/ml), but had recovered to starting levels after 3 weeks (43 ng/ml). Handling and isolation in silver perch (Bidyanus bidyanus) led to a gradual decline in IGF-I over a 12 h period (36-19 ng/ml) but showed signs of recovery by 24 h (24 ng/ml) and had recovered fully 72 h after treatment (40 ng/ml). A similar trial in black bream (Acanthopagrus butcherii) showed comparable results with IGF-I levels gradually decreasing (40-26 ng/ml) over 24 h, results that were mirrored by cortisol concentrations which increased during this time (1-26 ng/ml). In the studies presented here changes in IGF-I levels were not

  4. Endothelial Cells Stimulate Self-Renewal and Expand Neurogenesis of Neural Stem Cells

    Science.gov (United States)

    Shen, Qin; Goderie, Susan K.; Jin, Li; Karanth, Nithin; Sun, Yu; Abramova, Natalia; Vincent, Peter; Pumiglia, Kevin; Temple, Sally

    2004-05-01

    Neural stem cells are reported to lie in a vascular niche, but there is no direct evidence for a functional relationship between the stem cells and blood vessel component cells. We show that endothelial cells but not vascular smooth muscle cells release soluble factors that stimulate the self-renewal of neural stem cells, inhibit their differentiation, and enhance their neuron production. Both embryonic and adult neural stem cells respond, allowing extensive production of both projection neuron and interneuron types in vitro. Endothelial coculture stimulates neuroepithelial cell contact, activating Notch and Hes1 to promote self-renewal. These findings identify endothelial cells as a critical component of the neural stem cell niche.

  5. Insulin-Like Growth Factor (IGF-I and Insulin in Normal and Growth-Restricted Mother/Infant Pairs

    Directory of Open Access Journals (Sweden)

    Ariadne Malamitsi-Puchner

    2007-01-01

    Full Text Available Insulin-like growth factor (IGF-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA and 20 intrauterine-growth-restricted (IUGR fetuses and neonates on day 1 (N1 and day 4 (N4 postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P<.001 and P=.037, resp.. N1 insulin levels were lower in IUGR (P=.048. Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r=.374, P=.035, r=.608, P<.001, r=.485, P=.006, and r=.654, P=.021, resp.. Female infants presented elevated fetal and N4 IGF-I levels (P=.023 and P=.016, resp.. Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

  6. Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice.

    Science.gov (United States)

    Svensson, Johan; Windahl, Sara H; Saxon, Leanne; Sjögren, Klara; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes

    2016-07-01

    Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice, serum IGF-I reduced by ≈70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading three times/wk for 2 wk, and measurements were performed using microcomputed tomography and mechanical testing by three-point bending. In the nonloaded left tibia, the LI-IGF-I(-/-) mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared with the controls. Mechanical loading induced a similar response in LI-IGF-I(-/-) and control mice in terms of cortical bone area and trabecular bone volume fraction. In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, which was associated with a less marked increase in cortical porosity, in the LI-IGF-I(-/-) mice compared with the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (nonloaded) conditions. However, despite an ∼70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I(-/-) mice.

  7. High intakes of skimmed milk, but not meat, increase serum IGF-I and IGFBP-3 in eight-year-old boys

    DEFF Research Database (Denmark)

    Hoppe, Camilla; Mølgaard, C; Juul, A

    2004-01-01

    To examine whether a high protein intake (PI) from either milk or meat, at a level often seen in late infancy, could increase s-IGF-I and s-IGF-I/s-IGFBP-3 in healthy, prepubertal children. IGF-I levels are positively associated with growth velocity in children and some studies suggest that a high...

  8. Impairment of IGF-I Expression and Anabolic Signaling Following Ischemia/Reperfusion in Skeletal Muscle of Old Mice

    Science.gov (United States)

    2011-04-01

    IGF-I Eb mRNA spice variant [often termed mechano-growth factor (MGF)] mediates satellite cell proliferation whereas mature IGF-I, supposedly derived... synthesis reactions. ELISA Tissue levels of IGF-I were measured by a method similar to that described by D’Ercole et al. (D’Ercole et al., 1984), with...in both age groups , however, p-Akt levels were higher in the young than old (p ≤ 0.05). These data indicate an age-related delay in Akt synthesis and

  9. Chondrocyte Regulation by IL-I and IGF-I: Interconnection Between Anabolic and Catabolic Factors

    OpenAIRE

    Porter, Ryan Michael

    2005-01-01

    Articular cartilage functions to reduce the mechanical stresses associated with diarthrodial joint movement, protecting these joints over a lifetime of use. Tissue function is maintained through the balance between synthesis and resorption (i.e., metabolism) of extracellular matrix (ECM) by articular chondrocytes (ACs). Two important hormonal regulators of cartilage metabolism are interleukin-1 (IL-1) and insulin-like growth factor-I (IGF-I). These factors have antagonistic effects on chondro...

  10. Serum leptin in obese patients with Laron syndrome before and during IGF-I treatment.

    Science.gov (United States)

    Laron, Z; Silbergeld, A; Lilos, P; Blum, F W

    1998-01-01

    Fifteen patients with primary GH resistance (Laron syndrome, LS) were studied before and during 6 months of daily replacement treatment with IGF-I. The main findings were that patients with LS and normal or high serum GH binding protein (GHBP) were less obese than those with a negative GHBP, and that serum leptin levels varied with body mass as in other types of obesity.

  11. Changes in IGF-I and its Binding Proteins Are Associated with Diabetes in Older Adults

    Science.gov (United States)

    Aneke, Chino S.; Parrinello, Christina M.; Rajpathak, Swapnil N.; Rohan, Thomas E.; Strotmeyer, Elsa S.; Kritchevsky, Stephen B.; Psaty, Bruce M.; Bůžková, Petra; Kizer, Jorge R.; Newman, Anne B.; Strickler, Howard D.; Kaplan, Robert C.

    2015-01-01

    Objectives Little is known about long-term changes in insulin-like growth Factor (IGF) proteins and glycemic status. We hypothesized that changes in IGF proteins are exaggerated in participants with type 2 diabetes or worsening glycemia versus those that remain normoglycemic over a 9-year follow-up period. Design Retrospective analysis of cohort study. Setting Participants were recruited from four States: North Carolina, California, Maryland and Pennsylvania. Participants 897 participants enrolled in CHS All Stars, a cohort study of community dwelling adults aged ≥65 years. Measurements Plasma IGF-I, IGFBP-1, and IGFBP-3 levels were assessed and ADA cut-points for IGT, IFG, and diabetes were used to classify participants at baseline (1996–1997) and follow-up (2005–2006). Results At baseline, mean age was 76.3 years (± 3.6) and 18.5% had diabetes. Individuals with IFG alone and IGT+IFG had the highest levels of IGF-I and lowest levels of IGFBP-1, compared to individuals with normoglycemia or diabetes. The greatest percent change in IGF levels occurred in those who had diabetes at baseline (9-year changes: −9.3% for IGF-I, 59.7% for IGFBP-1, −13.4% for IGFBP-3); the smallest in individuals who remained normoglycemic at follow-up (9-year changes: −3.7% for IGF-I, 25.6% for IGFBP-1, −6.4% for IGFBP-3); and intermediate changes in those who were normoglycemic but developed IFG at follow-up. Conclusion Our results demonstrate that degrees of glycemic impairment are associated with varying levels of changes in IGF proteins. The exaggerated changes observed in the diabetes group have been previously shown to be associated with heart failure, cancer and non-cancer mortality. PMID:25989565

  12. IGF-I maintains calpastatin expression and attenuates apoptosis in several models of photoreceptor cell death.

    Science.gov (United States)

    Arroba, Ana I; Wallace, Deborah; Mackey, Ashley; de la Rosa, Enrique J; Cotter, Thomas G

    2009-09-01

    Retinitis pigmentosa is a heterogeneous group of inherited retinal dystrophies in which the loss of photoreceptor cells via apoptosis leads to blindness. In this study we have experimentally mimicked this condition by treating 661W cells and wild-type mouse retinal explants with a Ca(2+) ionophore. Ca(2+) overload induced apoptosis, which was correlated with calpain-2 activation, loss of calpastatin, its endogenous inhibitor, as well as the loss of its transcriptional activator, phospho-cAMP response element binding (CREB). All are similar changes to those observed in the rd1 mouse model of retinitis pigmentosa. Insulin like-growth factor-I (IGF-I) attenuated this Ca(2+)-induced apoptosis, as well as decreased the activation of calpain-2 and maintained calpastatin levels through the activation of the Akt-CREB pathway. Similarly, IGF-I decreased photoreceptor apoptosis in rd1 mouse retinal explants in parallel with reduced activation of calpain-2 and increased levels of calpastatin and activation of phospho-CREB. In conclusion, IGF-I seems to protect neural cells following a physiopathological or an experimental increase in intracellular Ca(2+), an observation that may have therapeutic consequences in neurodegenerative diseases such as retinitis pigmentosa.

  13. USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination.

    Science.gov (United States)

    Fukushima, Toshiaki; Yoshihara, Hidehito; Furuta, Haruka; Hakuno, Fumihiko; Iemura, Shun-Ichiro; Natsume, Tohru; Nakatsu, Yusuke; Kamata, Hideaki; Asano, Tomoichiro; Komada, Masayuki; Takahashi, Shin-Ichiro

    2017-03-11

    Insulin receptor substrates (IRSs) are phosphorylated by IGF-I receptor tyrosine kinase in a ligand-dependent manner. In turn, they bind to and activate effector proteins such as PI3K, leading to various cell responses including cell proliferation. We had reported that ubiquitin ligase Nedd4 induces mono-ubiquitination of IRS-2, thereby enhancing IRS-2 tyrosine phosphorylation, leading to increased IGF signaling and mitogenic activity. Here we show that ubiquitin-specific protease 15 (USP15) antagonizes the effect of Nedd4 on IRS-2. We identified USP15 as a protein that preferentially bound to IRS-2 when IRS-2 was conjugated with ubiquitin. In HEK293 cells, Nedd4 overexpression induced IRS-2 ubiquitination, which was decreased by USP15 co-expression while increased by USP15 knockdown. Nedd4 overexpression enhanced IGF-I-dependent IRS-2 tyrosine phosphorylation, and USP15 co-expression suppressed it. Conversely, USP15 knockdown increased IRS-2 tyrosine phosphorylation and downstream signaling in prostate cancer PC-3 cells. We concluded that USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination.

  14. Methodology for Anti-Gene Anti-IGF-I Therapy of Malignant Tumours

    Directory of Open Access Journals (Sweden)

    Jerzy Trojan

    2012-01-01

    Full Text Available The aim of this study was to establish the criteria for methodology of cellular “anti-IGF-I” therapy of malignant tumours and particularly for glioblastoma multiforme. The treatment of primary glioblastoma patients using surgery, radiotherapy, and chemotherapy was followed by subcutaneous injection of autologous cancer cells transfected by IGF-I antisense/triple helix expression vectors. The prepared cell “vaccines” should it be in the case of glioblastomas or other tumours, have shown a change of phenotype, the absence of IGF-I protein, and expression of MHC-I and B7. The peripheral blood lymphocytes, PBL cells, removed after each of two successive vaccinations, have demonstrated for all the types of tumour tested an increasing level of CD8+ and CD8+28+ molecules and a switch from CD8+11b+ to CD8+11. All cancer patients were supervised for up to 19 months, the period corresponding to minimum survival of glioblastoma patients. The obtained results have permitted to specify the common criteria for “anti-IGF-I” strategy: characteristics sine qua non of injected “vaccines” (cloned cells IGF-I(− and MHC-I(+ and of PBL cells (CD8+ increased level.

  15. Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells.

    Science.gov (United States)

    Attias-Geva, Zohar; Bentov, Itay; Ludwig, Dale L; Fishman, Ami; Bruchim, Ilan; Werner, Haim

    2011-07-01

    Specific insulin-like growth factor-I receptor (IGF-IR) targeting emerged in recent years as a promising therapeutic strategy in cancer. Endometrial cancer is the most common gynaecological cancer in the Western world. The aim of this study was to evaluate the potential of cixutumumab (IMC-A12, ImClone Systems), a fully human monoclonal antibody against the IGF-IR, to inhibit IGF-I-mediated biological actions and cell signalling events in four endometrial carcinoma-derived cell lines (ECC-1, Ishikawa, USPC-1 and USPC-2). Our results demonstrate that cixutumumab was able to block the IGF-I-induced autophosphorylation of the IGF-IR. In addition, the PI3K and MAPK downstream signalling pathways were also inactivated by cixutumumab in part of the cell lines. Prolonged (24h and 48h) exposures to cixutumumab reduced IGF-IR expression. Furthermore, confocal microscopy of GFP-tagged receptors shows that cixutumumab treatment led to IGF-IR redistribution from the cell membrane to the cytoplasm. Antiapoptotic effects were evaluated by cleavage of caspase 3 and PARP, and mitogenicity and transformation by proliferation and cell cycle assays. Results obtained showed that cixutumumab abrogated the IGF-I-stimulated increase in proliferation rate, and increased caspase-3 and PARP cleavage, two markers of apoptosis. Of importance, cixutumumab had no effect neither on insulin receptor (IR) expression nor on IGF-I activation of IR. In summary, in a cellular model of endometrial cancer cixutumumab was able to inhibit the IGF-I-induced activation of intracellular cascades, apoptosis and proliferation.

  16. Short-term galvanic vestibular stimulation promotes functional recovery and neurogenesis in unilaterally labyrinthectomized rats.

    Science.gov (United States)

    Shaabani, Moslem; Lotfi, Yones; Karimian, Seyed Morteza; Rahgozar, Mehdi; Hooshmandi, Mehdi

    2016-10-01

    Current experimental research on the therapeutic effects of galvanic vestibular stimulation (GVS) has mainly focused on neurodegenerative disorders. However, it primarily stimulates the vestibular nuclei and could be potentially effective in modulating imbalance between them in the case of unilateral labyrinthectomy (UL). Fifty male Wistar rats (180-220g) were used in 5 groups of 10: intact, sham, right-UL (RUL; without intervention), and two other right-UL groups with GVS intervention [one group treated with low rate GVS (GVS.LF; 6-7Hz), and the other treated with high rate GVS (GVS.HF; 17-18Hz)]. The UL models were prepared by intratympanic injection of sodium arsanilate. GVS protocols were implemented 30min/day and continued for 14 days via ring-shaped copper electrodes inserted subcutaneously over each mastoid. Functional recovery was assessed by several postural tests including support surface area, landing and air-righting reflexes, and rotarod procedure. Immunohistochemical investigations were performed on ipsi- and contra-lesional medial vestibular nuclei (MVN) using bromodeoxyuridine (BrdU) and Ki67, as markers of cell proliferation. Behavioral evaluations showed significant functional recovery of GVS-treated groups compared to RUL group. The percent of marked cells with BrdU and Ki67 were significantly higher in the ipsilesional MVN of both GVS-treated groups compared with other groups. Our findings confirmed the effectiveness of GVS-intervention in accelerating static and dynamic vestibular compensation. This could be explained by the cell proliferation in ipsilesional MVN cells and rapid rebalancing of the VNs and the modulation of their motor outputs. Therefore, GVS could be promising for rehabilitating patients with unilateral vestibular weakness.

  17. The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I

    Science.gov (United States)

    Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

    1999-01-01

    skeletal unloading. We have focussed on the role of IGF- 1 as the local factor mediating the effects of skeletal unloading on bone formation. IGF-I is produced by bone cells and chondrocytes; these cells have receptors for IGF-I, and respond to IGF-I with an increase in proliferation and function (e.g. collagen, and glycosaminoglycan production, respectively). IGF-I production by bone is under hormonal control, principally by GH and PTH, and IGF-I is thought to mediate some if not all of the effects of GH and PTH on bone growth. Thus, systemic changes in hormones such as GH and PTH may still have effects which vary from bone to bone depending on the loading history.

  18. IGF-I/PI3K/Akt and IGF-I/MAPK/ERK pathways in vivo in skeletal muscle are regulated by nutrition and contribute to somatic growth in the fine flounder.

    Science.gov (United States)

    Fuentes, Eduardo N; Björnsson, Björn Thrandur; Valdés, Juan Antonio; Einarsdottir, Ingibjörg Eir; Lorca, Belen; Alvarez, Marco; Molina, Alfredo

    2011-06-01

    The insulin-like growth factor-I (IGF-I) is a key regulator of skeletal muscle growth in vertebrates, promoting mitogenic and anabolic effects through the activation of the MAPK/ERK and the PI3K/Akt signaling pathways. Nutrition also affects skeletal muscle growth, activating intracellular pathways and inducing protein synthesis and accretion. Thus, both hormonal and nutritional signaling regulate muscle mass. In this context, plasma IGF-I levels and the activation of both pathways in response to food were evaluated in the fine flounder using fasting and refeeding trials. The present study describes for the first time in a nonmammalian species that the MAPK/ERK and PI3K/Akt are activated by exogenous circulating IGF-I, as well as showing that the MAPK/ERK pathway activation is modulated by the nutritional status. Also, these results show that there is a time-dependent regulation of IGF-I plasma levels and its signaling pathways in muscle. Together, these results suggest that the nutritionally managed IGF-I could be regulating the activation of the MAPK/ERK and the PI3K/Akt signaling pathways differentially according to the nutritional status, triggering different effects in growth parameters and therefore contributing to somatic growth in fish. This study contributes to the understanding of the nutrient regulation of IGF-I and its signaling pathways in skeletal muscle growth in nonmammalian species, therefore providing insight concerning the events controlling somatic growth in vertebrates.

  19. Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Pedersen, S B;

    1997-01-01

    PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate......% (p prostate. The mean weight of the dorsolateral lobe of the prostate increased by 39% (p prostate was significantly...... increased by IGF-I after 3 days of treatment, and administration of IGF-I concomitantly with DFMO significantly inhibited ODC activity and the weight increase of the prostate. Stereological examination of the prostate in the IGF-I-treated animals showed growth of the epithelial component of the gland...

  20. Alterations in tumorigenicity of embryonal carcinoma cells by IGF-I triple-helix induced changes in immunogenicity and apoptosis.

    Science.gov (United States)

    Ly, A; Francois, J C; Upegui-Gonzalez, L C; Swiercz, B; Bedel, C; Duc, H T; Bout, D; Trojan, J

    2000-12-08

    IGF-I antisense gene therapy has been applied successfully to animal models of glioma, hepatoma and teratocarcinoma. The antisense strategy has shown that tumor cells transfected with vectors encoding IGF-I antisense RNA lose tumorigenicity, become immunogenic and are associated with tumor specific immune response involving CD8+ lymphocytes. An IGF-I triple helix approach to gene therapy for glioma was recently described. The approach we have taken is to establish parameters of change using the IGF-I triple helix strategy. PCC-3 embryonal carcinoma cells derived from murine teratocarcinoma which express IGF-I were used as a model. The cells were transfected with vector which encodes an oligoribonucleotide that forms RNA-IGF-I DNA triple-helix structure. The triple-helix stops the production of IGF-I. Cells transfected in this manner underwent changes in phenotype and an increase in MHC-I and B-7 cell surface molecules. They also showed enhancement in the production of apoptotic cells (60-70%). The "triple helix" transfected cells lost the ability to induce tumor when injected subcutaneously in syngeneic 129 Sv mice. When co-transfected in vitro with expression vectors encoding both MHC-I and B-7 cDNA in antisense orientation, the "triple-helix" transfected cells were down-regulated in expression of MHC-I and B-7 and the number of apoptotic cells was significantly decreased. Injection of the doubly co-transfected cells into 129 Sv mice was associated with induction of teratocarcinoma. Comparison between antisense and triple-helix transfected cells strategies showed similar immunogenic and apoptotic changes. The findings suggest that triple-helix technology may offer a new clinical approach to treatement of tumors expressing IGF-I.

  1. Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-I treatment

    Science.gov (United States)

    McCall, G. E.; Allen, D. L.; Linderman, J. K.; Grindeland, R. E.; Roy, R. R.; Mukku, V. R.; Edgerton, V. R.

    1998-01-01

    The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 +/- 8 vs. 123 +/- 16 mg. Muscle weight in the FO + GH/IGF-I group (196 +/- 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 +/- 445 microm2) was increased compared with the Con (2,044 +/- 108 microm2) and FO (2,267 +/- 301 microm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 +/- 15 myonuclei/mm) and FO + GH/IGF-I (217 +/- 23 myonuclei/mm) rats compared with Con (155 +/- 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.

  2. Effect of hyperthyroidism on circulating levels of free and total IGF-I and IGFBPs in rats.

    Science.gov (United States)

    Frystyk, J; Grønbaek, H; Skjaerbaek, C; Flyvbjerg, A

    1995-11-01

    Thyroid hormones are suggested to have a permissive role in growth hormone (GH) and insulin-like growth factor I (IGF-I) action and a specific effect on plasma levels of some of the GH-independent IGF binding proteins (IGFBPs). We have investigated the effect of thyroxine (T4) administration on circulating levels of free and total (extractable) IGF-I and IGFBPs in 8-wk-old rats treated with 0, 200, 400, and 600 micrograms/kg T4, respectively. Serum free IGF-I was determined by an ultrafiltration method, serum total IGF-I after acid-ethanol extraction, and serum IGFBPs using Western ligand blotting, which yielded four distinct molecular bands: two single bands at 24 and 30 kDa and a double band at 38 and 42 kDa (38-42 kDa). After 13 days of hyperthyroidism, serum total IGF-I and the high-molecular 38-42 kDa IGFBP were unchanged, whereas the 24-kDa IGFBP and 30-kDa IGFBP increased significantly (P < 0.05). Serum free IGF-I was significantly (P < 0.05) decreased in animals treated with 400 and 600 micrograms/kg T4. In addition, free IGF-I correlated inversely (P < 0.005) with the 24-kDa IGFBP, 30-kDa IGFBP, and serum total triiodothyronine. We conclude that hyperthyroidism in rats increases the circulating low-molecular IGFBPs and induces a reduction in free IGF-I. This may provide an important regulation of IGF bioactivity by thyroid hormones.

  3. Circulating bioactive and immunoreactive IGF-I remain stable in women, despite physical fitness improvements after 8 weeks of resistance, aerobic, and combined exercise training.

    Science.gov (United States)

    Nindl, Bradley C; Alemany, Joseph A; Tuckow, Alexander P; Rarick, Kevin R; Staab, Jeffery S; Kraemer, William J; Maresh, Carl M; Spiering, Barry A; Hatfield, Disa L; Flyvbjerg, Allan; Frystyk, Jan

    2010-07-01

    Insulin-like growth factor-I (IGF-I) is regulated by a number of IGF-binding proteins (IGFBPs) and proteases that influence IGF-I bioactivity. A specific IGF-I kinase receptor activation assay (KIRA) has been developed that determines the ability of IGF-I to activate the IGF-I receptor by quantification of intracellular receptor autophosphorylation on IGF-I binding. KIRA-assessed IGF-I bioactivity has not been utilized within the context of chronic exercise training paradigms. This study measured total and free immunoreactive IGF-I, bioactive IGF-I, and IGFBP-1, -2, and -3 before (Pre), during (Mid), and after (Post) 8 wk of exercise training in young, healthy women, who were randomized into one of four groups: control (n = 10), resistance (n = 18), aerobic (n = 13), and combined (n = 15) exercise training. The training programs were effective in improving physical fitness specific to the exercise mode engaged in: increases were observed for lean mass ( approximately 2%), aerobic fitness (6-7%), and upper (20-24%) and lower (15-48%) body strength (all P values fitness, and upper and lower body strength resulting from an 8-wk exercise training programs can occur without concomitant increases in either circulating bioactive or immunoreactive IGF-I, as well as associated IGFBPs. In terms of reflecting positive anabolic neuromuscular outcomes, these data do not support a role for endocrine-derived IGF-I.

  4. Growth hormone, IGF-I, and exercise effects on non-weight-bearing fast muscles of hypophysectomized rats

    Science.gov (United States)

    Grossman, E. J.; Grindeland, R. E.; Roy, R. R.; Talmadge, R. J.; Evans, J.; Edgerton, V. R.

    1997-01-01

    The effects of growth hormone (GH) or insulin-like growth factor I (IGF-I) with or without exercise (ladder climbing) in countering the effects of unweighting on fast muscles of hypophysectomized rats during 10 days of hindlimb suspension were determined. Compared with untreated suspended rats, muscle weights were 16-29% larger in GH-treated and 5-15% larger in IGF-I-treated suspended rats. Exercise alone had no effect on muscle weights. Compared with ambulatory control, the medial gastrocnemius weight in suspended, exercised rats was larger after GH treatment and maintained with IGF-I treatment. The combination of GH or IGF-I plus exercise in suspended rats resulted in an increase in size of each predominant fiber type, i.e., types I, I + IIa and IIa + IIx, in the medial gastrocnemius compared with untreated suspended rats. Normal ambulation or exercise during suspension increased the proportion of fibers expressing embryonic myosin heavy chain in hypophysectomized rats. The phenotype of the medial gastrocnemius was minimally affected by GH, IGF-I, and/or exercise. These results show that there is an IGF-I, as well as a GH, and exercise interactive effect in maintaining medial gastrocnemius fiber size in suspended hypophysectomized rats.

  5. Children with severe Osteogenesis imperfecta and short stature present on average with normal IGF-I and IGFBP-3 levels.

    Science.gov (United States)

    Hoyer-Kuhn, Heike; Höbing, Laura; Cassens, Julia; Schoenau, Eckhard; Semler, Oliver

    2016-07-01

    Osteogenesis imperfecta (OI) is characterized by bone fragility and short stature. Data about IGF-I/IGFBP-3 levels are rare in OI. Therefore IGF-I/IGFBP-3 levels in children with different types of OI were investigated. IGF-I and IGFBP-3 levels of 60 children (male n=38) were assessed in a retrospective cross-sectional setting. Height/weight was significant different [height z-score type 3 versus type 4: p=0.0011 and weight (p≤0.0001)] between OI type 3 and 4. Mean IGF-I levels were in the lower normal range (mean±SD level 137.4±109.1 μg/L). Mean IGFBP-3 measurements were in the normal range (mean±SD 3.105±1.175 mg/L). No significant differences between OI type 3 and 4 children have been observed (IGF-I: p=0.0906; IGFBP-3: p=0.2042). Patients with different severities of OI have IGF-I and IGFBP-3 levels in the lower normal range. The type of OI does not significantly influence these growth factors.

  6. Growth hormone, IGF-I, and exercise effects on non-weight-bearing fast muscles of hypophysectomized rats

    Science.gov (United States)

    Grossman, E. J.; Grindeland, R. E.; Roy, R. R.; Talmadge, R. J.; Evans, J.; Edgerton, V. R.

    1997-01-01

    The effects of growth hormone (GH) or insulin-like growth factor I (IGF-I) with or without exercise (ladder climbing) in countering the effects of unweighting on fast muscles of hypophysectomized rats during 10 days of hindlimb suspension were determined. Compared with untreated suspended rats, muscle weights were 16-29% larger in GH-treated and 5-15% larger in IGF-I-treated suspended rats. Exercise alone had no effect on muscle weights. Compared with ambulatory control, the medial gastrocnemius weight in suspended, exercised rats was larger after GH treatment and maintained with IGF-I treatment. The combination of GH or IGF-I plus exercise in suspended rats resulted in an increase in size of each predominant fiber type, i.e., types I, I + IIa and IIa + IIx, in the medial gastrocnemius compared with untreated suspended rats. Normal ambulation or exercise during suspension increased the proportion of fibers expressing embryonic myosin heavy chain in hypophysectomized rats. The phenotype of the medial gastrocnemius was minimally affected by GH, IGF-I, and/or exercise. These results show that there is an IGF-I, as well as a GH, and exercise interactive effect in maintaining medial gastrocnemius fiber size in suspended hypophysectomized rats.

  7. IGF-I Signaling in Osterix-Expressing Cells Regulates Secondary Ossification Center Formation, Growth Plate Maturation, and Metaphyseal Formation During Postnatal Bone Development.

    Science.gov (United States)

    Wang, Yongmei; Menendez, Alicia; Fong, Chak; ElAlieh, Hashem Z; Kubota, Takuo; Long, Roger; Bikle, Daniel D

    2015-12-01

    To investigate the role of IGF-I signaling in osterix (OSX)-expressing cells in the skeleton, we generated IGF-I receptor (IGF-IR) knockout mice ((OSX)IGF-IRKO) (floxed-IGF-IR mice × OSX promoter-driven GFP-labeled cre-recombinase [(OSX)GFPcre]), and monitored postnatal bone development. At day 2 after birth (P2), (OSX)GFP-cre was highly expressed in the osteoblasts in the bone surface of the metaphysis and in the prehypertrophic chondrocytes (PHCs) and inner layer of perichondral cells (IPCs). From P7, (OSX)GFP-cre was highly expressed in PHCs, IPCs, cartilage canals (CCs), and osteoblasts (OBs) in the epiphyseal secondary ossification center (SOC), but was only slightly expressed in the OBs in the metaphysis. Compared with the control mice, the IPC proliferation was decreased in the (OSX)IGF-IRKOs. In these mice, fewer IPCs invaded into the cartilage, resulting in delayed formation of the CC and SOC. Immunohistochemistry indicated a reduction of vessel number and lower expression of VEGF and ephrin B2 in the IPCs and SOC of (OSX)IGF-IRKOs. Quantitative real-time PCR revealed that the mRNA levels of the matrix degradation markers, MMP-9, 13 and 14, were decreased in the (OSX)IGF-IRKOs compared with the controls. The (OSX)IGF-IRKO also showed irregular morphology of the growth plate and less trabecular bone in the tibia and femur from P7 to 7 weeks, accompanied by decreased chondrocyte proliferation, altered chondrocyte differentiation, and decreased osteoblast differentiation. Our data indicate that during postnatal bone development, IGF-I signaling in OSX-expressing IPCs promotes IPC proliferation and cartilage matrix degradation and increases ephrin B2 production to stimulate vascular endothelial growth factor (VEGF) expression and vascularization. These processes are required for normal CC formation in the establishment of the SOC. Moreover, IGF-I signaling in the OSX-expressing PHC is required for growth plate maturation and osteoblast differentiation in

  8. Neurogenesis in Stroke Recovery.

    Science.gov (United States)

    Koh, Seong-Ho; Park, Hyun-Hee

    2017-02-01

    Stroke, resulting from limited blood flow to the brain, is one of the most important causes of morbidity and mortality worldwide. Stroke is classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding. Because 87 % of strokes are classified as ischemic, this type will be the predominant focus of this review. Except for thrombolytic therapy, there is no established treatment to reduce the neurological deficits caused by ischemic stroke. Therefore, it is necessary to develop new therapeutic strategies designed to improve neurological functions after ischemic stroke. Recently, therapies to enhance neurogenesis after ischemic stroke have been investigated. However, these approaches have not led to successful clinical outcomes. This review addresses the pathophysiology of stroke, neurogenesis after stroke, and how to stimulate these processes based on the current literature. Finally, ongoing clinical trials to improve neurological functions after stroke by enhancing neurogenesis are discussed in this review.

  9. Stimulation of the Sigma-1 Receptor by DHEA Enhances Synaptic Efficacy and Neurogenesis in the Hippocampal Dentate Gyrus of Olfactory Bulbectomized Mice

    Science.gov (United States)

    Moriguchi, Shigeki; Shinoda, Yasuharu; Yamamoto, Yui; Sasaki, Yuzuru; Miyajima, Kosuke; Tagashira, Hideaki; Fukunaga, Kohji

    2013-01-01

    Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX) mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831) phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473), Akt (Ser-308) and ERK in the DG. Furthermore, GSK-3β (Ser-9) phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway. PMID:23593332

  10. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.

    Directory of Open Access Journals (Sweden)

    Shigeki Moriguchi

    Full Text Available Dehydroepiandrosterone (DHEA is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII, protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831 phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473, Akt (Ser-308 and ERK in the DG. Furthermore, GSK-3β (Ser-9 phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.

  11. RSC96 Schwann Cell Proliferation and Survival Induced by Dilong through PI3K/Akt Signaling Mediated by IGF-I

    Directory of Open Access Journals (Sweden)

    Yung-Ming Chang

    2011-01-01

    Full Text Available Schwann cell proliferation is critical for the regeneration of injured nerves. Dilongs are widely used in Chinese herbal medicine to remove stasis and stimulate wound-healing functions. Exactly how this Chinese herbal medicine promotes tissue survival remains unclear. The aim of the present study was to investigate the molecular mechanisms by which Dilong promote neuron regeneration. Our results show that treatment with extract of Dilong induces the phosphorylation of the insulin-like growth factor-I (IGF-I-mediated phosphatidylinositol 3-kinase/serine-threonine kinase (PI3K/Akt pathway, and activates protein expression of cell nuclear antigen (PCNA in a time-dependent manner. Cell cycle analysis showed that G1 transits into the S phase in 12–16 h, and S transits into the G2 phase 20 h after exposure to earthworm extract. Strong expression of cyclin D1, cyclin E and cyclin A occurs in a time-dependent manner. Small interfering RNA (siRNA-mediated knockdown of PI3K significantly reduced PI3K protein expression levels, resulting in Bcl2 survival factor reduction and a marked blockage of G1 to S transition in proliferating cells. These results demonstrate that Dilong promotes the proliferation and survival of RSC96 cells via IGF-I signaling. The mechanism is mainly dependent on the PI3K protein.

  12. Role of IGFBP2, IGF-I and IGF-II in regulating long bone growth.

    Science.gov (United States)

    Fisher, Melanie C; Meyer, Carissa; Garber, Graham; Dealy, Caroline N

    2005-12-01

    The IGF axis is important for long bone development, homeostasis and disease. The activities of IGF-I and IGF-II are regulated by IGF binding proteins (IGFBPs). IGF-I and IGFBP2 are co-expressed in dynamic fashions in the developing long bones of the chick wing, and we have found that IGF-II is present in the cartilage model and surrounding perichondrium, proliferative and hypertrophic chondrocytes and developing periosteum. To gain insight into endogenous roles of IGF-I, IGF-II and IGFBP2 in long bone development, we have overexpressed IGFBP2 in the developing skeletal elements of the embryonic chick wing in vivo, using an RCAS retroviral vector. IGFBP2 overexpression led to an obvious shortening of the long bones of the wing. We have investigated, at the cellular and molecular levels, the mechanism of action whereby IGFBP2 overexpression impairs long bone development in vivo. At an early stage, IGFBP2 excess dramatically inhibits proliferation by the chondrocytes of the cartilage models that prefigure the developing long bones. Later, IGFBP2 excess also reduces proliferation of the maturing chondrocytes and attenuates proliferation by the perichondrium/developing periosteum. IGFBP2 excess does not affect morphological or molecular indicators of chondrocyte maturation, osteoblast differentiation or cell/matrix turnover, such as expression of Ihh, PTHrP, type X collagen and osteopontin, or distribution and relative abundance of putative clast cells. We also have found that IGFBP2 blocks the ability of IGF-I and IGF-II to promote proliferation and matrix synthesis by wing chondrocytes in vitro. Together, our results suggest that the mechanism of action whereby IGFBP2 excess impairs long bone development is to inhibit IGF-mediated proliferation and matrix synthesis by the cartilage model; reduce the proliferation and progression to hypertrophy by the maturing chondrocytes; and attenuate proliferation and formation of the periosteal bony collar. These actions retard

  13. IGF-I and amino acids effects through TOR signaling on proliferation and differentiation of gilthead sea bream cultured myocytes.

    Science.gov (United States)

    Vélez, Emilio J; Lutfi, Esmail; Jiménez-Amilburu, Vanesa; Riera-Codina, Miquel; Capilla, Encarnación; Navarro, Isabel; Gutiérrez, Joaquim

    2014-09-01

    Skeletal muscle growth and development is controlled by nutritional (amino acids, AA) as well as hormonal factors (insulin-like growth factor, IGF-I); however, how its interaction modulates muscle mass in fish is not clearly elucidated. The purpose of this study was to analyze the development of gilthead sea bream cultured myocytes to describe the effects of AA and IGF-I on proliferating cell nuclear antigen (PCNA) and myogenic regulatory factors (MRFs) expression, as well as on the transduction pathways involved in its signaling (TOR/AKT). Our results showed that AA and IGF-I separately increased the number of PCNA-positive cells and, together produced a synergistic effect. Furthermore, AA and IGF-I, combined or separately, increased significantly Myogenin protein expression, whereas MyoD was not affected. These results indicate a role for these factors in myocyte proliferation and differentiation. At the mRNA level, AA significantly enhanced PCNA expression, but no effects were observed on the expression of the MRFs or AKT2 and FOXO3 upon treatment. Nonetheless, we demonstrated for the first time in gilthead sea bream that AA significantly increased the gene expression of TOR and its downstream effectors 4EBP1 and 70S6K, with IGF-I having a supporting role on 4EBP1 up-regulation. Moreover, AA and IGF-I also activated TOR and AKT by phosphorylation, respectively, being this activation decreased by specific inhibitors. In summary, the present study demonstrates the importance of TOR signaling on the stimulatory role of AA and IGF-I in gilthead sea bream myogenesis and contributes to better understand the potential regulation of muscle growth and development in fish.

  14. Free and protein-bound insulin-like growth factor-I (IGF-I) and IGF-binding proteins in plasma of coho salmon, Oncorhynchus kisutch.

    Science.gov (United States)

    Shimizu, M; Swanson, P; Dickhoff, W W

    1999-09-01

    Total and free insulin-like growth factor-I (IGF-I) levels were quantified in plasma from growth hormone (GH)-treated and fasted coho salmon. Total IGF-I was measured by radioimmunoassay after acid-ethanol extraction and free IGF-I was separated from protein-bound IGF-I using ultrafiltration by centrifugation. Total and free IGF-I increased in plasma after GH treatment and decreased after fasting. The level of free IGF-I, however, was maintained at approximately 0.3% in both experiments. Unsaturated binding activity in plasma for IGF-I was assessed by incubation with (125)I-recombinant salmon IGF-I ((125)I-sIGF-I). Although there was no difference in binding activity between GH-treated and control fish, fasted fish showed higher binding activity than did fed fish, suggesting induction of unsaturated binding protein by fasting. IGF-binding protein (IGFBP) bands were observed in plasma of coho salmon by Western ligand blotting using (125)I-sIGF-I. A low-molecular-weight (22 kDa) band was clear in fasted fish but not detectable in fed fish. The IGFBP band, which has molecular weight similar to that of human IGFBP-3 (41 kDa), was more intense in GH-treated fish than in controls. The molecular distribution of IGF-I in plasma was examined by gel filtration under neutral conditions. Most IGF-I was eluted around 40 kDa. This result suggests that the major form of bound IGF-I in the circulation of coho salmon may be in a 40-kDa binary complex rather than in a 150-kDa ternary complex, as in mammals.

  15. Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.

    Science.gov (United States)

    Kanety, H; Silbergeld, A; Klinger, B; Karasik, A; Baxter, R C; Laron, Z

    1997-12-01

    A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

  16. Continuous s.c. infusion rather than twice-daily injections of IGF-I more effectively increases serum IGF binding protein-3 in female monkeys.

    Science.gov (United States)

    Wilson, M E; Lackey, S L

    1999-09-01

    In order to better understand how the IGF-I axis is affected by exogenous IGF-I, this study compared the effects of a constant s.c. infusion of IGF-I with that of twice-daily injections of IGF-I in young adult female rhesus monkeys. Clinical studies suggest that circulating concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) are decreased or unaffected by IGF-I administration, whereas acute increases in IGF-I may increase serum IGFBP-1. However, studies in monkeys indicate that acute or continuous infusion of IGF-I effectively increases serum IGFBP-3. Female monkeys were studied for 5 days with no IGF-I supplementation (baseline) and for 5 days of IGF-I treatment by either constant infusion (120 microg/kg per day s.c., n = 5) or twice-daily injections of IGF-I (60 microg/kg per injection s.c., n = 5). Serum samples were collected daily at 0800 h and at 0800, 0900, 1100, 1500, and 2000 h on days 1 and 4 for each condition. Samples were assayed for IGF-I, IGFBPs-1 and -3, insulin, and glucose. Serum IGF-I was consistently increased above baseline within 24 h of the initiation of constant infusion, but was delayed until the second day of treatment in the injection group. Serum IGFBP-3 followed the pattern of IGF-I, with concentrations increased by day 1 during constant infusion and by day 2 during intermittent injections. Although both treatments effectively increased serum IGFBP-3, the increase was greater during constant infusion (31% above baseline) compared with injection (17%). Immunoblotting revealed that the constant infusion of IGF-I resulted in quantitatively more lower-molecular-mass fragments of IGFBP-3 than were observed during baseline or intermittent injections. Size-exclusion chromatography and ultrafiltration indicated that most IGFBP-3 was found in the ternary complex, with a greater percentage found in the ternary complex during baseline (90%) than during constant infusion (86%) or intermittent injections of IGF-I (87%). In

  17. The Role of GH/IGF-I Axis in Muscle Homeostasis During Weightlessness

    Science.gov (United States)

    Schwartz, Robert J.

    1997-01-01

    Exposure to reduced gravity during space travel profoundly alters the loads placed on bone and muscle. Astronauts suffer significant losses of muscle and bone strength during weightlessness. Exercise as a countermeasure is only partially effective in remedying severe muscle atrophy and bone demineralization. Similar wasting of muscles and bones affects people on Earth during prolonged bed rest or immobilization due to injury. In the absence of weight bearing activity, atrophy occurs primarily in the muscles that act in low power, routine movements and in maintaining posture. Hormonal disfunction could contribute in part to the loss of muscle and bone during spaceflight. Reduced levels of human Growth Hormone (hGH) were found in astronauts during space flight, as well as reduced GH secretory activity was observed from the anterior pituitary in 7-day space flight rats. Growth hormone has been shown to be required for maintenance of muscle mass and bone mineralization, in part by mediating the biosynthesis IGF-I, a small polypeptide growth factor. IGF biosynthesis and secretion plays an important role in potentiating muscle cell differentiation and has been shown to drive the expression of myogenin, a myogenic specific basic helix-loop-helix factor. IGF-I has also been shown to have an important role in potentiating muscle regeneration, repair and adult muscle hypertrophy.

  18. Circulating levels of insulin-like growth factor-I (IGF-I correlate with disease status in leprosy

    Directory of Open Access Journals (Sweden)

    Rodrigues Luciana

    2011-12-01

    Full Text Available Abstract Background Caused by Mycobacterium leprae (ML, leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems. Methods In the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT, borderline lepromatous (NR BL, and lepromatous (NR LL leprosy patients in addition to healthy controls (HC. LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α were evaluated at diagnosis and during development of reversal (RR or erythema nodosum leprosum (ENL reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method. Results The circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients. Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients

  19. GENETIC DEFECTS IN THE GROWTH HORMONE-IGF-I AXIS CAUSING GROWTH HORMONE INSENSITIVITY AND IMPAIRED LINEAR GROWTH

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    Martin O. Savage

    2011-12-01

    Full Text Available Human genetic defects in the growth hormone (GH –IGF-I axis affecting the IGF system present with growth failure as their principal clinical feature. This is usually associated with GH insensitivity (GHI presenting in childhood as severe or mild short stature. Dysmorphic features and metabolic abnormalities may also be present. The field of GHI due to mutations affecting GH action has evolved radidly since the first description of the extreme phenotype related to homozygous GH receptor (GHR mutations in 1966. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The mechanisms of the GH–IGF-I axis in the regulation of normal human growth is discussed followed by descriptions of mutations in GHR, STAT5B, IGF-I, IGFALS, IGF1R and GH1 defects causing bioinactive GH or anti-GH antibodies. These GH-IGF-I axis defects are associated with a range of clinical, and hormonal characteristics. An up-dated approach to the clinical assessment of the patient with GHI focussing on investigation of the GH–IGF-I axis and relevant molecular studies contributing to the identification of causative genetic defects is also discussed.

  20. Expression of IGF-I and Protein Degradation Markers During Hindlimb Unloading and Growth Hormone Administration in Rats

    Science.gov (United States)

    Leinsoo, T. A.; Turtikova, O. V.; Shenkman, B. S.

    2013-02-01

    It is known that hindlimb unloading or spaceflight produce atrophy and a number of phenotypic alterations in skeletal muscles. Many of these processes are triggered by the axis growth hormone/insulin-like growth factor I. However growth hormone (GH) and insulin-like growth factor I (IGF-I) expression relationship in rodent models of gravitational unloading is weakly investigated. We supposed the IGF-I is involved in regulation of protein turnover. In this study we examined the IGF-I expression by RT-PCR assay in the rat soleus, tibialis anterior and liver after 3 day of hindlimb suspension with growth hormone administration. Simultaneously were studied expression levels of MuRF-1 and MAFbx/atrogin as a key markers of intracellular proteolysis. We demonstrated that GH administration did not prevent IGF-I expression decreasing under the conditions of simulated weightlessness. It was concluded there are separate mechanisms of action of GH and IGF-I on protein metabolism in skeletal muscles. Gravitational unloading activate proteolysis independently of growth hormone activity.

  1. Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action.

    Science.gov (United States)

    Liu, Wei; Guo, Miao; Ezzat, Shereen; Asa, Sylvia L

    2011-01-01

    Population studies suggest putative links between vitamin D (VD)-deficiency and risk of cancer and diabetes. The insulin/IGF-I receptor represents a signaling target of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) that is implicated in both diabetes and cancer, therefore we hypothesized that VD actions may be mediated through this adhesion molecule. In this study, we show that 1,25 vitamin D3 and its analogues EB1089 and KH1060 potently inhibit CEACAM1 expression in cancer cells. This effect was associated with significant reductions in mRNA and protein levels, resulting from transcriptional and posttranslational actions respectively. Insulin/IGF-I-mediated IRS-1 and Akt activation were enhanced by VD treatment. Similarly, CEACAM1 downregulation significantly upregulated the insulin and IGF-I receptors and mimicked the effect of VD-mediated enhanced insulin/IGF-I receptor signaling. Despite improved insulin/IGF-I signaling, the anti-proliferative actions of VD were preserved in the absence or presence of forced CEACAM1 expression. Forced CEACAM1, however, abrogated the anti-invasive actions of VD. Our findings highlight CEACAM1 as a target of VD action. The resulting inhibition of CEACAM1 has potentially beneficial effects on metabolic disorders without necessarily compromising the anticancer properties of this vitamin.

  2. An IGF-I gene polymorphism modifies the risk of developing persistent microalbuminuria in type 1 diabetes

    DEFF Research Database (Denmark)

    Hovind, Peter; Lamberts, Steven; Hop, Wim

    2007-01-01

    OBJECTIVE: Derangements of the GH-IGF-I axis have been associated with microalbuminuria (MA) in type 1 diabetes. The aim of this study was to investigate whether an IGF-I gene promoter polymorphism influenced the development of persistent MA in type 1 diabetes. DESIGN: A prospective follow-up study...... mg/24 h. RESULTS: During a median follow-up of 18.0 years (range 1.0-21.5), 79 of 277 patients developed persistent MA. IGF-I gene genotype was available for 216 subjects; in 73% of the subjects, the wild-type genotype of this IGF-I gene polymorphism was present, while 27% had the variant type....... At baseline, there were no differences in IGF-I levels and HbA(1c) values between subjects with the wild type and subjects with variant type. By Kaplan-Meier analysis, subjects with the variant type of this polymorphism had during follow-up a higher risk of development of MA compared subjects with the wild...

  3. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats.

    Science.gov (United States)

    Galvão, Rui P; Garcia-Verdugo, José Manuel; Alvarez-Buylla, Arturo

    2008-12-10

    In rodents, the adult subventricular zone (SVZ) generates neuroblasts which migrate to the olfactory bulb (OB) and differentiate into interneurons. Recent work suggests that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) can enhance adult SVZ neurogenesis, but the mechanism by which it acts is unknown. Here, we analyzed the role of BDNF and its receptor TrkB in adult SVZ neurogenesis. We found that TrkB is the most prominent neurotrophin receptor in the mouse SVZ, but only the truncated, kinase-negative isoform (TrkB-TR) was detected. TrkB-TR is expressed in SVZ astrocytes and ependymal cells, but not in neuroblasts. TrkB mutants have reduced SVZ proliferation and survival and fewer new OB neurons. To test whether this effect is cell-autonomous, we grafted SVZ cells from TrkB knock-out mice (TrkB-KO) into the SVZ of wild-type mice (WT). Grafted progenitors generated neuroblasts that migrated to the OB in the absence of TrkB. The survival and differentiation of granular interneurons and Calbindin(+) periglomerular interneurons seemed unaffected by the loss of TrkB, whereas dopaminergic periglomerular neurons were reduced. Intra-ventricular infusion of BDNF yielded different results depending on the animal species, having no effect on neuron production from mouse SVZ, while decreasing it in rats. Interestingly, mice and rats also differ in their expression of the neurotrophin receptor p75. Our results indicate that TrkB is not essential for adult SVZ neurogenesis and do not support the current view that delivering BDNF to the SVZ can enhance adult neurogenesis.

  4. A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process.

    Science.gov (United States)

    McCarty, Mark F

    2003-06-01

    A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention-most notably salt restriction-may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

  5. Factor de crecimiento semejante a la insulina tipo I (IGF-I y cirrosis hepática Insulin-like growth factor I (IGF-I and liver cirrhosis

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    M. Conchillo

    2007-03-01

    Full Text Available El factor de crecimiento semejante a la insulina tipo I (IGF-I es una hormona polipeptídica segregada en múltiples tejidos por efecto de la hormona de crecimiento (GH. Es responsable de parte de las acciones de la GH y además tiene efecto hipoglucemiante y anabolizante. El 90% del IGF-I circulante es de origen hepático y ejerce efectos autocrinos, paracrinos y endocrinos, estos últimos en múltiples tejidos. En la cirrosis hepática se produce una disminución progresiva de la producción hepática de IGF-I que llega a ser indetectable en la enfermedad avanzada. Algunas de las complicaciones de la cirrosis, fundamentalmente nutricionales y metabólicas (resistencia a insulina, desnutrición, osteopenia, hipogonadismo, alteraciones intestinales podrían estar, al menos en parte, relacionadas con esta carencia de IGF-I dado que algunas acciones de IGF-I representan la imagen inversa de las complicaciones de la cirrosis. A pesar de ello, nunca se había propuesto tratamiento sustitutivo con IGF-I en la cirrosis. En una serie de estudios experimentales realizados en ratas cirróticas se demostró que el tratamiento con dosis bajas de IGF-I recombinante produce dos tipos de efectos en la cirrosis experimental: a mejoría del hígado, dado que mejora la función hepatocelular, la hipertensión portal y la fibrosis hepática; y b mejoría de las alteraciones extrahepáticas de la cirrosis dado que mejora la eficiencia del alimento ingerido, la masa muscular, la masa ósea, la función y estructura gonadales y la función y estructura intestinales con normalización de la malabsorción de azúcares y aminoácidos y la mejoría de la función intestinal de barrera manifestada por disminución de la endotoxemia y la translocación bacteriana. Posteriormente el primer ensayo clínico piloto, aleatorizado, doble ciego y controlado con placebo llevado a cabo en un número reducido de pacientes cirróticos demostró aumento de la albúmina sérica y

  6. Hepatic mRNA expression and plasma levels of insulin-like growth factor-I (IGF-I in broiler chickens selected for different growth rates

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    Poliana Fernanda Giachetto

    2004-01-01

    Full Text Available The hepatic expression and plasma concentrations of IGF-I were investigated in three broiler chicken strains selected for different growth rates (HP-Hubbard-Pettersen, a fast growing strain; NN-Naked-neck, a strain with an intermediate growth rate and a heterozygous genotype, and C-Caipira, a slow growing crossbred strain. The chickens were studied at 1, 21 and 42 days of age and had free access to food throughout the study. Hepatic IGF-I mRNA expression was assessed by dot blot analysis using a randomly labeled chicken IGF-I cDNA as the probe and plasma IGF-I concentrations were assayed by radioimmunoassay. The hepatic levels of IGF-I mRNA increased from 1 to 21 days of age in all strains, with NN chickens showing a higher (p < 0.05 IGF-I expression than the other strains. Plasma IGF-I concentrations increased (p < 0.05 with broiler chicken age, but there were no significant differences among the strains. These results indicate that despite differences in the growth rates among the strains, the changes in the expression of IGF-I mRNA in liver and in the plasma levels of IGF-I were independent of broiler chicken strain, but varied with chicken age.

  7. Expression of hIGF-I in the silk glands of transgenic silkworms and in transformed silkworm cells

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    To express human insulin-like growth factor-I (hIGF-I) in transformed Bombyx mori cultured cells and silk glands, the transgenic vector pigA3GFP-hIGF-ie-neo was constructed with a neomycin resistance gene driven by the baculovirus ie-1 promoter, and with the hIGF-I gene under the control of the silkworm sericin promoter Ser-1. The stably transformed BmN cells expressing hIGF-I were selected by using the antibiotic G418 at a final concentration of 700-800 μg/mL after the BmN cells were transfected with the piggyBac vector and the helper plasmid. The specific band of hIGF-I was detected in the transformed cells by Western blot. The expression level of hIGF-I, determined by ELISA, was about 7800 pg in 5×105 cells. Analysis of the chromosomal insertion sites by inverse PCR showed that exogenous DNA could be inserted into the cell genome randomly or at TTAA target sequence specifically for piggyBac element transposition. The transgenic vector pigA3GFP-hIGF-ie-neo was transferred into the eggs using sperm-mediated gene transfer. Finally, two transgenic silkworms were obtained after screening for the neo and gfp genes and verified by PCR and dot hybridization. The expression level of hIGF-I determined by ELISA was about 2440 pg/g of silk gland of the transgenic silkworms of the G1 generation.

  8. Effect of growth hormone on small intestinal homeostasis relation to cellular mediators IGF-I and IGFBP-3

    Institute of Scientific and Technical Information of China (English)

    Betul Ersoy; Kemal Ozbilgin; Erhun Kasirga; Sevinc Inan; Senol Coskun; Ibrahim Tuglu

    2009-01-01

    AIM: To evaluate the effects of growth hormone (GH) on the histology of small intestines which might be related to the role of insulin like growth factor (IGF)-I, IGF-binding protein 3 (IGFBP-3) and its receptors.METHODS: Twelve week-old adult male Wistar albino rats were divided into two groups.The study group ( n = 10), received recombinant human growth hormone (rGH) at a dose of 2 mg/kg per day subcutaneously for 14 d and the control group ( n = 10) received physiologic serum.Paraffin sections of jejunum were stained with periodic acid shift (PAS) and hematoxylin and eosin (HE) for light microscopy.They were also examined for IGF-I, IGFBP-3 and IGF-receptor immunoreactivities.Staining intensity was graded semi-quantitatively using the HSCORE.RESULTS: Goblet cells and the cells in crypt epithelia were significantly increased in the study group compared to that of the control group.We have demonstrated an increase of IGF-I and IGFBP-3 immunoreactivities in surface epithelium of the small intestine by GH application.IGF-I receptor immunoreactivities of crypt, villous columnar cells, enteroendocrine cells and muscularis mucosae were also more strongly positive in the study group compared to those of in the control group.CONCLUSION: These findings confirm the important trophic and protective role of GH in the homeostasis of the small intestine.The trophic effect is mediated by an increase in IGF-I synthesis in the small intestine, but the protective effect is not related to IGF-I.

  9. Mature IGF-I excels in promoting functional muscle recovery from disuse atrophy compared with pro-IGF-IA.

    Science.gov (United States)

    Park, Soohyun; Brisson, Becky K; Liu, Min; Spinazzola, Janelle M; Barton, Elisabeth R

    2014-04-01

    Prolonged disuse of skeletal muscle results in atrophy, and once physical activity is resumed, there is increased susceptibility to injury. Insulin-like growth factor-I (IGF-I) is considered a potential therapeutic target to attenuate atrophy during unloading and to enhance rehabilitation upon reloading of skeletal muscles, due to its multipronged actions on satellite cell proliferation, differentiation, and survival, as well as its actions on muscle fibers to boost protein synthesis and inhibit protein degradation. However, the form of IGF-I delivered may alter the success of treatment. Using the hindlimb suspension model of disuse atrophy, we compared the efficacy of two IGF-I forms in protection against atrophy and enhancement of recovery: mature IGF-I (IGF-IS) lacking the COOH-terminal extension, called the E-peptide, and IGF-IA, which is the predominant form retaining the E-peptide. Self-complementary adeno-associated virus harboring the murine Igf1 cDNA constructs were delivered to hindlimbs of adult female C57BL6 mice 3 days prior to hindlimb suspension. Hindlimb muscles were unloaded for 7 days and then reloaded for 3, 7, and 14 days. Loss of muscle mass following suspension was not prevented by either IGF-I construct. However, IGF-IS expression maintained soleus muscle force production. Further, IGF-IS treatment caused rapid recovery of muscle fiber morphology during reloading and maintained muscle strength. Analysis of gene expression revealed that IGF-IS expression accelerated the downregulation of atrophy-related genes compared with untreated or IGF-IA-treated samples. We conclude that mature-IGF-I may be a better option than pro-IGF-IA to promote skeletal muscle recovery following disuse atrophy.

  10. Regulation of hypoxia-inducible factor-1α (HIF-1α expression by interleukin-1β (IL-1 β, insulin-like growth factors I (IGF-I and II (IGF-II in human osteoarthritic chondrocytes

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    Angelica Rossi Sartori-Cintra

    2012-01-01

    Full Text Available OBJECTIVE: Hypoxia-inducible factor 1 alpha regulates genes related to cellular survival under hypoxia. This factor is present in osteroarthritic chondrocytes, and cytokines, such as interleukin-1 beta, participate in the pathogenesis of osteoarthritis, thereby increasing the activities of proteolytic enzymes, such as matrix metalloproteinases, and accelerating cartilage destruction. We hypothesize that Hypoxia Inducible Factor-1 alpha (HIF-1α can regulate cytokines (catabolic action and/or growth factors (anabolic action in osteoarthritis. The purpose of this study was to investigate the modulation of HIF-1α in human osteoarthritic chondrocytes by interleukin-1 beta (IL-1β and insulin-like growth factors I (IGF-I and II (IGF-II and to determine the involvement of the phosphatidylinositol-3kinase (PI-3K pathway in this process. METHODS: Human osteroarthritic chondrocytes were stimulated with IL-1β, IGF-I and IGF-II and LY294002, a specific inhibitor of PI-3K. Nuclear protein levels and gene expression were analyzed by western blot and quantitative reverse transcription-polymerase chain reaction analyses, respectively. RESULTS: HIF-1α expression was upregulated by IL-1β at the protein level but not at the gene level. IGF-I treatment resulted in increases in both the protein and mRNA levels of HIF-1α , whereas IGF-II had no effect on its expression. However, all of these stimuli exploited the PI-3K pathway. CONCLUSION: IL-1β upregulated the levels of HIF-1α protein post-transcriptionally, whereas IGF-I increased HIF-1α at the transcript level. In contrast, IGF-II did not affect the protein or gene expression levels of HIF-1α . Furthermore, all of the tested stimuli exploited the PI-3K pathway to some degree. Based on these findings, we are able to suggest that Hypoxia inducible Factor-1 exhibits protective activity in chondrocytes during osteoarthritis.

  11. Development and biological function of the female gonads and genitalia in IGF-I deficiency -- Laron syndrome as a model.

    Science.gov (United States)

    Laron, Zvi

    2006-01-01

    Laron syndrome (LS) or primary GH insensitivity is a unique human model to study the effects of congenital IGF-I deficiency. Within our cohort of 63 patients with LS, 15 female patients were regularly followed since birth or infancy, throughout puberty. We observed that they were short at birth, with small genitalia and gonads -- during puberty, developed delayed puberty but eventually reached between 16 and 19 1/2 years full sexual development. Reproduction is unaffected at a young adult age. It is concluded that IGF-I in concert with the sex hormones has a modulatory but not essential function on female sexual development and maturation.

  12. Lower levels of circulating IGF-I in Type 1 diabetic women with frequent severe hypoglycaemia during pregnancy

    DEFF Research Database (Denmark)

    Ringholm Nielsen, L; Juul, A; Pedersen-Bjergaard, U

    2008-01-01

    Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin-like growth factor I (IGF-I) levels.......Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin-like growth factor I (IGF-I) levels....

  13. Glomerular ultrafiltration and apical tubular action of IGF-I, TGF-beta, and HGF in nephrotic syndrome.

    Science.gov (United States)

    Wang, S N; Lapage, J; Hirschberg, R

    1999-10-01

    In nephrotic glomerulopathies, there is ultrafiltration of high molecular weight forms of insulin-like growth factor-I (IGF-I), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-beta), which are bioactive in tubular fluid and act through apical tubular receptors. Experimental evidence indicates that ultrafiltered IGF-I, HGF, and TGF-beta may contribute to increased tubular phosphate and sodium absorption, synthesis of extracellular matrix proteins, and secretion of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Through these mechanisms, glomerular proteinuria may contribute to tubulointerstitial pathobiology in nephrotic syndrome.

  14. Alteration in IGF-I binding in the cerebral cortex and cerebellum of neonatal rats during protein-calorie malnutrition.

    Science.gov (United States)

    Maheshwari, H G; Mermelstein, S; vonSchlegell, A S; Shambaugh, G E

    1997-03-01

    Neonatal brain development in the rat is adversely affected by malnutrition. Alterations in tissue binding of IGF-I in the malnourished brain were tested in rat pups from mothers who were fed a 20% protein diet (C) or a 4% protein diet (M) starting from day 21 of gestation and continued throughout suckling. IGF-I binding in both cortex and cerebellum decreased progressively in C and M groups from day 6 to day 13. At day 9, 11, and 13, the binding was significantly greater (p < 0.02) in M compared to C groups. To investigate whether these changes might be related to the alteration in receptor activity, membranes were incubated with 125I-IGF in the presence of excess insulin with or without unlabeled IGF-I. In the absence of insulin, specific IGF-I binding in the M group was increased by 41.8 +/- 13.8% (mean +/- SEM p < 0.05) relative to C group. Insulin produced a consistent but incomplete inhibition of binding in both C and M, of 75% and 67% respectively. In addition, the specific IGF-I binding in the presence of insulin was increased in M group by 70.2 +/- 9.4% relative to C, p < 0.05. To characterize the nature of this binding, cerebral cortical membranes, from both groups, incubated with 125I-IGF-I were cross-linked, and electrophoresed on 6% and 10% SDS-PAGE gels under reducing conditions. Autoradiography of the 6% gel showed two specific bands at 115 kD and 240 kD, consistent with monomeric and dimeric forms of the IGF-I receptor, which were inhibited by excess insulin. In contrast, a 10% gel showed an additional band at 35 kD (IGF-binding protein) that was not inhibited by insulin. In both gels, membrane preparations from the M group showed a heightened intensity of the bands relative to C. The increase in binding protein relative to the receptor suggests a disequilibrium that may limit the availability of exogenous IGF-I to the tissues.

  15. Contribución de IGF-I en la hiperplasia mamaria promovida por AIB1

    OpenAIRE

    Señoret Molina, Vanesa

    2015-01-01

    El oncogén AIB1 (Amplified in Breast Cancer 1) es un coactivador de la transcripción de genes implicados en la respuesta fisiológica a hormonas y factores de crecimiento. La sobreexpresión de AIB1 es una característica frecuente en muchos tipos de cáncer, incluyendo el de mama. Diferentes estudios con líneas celulares y modelos animales han demostrado que AIB1 interacciona con la ruta de señalización de IGF-I/PI3K/AKT a diferentes niveles moleculares. Por otra parte, la señalización mediada ...

  16. Characterization data of gilthead sea bream (Sparus aurata) IGF-I receptors (IGF-IRa/Rb).

    Science.gov (United States)

    Vélez, Emilio J; Azizi, Sheida; Salmerón, Cristina; Chan, Shu Jin; Nematollahi, Mohammad Ali; Amiri, Bagher Mojazi; Navarro, Isabel; Capilla, Encarnación; Gutiérrez, Joaquim

    2016-03-01

    In this data article we describe the coding sequence of two IGF-IR paralogues (IGF-IRa and IGF-IRb) obtained from gilthead sea bream embryos. The putative protein architecture (domains and other important motifs) was determined and, amino acid sequences alignment and phylogenetic analysis of both receptors together with IGF-IR orthologues from different vertebrates was performed. Additionally, a semi-quantitative conventional PCR was done to analyze the mRNA expression of both receptors in different tissues of gilthead sea bream. These data will assist in further physiological studies in this species. In this sense, the expression of both receptors during ontogeny in muscle as well as the differential effects of IGF-I and IGF-II on their regulation during in vitro myogenesis has been recently studied (doi: 10.1016/j.ygcen.2015.11.011; [1]).

  17. Characterization data of gilthead sea bream (Sparus aurata IGF-I receptors (IGF-IRa/Rb

    Directory of Open Access Journals (Sweden)

    Emilio J. Vélez

    2016-03-01

    Full Text Available In this data article we describe the coding sequence of two IGF-IR paralogues (IGF-IRa and IGF-IRb obtained from gilthead sea bream embryos. The putative protein architecture (domains and other important motifs was determined and, amino acid sequences alignment and phylogenetic analysis of both receptors together with IGF-IR orthologues from different vertebrates was performed. Additionally, a semi-quantitative conventional PCR was done to analyze the mRNA expression of both receptors in different tissues of gilthead sea bream. These data will assist in further physiological studies in this species. In this sense, the expression of both receptors during ontogeny in muscle as well as the differential effects of IGF-I and IGF-II on their regulation during in vitro myogenesis has been recently studied (doi: 10.1016/j.ygcen.2015.11.011; [1].

  18. Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits

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    Maximilian Bielohuby

    2014-11-01

    Full Text Available The development of new growth hormone (GH agonists and growth hormone antagonists (GHAs requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS. Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs. Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7–3.3% coefficient of variation and linearity (90.4–105.6% were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; P<0.01 and were highly correlated (P<0.0001. Treatment with the GHA lowered IGF-I levels from the fourth injection onwards (P<0.01. In summary, we demonstrated that the IDS-iSYS IGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on

  19. Chronic hypoxia induces the in vivo activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1deltaE9 transgenic mice

    Directory of Open Access Journals (Sweden)

    Lorena eVarela-Nallar

    2014-02-01

    Full Text Available Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin a key component of the canonical Wnt signaling pathway. Here we studied in vivo the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice. As a molecular control of the physiological hypoxic response the hypoxia-inducible transcription factor-1α (HIF-1α was analyzed. Exposure to chronic hypoxia (10% oxygen for 6-72 h stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, BrdU incorporation and double labeling with doublecortin. Chronic hypoxia also induced neurogenesis in double transgenic APPswe-PS1deltaE9 mouse model of Alzheimer’s disease (AD, which shows decreased levels of neurogenesis at the SGZ. Our results show for the first time that in vivo exposure to hypoxia can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorder associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.

  20. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    Science.gov (United States)

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  1. Antioxidant effects of insulin-like growth factor-I (IGF-I in rats with advanced liver cirrhosis

    Directory of Open Access Journals (Sweden)

    Puche Juan

    2005-03-01

    Full Text Available Abstract Background The exogenous administration of Insulin-like Growth Factor-I (IGF-I induces hepatoprotective and antifibrogenic actions in experimental liver cirrhosis. To better understand the possible pathways behind the beneficial effect of IGF-I, the aim of this work was to investigate severe parameters involved in oxidative damage in hepatic tissue from cirrhotic animals treated with IGF-I (2 μg. 100 g-1. day-1. Iron and copper play an important role in oxidative mechanisms, producing the deleterious hydroxyl radical (*OH that peroxides lipid membranes and damages DNA. Myeloperoxidase (MPO and nitric oxide (NO are known sources of free radicals and induce reduction of ferritin-Fe3+ into free Fe2+, contributing to oxidative damage. Methods Liver cirrhosis was induced by CCl4 inhalation in Wistar male rats for 30 weeks. Healthy controls were studied in parallel (n = 10. Fe and Cu were assessed by atomic absoption spectrometry and iron content was also evaluated by Perls' staining. MPO was measured by ELISA and transferrin and ferritin by immunoturbidimetry. iNOS expression was studied by immuno-histochemistry. Results Liver cirrhosis was histologically proven and ascites was observed in all cirrhotic rats. Compared to controls untreated cirrhotic rats showed increased hepatic levels of iron, ferritin, transferrin (p Conclusion the hepatoprotective and antifibrogenic effects of IGF-I in cirrhosis are associated with a diminution of the hepatic contents of several factors all of them involved in oxidative damage.

  2. Acromegaly: the significance of serum total and free IGF-I and IGF-binding protein-3 in diagnosis

    NARCIS (Netherlands)

    A-J. van der Lely (Aart-Jan); W.W. de Herder (Wouter); J.A.M.J.L. Janssen (Joop); S.W.J. Lamberts (Steven)

    1997-01-01

    textabstractWe have studied the physiological and clinical relevance of measurements of serum total and free IGF-I and IGF-binding protein-3 (IGFBP-3) in 57 previously untreated patients with active acromegaly (32 males, 25 females; mean age 47 years) as compared with sex- and age-

  3. Growth hormone/IGF-I and/or resistive exercise maintains myonuclear number in hindlimb unweighted muscles

    Science.gov (United States)

    Allen, D. L.; Linderman, J. K.; Roy, R. R.; Grindeland, R. E.; Mukku, V.; Edgerton, V. R.

    1997-01-01

    In the present study of rats, we examined the role, during 2 wk of hindlimb suspension, of growth hormone/insulin-like growth factor I (GH/IGF-I) administration and/or brief bouts of resistance exercise in ameliorating the loss of myonuclei in fibers of the soleus muscle that express type I myosin heavy chain. Hindlimb suspension resulted in a significant decrease in mean soleus wet weight that was attenuated either by exercise alone or by exercise plus GH/IGF-I treatment but was not attenuated by hormonal treatment alone. Both mean myonuclear number and mean fiber cross-sectional area (CSA) of fibers expressing type I myosin heavy chain decreased after 2 wk of suspension compared with control (134 vs. 162 myonuclei/mm and 917 vs. 2,076 micron2, respectively). Neither GH/IGF-I treatment nor exercise alone affected myonuclear number or fiber CSA, but the combination of exercise and growth-factor treatment attenuated the decrease in both variables. A significant correlation was found between mean myonuclear number and mean CSA across all groups. Thus GH/IGF-I administration and brief bouts of muscle loading had an interactive effect in attenuating the loss of myonuclei induced by chronic unloading.

  4. Effects of selection for blood serum IGF-I concentration on reproductive performance of female Angus beef cattle.

    Science.gov (United States)

    Zhang, X; Davis, M E; Moeller, S J; Ottobre, J S

    2013-09-01

    Reproductive performance of animals affects lifetime productivity. However, improvement of reproductive traits via direct selection is generally slow due to low heritability. Therefore, identification of indicator traits for reproductive performance may enhance genetic response. Previous studies showed that serum IGF-I concentration is a candidate indicator for growth and reproductive traits. The objective of our study was to estimate the variances or covariances of IGF-I concentration with reproductive traits. Data were collected from a divergent selection experiment for serum IGF-I concentration at the Eastern Agricultural Research Station owned by The Ohio State University. The study included a total of 2,662 calves in the 1989 to 2005 calf crops. Variance or covariance components were estimated for direct and maternal genetic effects, maternal environment effects, environment effects, and phenotypic effects using an animal model in a multiple-trait, derivative-free, restricted maximum likelihood (MTDFREML, Boldman et al., 1995) computer program. Direct additive genetic correlations suggest that selection for greater IGF-I concentration (heritability = 0.50 ± 0.07) could lead to increased conception rate (heritability = 0.11 ± 0.06, r = 0.32, P < 0.001) and calving rate (heritability = 0.13 ± 0.06, r = 0.43, P < 0.001) and decreased age at first calving in heifers (heritability = 0.35 ± 0.20, r = -0.40, P < 0.001).

  5. Co-induction of hepatic IGF-I and progranulin mRNA by growth hormone in tilapia, Oreochromis mossambiccus

    Science.gov (United States)

    Like IGF-I, progranulin (pgrn) is a growth factor involved in tumorigenesis and wound healing. We report here the identification and characterization of pgrn cDNA in tilapia and the regulation of its expression by growth hormone(GH). The tilapia pgrn cDNA was cloned by RT-PCR ampliWcation, using g...

  6. Bioactive rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients

    NARCIS (Netherlands)

    M.P. Brugts (Michael); H.L. Tjiong (Hoey Lan); T. Rietveld (Trinet); J.L.D. Wattimena (Josias); J.W.O. van den Berg (Willem); M.W.J.A. Fieren (Marien); J.A.M.J.L. Janssen (Joseph)

    2010-01-01

    textabstractBackground. Inadequate food intake plays an important role in the development of malnutrition in continuous ambulatory peritoneal dialysis (CAPD) patients.Aim of the study. The aim of the study was to investigate in CAPD patients whether circulating insulin-like growth factor-I (IGF-I) b

  7. Growth hormone/IGF-I and/or resistive exercise maintains myonuclear number in hindlimb unweighted muscles

    Science.gov (United States)

    Allen, D. L.; Linderman, J. K.; Roy, R. R.; Grindeland, R. E.; Mukku, V.; Edgerton, V. R.

    1997-01-01

    In the present study of rats, we examined the role, during 2 wk of hindlimb suspension, of growth hormone/insulin-like growth factor I (GH/IGF-I) administration and/or brief bouts of resistance exercise in ameliorating the loss of myonuclei in fibers of the soleus muscle that express type I myosin heavy chain. Hindlimb suspension resulted in a significant decrease in mean soleus wet weight that was attenuated either by exercise alone or by exercise plus GH/IGF-I treatment but was not attenuated by hormonal treatment alone. Both mean myonuclear number and mean fiber cross-sectional area (CSA) of fibers expressing type I myosin heavy chain decreased after 2 wk of suspension compared with control (134 vs. 162 myonuclei/mm and 917 vs. 2,076 micron2, respectively). Neither GH/IGF-I treatment nor exercise alone affected myonuclear number or fiber CSA, but the combination of exercise and growth-factor treatment attenuated the decrease in both variables. A significant correlation was found between mean myonuclear number and mean CSA across all groups. Thus GH/IGF-I administration and brief bouts of muscle loading had an interactive effect in attenuating the loss of myonuclei induced by chronic unloading.

  8. Molecular genetic and physiologic background of the growth hormone-IGF-I axis in relation to breeding for growth rate and leanness in pigs

    NARCIS (Netherlands)

    Pas, te M.F.W.; Visscher, A.H.; Greef, de K.H.

    2004-01-01

    The GH-IGF-I axis is of major importance for the regulation of body growth and composition, and cellular proliferation and differentiation processes. Selective breeding aiming to improve growth rate and/or body composition is accompanied by changes of the GH-IGF-I axis. Research aiming to elucidate

  9. Molecular genetic and physiologic background of the growth hormone-IGF-I axis in relation to breeding for growth rate and leanness in pigs

    NARCIS (Netherlands)

    Pas, te M.F.W.; Visscher, A.H.; Greef, de K.H.

    2004-01-01

    The GH-IGF-I axis is of major importance for the regulation of body growth and composition, and cellular proliferation and differentiation processes. Selective breeding aiming to improve growth rate and/or body composition is accompanied by changes of the GH-IGF-I axis. Research aiming to elucidate

  10. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders;

    2008-01-01

    To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia.......To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia....

  11. Gender differences in serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly.

    Science.gov (United States)

    Tanaka, Satoshi; Fukuda, Izumi; Hizuka, Naomi; Takano, Kazue

    2010-01-01

    Gender affects the GH secretory pattern both in normal subjects and in patients with acromegaly by an uncertain mechanism. Here, we report the influence of gender on the relationship between serum GH and IGF-I levels and the GH response to dynamic tests in patients with acromegaly. Seventy-four patients with untreated acromegaly (M/F 27/47, age range 22-86 yr.) were studied. The serum GH levels did not differ between male and female (6.1 vs. 8.7 ng/ml; p=0.26), while serum IGF-I levels, IGF-I SDS and the IGF-I/GH ratio were lower in female than those in male (679 vs. 769 ng/ml; p50 yr, serum IGF-I levels and IGF-I/GH ratios were lower in female than those in male in patients 50 yrs (684 vs. 680 ng/ml; p=0.39 and 98.7 vs. 118.4; p=0.40). The GH responses to OGTT, TRH, octreotide, and bromocriptine tests were similar in male and female. In conclusion, IGF-I/GH ratio was significantly lower in female than that in male particularly in younger patients with acromegaly. These data suggest that gender, presumably sex steroids in female, may partially modulate the relationship between circulating IGF-I and GH levels in patients with acromegaly.

  12. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis : Results of a pilot randomized controlled clinical trial

    NARCIS (Netherlands)

    Conchillo, M; de Knegt, RJ; Payeras, M; Quiroga, J; Sangro, B; Herrero, JI; Castilla-Cortazar, [No Value; Frystyk, J; Flyvbjerg, A; Yoshizawa, C; Jansen, PLM; Scharschmidt, B; Prieto, J

    2005-01-01

    Background/Aims: Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesized in the liver whose levels decrease sharply in liver cirrhosis. Methods: We conducted a randomized double-blind placebo-controlled clinical trial to evaluate the effect of subcutaneous administration of IGF-I (20

  13. The effects of insulin-like growth factor I (IGF-I complex from seminal plasma on capacitation, membrane integrity and DNA fragmentation in goat spermatozoa

    Directory of Open Access Journals (Sweden)

    Suherni Susilowati

    2015-09-01

    Conclusions: Sperm quality include motility, viability and membrane integrity were lower after centrifugation. Whereas DNA fragmentation after incubation in the IGF-I complex medium also was lower compared to that of specimens in the BO and BO + IGF-I complex media.

  14. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis : Results of a pilot randomized controlled clinical trial

    NARCIS (Netherlands)

    Conchillo, M; de Knegt, RJ; Payeras, M; Quiroga, J; Sangro, B; Herrero, JI; Castilla-Cortazar, [No Value; Frystyk, J; Flyvbjerg, A; Yoshizawa, C; Jansen, PLM; Scharschmidt, B; Prieto, J

    2005-01-01

    Background/Aims: Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesized in the liver whose levels decrease sharply in liver cirrhosis. Methods: We conducted a randomized double-blind placebo-controlled clinical trial to evaluate the effect of subcutaneous administration of IGF-I (20

  15. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    Directory of Open Access Journals (Sweden)

    Eleni Paizanis

    2007-01-01

    Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

  16. Forkhead box A1 (FOXA1) is a key mediator of insulin-like growth factor I (IGF-I) activity.

    Science.gov (United States)

    Potter, Adam S; Casa, Angelo J; Lee, Adrian V

    2012-01-01

    The insulin-like growth factor receptor (IGF-IR) has been implicated in a number of human tumors, including breast cancer. Data from human breast tumors has demonstrated that IGF-IR is over-expressed and hyper-phosphorylated. Additionally, microarray analysis has shown that IGF-I treatment of MCF7 cells leads to a gene signature comprised of induced and repressed genes, which correlated with luminal B tumors. FOXA1, a forkhead family transcription factor, has been shown to be crucial for mammary ductal morphogenesis, similar to IGF-IR, and expressed at high levels in luminal subtype B breast tumors. Here, we investigated the relationship between FOXA1 and IGF-I action in breast cancer cells. We show that genes regulated by IGF-I are enriched for FOXA1 binding sites, and knock down of FOXA1 blocked the ability of IGF-I to regulate gene expression. IGF-I treatment of MCF7 cells increased the half-life of FOXA1 protein and this increase in half-life appeared to be dependent on canonical IGF-I signal transduction through both MAPK and AKT pathways. Finally, knock down of FOXA1 led to a decreased ability of IGF-I to induce proliferation and protect against apoptosis. Together, these results demonstrate that IGF-I can increase the stability of FOXA1 protein expression and place it as a critical mediator of IGF-I regulation of gene expression and IGF-I-mediated biological responses. Copyright © 2011 Wiley Periodicals, Inc.

  17. Effects of Growth Hormone/IGF-I and Exercise on Unloaded Bones

    Science.gov (United States)

    Harper, J. S.; Arnaud, S. B.; Gosselink, K. L.; Grindeland, R. E.

    1994-01-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in combination with exercise prevent muscle atrophy induced by unloading in the tail-suspension rat model for space flight (Gosselink et al, FASEB J 1994). This study evaluated the effects of these treatments on bone. Hypophysectomized rats were suspended (S) and treated with 1mg/kg/day CH plus IGF-I (H) or vehicle (Sal) daily by injection and exercised (Ex) by 3 climbs up a 1m ladder carrying a load equal to 30% the initial body weight (BW) 3x/day for 10 days. Tibial epiphysis (Epi) widths were measured by micrometry and femoral Bone Mineral Content (fBMC) in excised femurs by DEXA (Lunar DPX-L). Serum calcium (Ca) and phosphorus (Pi) were measured by COBAS Autoanalyzer (Roche Diag.). Ambulatory (Amb)-H treated rats showed growth rates of 6.6+-0.9 g/day, similar to S-H-Ex and higher than S-H (3.210.6, p less than 0.05) and S-Sal (-0.711.0, p less than 0.05). Epi widths were 10% lower in S-Sal, and S-Sal-Ex, and increased 100% in all H groups. fBMC was less in S than Amb, only when all S groups are compared to both Amb groups (p less than 0.03). H treatment increased fBMC (p less than 0.05) but reduced fBMC/100g BW in all H groups (p less than 0.001). The reduced density of H bone cannot be attributed to low circulating Ca. and Pi since they were higher in H than Sal (p less than 0.001). H treatment for 10 days in doses sufficient to support normal growth in BW failed to produce normal Epi widths or fBMC, even when combined with exercise. The suspension effect observed in Epi widths was not corrected by H or Ex alone, but was improved by H plus a This regimen. although effective in preventing muscle atrophy, failed to return bone measures, Epi widths and fBMC, to normal.

  18. Effects of Growth Hormone/IGF-I and Exercise on Unloaded Bones

    Science.gov (United States)

    Harper, J. S.; Arnaud, S. B.; Gosselink, K. L.; Grindeland, R. E.

    1994-01-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in combination with exercise prevent muscle atrophy induced by unloading in the tail-suspension rat model for space flight (Gosselink et al, FASEB J 1994). This study evaluated the effects of these treatments on bone. Hypophysectomized rats were suspended (S) and treated with 1mg/kg/day CH plus IGF-I (H) or vehicle (Sal) daily by injection and exercised (Ex) by 3 climbs up a 1m ladder carrying a load equal to 30% the initial body weight (BW) 3x/day for 10 days. Tibial epiphysis (Epi) widths were measured by micrometry and femoral Bone Mineral Content (fBMC) in excised femurs by DEXA (Lunar DPX-L). Serum calcium (Ca) and phosphorus (Pi) were measured by COBAS Autoanalyzer (Roche Diag.). Ambulatory (Amb)-H treated rats showed growth rates of 6.6+-0.9 g/day, similar to S-H-Ex and higher than S-H (3.210.6, p less than 0.05) and S-Sal (-0.711.0, p less than 0.05). Epi widths were 10% lower in S-Sal, and S-Sal-Ex, and increased 100% in all H groups. fBMC was less in S than Amb, only when all S groups are compared to both Amb groups (p less than 0.03). H treatment increased fBMC (p less than 0.05) but reduced fBMC/100g BW in all H groups (p less than 0.001). The reduced density of H bone cannot be attributed to low circulating Ca. and Pi since they were higher in H than Sal (p less than 0.001). H treatment for 10 days in doses sufficient to support normal growth in BW failed to produce normal Epi widths or fBMC, even when combined with exercise. The suspension effect observed in Epi widths was not corrected by H or Ex alone, but was improved by H plus a This regimen. although effective in preventing muscle atrophy, failed to return bone measures, Epi widths and fBMC, to normal.

  19. Delayed treatment of 6-Bromoindirubin-3'-oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice.

    Science.gov (United States)

    Wang, Li-Li; Li, Jimei; Gu, Xiaohuan; Wei, Ling; Yu, Shan Ping

    2017-04-01

    Glycogen synthase kinase 3β (GSK3β) was originally identified as a regulator for glycogen metabolism and is now an important therapeutic target for a variety of brain disorders including neurodegenerative diseases due to it's pivotal role in cellular metabolism, proliferation and differentiation. In the development of stroke therapies focusing on tissue repair and functional recovery, promoting neurogenesis is a main approach in regenerative medicine. In the present investigation, we explored the effects of a GSK3β specific inhibitor, 6-Bromoindirubin-3'-oxime (BIO), on regenerative activities of neuroblasts in the subventricular zone (SVZ) and functional recovery after focal cerebral ischemia. Adult C57/BL mice were subjected to occlusion of distal branches of middle cerebral artery (MCA) supplying the sensorimotor barrel cortex. Three days later, BIO (8.5μg/kg, i.p.) was administered every 2days until sacrificed at 14 or 21days after stroke. The BIO treatment significantly increased generation of neuroblasts labeled with BrdU and BrdU/doublecortin (DCX) in the SVZ. Comparing to vehicle controls, increased number of neuroblasts migrated to the peri-infarct region where they differentiate into mature neurons. Along with the elevated BDNF expression at the peri-infarct area, the number of newly formed neurons was significantly increased. BIO treatment significantly enhanced sensorimotor functional recovery after the focal ischemia. It is suggested that the GSK3 signaling may be a potential therapeutic target for regenerative treatment after ischemic stroke.

  20. Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention?

    Directory of Open Access Journals (Sweden)

    Marchalant Yannick

    2012-01-01

    Full Text Available Abstract Background Alzheimer's disease has become a growing socio-economical concern in developing countries where increased life expectancy is leading to large aged populations. While curing Alzheimer's disease or stopping its progression does not appear within reach in a foreseeable future, new therapies capable of delaying the pathogenesis would represent major breakthroughs. Presentation of the hypothesis The growing number of medical benefits of cannabinoids, such as their ability to regulate age-related processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of AD. Testing the hypothesis To test this hypothesis, epidemiological studies on long term, chronic cannabinoid users could enlighten us on the potential benefits of these compounds in normal and pathological ageing processes. Systematic pharmacological (and thus more mechanistic investigations using animal models of Alzheimer's disease that have been developed would also allow a thorough investigation of the benefits of cannabinoid pharmacotherapy in the pathogenesis of Alzheimer's disease. Implications of the hypothesis The chronic administration of non-selective cannabinoids may delay the onset of cognitive deficits in AD patients; this will dramatically reduce the socio-economic burden of AD and improve the quality of life of the patients and their families.

  1. IGF-I and relation to growth in infancy and early childhood in very-low-birth-weight infants and term born infants

    Science.gov (United States)

    de Jong, Miranda; Cranendonk, Anneke; Twisk, Jos W. R.; van Weissenbruch, Mirjam M.

    2017-01-01

    Background In very-low-birth-weight infants IGF-I plays an important role in postnatal growth restriction and is probably also involved in growth restriction in childhood. We compared IGF-I and its relation to growth in early childhood in very-low-birth-weight infants and term appropriate for gestational age born infants. Methods We included 41 very-low-birth-weight and 64 term infants. Anthropometry was performed at all visits to the outpatient clinic. IGF-I and insulin were measured in blood samples taken at 6 months and 2 years corrected age (very-low-birth-weight children) and at 3 months, 1 and 2 years (term children). Results Over the first 2 years of life growth parameters are lower in very-low-birth-weight children compared to term children, but the difference in length decreases significantly. During the first 2 years of life IGF-I is higher in very-low-birth-weight children compared to term children. In both groups there is a significant relationship between IGF-I and (change in) length and weight over the first 2 years of life and between insulin and change in total body fat. Conclusions Considering the relation of IGF-I to growth and the decrease in difference in length, higher IGF-I levels in very-low-birth-weight infants in early childhood probably have an important role in catch-up growth in length. PMID:28182752

  2. The effects of insulin-like growth factorI (IGF I) complex from seminal plasma on capacitation, membrane integrity andDNA fragmentation in goat spermatozoa

    Institute of Scientific and Technical Information of China (English)

    Suherni Susilowati; Indah Norma Triana; Abdul Malik

    2015-01-01

    Objective:To evaluate the effects of the insulin-like growth factor I (IGF I) complex from seminal plasma on capacitation, membrane integrity and DNA fragmentation.Methods:A total of 0.5 mL of fresh semen was added to 1 mL of Bracket-Oliphant (BO) medium, and the sample was then centrifuged at a speed of 1 800 rpm for 10 minutes. The samples were analyzed before and after centrifugation for sperm viability, motility, membrane integrity and capacitation. The centrifuged samples were divided into three groups, each consisting of 3í 106spermatozoa. BO medium was added to group 1, BO ¬+ 12 ng IGF I complex medium was added to group 2, and 12 ng IGF I complex was added to group 3. Then, the samples were incubated for 15 minutes. Results:The result showed that sperm motility, viability and membrane integrity were significantly lower (P<0.05) after centrifugation. Furthermore, the sperm capacitation was significantly increased (P<0.05) after centrifugation. The percentages of sperm capacitation, membrane integrity and DNA fragmentation were significantly different (P< 0.05) in all media, including BO, BO + IGF-I complex and the IGF-I complex alone. Conclusions:Sperm quality include motility, viability and membrane integrity were lower after centrifugation. whereas DNA fragmentation after incubation in the IGF-I complex medium also was lower compared to that of specimens in the BO and BO + IGF-I complex media.

  3. Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors.

    Science.gov (United States)

    Plymate, Stephen R; Tennant, Marie K; Culp, Stephen H; Woodke, Lillie; Marcelli, Marco; Colman, Ilsa; Nelson, Peter S; Carroll, Julie M; Roberts, Charles T; Ware, Joy L

    2004-11-01

    Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo. 2004 Wiley-Liss, Inc.

  4. Combined treatment with GH and IGF-I: additive effect on cortical bone mass but not on linear bone growth in female rats.

    Science.gov (United States)

    Sundström, Katja; Cedervall, Therese; Ohlsson, Claes; Camacho-Hübner, Cecilia; Sävendahl, Lars

    2014-12-01

    The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.

  5. Free and total insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and IGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hyperfiltration in insulin-dependent diabetes mellitus

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); M.L. Jacobs (Marloes); F.H.M. Derkx (Frans); R.F.A. Weber (Robert); A-J. van der Lely (Aart-Jan); S.W.J. Lamberts (Steven)

    1997-01-01

    textabstractThe existing literature on serum insulin-like growth factor I (IGF-I) levels in insulin-dependent diabetes mellitus (IDDM) is conflicting. Free IGF-I may have greater physiological and clinical relevance than total IGF-I. Recently, a validated method has

  6. Association of IGF-I gene polymorphisms with milk yield and body size in Chinese dairy goats

    Directory of Open Access Journals (Sweden)

    Chanjuan Deng

    2010-01-01

    Full Text Available The association of IGF-I gene polymorphisms with certain traits in 708 individuals of two Chinese dairy-goat breeds (Guanzhong and Xinong Saanen was investigated. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP and DNA sequencing methods were employed in screening for genetic variation. Two novel mutations were detected in the 5'-flanking region and in intron 4 of IGF-I gene, viz., g.1617 G > A and g.5752 G > C (accession D26119.2, respectively. The associations of the g.1617 G > A mutation with milk yield and the body size were not significant (p > 0.05. However, in the case of g.5752 G > C, Xinong Saanen dairy goats with the CG genotype presented longer bodies (p C mutation could facilitate association analysis and serve as a genetic marker for Chinese dairy-goat breeding and genetics.

  7. Liver-spleen axis, insulin-like growth factor-(IGF-I axis and fat mass in overweight/obese females

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    Lombardi Gaetano

    2011-08-01

    Full Text Available Abstract Background Fat mass (FM in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance (IR and ectopic lipid storage within the liver. Obesity, aging, and FM influence the growth hormone/insulin-like growth factor (IGF-I axis, and chronic inflammation might reduce IGF-I signaling. Altered IGF-I axis is frequently observed in patients with Hepatic steatosis (HS. We tested the hypothesis that FM, or spleen volume and C-reactive protein (CRP--all indexes of chronic inflammation--could affect the IGF-I axis status in overweight/obese, independently of HS. Methods The study population included 48 overweight/obese women (age 41 ± 13 years; BMI: 35.8 ± 5.8 kg/m2; range: 25.3-53.7, who underwent assessment of fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA, cholesterol and triglycerides, HDL-cholesterol, transaminases, high-sensitive CRP, uric acid, IGF-I, IGF binding protein (BP-1, IGFBP-3, and IGF-I/IGFBP-3 ratio. Standard deviation score of IGF-I according to age (zSDS were also calculated. FM was determined by bioelectrical impedance analysis. HS severity grading (score 0-4 according liver hyperechogenicity and spleen longitudinal diameter (SLD were evaluated by ultrasound. Results Metabolic syndrome (MS and HS were present in 33% and 85% of subjects, respectively. MS prevalence was 43% in subjects with increased SLD. IGF-I values, but not IGF-I zSDS, and IGF-I/IGFBP-3 ratio were significantly lower, while FM%, FPI, HOMA, ALT, CRP, were significantly higher in patients with severe HS than in those with mild HS. IGF-I zSDS (r = -0.42, r = -0.54, respectively; p Conclusions The present study suggests that lower IGF-I status in our study population is associated with higher FM, SLD, CRP and more severe HS.

  8. IGF-I at 9 and 36 months of age — relations with body composition and diet at 3 years — the SKOT cohort.

    Science.gov (United States)

    Ejlerskov, K T; Larnkjaer, A; Pedersen, D; Ritz, C; Mølgaard, C; Michaelsen, K F

    2014-12-01

    High infancy levels of insulin-like growth factor-I (IGF-I) have been associated with increased linear growth and fat-free mass (FFM) but also with risk of obesity. This paper examines how IGF-I at 9 and 36 months relates to diet and body composition. Healthy term infants from the prospective cohort study, SKOT, were examined at 9 and 36 months with anthropometry, bioelectrical impedance (36 months), 7-day food records and blood analysis of IGF-I and IGFBP-3 by chemiluminescent immunometric assay. IGF-I at 36 months (n = 229) was positively correlated with 9 months values and values were considerably higher in girls (43%). Children breastfed at 9 months had lower IGF-I concentrations at 9 months but reached the same IGF-I concentrations at 36 months as infants not breastfed at 9 months. IGF-I at 36 months was positively associated with height, weight, BMI, predicted FFM and FFM index (FFM/height (kg/m2)). Although there also was a positive association with predicted fat mass (FM) there was no association with FM index (FM/height (kg/m2)). Further, a negative association with skin fold thickness was observed. A change in IGF-I from 9–36 months was positively related to FFM and FFM index but not BMI, FM and FM index. No associations were seen between IGF-I and current intake of milk, meat or protein energy percentage, but both fat and saturated fat energy percentage were negatively associated with IGF-I. IGF-I concentrations were positively associated with growth but not with adiposity at this age. However, the higher tempo of growth may influence age at adiposity rebound and thereby later risk of obesity. Milk and protein intake at 36 months did not influence IGF-I but there was a negative association with intake of fat and saturated fat. The implications of this finding for development of obesity need further exploration.

  9. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    Correlation studies have suggested that IGF-binding protein (IGFBP)-1 is a dynamic regulator of free IGF-I. To further study this, we developed a monoclonal immunofluorometric assay specific for the binary complex of IGF-I and IGFBP-1 in human serum. An IGFBP-1 antibody, which recognizes all...... healthy subjects were fasted for 72 h. Samples were collected every 3 h. During fasting, free IGF-I was reduced by two thirds (P positively in all subjects (0.89 ...), because these patients show profound alterations in their IGF-system. In both groups, the binary complex was increased about 2.5-fold (P

  10. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

    DEFF Research Database (Denmark)

    Teumer, Alexander; Qi, Qibin; Nethander, Maria

    2016-01-01

    The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer...... IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity...

  11. Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency

    DEFF Research Database (Denmark)

    Skjaerbaek, Christian; Frystyk, Jan; Kaal, Andreas

    2000-01-01

    to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were studied with and without treatment...... no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h...

  12. Circadian variation in serum free and total insulin-like growth factor (IGF)-I and IGF-II in untreated and treated acromegaly and growth hormone deficiency

    DEFF Research Database (Denmark)

    Skjaerbaek, Christian; Frystyk, Jan; Kaal, Andreas;

    2000-01-01

    to the nocturnal increase in IGF binding protein-1. In this study we have investigated the circadian variation in circulating free IGF-I and IGF-II in patients with acromegaly and patients with adult onset growth hormone deficiency. PATIENTS: Seven acromegalic patients were studied with and without treatment...... no significant circadian variations in free IGF-I or free IGF-II in either of the two occasions. In contrast, there was a significant circadian variation of total IGF-I after adjustment for changes in plasma volume in both treated and untreated acromegaly and GH deficiency in all cases with a peak between 0300 h...

  13. Nandrolone and stanozolol induce Leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system.

    Science.gov (United States)

    Chimento, Adele; Sirianni, Rosa; Zolea, Fabiana; De Luca, Arianna; Lanzino, Marilena; Catalano, Stefania; Andò, Sebastiano; Pezzi, Vincenzo

    2012-05-01

    Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer.

  14. Autocrine/paracrine proliferative effect of ovarian GH and IGF-I in chicken granulosa cell cultures.

    Science.gov (United States)

    Ahumada-Solórzano, S Marisela; Martínez-Moreno, Carlos G; Carranza, Martha; Ávila-Mendoza, José; Luna-Acosta, José Luis; Harvey, Steve; Luna, Maricela; Arámburo, Carlos

    2016-08-01

    It is known that growth hormone (GH) and its receptor (GHR) are expressed in granulosa cells (GC) and thecal cells during the follicular development in the hen ovary, which suggests GH is involved in autocrine/paracrine actions in the female reproductive system. In this work, we show that the knockdown of local ovarian GH with a specific cGH siRNA in GC cultures significantly decreased both cGH mRNA expression and GH secretion to the media, and also reduced their proliferative rate. Thus, we analyzed the effect of ovarian GH and recombinant chicken GH (rcGH) on the proliferation of pre-hierarchical GCs in primary cultures. Incubation of GCs with either rcGH or conditioned media, containing predominantly a 15-kDa GH isoform, showed that both significantly increased proliferation as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferating cell nuclear antigen (PCNA) quantification and ((3)H)-thymidine incorporation ((3)H-T) assays in a dose response fashion. Both, locally produced GH and rcGH also induced the phosphorylation of Erk1/2 in GC cultures. Furthermore, GH increased IGF-I synthesis and its release into the GC culture incubation media. These results suggest that GH may act through local IGF-I to induce GC proliferation, since IGF-I immunoneutralization completely abolished the GH-induced proliferative effect. These data suggest that GH and IGF-I may play a role as autocrine/paracrine regulators during the follicular development in the hen ovary at the pre-hierarchical stage.

  15. Gene expression profiling of preovulatory follicle in the buffalo cow: effects of increased IGF-I concentration on periovulatory events.

    Directory of Open Access Journals (Sweden)

    Jyotsna U Rao

    Full Text Available The preovulatory follicle in response to gonadotropin surge undergoes dramatic biochemical, and morphological changes orchestrated by expression changes in hundreds of genes. Employing well characterized bovine preovulatory follicle model, granulosa cells (GCs and follicle wall were collected from the preovulatory follicle before, 1, 10 and 22 h post peak LH surge. Microarray analysis performed on GCs revealed that 450 and 111 genes were differentially expressed at 1 and 22 h post peak LH surge, respectively. For validation, qPCR and immunocytochemistry analyses were carried out for some of the differentially expressed genes. Expression analysis of many of these genes showed distinct expression patterns in GCs and the follicle wall. To study molecular functions and genetic networks, microarray data was analyzed using Ingenuity Pathway Analysis which revealed majority of the differentially expressed genes to cluster within processes like steroidogenesis, cell survival and cell differentiation. In the ovarian follicle, IGF-I is established to be an important regulator of the above mentioned molecular functions. Thus, further experiments were conducted to verify the effects of increased intrafollicular IGF-I levels on the expression of genes associated with the above mentioned processes. For this purpose, buffalo cows were administered with exogenous bGH to transiently increase circulating and intrafollicular concentrations of IGF-I. The results indicated that increased intrafollicular concentrations of IGF-I caused changes in expression of genes associated with steroidogenesis (StAR, SRF and apoptosis (BCL-2, FKHR, PAWR. These results taken together suggest that onset of gonadotropin surge triggers activation of various biological pathways and that the effects of growth factors and peptides on gonadotropin actions could be examined during preovulatory follicle development.

  16. Cord blood triglycerides are associated with IGF-I levels and contribute to the identification of growth-restricted neonates.

    Science.gov (United States)

    Sifianou, Popi; Zisis, Dimitris

    2012-12-01

    The aim of this study was to investigate whether readily available laboratory tests may aid in the identification of growth-restricted neonates. Cord serum levels of 15 chemical analytes, including insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) were measured in newborns ≥36 weeks gestational age (GA). Based on the number of anthropometric indices (out of four) with values ≤25th centile for GA, the babies were allocated into three groups, i.e., Group(25)0, Group(25)1 and Group(25)2 corresponding to neonates with 0, 1 and 2 or more indices, respectively, that were ≤25th centile for GA. Furthermore, two composite variables were developed: A25 (Group(25)0 and Group(25)1) and B25 (Group(25)0 and Group(25)2). The data were evaluated by the Mann-Whitney test and multiple regression analyses. Cord serum triglycerides and total cholesterol levels were significantly higher in Group(25)2 compared to Group(25)0 (p values 0.004 and 0.0009, respectively). The triglycerides almost doubled the power of the variable B25 for predicting IGF-I levels and were found to have a highly significant, negative association with the IGF-I levels (ptriglycerides. Cord serum triglycerides can assist in the identification of growth-restricted neonates. The novel finding of the association of triglycerides with IGF-I calls for further research as this can illuminate unknown aspects of the fetal lipid metabolism. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Use of multifactorial analysis to develop aqueous two-phase systems for isolation of non-native IGF-I.

    Science.gov (United States)

    Hart, R A; Ogez, J R; Builder, S E

    1995-04-01

    A high yield procedure was developed to solubilize and extract IGF-I from recombinant E. coli by adding chaotrope and disulfide reductant to alkaline fermentation broth. To enhance centrifugation performance and recovery yield, a salt/polymer aqueous two-phase extraction procedure was developed whereby soluble non-native IGF-I and biomass solids are enriched in separate liquid phases. To develop this extraction system a multifactorial experimental approach was used to simultaneously map the phase diagram and identify conditions to suitably partition IGF-I and cell remnants. The presence of urea in these systems tended to disrupt two-phase formation and solids sedimentation. This, in turn, constrained the concentrations of phase forming solutes which could be effectively used. Systems containing low levels of salt (less than about 4% w/w) and polymer (less than about 10% w/w) did not form two phases. Systems containing high levels of salt (greater than about 7% w/w) and polymer (greater than about 18% w/w) formed two phases with floating solids. Intermediate levels of salt (between about 4% and 7% w/w) and polymer (between about 10% and 18% w/w) formed two phases in which solids were enriched in the heavy phase. Systems in this latter desired category were produced with a variety of different salts and polymers and all enriched non-native IGF-I in the light phase. Highest recovery yield (about 90%) was obtained with systems composed of 5% sodium sulfate and 14% PEG-8000.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Developmental changes in IGF-I and MyoG gene expression and their association with meat traits in sheep.

    Science.gov (United States)

    Sun, W; Su, R; Li, D; Musa, H H; Kong, Y; Ding, J T; Ma, Y H; Chen, L; Zhang, Y F; Wu, W Z

    2014-04-14

    In the present study, real time-polymerase chain reaction was applied to analyze the expression of IGF-I and MyoG genes in Hu sheep longissimus dorsi at different growth stages and their association with meat traits. Expression of the IGF-I gene in Hu sheep differed significantly between males and females at the two day-old (0.01 0.05) between males and females at any growth stage in expression of the MyoG gene. MyoG gene expression in male longissimus muscles tended to be higher than that of females at all growth stages, except for the six month-old stage. IGF-I gene expression was significantly and positively correlated with live weight (P meat weight (P > 0.05). In contrast, MyoG gene expression was non-significantly and positively correlated with live weight, carcass, and net meat weight (P > 0.05). Carcass traits showed highly significant positive correlations (P sheep.

  19. Concentrations of insulin glargine and its metabolites during long-term insulin therapy in type 2 diabetic patients and comparison of effects of insulin glargine, its metabolites, IGF-I, and human insulin on insulin and IGF-I receptor signaling

    NARCIS (Netherlands)

    A.J. Varewijck (Aimee); H. Yki-Jarvinen (Hannele); R. Schmidt (Reinhold); N. Tennagels (Norbert); J.A.M.J.L. Janssen (Joseph)

    2013-01-01

    textabstractWe investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during longterm insulin therapy in type 2

  20. Synergistic Effects of FGF-2 with Insulin or IGF-I on the Proliferation of Human Auricular Chondrocytes.

    Science.gov (United States)

    Takahashi, Tsuguharu; Ogasawara, Toru; Kishimoto, Junji; Liu, Guangyao; Asato, Hirotaka; Nakatsuka, Takashi; Uchinuma, Eijyu; Nakamura, Kozo; Kawaguchi, Hiroshi; Takato, Tsuyoshi; Hoshi, Kazuto

    2005-10-01

    Chondrocyte preparation with the safety and efficiency is the first step in cartilage regenerative medicine. To prepare a chondrocyte proliferation medium that does not contain fetal bovine serum (FBS) and that provides more than a 1000-fold increase in cell numbers within approximately 1 month, we attempted to use the medium containing 5% human serum (HS), but it exerted no more than twofold increase in 2 weeks. To compensate for the limited proliferation ability in HS, we investigated the combinational effects of 12 factors [i.e., fibroblast growth factor(FGF)-2, insulin-like growth factor(IGF)-I, insulin, bone morphogenetic protein-2, parathyroid hormone, growth hormone, dexamethasone, 1α25-dihydroxy vitamin D3, L-3,3',5'-triodothyronine, interleukine-1 receptor antagonist, 17β-estradiol, and testosterone] on the proliferation of human auricular chondrocytes by analysis of variance in fractional factorial design. As a result, FGF-2, dexamethasone, insulin, and IGF-I possessed promotional effects on proliferation, while the combination of FGF-2 with insulin or IGF-I synergistically enhanced the proliferation. Actually, the chondrocytes increased 7.5-fold in number in 2 weeks in a medium containing 5% HS with 10 ng/ml FGF-2, while the cell number synergistically gained a 10-12-fold increase with 5 μg/ml insulin or 100 ng/ml IGF-I in the same period. The proliferation effects were more enhanced at a concentration of 100 ng/ml for FGF-2, and especially for the combination of 100 ng/ml FGF-2 and 5 μg/ml insulin (approximately 16-fold within 2 weeks). In the long-term culture with repeated passaging, this combination provided more than 10,000-fold within 8 weeks (i.e., passage 4). Thus, we concluded that such a combination of FGF-2 with insulin or IGF-I may be useful for promotion of auricular chondrocyte proliferation in a clinical application for cartilage regeneration.

  1. The atypical alpha2beta2 IGF receptor expressed in inducible c2.7 myoblasts is derived from post-translational modifications of the mouse IGF-I receptor.

    Science.gov (United States)

    Navarro, Magali; Joulia, Dominique; Fedon, Yann; Levin, Jonathan; Barenton, Bruno; Bernardi, Henri

    2008-10-01

    Unlike parental permissive C2.7 myoblasts, inducible C2.7 myoblasts require IGF-I or IGF-II to differentiate and expression of MyoD is not constitutive. Our previous studies indicated that inducible myoblasts express an atypical alpha2beta2 IGF receptor that differs from the classical IGF-I receptor by its higher affinity for IGF-II compared with IGF-I and the higher molecular weight of its alpha and beta subunits. Expression of this atypical IGF-I receptor is developmentally regulated; hence this receptor is lost upon terminal differentiation. Muscle cell differentiation is a system in which IGF-II plays an essential role and developmentally regulated atypical IGF-I receptor may represent a candidate for mediating differentiation signals provided by IGF-II. To further understand the structure and the role of the atypical IGF-I receptor, (i) we investigated for a putative IGF-I receptor transcript polymorphism by extensive sequencing of RT-PCR products; (ii) we overexpressed cloned mouse IGF-I receptor in permissive and inducible C2.7 myoblasts and characterized the binding and structural properties of overexpressed IGF-I receptor and (iii) we analysed the effects of this overexpression on myoblasts differentiation. Cultured mouse myoblasts C2.7 and subclone variant inducible C2.7 cell lines were used. Mouse IGF-I receptor cDNA was cloned by cDNA library screening. Gene expression was measured by semi-quantitative RT-PCR analysis and receptor affinity by ligand binding. Receptor protein autophosphorylation of IGF-IR was analysed by immunoprecipitation and Western blot. Myoblastic differentiation was accessed by myogenic factors expression and immunofluorescence study. Atypical IGF-I receptor may correspond to a new receptor belonging to the insulin/IGF-I receptor family, or it may also derive from alternate splicing of the gene of the insulin/IGF-I receptors and/or post-translational modifications of the insulin/IGF-I receptors. Our results exclude the existence of

  2. Changes in circulating level of IGF-I and IGF-binding protein-1 from the first to second trimester as predictors of preeclampsia

    DEFF Research Database (Denmark)

    Vatten, Lars J; Nilsen, Tom I L; Juul, Anders;

    2008-01-01

    OBJECTIVE: To assess whether circulating IGF-I and IGF-binding protein-1 (IGFBP-1) in the first and second trimester are associated with subsequent risk of preterm and term preeclampsia. METHODS: Nested case-control study within a cohort of 29 948 pregnant women. Cases were women, who later...... developed preeclampsia, and controls were randomly selected women, who did not develop preeclampsia. IGF-I and IGFBP-1 were measured with ELISA in maternal blood samples that were collected in the first and second trimesters. We assessed associations of IGF-I and IGFBP-1 concentrations with later...... development of preterm (before the 37th week of gestation) and term preeclampsia. RESULTS: An increase in IGF-I from the first to second trimester was associated with higher risk of preterm preeclampsia; the odds ratio (OR) for the highest compared with lowest quartile of increase was 4.9 (95% confidence...

  3. Short- and long-term metabolic effects of recombinant human IGF-I treatment in patients with severe insulin resistance and diabetes mellitus

    DEFF Research Database (Denmark)

    Vestergaard, H; Rossen, M; Urhammer, S A

    1997-01-01

    the metabolic and hormonal responses to an unchanged insulin therapy with the addition of a subcutaneous administration of recombinant human IGF-I (rhIGF-I) during (a) a short-term (2 weeks) period with rhIGF-I given twice a day in a high dose (80 micrograms/kg body weight) in four patients with extreme insulin......-resistant diabetes mellitus and (b) during a long-term (10 weeks) period with rhIGF-I given once a day in a low dose (40 micrograms/kg body weight) in three of the four patients. Two siblings had known mutations in the tyrosine kinase domain of the insulin receptor and a deletion of exon 17 in part of their insulin...

  4. Pregnancy-induced increase in circulating IGF-I is associated with progression of diabetic retinopathy in women with type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lene Ringholm; Laugesen, Caroline S; Juul, Anders;

    2011-01-01

    To evaluate the influence of Insulin-like Growth factor-I (IGF-I) and Placental Growth Hormone (GH) on progression of diabetic retinopathy during pregnancy in women with type 1 diabetes.......To evaluate the influence of Insulin-like Growth factor-I (IGF-I) and Placental Growth Hormone (GH) on progression of diabetic retinopathy during pregnancy in women with type 1 diabetes....

  5. Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin.

    Directory of Open Access Journals (Sweden)

    Alicia Villa-Osaba

    Full Text Available Locally produced growth hormone (GH and IGF-I are key factors in the regulation of mammary gland (MG development and may be important in breast cancer development/progression. Somatostatin (SST and cortistatin (CORT regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs of SST- or CORT-knockout (KO mice and their respective littermate-controls fed a low-fat (LF or a high-fat (HF diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.

  6. Fasting modulates GH/IGF-I axis and its regulatory systems in the mammary gland of female mice: Influence of endogenous cortistatin.

    Science.gov (United States)

    Villa-Osaba, Alicia; Gahete, Manuel D; Cordoba-Chacon, José; de Lecea, Luis; Castaño, Justo P; Luque, Raúl M

    2016-10-15

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/cortistatin and ghrelin) in MG during fasting. Therefore, this study was aimed at characterizing the regulation of GH/IGF-I/somatostatin/cortistatin/ghrelin-systems expression in MG of fasted female-mice (compared to fed-controls) and the influence of endogenous-cortistatin (using cortistatin-knockouts). Fasting decreased IGF-I while increased IGF-I/Insulin-receptors expression in MGs. Fasting provoked an increase in GH expression that might be associated to enhanced ghrelin-variants/ghrelin-O-acyl-transferase enzyme expression, while an upregulation of somatostatin-receptors was observed. However, cortistatin-knockouts mice showed a decrease in GH and somatostatin receptor-subtypes expression. Altogether, we demonstrate that GH/IGF-I, somatostatin/cortistatin and ghrelin systems expression is altered in MG during fasting, suggesting a relevant role in coordinating its response to metabolic stress, wherein endogenous cortistatin might be essential for an appropriate response.

  7. Polymorphism of Insulin-like growth factor-I (IGF-I gene and their effect on growth traits in Indonesia native chicken

    Directory of Open Access Journals (Sweden)

    M.A Mu'in

    2009-12-01

    Full Text Available The research was aimed is to detect Insulin-like growth factor-I (IGF-I gene polymorphism and their effect on growth traits in Indonesia natives chicken. Seventy two Indonesian native chicken are going to be used in this research. The polymorphism of IGF-I gene was detected by PCR-RFLP/Pst-I. Four growth traits (body weight at 1, 2, 3, and 4 months were recorded for analyzing the association between IGF-I gene polymorphism and growth performance.The results showed that allele A (621 bp and allele B (364 and 257 bp were found in this research. It was found that Indonesian native chicken carried high frequencies of allele A (0.82, and frequencies of IGF-I genotypes (AA, AB, BB were 68.0, 27.8, and 4,2%, respectively. When compared to the IGF-I genotypes, the BB genotype had the highest body weight at 1, 2, 3, and 4 month (P<0.05. The results showed that the B allele was positive of associated to a higher growth rate. Therefore, these results suggest that there is a possibility of IGF-I genotypes acting as a molecular marker for growth rate of Indonesia native.

  8. Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation

    DEFF Research Database (Denmark)

    Yu, Hao; Mistry, J; Nicar, M J

    1999-01-01

    Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play an important role in cell growth and differentiation. Clinical and epidemiological studies have indicated that measuring IGFs and IGFBPs in blood has potential implications in assessing growth-related abnormalities and risks...... of certain types of cancer. To facilitate the application, we reported a large collection of reference ranges of IGFs and IGFBPs in normal population and evaluations of these molecules in serum and plasma as well as the impact of freeze-thaw cycles on the measurement. IGF-I, IGFBP-3 andALS showed a similar...

  9. Muscle atrophy in patients wirh ckd results from fgf23/klotho-mediated supression of insulin/igf-i signaling

    Directory of Open Access Journals (Sweden)

    Shinsuke Kido

    2012-06-01

    Full Text Available Muscle atrophy is a significant consequence of chronic kidney disease (CKD that increases a patient’s risk of mortality and decrease their quality of life. In CKD patients, the circulation levels of FGF23 are significantly increased, but the exact pathological significance of the increase and relationship between FGF23 and muscle atrophy are not clear. Because of Klohto, acts as a co-receptor of FGF23 is detectable in limited tissues including in kidney and brain, but not in skeletal muscles. In contrast, recently reports indicated that the extracellular domain of klohto is cleavage for some reason on the cell surface and detected in the blood in animals. In this study, we attempted to identify the causative factors responsible for the shedding of Klotho, and whether both FGF23 and Klohto induced muscle atrophy via reduction of insulin/IGF-I signaling. We first investigated by treating kidney cells with various factors related in pathological factors in CKD. As a result, we found that advanced glycation endproducts (AGEs, an accumulated in patients with CKD and diabetes mellitus, increases shedding of Klohto in kidney cells. It is common knowledge that insulin/IGF-I signaling is necessary for normal skeletal growth. As a result, we showed that both FGF23 and Klohto inhibited differentiation of cultured skeletal muscle cells through down-regulation of insulin/IGF-I signaling. These observations suggested a divergent role of FGF23 and soluble klohto in the regulation of skeletal muscle differentiation and thereby muscle atrophy under pathological conditioned in CKD patients. Our results further imply that FGF23/Klohto may serve a new therapeutic target for CKD-induced muscle atrophy.

  10. Genetic polymorphisms in IGF-I and IGFBP-3 are associated with prostate cancer in the Chinese population.

    Directory of Open Access Journals (Sweden)

    Jian Qian

    Full Text Available Insulin-like growth factor-I (IGF-I and IGF binding protein-3 (IGFBP-3 are members of the insulin-like growth factor (IGF family that play important roles in carcinogenesis. We hypothesized that the functional polymorphisms in IGF-I and IGFBP-3 may be associated with the risk of prostate cancer (PCa in the Chinese population. This hospital-based case-control study included 664 PCa patients and 702 cancer-free controls. Nine SNPs in IGF-I and IGFBP-3 were genotyped using the TaqMan assay. The genetic associations between the pathogenesis and progression of PCa were assessed by logistic regression. We found that the genotype and allele frequency distribution of rs6218, rs35767 and rs5742612 were significantly different when comparing PCa cases to controls (P  = 0.005, 0.005 and 0.020, respectively. In the combined analysis, individuals with 2-6 risk alleles had an elevated risk of PCa compared to those with 0-1 risk alleles. We also found that the association between the combined risk alleles and the risk of PCa appeared stronger in the following subgroups: individuals older than 71 years of age (OR  = 1.41, 95%CI  = 1.05-1.91, P  = 0.020, nonsmokers (OR  = 1.68, 95%CI  = 1.21-2.32, P  = 0.002, nondrinkers (OR  = 1.32, 95%CI  = 1.02-1.61, P  = 0.002, and those with a negative family history of PCa (OR  = 1.28, 95%CI  = 1.02-1.71, P  = 0.022. Our results indicate that the three SNPs (rs6218, rs35767 and rs5742612 and the joint genotypes with 2-6 risk alleles, may contribute to the susceptibility to PCa, but not the progression, in the Chinese population.

  11. IGF-I activity may be a key determinant of stroke risk--a cautionary lesson for vegans.

    Science.gov (United States)

    McCarty, M F

    2003-09-01

    IGF-I acts on vascular endothelium to activate nitric oxide synthase, thereby promoting vascular health; there is reason to believe that this protection is especially crucial to the cerebral vasculature, helping to ward off thrombotic strokes. IGF-I may also promote the structural integrity of cerebral arteries, thereby offering protection from hemorrhagic stroke. These considerations may help to explain why tallness is associated with low stroke risk, whereas growth hormone deficiency increases stroke risk--and why age-adjusted stroke mortality has been exceptionally high in rural Asians eating quasi-vegan diets, but has been declining steadily in Asia as diets have become progressively higher in animal products. There is good reason to suspect that low-fat vegan diets tend to down-regulate systemic IGF-I activity; this effect would be expected to increase stroke risk in vegans. Furthermore, epidemiology suggests that low serum cholesterol, and possibly also a low dietary intake of saturated fat--both characteristic of those adopting low-fat vegan diets--may also increase stroke risk. Vegans are thus well advised to adopt practical countermeasures to minimize stroke risk--the most definitive of which may be salt restriction. A high potassium intake, aerobic exercise training, whole grains, moderate alcohol consumption, low-dose aspirin, statin or policosanol therapy, green tea, and supplementation with fish oil, taurine, arginine, and B vitamins--as well as pharmacotherapy of hypertension if warranted--are other practical measures for lowering stroke risk. Although low-fat vegan diets may markedly reduce risk for coronary disease, diabetes, and many common types of cancer, an increased risk for stroke may represent an 'Achilles heel'. Nonetheless, vegans have the potential to achieve a truly exceptional 'healthspan' if they face this problem forthrightly by restricting salt intake and taking other practical measures that promote cerebrovascular health.

  12. Assessment of Relationship Between IGF-I Concentration Before Parturition and Postpartum Endometritis and Ovarian Cysts in Dairy Cattle

    Directory of Open Access Journals (Sweden)

    Mohammad Rahim AHMADI

    2015-01-01

    Full Text Available This study was carried out to assess the IGF-I, non-esterified fatty acids (NEFA, beta hydroxybutyrate (BHB and glucose concentrations during the peripartum period of dairy cows in normal condition, and cows with endometritis puerperalis and cystic ovarian disease. The study was conducted on 87 lactating Holstein cows (parity: 1-7 in the 9th month of pregnancy in Shiraz, Iran. Blood samples were collected every 2 weeks from 2 weeks before until 6 weeks after calving. Two, four and six weeks after calving, palpation of the reproductive tract was performed. Cows were first inspected for the presence of fresh abnormal discharge on the vulva, perineum, or tail then those were examined intra-vaginally. Following inspection, ultrasonographic assessment of uterus and ovaries was also performed and ovarian structures (palpable follicle, CL and cyst were scanned. Prepartum IGF-I concentration was significantly lower in cows that developed cystic ovaries than non-cystic (35.89±9.09 versus 41.99±3.65 μg/L and cows with clinical endometritis early postpartum than normal cows (36.65±5.38 versus 43.64±4.32 μg/L. Calving-first service interval and ovarian cycle resumption after calving was significantly shorter for cows without clinical endometritis than cows with clinical endometritis. In conclusion, prepartum IGF-I concentration was the main factor associated with occurrence of endometritis and cystic ovarian disease after calving and it was a notable feature of the current study.

  13. Material and mechanical factors:new strategy in cellular neurogenesis

    Institute of Scientific and Technical Information of China (English)

    Hillary Stoll; Il Keun Kwon; Jung Yul Lim

    2014-01-01

    Since damaged neural circuits are not generally self-recovered, developing methods to stimulate neurogenesis is critically required. Most studies have examined the effects of soluble pharma-cological factors on the cellular neurogenesis. On the other hand, it is now recognized that the other extracellular factors, including material and mechanical cues, also have a strong potential to induce cellular neurogenesis. This article will review recent data on the material (chemical patterning, micro/nano-topography, carbon nanotube, graphene) and mechanical (static cue from substrate stiffness, dynamic cue from stretch and lfow shear) stimulations of cellular neuro-genesis. These approaches may provide new neural regenerative medicine protocols. Scaffolding material templates capable of triggering cellular neurogenesis can be explored in the presence of neurogenesis-stimulatory mechanical environments, and also with conventional soluble factors, to enhance axonal growth and neural network formation in neural tissue engineering.

  14. Adult Neurogenesis in Drosophila

    OpenAIRE

    Ismael Fernández-Hernández; Christa Rhiner; Eduardo Moreno

    2013-01-01

    Adult neurogenesis has been linked to several cognitive functions and neurological disorders. Description of adult neurogenesis in a model organism like Drosophila could facilitate the genetic study of normal and abnormal neurogenesis in the adult brain. So far, formation of new neurons has not been detected in adult fly brains and hence has been thought to be absent in Drosophila. Here, we used an improved lineage-labeling method to show that, surprisingly, adult neurogenesis occurs in the m...

  15. RNA microarray analysis in prenatal mouse cochlea reveals novel IGF-I target genes: implication of MEF2 and FOXM1 transcription factors.

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    Hortensia Sanchez-Calderon

    Full Text Available BACKGROUND: Insulin-like growth factor-I (IGF-I provides pivotal cell survival and differentiation signals during inner ear development throughout evolution. Homozygous mutations of human IGF1 cause syndromic sensorineural deafness, decreased intrauterine and postnatal growth rates, and mental retardation. In the mouse, deficits in IGF-I result in profound hearing loss associated with reduced survival, differentiation and maturation of auditory neurons. Nevertheless, little is known about the molecular basis of IGF-I activity in hearing and deafness. METHODOLOGY/PRINCIPAL FINDINGS: A combination of quantitative RT-PCR, subcellular fractionation and Western blotting, along with in situ hybridization studies show IGF-I and its high affinity receptor to be strongly expressed in the embryonic and postnatal mouse cochlea. The expression of both proteins decreases after birth and in the cochlea of E18.5 embryonic Igf1(-/- null mice, the balance of the main IGF related signalling pathways is altered, with lower activation of Akt and ERK1/2 and stronger activation of p38 kinase. By comparing the Igf1(-/- and Igf1(+/+ transcriptomes in E18.5 mouse cochleae using RNA microchips and validating their results, we demonstrate the up-regulation of the FoxM1 transcription factor and the misexpression of the neural progenitor transcription factors Six6 and Mash1 associated with the loss of IGF-I. Parallel, in silico promoter analysis of the genes modulated in conjunction with the loss of IGF-I revealed the possible involvement of MEF2 in cochlear development. E18.5 Igf1(+/+ mouse auditory ganglion neurons showed intense MEF2A and MEF2D nuclear staining and MEF2A was also evident in the organ of Corti. At P15, MEF2A and MEF2D expression were shown in neurons and sensory cells. In the absence of IGF-I, nuclear levels of MEF2 were diminished, indicating less transcriptional MEF2 activity. By contrast, there was an increase in the nuclear accumulation of FoxM1 and a

  16. Collagen study and regulation of the de novo synthesis by IGF-I in hemocytes from the gastropod mollusc, Haliotis tuberculata.

    Science.gov (United States)

    Serpentini, A; Ghayor, C; Poncet, J M; Hebert, V; Galéra, P; Pujol, J P; Boucaud-Camou, E; Lebel, J M

    2000-09-01

    To evidence a collagen synthesis and identify which type(s) of collagen is present in hemocytes from the mollusc Haliotis tuberculata, we have performed three separate approaches, namely, de novo synthesis by cultured cells, immunological approaches, and northern blot analysis. We demonstrated first that after 40-hr labeling, the de novo synthesis of collagen in the cell layer of cultured hemocytes represents 9.48 +/- 1.25% with respect to the total [(3)H]proline-labeled protein synthesis. In addition, IGF-I elicited a significant stimulation of collagen synthesis in cultured hemocytes in a dose-dependent manner from 10(-10) to 10(-8) M. The maximal stimulation (10(-9) M) induced an increase of 286 +/- 56% with respect to 100% control. By immunocytochemistry and immunoblotting, we showed that hemocytes present immunoreactive molecules to antibodies directed against the type I fibrillar collagen. In addition, using as a probe Hf 677 corresponding to a human pro alpha1(I) collagen cDNA and which encompasses the (Gly-X-Y) repeated sequence found in all Metazoa, four collagen transcripts of approximately 6.4, 5, 2.2, and 2 kb in length have been detected. These data suggest the presence of fibrillar type I collagen in hemocytes and are compatible with the concept that these cells are involved in the extracellular matrix deposition, a cardinal function in tissue repair as well as in developmental processes. Our model may appear as an excellent system to study the role of growth factors on the regulation of collagen synthesis by molluscan hemocytes. J. Exp. Zool. 287:275-284, 2000.

  17. Systemic treatment with Epidermal Growth Factor (EGF)but not Insulin like Growth Factor (IGF-I) decrease the involution of the Prostate in Castrated Rats

    DEFF Research Database (Denmark)

    Tørring, Niels; Lars, Vinter-Jensen; Sørensen, Flemming Brandt;

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...... Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme......-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular...

  18. IGF-I at 9 and 36 months of age — relations with body composition and diet at 3 years — the SKOT cohort

    DEFF Research Database (Denmark)

    Ejlerskov, Katrine Tschentscher; Larnkjær, A.; Pedersen, D.

    2014-01-01

    Objective High infancy levels of insulin-like growth factor-I (IGF-I) have been associated with increased linear growth and fat-free mass (FFM) but also with risk of obesity. This paper examines how IGF-I at 9 and 36 months relates to diet and body composition. Design Healthy term infants from...... with growth but not with adiposity at this age. However, the higher tempo of growth may influence age at adiposity rebound and thereby later risk of obesity. Milk and protein intake at 36 months did not influence IGF-I but there was a negative association with intake of fat and saturated fat. The implications...... of this finding for development of obesity need further exploration....

  19. Influence of Insulin-like Growth Factor I (IGF-I on the survival and the in vitro development of caprine preantral follicles

    Directory of Open Access Journals (Sweden)

    Sanely L. Costa

    2014-10-01

    Full Text Available The aim of this study was to investigate the effects of the insulin-like growth factor -I (IGF-I on survival, activation (transition from primordial to primary follicles and growth of caprine preantral follicles cultured in vitro. Fragments of ovarian cortex were cultured for one and seven days in the absence or presence of IGF-I (0, 50 and 100ng/ml. The non-cultured and cultured tissues were processed and analyzed by histology and transmission electron microscopy. The culture for one day in a medium with 100ng/ml of IGF-I showed 86.7% of morphologically normal follicles. These results were similar (P>0.05 to the percentage of normal follicles found in the control (96.7%. It was also found that this medium increased the percentage of follicular activation (developing follicles with one day of culture. The oocyte and follicular diameters remained similar to the control by culturing for one day in a medium containing 100ng/ml of IGF-I. The ultrastructural analysis did not confirm the integrity of the follicular fragments in a medium containing IGF-I (100ng/ml after one and seven days of culture. In conclusion, this study demonstrated that the addition of 100 ng/ml of IGF-I in the culture medium enables the development of preantral follicles of goats with one day of culture. However, it is not sufficient to maintain the follicular integrity and the follicular survival rate after seven days of culture.

  20. Postpartum IGF-I and IGFBP-2 levels are prospectively associated with the development of type 2 diabetes in women with previous gestational diabetes mellitus.

    Science.gov (United States)

    Lappas, M; Jinks, D; Shub, A; Willcox, J C; Georgiou, H M; Permezel, M

    2016-12-01

    Women with previous gestational diabetes mellitus (GDM) are at greater risk of developing type 2 diabetes. In the general population, the insulin-like growth factor (IGF) system has been implicated in the development of type 2 diabetes. The aim of this study was to determine if circulating IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels 12weeks following a GDM pregnancy are associated with an increased risk of developing type 2 diabetes. IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels were measured in 98 normal glucose tolerant women, 12weeks following an index GDM pregnancy using enzyme immunoassay. Women were assessed for up to 10years for the development of overt type 2 diabetes. Among the 98 women with previous GDM, 21 (21%) developed diabetes during the median follow-up period of 8.5years. After adjusting for age and BMI, IGF-I and IGFBP-2 were significantly associated with the development of type 2 diabetes. In a clinical model of prediction of type 2 diabetes that included age, BMI, pregnancy fasting glucose and postnatal fasting glucose, the addition of IGF-I and IGFBP-2 resulted in an improvement in the net reclassification index of 17.8%. High postpartum IGF-I and low postpartum IGFBP-2 levels are a significant risk factor for the development of type 2 diabetes in women with a previous history of GDM. This is the first report that identifies IGF-I and IGFBP-2 as a potential biomarker for the prediction of type 2 diabetes in women with a history of GDM. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Enhancement of cortical network activity in vitro and promotion of GABAergic neurogenesis by stimulation with an electromagnetic field with a 150 MHz carrier wave pulsed with an alternating 10 and 16 Hz modulation.

    Directory of Open Access Journals (Sweden)

    Alexandra eGramowski-Voss

    2015-07-01

    Full Text Available In recent years, various stimuli were identified capable of enhancing neurogenesis, a process which is dysfunctional in the senescent brain and in neurodegenerative and certain neuropsychiatric diseases. Applications of electromagnetic fields to brain tissue have been shown to affect cellular properties and their importance for therapies in medicine is recognized.In this study, differentiating murine cortical networks on multiwell microelectrode arrays were repeatedly exposed to an extremely low electromagnetic field (ELEMF with alternating 10 and 16 Hz frequencies piggy-backed onto a 150 MHz carrier frequency. The ELEMF exposure stimulated the electrical network activity and intensified the structure of bursts. Further, the exposure with an electromagnetic field within the first 28 days of the differentiation the network activity induced also reorganization within the burst structure. This effect was already most pronounced at 14 days in vitro after 10 days of exposure. Overall, the development of cortical activity under these conditions was accelerated. These functional electrophysiological changes were accompanied by morphological ones. The percentage of neurons in the neuron glia co-culture was increased without affecting the total number of cells, indicating an enhancement of neurogenesis. The ELEMF exposure selectively promoted the proliferation of a particular population of neurons, evidenced by the increased proportion of GABAergic neurons. The results support the initial hypothesis that this kind of ELEMF stimulation is a treatment option for specific indications with promising potential for CNS applications, especially for degenerative diseases such as Alzheimer’s disease and other dementias.

  2. Effect of oral alpha-tocopherol and zinc on plasma status, IGF-I levels, weight gain and immune response in young calves

    DEFF Research Database (Denmark)

    Sehested, J.; Jørgensen, C.; Mortensen, S.B.

    2004-01-01

    Thirty newborn calves were supplemented with a-tocopherol (vit. E) (n = 10), zinc (Zn) (n = 10) or nothing (control) (n = 10) for 8 weeks. All calves were vaccinated against tetanus at week 5. Plasma Zn and cc-tocopherol were significantly increased in the Zn and vit. E groups, respectively. Plasma...... IGF-I levels generally increased from birth to week 8, but were not affected by Zn or vit. E. Daily weight gain was highest in the Zn group, but this was not related to an increased IGF-I level. The vit. E group responded earlier than the Zn and control groups to the tetanus vaccination....

  3. In Vitro and In Vivo Effects of IGF-I on Adiposity in HIV-associated Metabolic Disease: A Pilot Study

    Science.gov (United States)

    Kim, Roy J.; Vaghani, Sumit; Zifchak, Larisa M.; Quinn, Joseph H.; He, Weimian; Tebas, Pablo; Frank, Ian

    2013-01-01

    Background and Aims We tested the effects of recombinant insulin-like growth factor-I (IGF-I) in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV lipodystrophy. Methods The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in vitro. We assessed lipid accumulation, IGF signaling, apoptosis, and gene expression. We conducted a 24-week open label trial of recombinant IGF-I in ten adults with HIV associated lipoatrophy. Laboratory assessments included glucose, insulin, lipids, and IGF-I. At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh. Results In vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect. In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7% vs. 34.6 ± 7%, p = 0.007). IGF-I levels increased with treatment (143 ± 28 µg/L at week 0 vs. 453 ± 212 µg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L vs. 3.235 ± 1.151 mg/L, p = 0.02). Insulin at week 12 week decreased significantly (90.1 ± 39.8 pmol/L vs. 33.2 ± 19.6 pmol/L, p = 0.002). There was a nonsignificant decrease in visceral adipose tissue (155.2 ± 68 cm2 at week 0 vs. 140.6 ± 70 cm2 at week 24, p = 0.08). Conclusions Use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection. Further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted. PMID:23867790

  4. Effects of an endurance cycling competition on resting serum insulin-like growth factor I (IGF-I) and its binding proteins IGFBP-1 and IGFBP-3

    Science.gov (United States)

    Chicharro, J; Lopez-Calderon, A; Hoyos, J; Martin-Velasco, A; Villa, G; Villanua, M; Lucia, A

    2001-01-01

    Objectives—To determine whether consecutive bouts of intense endurance exercise over a three week period alters serum concentrations of insulin-like growth factor I (IGF-I) and/or its binding proteins. Methods—Seventeen professional cyclists (mean (SEM) VO2MAX, 74.7 (2.1) ml/kg/min; age, 27 (1) years) competing in a three week tour race were selected as subjects. Blood samples were collected at each of the following time points: t0 (control, before the start of competition), t1 (end of first week), and t3 (end of third week). Serum levels of both total and free IGF-I and IGF binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured in each of the samples. Cortisol levels were measured in nine subjects. Results—A significant (p<0.01) increase was found in total IGF-I and IGFBP-1 at both t1 and t3 compared with to (IGF-I: 110.9 (17.7), 186.8 (12.0), 196.9 (14.7) ng/ml at t0, t1, and t3 respectively; IGFBP-1: 54.6 (6.6), 80.6 (8.0), and 89.2 (7.9) ng/ml at t0, t1, and t3 respectively). A significant (p<0.01) decrease was noted in free IGF-I at t3 compared with both to and t1 (t0: 0.9 (0.1) ng/ml; t1: 0.9 (0.1) ng/ml; t3: 0.7 (0.1) ng/ml); in contrast, IGFBP-3 levels remained stable throughout the race. Conclusions—It would appear that the increase in circulating levels of both IGF-I and its binding protein IGFBP-1 is a short term (one week) endocrine adaptation to endurance exercise. After three weeks of training, total IGF-I and IGFBP-1 remained stable, whereas free IGF-I fell below starting levels. Key Words: cycling; insulin-like growth factor; exercise; endurance; binding proteins PMID:11579061

  5. Insulin-like growth factor I (IGF-I) in Chinese alligator, Alligator sinensis: Molecular characterization, tissue distribution and mRNA expression changes during the active and hibernating periods.

    Science.gov (United States)

    Zhu, Xue; Zhang, Shengzhou; Zhao, Shuai; Zhang, Rui; Zhou, Yongkang; Wu, Xiaobing

    2017-02-01

    The Chinese alligator Alligator sinensis is an endangered species endemic to China, up to date, little is known about the regulation of its growth and development. Insulin-like growth factor I (IGF-I) plays a vital role in regulating vertebrate growth and development. In this study, the full-length cDNA of IGF-I in Chinese alligator (caIGF-I) was obtained for the first time, it contains 890-bp nucleotides encoding a 153-amino acid precursor, the mature caIGF-I consists of 70 amino acids by cleaving the signal peptide and C-terminal extension (E domain). The caIGF-I contains all the features of IGF-I peptide with B, C, A, and D domains and the six conservative cysteine residues involved in the stable tertiary structure. Multiple alignment analysis showed that the amino acid sequence of caIGF-I shares high identity with American alligator Alligator mississippiensis (100%) and birds (95-97%). Phylogenetic tree analysis of the IGF-I amino acid sequences indicated that alligators cluster into the bird branch. Real-time quantitative PCR technique showed that caIGF-I is widely expressed in all the examined tissues with the highest expression level in liver, higher in pancreas and oviduct while lower in heart, spleen, lung, kidney, stomach, intestines, ovary and muscles. During hibernation, the caIGF-I expression level decreased significantly in liver, pancreas, oviduct and kidney, while did not significantly change in heart, spleen, lung, stomach, small intestine, ovary and muscles. The mRNA expression changes during the two periods implicate that caIGF-I might play an important role in the regulation of feeding and growth in the Chinese alligator.

  6. Hippocampal Neurogenesis and Ageing

    OpenAIRE

    Couillard-Després, Sébastien

    2012-01-01

    Although significant inconsistencies remain to be clarified, a role for neurogenesis in hippocampal functions, such as cognition, has been suggested by several reports. Yet, investigation in various species of mammals, including humans, revealed that rates of hippocampal neurogenesis are steadily declining with age. The very low levels of hippocampal neurogenesis persisting in the aged brain have been suspected to underlie the cognitive deficits observed in elderly. However, current evidence ...

  7. Detrimental effects of physical inactivity on neurogenesis

    Directory of Open Access Journals (Sweden)

    Trenton Lippert

    2016-01-01

    Full Text Available Patients diagnosed with neurological disorders exhibit a variety of physical and psychiatric symptoms, including muscle atrophy, general immobility, and depression. Patients who participate in physical rehabilitation at times show unexpected clinical improvement, which includes diminished depression and other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for central nervous system (CNS disorders, transplantation of exogenous stem cells, and enhancing the endogenous neurogenesis. The latter therapy utilizes a natural method of re-innervating the injured brain, which may mend neurological impairments. In this study, we examine how inactivity-induced atrophy, using the hindlimb suspension model, alters neurogenesis in rats. The hypothesis is that inactivity inhibits neurogenesis by decreasing circulation growth or trophic factors, such as vascular endothelial growth or neurotrophic factors. The restriction modifies neurogenesis and stem cell differentiation in the CNS, the stem cell microenvironment is examined by the trophic and growth factors, including stress-related proteins. Despite growing evidence revealing the benefits of "increased" exercise on neurogenesis, the opposing theory involving "physical inactivity," which simulates pathological states, continues to be neglected. This novel theory will allow us to explore the effects on neurogenesis by an intransigent stem cell microenvironment likely generated by inactivity. 5-bromo-2-deoxyuridine labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid, and brain levels of trophic factors, growth factors, and stress-related proteins are suggested identifiers of neurogenesis, while evaluation of spontaneous movements will give insight into the psychomotor effects of inactivity. Investigations devised to show how in vivo stimulation, or lack thereof, affects the stem cell microenvironment are necessary to establish

  8. Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial

    DEFF Research Database (Denmark)

    Andries, Alin; Frystyk, Jan; Flyvbjerg, Allan

    2015-01-01

    , separated by a four-week washout period. Bioactive IGF was determined by a cell-based bioassay, whereas total IGF-I, IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays. The UFC excretion was determined by mass spectrometry. RESULTS: As previously reported...

  9. Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum

    DEFF Research Database (Denmark)

    Frystyk, Jan; Højlund, Kurt; Rasmussen, Kirsten Nyborg

    2002-01-01

    IGFBP-2, -3, -4, nor IGF-II caused any cross-reaction. The linear standard curve covered 3 orders of magnitude, and within and in-between assay coefficients of variation were less than 5 and 15%, respectively. To study the dynamic relationship between free IGF-I and binary complex formation, seven...

  10. An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

    NARCIS (Netherlands)

    te Velde, S.J.; van Rossum, E.F.; Voorhoeve, P.G.; Twisk, J.W.; van de Delemarre Waal, H.A.; Stehouwer, C.D.A.; van Mechelen, W.; Lamberts, S.W.; Kemper, H.C.

    2005-01-01

    OBJECTIVE: To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD) and type 2 diabetes (T2DM), and whether the birth weight--risk factor relationship was the same for each genotype. DESIGN AND PARTICIPANTS: 264 subjects (m

  11. A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly

    NARCIS (Netherlands)

    S. Kalmijn (Sandra); H.A.P. Pols (Huib); S.W.J. Lamberts (Steven); M.M.B. Breteler (Monique); J.A.M.J.L. Janssen (Joseph)

    2000-01-01

    textabstractThe objective of this study was to investigate the longitudinal relation between the insulin-like growth factor I (IGF-I)/IGF-binding protein (IGFBP) system and cognitive function. The study population consisted of a sample of 186 healthy participants from the populatio

  12. Leptin and IGF-I/II during the first weeks of life determine body composition at 2 years in infants born with very low birth weight.

    Science.gov (United States)

    Hernandez, Maria Isabel; Rossel, Katherine; Peña, Verónica; Cavada, Gabriel; Avila, Alejandra; Iñiguez, German; Mericq, Verónica

    2012-01-01

    Rapid early growth is associated with adverse metabolic outcome. The aim of this study was to determine whether there are differences in body composition (BC) between very-low-birth-weight preterm (VLBWPT) infants born appropriate for gestational age (AGA) and small for gestational age (SGA) and whether these differences relate to first-year growth. Twenty-six VLBWPT (15 AGA and 11 SGA). The BC was analyzed by dual X-ray absorptiometry at 2 years, and insulin-like growth factors (IGFs) I and II and leptin were administered weekly for 8 weeks and at 1, 3, 6, and 12 months. At 24 months, the VLBW SGA infants were lighter and had less peripheral fat and lean mass than VLBW AGA infants. In all patients, the percentage of fat mass correlated inversely with the change in weight [standard deviation scores (SDS)] from newborn to 2 and 4 weeks and the 1-month leptin and lean mass (SDS) correlated inversely with the change in weight (SDS) from newborn to 2, 4, and 8 weeks and with 4-week IGF-I and 8-week IGF-II. Lean mass (SDS) inversely correlated with 6-month IGF-I and directly correlated with 1-week and 3-month IGF-I in SGA VLBW infants only. A longer follow-up period will show whether additional differences will develop later.

  13. Effects of bovine colostrum supplementation on serum IGF-I, IgG, hormone, and saliva IgA during training.

    Science.gov (United States)

    Mero, A; Miikkulainen, H; Riski, J; Pakkanen, R; Aalto, J; Takala, T

    1997-10-01

    The purpose of this study was to examine the effects of bovine colostrum supplementation (Bioenervi) on serum insulin-like growth factor I (IGF-I), immunoglobulin G, hormone, and amino acid and saliva immunoglobulin A concentrations during a strength and speed training period. Nine male sprinters and jumpers underwent three randomized experimental training treatments of 8 days separated by 13 days. The only difference in the treatments was the drink of 125 ml consumed per day. Posttraining increases were noticed for serum IGF-I in the 25-ml Bioenervi treatment (125 ml contained 25 ml Bioenervi) and especially in the 125-ml Bioenervi treatment (125 ml contained 125 ml Bioenervi) compared with the placebo (normal milk whey) treatment (P < 0.05). The change in IGF-I concentration during the 8-day periods correlated positively with the change in insulin concentration during the same periods with 25-ml Bioenervi treatment (r = 0.68; P = 0.045) and with 125-ml Bioenervi treatment (r = 0.69; P = 0.038). Serum immunoglobulin G, hormone, and amino acid and saliva immunoglobulin A responses were similar during the three treatments. It appears that a bovine colostrum supplement (Bioenervi) may increase serum IGF-I concentration in athletes during strength and speed training.

  14. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

    NARCIS (Netherlands)

    A. Teumer (Alexander); Q. Qi; M. Nethander (Maria); H. Aschard (Hugues); S. Bandinelli (Stefania); M. Beekman (Marian); S.I. Berndt (Sonja); M. Bidlingmaier (Martin); L. Broer (Linda); A.R. Cappola (Anne); Ceda, G.P. (Gian Paolo); S.J. Chanock (Stephen); M.-H. Chen (Ming-Huei); Chen, T.C. (Tai C.); Y.D. Chen (Y.); Chung, J. (Jonathan); Del Greco Miglianico, F. (Fabiola); J. Eriksson (Joel); L. Ferrucci (Luigi); N. Friedrich (Nele); C. Gnewuch (Carsten); M. Goodarzi (Mark); N. Grarup (Niels); Guo, T. (Tingwei); Hammer, E. (Elke); R.B. Hayes (Richard); A.A. Hicks (Andrew); A. Hofman (Albert); J.J. Houwing-Duistermaat (Jeanine); Hu, F. (Frank); D. Hunter (David); L.L.N. Husemoen (Lise Lotte); A.J. Isaacs (Aaron); K.B. Jacobs (Kevin); J.A.M.J.L. Janssen (Joseph); J.-O. Jansson (John-Olov); Jehmlich, N. (Nico); Johnson, S. (Simon); A. Juul (Anders); M. Karlsson (Magnus); T.O. Kilpeläinen (Tuomas); P. Kovacs (Peter); P. Kraft (Peter); Li, C. (Chao); A. Linneberg (Allan); Y. Liu (Yongmei); R.J.F. Loos (Ruth); M. Lorentzon (Mattias); Y. Lu (Yingchang); M. Maggio (Marcello); R. Mägi (Reedik); J.B. Meigs (James); D. Mellström (Dan); M. Nauck (Matthias); A.B. Newman (Anne B.); M.N. Pollak (Michael); P.P. Pramstaller (Peter Paul); I. Prokopenko (Inga); B.M. Psaty (Bruce); M. Reincke (Martin); E.B. Rimm (Eric B.); Rotter, J.I. (Jerome I.); Saint Pierre, A. (Aude); C. Schurmann (Claudia); S. Seshadri (Sudha); Sjögren, K. (Klara); P.E. Slagboom (Eline); Strickler, H.D. (Howard D.); M. Stumvoll (Michael); Y. Suh (Yousin); Q. Sun (Qi); Zhang, C. (Cuilin); Svensson, J. (Johan); T. Tanaka (Toshiko); Tare, A. (Archana); A. Tönjes (Anke); H.-W. Uh (Hae-Won); C.M. van Duijn (Cock); D. van Heemst (Diana); L. Vandenput (Liesbeth); R.S. Vasan (Ramachandran Srini); U. Völker (Uwe); S.M. Willems (Sara); C. Ohlsson (Claes); H. Wallaschofski (Henri); R.C. Kaplan (Robert)

    2016-01-01

    textabstractThe growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes,

  15. An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

    Directory of Open Access Journals (Sweden)

    Stehouwer Coen DA

    2005-06-01

    Full Text Available Abstract Objective To investigate whether IGF-I promoter polymorphism was associated with birth weight and risk factors for cardiovascular disease (CVD and type 2 diabetes (T2DM, and whether the birth weight – risk factor relationship was the same for each genotype. Design and participants 264 subjects (mean age 36 years had data available on birth weight, IGF-I promoter polymorphism genotype, CVD and T2DM risk factors. Student's t-test and regression analyses were applied to analyse differences in birth weight and differences in the birth weight – risk factors relationship between the genotypes. Results Male variant carriers (VCs of the IGF-I promoter polymorphism had a 0.2 kg lower birth weight than men with the wild type allele (p = 0.009. Of the risk factors for CVD and T2DM, solely LDL concentration was associated with the genotype for the polymorphism. Most birth weight – risk factor relationships were stronger in the VC subjects; among others the birth weight – systolic blood pressure relationship: 1 kg lower birth weight was related to an 8.0 mmHg higher systolic blood pressure Conclusion The polymorphism in the promoter region of the IGF-I gene is related to birth weight in men only, and to LDL concentration only. Furthermore, the genotype for this polymorphism modified the relationships between birth weight and the risk factors, especially for systolic and diastolic blood pressure.

  16. A common polymorphism in the promoter of the IGF-I gene associates with increased fasting serum triglyceride levels in glucose-tolerant subjects

    DEFF Research Database (Denmark)

    Nielsen, Eva-Maria D; Hansen, Lars; Lajer, Maria

    2004-01-01

    The aim of the present study was to examine if absence of a common allele in a microsatellite polymorphism in the insulin-like growth factor I (IGF-I) promoter was associated with type 2 diabetes and alterations in quantitative traits in glucose-tolerant subjects....

  17. Biochemical and hormonal changes induced by one week of administration of rIGF-I to patients with Laron type dwarfism

    DEFF Research Database (Denmark)

    Laron, Z; Klinger, B; Jensen, L T

    1991-01-01

    OBJECTIVE: The purpose of this investigation was to evaluate the effectiveness of short-term administration of recombinant biosynthetic IGF-I on patients with an hereditary inability to generate this hormone. DESIGN AND PATIENTS: Ten patients with Laron type dwarfism (LTD) (4 males, six females) ...

  18. The relationship between dioxin-like polychlorobiphenyls and IGF-I serum levels in healthy adults: evidence from a cross-sectional study.

    Directory of Open Access Journals (Sweden)

    Octavio P Luzardo

    Full Text Available OBJECTIVE: Insulin-like growth factor I (IGF-I and dioxin-like polychlorobiphenyls (DL-PCBs have been associated with the pathogenesis of several diseases like cancer, diabetes and growth disorders. Because it has been suggested that organohalogenated contaminants could influence IGF-I levels in adults, the potential relationship between DL-PCBs and IGF-I serum levels was studied in 456 healthy adults from a representative sample of the general population of the Canary Islands (Spain. DESIGN: Free circulating serum levels of IGF-I and IGFBP-3 were measured through an ELISA methodology, while the serum levels of the 12 DL-PCBs congeners (IUPAC numbers # 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189 were measured by gas chromatography/mass spectrometry (GC-MS. RESULTS: DL-PCBs 156 and 167, Total DL-PCBs body burden (∑PCBs: sum over the 12 measured DL-PCBs, and Total toxic burden (in terms of toxic equivalence to dioxins: ∑TEQs showed a trend of inverse association with IGF-I serum levels in the whole studied population. After adjusting for potential confounders, including gender, body mass index (BMI, age, and IGF-binding protein-3 (IGFBP-3, younger (18-45 years women with lower BMI (<27 kg/m(2 and detectable levels of DL-PCB-156 showed significantly lower IGF-I levels than those in the same age and BMI subgroup with non-detectable levels of DL-PCB-156 (p<0.001. Similarly, ∑PCBs and ∑TEQs showed a tendency to an inverse association with IGF-I levels in the same group of women (p=0.017 and p=0.019 respectively. CONCLUSIONS: These findings suggest that DL-PCBs could be involved in the regulation of the IGF-system in a way possibly influenced by gender, age and BMI. Although these results should be interpreted with caution, such circumstances could contribute to explain the development of diseases associated to the IGF system.

  19. Nandrolone and stanozolol upregulate aromatase expression and further increase IGF-I-dependent effects on MCF-7 breast cancer cell proliferation.

    Science.gov (United States)

    Sirianni, Rosa; Capparelli, Claudia; Chimento, Adele; Panza, Salvatore; Catalano, Stefania; Lanzino, Marilena; Pezzi, Vincenzo; Andò, Sebastiano

    2012-11-05

    Several doping agents, such as anabolic androgenic steroids (AAS) and peptide hormones like insulin-like growth factor-I (IGF-I), are employed without considering the potential deleterious effects that they can cause. In addition, androgens are used in postmenopausal women as replacement therapy. However, there are no clear guidelines regarding the optimal therapeutic doses of androgens or long-term safety data. In this study we aimed to determine if two commonly used AAS, nandrolone and stanozolol, alone or in combination with IGF-I, could activate signaling involved in breast cancer cell proliferation. Using a human breast cancer cell line, MCF-7, as an experimental model we found that both nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and, consequently, estradiol production. Moreover, when nandrolone and stanozolol were combined with IGF-I, higher induction in aromatase expression was observed. This increase involved phosphatidylinositol 3-kinase (PI3K)/AKT and phospholipase C (PLC)/protein kinase C (PKC), which are part of IGF-I transductional pathways. Specifically, both AAS were able to activate membrane rapid signaling involving IGF-I receptor, extracellular regulated protein kinases 1/2 (ERK1/2) and AKT, after binding to estrogen receptor (ER), as confirmed by the ability of the ER antagonist ICI182, 780 to block such activation. The estrogenic activity of nandrolone and stanozolol was further confirmed by their capacity to induce the expression of the ER-regulated gene, CCND1 encoding for the cell cycle regulator cyclin D1, which represents a key protein for the control of breast cancer cell proliferation. In fact, when nandrolone and stanozolol were combined with IGF-I, they increased cell proliferation to levels higher than those elicited by the single factors. Taken together these data clearly indicate that the use of high doses of AAS, as occurs in doping practice, may increase the risk of breast cancer. This

  20. mRNA expression patterns for GH, PRL, SL, IGF-I and IGF-II during altered feeding status in rabbitfish, Siganus guttatus.

    Science.gov (United States)

    Ayson, Felix G; de Jesus-Ayson, Evelyn Grace T; Takemura, Akihiro

    2007-01-15

    Feeding time is a major synchronizer of many physiological rhythms in many organisms. Alteration in the nutritional status, specifically fasting, also affects the secretion rhythms of growth hormone (GH) and insulin-like growth factor-I (IGF-I). In this study, we investigated whether the expression patterns for the mRNAs of GH, prolactin (PRL) and somatolactin (SL) in the pituitary gland, and insulin-like growth factor I and II (IGF-I and IGF-II) in the liver of juvenile rabbitfish (Siganus guttatus) follow a rhythm according to feeding time and whether these hormone rhythms changes with starvation. Hormone mRNA levels were determined by real time PCR. The daily expression pattern for the mRNAs of GH, PRL and SL was not altered whether food was given in the morning (10:00 h) or in the afternoon (15:00 h). The daily GH mRNA expression pattern, however, was affected when food was not available for 3 days. In contrast, the daily expression pattern for IGF-I mRNA reaches its peak at roughly 5-6h after feeding. This pattern, however, was not observed with IGF-II mRNA. During 15-day starvation, GH mRNA levels in starved fish were significantly higher than the control fish starting on the 9th day of starvation until day 15. The levels returned to normal after re-feeding. In contrast to GH, PRL mRNA levels in starved fish were significantly lower than the control group starting on the 6th day of starvation until 3 days after re-feeding. SL mRNA levels were not significantly different between the control and starved group at anytime during the experiment. Both IGF-I and IGF-II mRNA levels in starved group were significantly higher than the control fish on the 3rd and 6th day of starvation. mRNA levels of both IGF-I and II in the starved fish decreased starting on the 9th day of starvation. While IGF-I mRNA levels in the starved group continued to decrease as starvation progressed, IGF-II mRNA levels were not significantly different from the control during the rest of the

  1. Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children’s Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations

    Directory of Open Access Journals (Sweden)

    Renata Stawerska

    2017-01-01

    Full Text Available Background. Some, however not all, children with growth hormone deficiency (GHD reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF-I is the main mediator of GH anabolic effects. Objective. The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. Methods. The analysis comprised 26 children with GHD, aged 5.7–15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1 with lower IGF-I/IGFBP-3 molar ratio and (2 with higher IGF-I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1–16.6 yrs, of normal height and body mass. Results. GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. Conclusions. A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis.

  2. Low serum levels of free and total insulin-like growth factor I (IGF-I) in patients with anorexia nervosa are not associated with increased IGF-binding protein-3 proteolysis

    DEFF Research Database (Denmark)

    Støving, R K; Flyvbjerg, A; Frystyk, J;

    1999-01-01

    Patients with anorexia nervosa (AN) are GH resistant, with elevated GH levels and low serum levels of total insulin-like growth factor I (IGF-I). IGF-I action is modulated by IGF-binding proteins (IGFBPs), and a variety of catabolic states has been characterized by the presence of increased IGFBP-3...

  3. The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients

    DEFF Research Database (Denmark)

    Juul, A; Main, K; Blum, W F

    1994-01-01

    administration. Serum levels of IGF-I and IGFBP-3 decrease with age in normal adults and are elevated in active acromegaly due to excessive GH secretion. However, the individual ratios between serum levels of IGF-I and IGFBP-3 in acromegalic and healthy adults have not been described previously....

  4. The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients

    DEFF Research Database (Denmark)

    Juul, A; Main, K; Blum, W F;

    1994-01-01

    administration. Serum levels of IGF-I and IGFBP-3 decrease with age in normal adults and are elevated in active acromegaly due to excessive GH secretion. However, the individual ratios between serum levels of IGF-I and IGFBP-3 in acromegalic and healthy adults have not been described previously....

  5. Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects

    DEFF Research Database (Denmark)

    Rasmussen, Michael Højby; Juul, Anders; Kjems, Lise Lund

    2006-01-01

    Decreased levels of GH and total IGF-I have been reported in obesity. It has been hypothesized that increased free (biologically active) IGF-I levels generated from IGF-binding protein (IGFBP) protease activity could be the mechanism for the low GH release in dieting obese subjects. However, no p...... a short-term very low-calorie diet (VLCD)....

  6. CLINICAL AND HORMONAL MILIEU OF 9 PATIENTS WITH PRIMARY GROWTH HORMONE INSENSITIVITY SYNDROME AND THEIR RESPONSE TO IGF-I GENERATION TEST

    Directory of Open Access Journals (Sweden)

    M. Razzaghy-Azar

    2006-05-01

    Full Text Available Primary growth hormone insensitivity syndrome (GHIS is a rare entity which can be due to defects in growth hormone (GH receptor that is called type 1 Laron syndrome (T1LS or post receptor defects (type 2 Laron syndrome . The aim of study was determining the clinical and hormonal milieu of the patients with primary GHIS and their response to IGF-I (insulin like growth factor-I generation test (IGT. GH, IGF-I, IGF-II, IGF binding protein 1 and 3 (BP-1 and BP-3, GH binding protein (GHBP and anti-GH antibody were detected by ELISA and RIA methods. IGF-I and BP-3 were measured before and after IGT. Nine patients (8 males, 1 female (mean age ± SD, 6.4 ± 5 years with severe short stature and high GH level were studied. Height SDS was - 8.5 ± 2.6. In 7 patients GHBP was zero, IGF-I and BP-3 were low and did not increase after IGT, so they had T1LS. Two brothers did not show the hormonal milieu of GH receptor defect, and were called non Laron syndrome (NLS. Birth weight in patients with T1LS and NLS was 3.65 ± 0.2 Kg and 1.65 ± 0.2 Kg, respectively (P = 0.001. All of the patients had typical clinical feature of GH-deficiency, but nasal bridge depression and microphallus were not seen in NLS. GH treatment of NLS, normalized their growth velocity, but without catch up growth. In conclusion IGT can differentiate Laron syndrome from other types of short stature. GH and IGF-I of fetus have no role in intrauterine growth.

  7. Postprandial changes in plasma growth hormone, insulin, insulin-like growth factor (IGF)-I, and IGF-binding proteins in coho salmon fasted for varying periods.

    Science.gov (United States)

    Shimizu, Munetaka; Cooper, Kathleen A; Dickhoff, Walton W; Beckman, Brian R

    2009-08-01

    We examined postprandial changes in circulating growth hormone (GH), insulin, insulin-like growth factor (IGF)-I, and IGF-binding proteins (IGFBPs) in yearling coho salmon under different feeding regimes. Fish were initially fasted for 1 day, 1 wk, or 3 wk. Fasted fish were then fed, and blood was collected at 4-h intervals over 26 h. After the various periods of fasting, basal levels of insulin were relatively constant, whereas those of IGF-I, IGFBPs and GH changed in proportion to the duration of the fast. A single meal caused a rapid, large increase in the circulating insulin levels, but the degree of the increase was influenced by the fasting period. IGF-I showed a moderate increase 2 h after the meal but only in the regularly fed fish. Plasma levels of 41-kDa IGFBP were increased in all groups within 6 h after the single meal. The fasting period did not influence the response of 41-kDa IGFBP to the meal. IGFBP-1 and GH decreased after the meal to the same extent among groups regardless of the fasting period. The present study shows that insulin and IGF-I respond differently to long (weeks)- and short (hours)-term nutritional changes in salmon; insulin maintains its basal level but changes acutely in response to food intake, whereas IGF-I adjusts its basal levels to the long-term nutritional status and is less responsive to acute nutritional input. IGFBPs maintain their sensitivity to food intake, even after prolonged fasting, suggesting their critical role in the nutritional regulation of salmon growth.

  8. Expression profile of IGF-I-calcineurin-NFATc3-dependent pathway genes in skeletal muscle during early development between duck breeds differing in growth rates.

    Science.gov (United States)

    Shu, Jingting; Li, Huifang; Shan, Yanju; Xu, Wenjuan; Chen, Wenfeng; Song, Chi; Song, Weitao

    2015-06-01

    The insulin-like growth factor I (IGF-I)-calcineurin (CaN)-NFATc signaling pathways have been implicated in the regulation of myocyte hypertrophy and fiber-type specificity. In the present study, the expression of the CnAα, NFATc3, and IGF-I genes was quantified by RT-PCR for the first time in the breast muscle (BM) and leg muscle (LM) on days 13, 17, 21, 25, and 27 of embryonic development, as well as at 7 days posthatching (PH), in Gaoyou and Jinding ducks, which differ in their muscle growth rates. Consistent expression patterns of CnAα, NFATc3, and IGF-I were found in the same anatomical location at different development stages in both duck breeds, showing significant differences in an age-specific fashion. However, the three genes were differentially expressed in the two different anatomical locations (BM and LM). CnAα, NFATc3, and IGF-I messenger RNA (mRNA) could be detected as early as embryonic day 13 (ED13), and the highest level appeared at this stage in both BM and LM. Significant positive relationships were observed in the expression of the studied genes in the BM and LM of both duck breeds. Also, the expression of these three genes showed a positive relationship with the percentage of type IIb fibers and a negative relationship with the percentage of type I fibers and type IIa fibers. Our data indicate differential expression and coordinated developmental regulation of the selected genes involved in the IGF-I-calcineurin-NFATc3 pathway in duck skeletal muscle during embryonic and early PH growth and development; these data also indicate that this signaling pathway might play a role in the regulation of myofiber type transition.

  9. 氯菊酯经 IGF-I 信号通路对类固醇激素合成的影响%Permethrin affect steroidogenesis through IGF-I signaling pathway in mouse leydig cells

    Institute of Scientific and Technical Information of China (English)

    费娟; 郑浩; 于洋; 孙宏; 丁震; 陈晓东; 王彩生

    2012-01-01

    目的 首次探讨氯菊酯影响类固醇激素合成与IGF-I信号通路之间的关系.方法 以小鼠睾丸间质瘤细胞株( MLTC-1)为染毒模型,讨论IGF-I信号通路在氯菊酯干扰孕酮合成中的作用.结果 随着氯菊酯染毒剂量增加,IGF-I mRNA表达量明显降低;在人绒毛膜促性腺激素(HCG)刺激下,氯菊酯显著抑制孕酮合成,且呈剂量—反应关系;培养液中加入IGF-I下游通路的抑制剂:LY294002(PI3kinase/Akt通路抑制剂),孕酮合成趋势与不加抑制剂一致;U0126( MEK1/2通路抑制剂),可明显抑制孕酮合成的下降趋势.结论 氯菊酯干扰类固醇激素的合成可能涉及IGF-I信号通路.

  10. Effects of eccentric cycling exercise on IGF-I splice variant expression in the muscles of young and elderly people

    DEFF Research Database (Denmark)

    Hameed, M.; Toft, A.D.; Harridge, S.D.

    2008-01-01

    growth factor (MGF) were studied in response to 1 h of eccentric cycling exercise in young and old individuals. Subjects (nine young, aged 20-27 years and eight elderly, aged 67-75 years) completed an eccentric exercise protocol that consisted of 60 min of reverse pedal cycling. Workloads were chosen....... No difference was observed between the baseline levels of the two splice variants between the two subject groups. Eccentric cycling exercise resulted in a significant increase in the mean MGF mRNA in both young and old subjects but did not alter IGF-IEa mRNA levels in either age group. As reported previously......Recovery from micro damage resulting from intensive exercise has been shown to take longer in older muscles. To investigate the factors that may contribute to muscle repair, we have studied the expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene. IGF-IEa and mechano...

  11. Serum insulin-like growth factor-I (IGF-I) and growth in children born after assisted reproduction

    DEFF Research Database (Denmark)

    Kai, Claudia Mau; Main, Katharina M; Andersen, Anders Nyboe

    2006-01-01

    CONTEXT: Concern has been raised about the safety of assisted reproduction techniques for the offspring. OBJECTIVES: The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF...... differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.......4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than...

  12. High-intensity interval training (HIIT) increases insulin-like growth factor-I (IGF-I) in sedentary aging men but not masters' athletes: an observational study.

    Science.gov (United States)

    Herbert, Peter; Hayes, Lawrence D; Sculthorpe, Nicholas; Grace, Fergal M

    2017-03-01

    The aim of this investigation was to examine the impact high-intensity interval training (HIIT) on serum insulin-like growth factor-I (IGF-I) in active compared with sedentary aging men. 22 lifetime sedentary (SED; 62 ± 2 years) and 17 masters' athletes (LEX; 60 ± 5 years) were recruited to the study. As HIIT requires preconditioning exercise in sedentary cohorts, the study required three assessment phases; enrollment (phase A), following preconditioning exercise (phase B), and post-HIIT (phase C). Serum IGF-I was determined by electrochemiluminescent immunoassay. IGF-I was higher in LEX compared to SED at baseline (p = 0.007, Cohen's d = 0.91), and phase B (p = 0.083, Cohen's d = 0.59), with only a small difference at C (p = 0.291, Cohen's d = 0.35). SED experienced a small increase in IGF-I following preconditioning from 13.1 ± 4.7 to 14.2 ± 6.0 μg·dl(-1) (p = 0.376, Cohen's d = 0.22), followed by a larger increase post-HIIT (16.9 ± 4.4 μg·dl(-1)), which was significantly elevated compared with baseline (p = 0.002, Cohen's d = 0.85), and post-preconditioning (p = 0.005, Cohen's d = 0.51). LEX experienced a trivial changes in IGF-I from A to B (18.2 ± 6.4 to 17.2 ± 3.7 μg·dl(-1) [p = 0.538, Cohen's d = 0.19]), and a small change post-HIIT (18.4 ± 4.1 μg·dl(-1) [p = 0.283, Cohen's d = 0.31]). Small increases were observed in fat-free mass in both groups following HIIT (p < 0.05, Cohen's d = 0.32-0.45). In conclusion, HIIT with preconditioning exercise abrogates the age associated difference in IGF-I between SED and LEX, and induces small improvements in fat-free mass in both SED and LEX.

  13. The Temporal and Spatial Characteristics of IGF-I Gene Expression in Broilers%肉鸡IGF-I基因mRNA的时空表达模式

    Institute of Scientific and Technical Information of China (English)

    顾海娟; 王星果; 王慧娟; 邵芳; 顾志良

    2014-01-01

    In this experiment, the real-time fluorescence quantitative PCR was applied to investigate the tissue expressional patterns of IGF-I mRNA in breast muscle, thigh muscle, adipose, heart, liver, spleen, lung, kidney, glandular stomach, muscular stomach, intestine, brain tissues and in various developmental stages (d1, w1, w2, w3, w4, w5, w6 and w7) of thigh muscle, liver, adipose tissue in three different broilers, and β-actin gene stan-dards was used as an inner control. The results showed that the expression of IGF-I gene in liver was significant-ly higher than that of the other tissues, and expressed at a certain amount of IGF-I gene in all tissues except for kidney, that the highest expression of IGF-I mRNA in thigh muscle was at age of six-week old, and the rest of the stage was also higher than one day, that the highest expression of IGF-I mRNA in liver was at three-week, and then declined, that the highest expression in adipose was at three-week, and then its expression gradually decreased with increasing age. These research results revealed the temporal and spatial expression characteris-tics of IGF-I mRNA gene in early growth broilers, and would contribute to the further study on genes related to growth axis regulation of growth and development in broilers.%采用实时荧光定量PCR技术,以β-actin为内参,检测了白羽AA肉鸡在4周龄时其胸肌、腿肌、脂肪、心、肝、脾、肺、肾、腺胃、肌胃、肠、脑共12个组织和在1日龄及1、2、3、4、5、6、7周龄时腿肌、肝脏、脂肪中类胰岛素生长因子-I(IGF-I)的表达量变化。结果显示,除肾外其余组织均表达一定量的IGF-I mRNA表达,且在肝脏中表达量显著高于其他组织;腿肌6周时IGF-I mRNA表达量达到最大值,其余各时期也都高于1日龄时的表达;肝脏中表达量最高时期是3周,然后又呈下降趋势;脂肪中在3周时表达量最高,然后其表达量随年龄增长而逐渐

  14. Sequence Variations in the Bovine IGF-I and IGFBP3 Genes and Their Association with Growth and Development Traits in Chinese Beef Cattle

    Institute of Scientific and Technical Information of China (English)

    GAO Xue; SHI Ming-yan; XU Xiu-rong; LI Jun-ya; REN Hong-yan; XU Shang-zhong

    2009-01-01

    The objective of this study was to determine the genotype effects of the bovine insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP3) genes on growth and development traits in beef cows,including 130 Chinese Simmental,42 Nanyang,and 47 Luxi Yellow cattle.Sequence variations in the bovine IGF-I and IGFBP3 genes were investigated by single strand conformation polymorphism (SSCP).SSCPs were detected in 6 fragments,which is the 5'-flanking region,the 2nd exon,the 5th exon,and the 5th intron of the IGF-I gene,and the 2nd exon,the 3rd exon of the IGFBP3 gene.Two polymorphisms,an A-to-G transition in the 2nd exon of the IGF-I gene and a T-to-C transition in the 2nd exon of IGFBP3 gene were detected in 3 breeds.The allele frequencies of 2 polymorphisms were 0.0411 (A),0.9589 (B),and 0.7237 (A),0.2763 (B),respectively.These 2 loci were analyzed to associate with body weight,height at withers,body length,heart girth,rump width,and beef production index (BPI) at 0,6,12,24,and 36-month old.The 1GFBP3 locus was shown to be associated with rump width,heart girth at 24-month and 36-month.Animals with BB genotype had higher rump width (24.86±0.47) cm at 24-month and (27.50±0.63) cm at 36-month.The heart girth was highest for the individuals with BB genotype (171.33±1.84) cm and higher than those with AB genotype (166.68±1.13) cm (P<0.05) at 36-month.

  15. The effects of in ovo rhIGF-I administration on expression of the growth hormone secretagogue receptor (GHSR) during chicken embryonic development.

    Science.gov (United States)

    Gahr, Scott A; Kocamis, Hakan; Richter, Jennifer J; Killefer, John

    2004-01-01

    Growth hormone secretion is under the control of a pair of hypothalamic factors, growth hormone releasing hormone and somatostatin. The growth hormone secretagogue receptor (GHSR) and its endogenous ligand represent a novel third method regulating the release of growth hormone. Early chicken embryonic development has been proposed to be independent of GH. However, recent evidence shows that peripheral GH secretion has paracrine/autocrine functions during embryonic development. In the current study, we used the reverse-transcriptase polymerase chain reaction to determine the expression pattern of the GHSR during embryonic development and the effects of in ovo recombinant human (rh) IGF-I administration on its expression pattern. Eggs were injected once with 100 ng rhIGF-I in 10 mM acetic acid, and 0.1% BSA per embryo on embryonic day 3. Total RNA was isolated from whole embryos on embryonic day (E) 0-6 (n=6 per day), thoracic/abdominal halves of the embryos on E7- E8 (n= 6 per day) and Pectoralis muscle on E9-E20 (n= 4 per day). We found that GHSR expression was low during E0-E4, followed by an increase on E5 and remained constant through E17. GHSR expression then increased on E18 before reducing on E20. A similar pattern was found in the rhIGF-I treated embryos with the exception of a significant increase in GHSR expression on E8. These data indicate that the GHSR may be active in regulating GH secretion during early embryonic development, and upregulation of the GHSR gene following IGF-I administration may have an important role in the determination of postnatal muscle growth.

  16. Whole body cortisol and expression of HSP70, IGF-I and MSTN in early development of sea bass subjected to heat shock.

    Science.gov (United States)

    Bertotto, Daniela; Poltronieri, Carlo; Negrato, Elena; Richard, Jacopo; Pascoli, Francesco; Simontacchi, Claudia; Radaelli, Giuseppe

    2011-10-01

    Whole body cortisol levels were determined during early larval developmental stages of sea bass (Dicentrarchus labrax) subjected to a heat shock with the aim to investigate the correlation between the stress event and the activation of the hypothalamic-pituitary-interrenal axis. Moreover, the mRNA expression of inducible heat shock protein 70 (HSP70), insulin-like growth factor I (IGF-I) and myostatin (MSTN) was also detected. Whole body cortisol was determined by a radio-immunoassay (RIA) technique whereas the expression of HSP70, IGF-I and MSTN mRNAs was quantified by Real-Time PCR. Cortisol was detectable in all the larvae from hatching but its level increased significantly in larvae submitted to heat shock from 2-day post hatching onwards. An effect of the sole transfer on cortisol levels was detectable at day 10, indicating an increase of the hypothalamic-pituitary-interrenal axis sensitivity from this stage of sea bass development. In animals exposed to heat shock, the expression of inducible HSP70 resulted in a marked increase of mRNA levels already at hatching. This increase was significantly higher from 6 days onwards if compared to controls. Moreover, heat shock resulted in a decrease (although not significant) in IGF-I mRNA expression of stressed larvae if compared to controls. On the contrary, heat shock did not influence the expression of MSTN mRNA in all groups. The results indicate a very early activation of the hypothalamic-pituitary-interrenal axis and in general of the stress response during the development of European sea bass. Moreover, these results suggest the importance of cortisol and inducible HSP70 as bioindicators of stress in aquaculture and confirm the role of IGF-I and MSTN as regulatory factors during development and growth of fish.

  17. A chimeric vitronectin: IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells.

    Science.gov (United States)

    Manton, Kerry J; Richards, Sean; Van Lonkhuyzen, Derek; Cormack, Luke; Leavesley, David; Upton, Zee

    2010-09-01

    The therapeutic use of human embryonic stem (hES) cells is severely limited by safety concerns regarding their culture in media containing animal-derived or nondefined factors and on animal-derived feeder cells. Thus, there is a pressing need to develop culture techniques that are xeno-free, fully defined, and synthetic. Our laboratory has discovered that insulin-like growth factor (IGF) and vitronectin (VN) bind to each other resulting in synergistic short-term functional effects in several cell types, including keratinocytes and breast epithelial cells. We have further refined this complex into a single chimeric VN:IGF-I protein that functionally mimics the effects obtained upon binding of IGF-I to VN. The aim of the current study was to determine whether hES cells can be serially propagated in feeder-cell-free and serum-free conditions using medium containing our novel chimeric VN:IGF-I protein. Here we demonstrate that hES cells can be serially propagated and retain their undifferentiated state in vitro for up to 35 passages in our feeder-cell-free, serum-free, chemically defined media. We have utilized real-time polymerase chain reaction (PCR), immunofluorescence, and fluorescence-activated cell sorter (FACS) analysis to show that the hES cells have maintained an undifferentiated phenotype. In vitro differentiation assays demonstrated that the hES cells retain their pluripotent potential and the karyotype of the hES cells remains unchanged. This study demonstrates that the novel, fully defined, synthetic VN:IGF-I chimera-containing medium described herein is a viable alternative to media containing serum, and that in conjunction with laminin-coated plates facilitates feeder-cell-free and serum-free growth of hES.

  18. Neuropeptides and hippocampal neurogenesis.

    Science.gov (United States)

    Zaben, M J; Gray, W P

    2013-12-01

    Hippocampal neurogenesis is important for modulating the behavioural responses to stress and for certain forms of learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and galanin have emerged as important mediators for signalling local and extrinsic interneuronal activity to subgranular zone precursors. Here we review the distribution of these neuropeptides and their receptors in the neurogenic area of the hippocampus and their precise effects on hippocampal neurogenesis. We also discuss neuropeptides' potential involvement in functional aspects of hippocampal neurogenesis particularly their involvement in the modulation of learning and memory and behavior responses.

  19. Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model.

    Science.gov (United States)

    Shevelev, A; Burfeind, P; Schulze, E; Rininsland, F; Johnson, T R; Trojan, J; Chernicky, C L; Hélène, C; Ilan, J; Ilan, J

    1997-01-01

    Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

  20. Selection for breed-specific growth hormone and IGF-I alleles in a synthetic beef cattle cross, Canchim

    Directory of Open Access Journals (Sweden)

    L.C.A. Regitano

    1999-12-01

    Full Text Available This study was developed to evaluate selection effects on gene frequencies in a synthetic beef cattle cross (5/8 Charolais, 3/8 Zebu named Canchim. A sample of 154 Canchim animals, representing three generation classes, was analyzed for seven molecular markers. Thirty-six Charolais cattle were also studied for comparison. A highly significant variation (P Este estudo foi desenvolvido com o objetivo de avaliar as freqüências gênicas em diferentes gerações de bovinos da raça sintética Canchim (5/8 Charolês, 3/8 Zebu. Uma amostra de 154 animais, representando três classes de gerações de um rebanho das raça Canchim, foi analisada para sete marcadores moleculares. Uma amostra da raça Charolesa (N = 36 foi incluída nas análises para permitir comparações. Observou-se um aumento linear, altamente significativo (P < 0,01, na freqüência do alelo que codifica o aminoácido valina na posição 127 do hormônio de crescimento, ao longo das gerações de Canchim. Este alelo foi observado na amostra da raça Charolesa e não é encontrado em raças zebuínas nacionais. Quatro alelos foram observados para o microssatélite localizado na região 5' não transcrita do gene do fator de crescimento semelhante à insulina do tipo I (IGF-I, com tamanhos variando de 231 a 225 pb. A freqüência do alelo de 225 pb apresentou um aumento significativo (P < 0,05 não linear ao longo das gerações. Este alelo não foi observado na raça Charolesa e é predominante nas raças zebuínas. Para o microssatélite CSFM50, seis alelos foram observados na raça Canchim, tendo sido verificada uma redução linear (P < 0,05 na freqüência do alelo de 168 bp. A hipótese de acasalamento preferencial com relação ao polimorfismo do hormônio de crescimento foi reforçada pelos resultados da análise de estatística F de Wright. O valor estimado de FIS para este loco foi 0,59 (P < 0,01. O aumento simultâneo de um alelo do hormônio de crescimento caracter

  1. Spatially regulated adult neurogenesis

    OpenAIRE

    Rikani, Azadeh A.; Choudhry, Zia; Choudhry, Adnan M; Zenonos, Georgios; Tariq, Sadaf; Mobassarah, Nusrat J

    2013-01-01

    Adult neurogenesis has been the center of attention for decades. Neuroscientists hope to understand the mechanism underlying this phenomenon that might provide a unique perception of brain repair in future. Neurogenesis is referred to the process in which neuronal stem cells and progenitors generate new neurons in non-pathologic setting. Although there are some similarities between two neurogenetic regions including hippocampus and olfactory bulb, however there are some important differences....

  2. Insulin-like growth factor I (IGF-I) replacement during growth hormone receptor antagonism normalizes serum IGF-binding protein-3 and markers of bone formation in ovariectomized rhesus monkeys.

    Science.gov (United States)

    Wilson, M E

    2000-04-01

    Previous work from this laboratory has shown that the constant sc infusion of insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP-3), whereas the acute administration of IGF-I to monkeys pretreated with a GH receptor antagonist produces a brief, but significant, elevation in serum IGFBP-3. The present study tested the hypothesis that the constant infusion of IGF-I would normalize serum concentrations of IGFBP-3 in females treated with the GH receptor antagonist. To assess the biological significance of these effects, serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation, osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five female rhesus monkeys were studied over 21 consecutive days involving 7 days of baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week, sc), and 7 days of treatment with the GH receptor antagonist supplemented with IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of the initiation of treatment with the GH receptor antagonist, serum IGF-I and IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels continued to decline through the remainder of treatment. However, within 48 h of the initiation of IGF-I administration during GH receptor antagonist treatment, both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values. Serum concentrations of ALS were also decreased by GH antagonism, but levels increased in some (n = 2), but not all, subjects upon administration of IGF-I. Size exclusion ultrafiltration indicated that the amount of IGF-I found in the high molecular mass complex (>100 kDa) decreased significantly during GH antagonism, but was similar during the baseline and IGF-I infusion phases. Finally, treatment with the GH receptor antagonist also significantly reduced serum levels of osteocalcin and

  3. Clonage de l'IGF-I et de son récepteur chez le turbot (Psetta maxima

    Directory of Open Access Journals (Sweden)

    ELIES G.

    1998-07-01

    Full Text Available Les IGF, leurs récepteurs et leurs protéines de liaison constituent une famille moléculaire qui joue un rôle essentiel dans la régulation de la croissance et du développement. Nous nous sommes intéressés à la caractérisation moléculaire de l'IGF-l et de son récepteur (IGF-1R chez le turbot (Psetta maxima, un poisson plat téléostéen. Par RT-PCR, nous avons clone un ADNc codant pour les quatre domaines de l'IGF-l mature. La protéine présente 70 à 96 % d'identité avec les autres IGF-I de vertébrés. Le clonage de la séquence codante entière du récepteur a nécessité la construction d'une banque d'ADNc d'embryons de turbots. Le récepteur est organisé en domaines dont la taille et les caractéristiques sont semblables à celles des autres récepteurs aux IGF de type 1 décrits chez les mammifères et le poulet. La région catalytique est particulièrement conservée. Dans certains domaines, notamment dans la région C-terminale du précurseur, quelques différences qui pourraient avoir une importance fonctionnelle sont cependant observées. Enfin, par RT-PCR, nous avons mis en évidence une régulation ontogénique du statut de polyadénylation des ARNm IGF-1R.

  4. Características ultraestruturais da mucosa intestinal de bezerros recém-nascidos alimentados na segunda refeição com colostro enriquecido com IGF-I e IgG Ultrastructural characteristics of the intestinal mucosa of newborn calves fed in the second meal with colostrum enriched with IGF-I and IgG

    Directory of Open Access Journals (Sweden)

    Liris Kindlein

    2008-01-01

    Full Text Available Objetivou-se estudar os efeitos do fornecimento adicional de colostro de diferentes concentrações de IGF-I e IgG, às 12 horas de vida, sobre as características morfológicas dos enterócitos, bem como a relação entre a quantidade total de IGF-I ingerida e a altura dos microvilos intestinais de bezerros até as 72 horas de vida. Adotou-se o fornecimento prolongado de colostros de diferentes concentrações, incluindo colostro enriquecido com colostro liofilizado. Oitenta e dois bezerros da raça Holandesa receberam, ao nascimento, colostro com concentrações variáveis de IgG e, às 12 horas de vida, receberam três pools de colostro com densidades variáveis: colostro baixo - IgG e IGF-I inferiores a 30 mg/mL e 90,65 µg/L, respectivamente; alto - IgG e IGF-I superiores a 100 mg/mL e 344,02 µg/L, respectivamente; ou enriquecido de colostro liofilizado - IgG e IGF-I superiores a 120 mg/mL e 864,68 µg/L, respectivamente. Às 0, 10, 24, 36 e 72 horas de vida, coletaram-se amostras do duodeno, do jejuno (proximal, médio e distal e do íleo para estudo ultraestrutural. Para determinação da altura dos microvilos, considerou-se o arranjo fatorial 3 × 3 + 1, correspondendo à quantidade total de IGF-I ingerida nas refeições de colostro (0-500, 500-1500, 1500-2500 µg, três idades de abate (10, 24 e 72 horas de vida e o grupo controle (nascimento. As características morfológicas dos enterócitos diferiram conforme a idade e as quantidades de IgG e IGF-I disponibilizadas. A quantidade total de IGF-I ingerida teve efeito local positivo sobre a altura dos microvilos intestinais.The objective of this study was to evaluate the effects of additional colostrum with different IGF-I and IgG concentrations, at 12 hours of life, on morphological characteristics of enterocytes, as well as the relationship of total amount of IGF-I ingested on the microvillus height of the calves small intestine in the first 72 hours after birth. It was utilized

  5. Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice.

    Directory of Open Access Journals (Sweden)

    Lourdes Rodríguez-de la Rosa

    Full Text Available Insulin-like growth factor-I (IGF-I deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH. PTH-related protein (PTHrP is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36 and PTHrP (107-111 (osteostatin to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype or saline vehicle (3 males and 3 females for each genotype. We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36 and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36 and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.

  6. Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-I deficient mice.

    Science.gov (United States)

    Rodríguez-de la Rosa, Lourdes; López-Herradón, Ana; Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Varela-Nieto, Isabel; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1-36) and PTHrP (107-111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a , cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1-36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1-36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone.

  7. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice

    Science.gov (United States)

    Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a, cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone. PMID:24503961

  8. The acute effect of dexamethasone on plasma leptin concentrations and the relationships between fasting leptin, the IGF-I/IGFBP system, dehydroepiandrosterone, androstenedione and testosterone in an elderly population

    NARCIS (Netherlands)

    Janssen, JAMJL; Huizenga, NATM; Stolk, RP; Grobbee, DE; Pols, HAP; de Jong, FH; Attanasio, AMF; Blum, WF; Lamberts, SWJ

    OBJECTIVE To investigate the acute effect of dexamethasone administration on serum leptin levels and the relationships between dehydroepiandrosterone (DHEAS), androstenedione, testosterone and the IGF-I/IGFBP system and leptin levels in healthy elderly humans. METHODS In 209 healthy elderly

  9. 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

    DEFF Research Database (Denmark)

    Møller, S; Juul, A; Becker, U

    1995-01-01

    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...... patients (6 +/- 2%; P pressure (r = -0.49; P

  10. Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

    Science.gov (United States)

    Gulati, Anil

    2016-01-01

    Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ETB receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest. Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant. Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ETA and ETB). In the central nervous system (CNS) ETA receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ETA receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ETA receptors. On the other hand, blocking ETB receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ETB receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ETB receptor stimulation on mitochondrial functions in the CNS following cerebral ischemia. Conclusion: The findings of this

  11. Effects of Microglia on Neurogenesis.

    Science.gov (United States)

    Sato, Kaoru

    2015-08-01

    This review summarizes and organizes the literature concerning the effects of microglia on neurogenesis, particularly focusing on the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) of the lateral ventricles, in which the neurogenic potential is progressively restricted during the life of the organism. A comparison of microglial roles in neurogenesis in these two regions indicates that microglia regulate neurogenesis in a temporally and spatially specific manner. Microglia may also sense signals from the surrounding environment and have regulatory effects on neurogenesis. We speculate microglia function as a hub for the information obtained from the inner and outer brain regions for regulating neurogenesis.

  12. Effects of tomato- and soy-rich diets on the IGF-I hormonal network: a crossover study of postmenopausal women at high risk for breast cancer.

    Science.gov (United States)

    McLaughlin, John M; Olivo-Marston, Susan; Vitolins, Mara Z; Bittoni, Marisa; Reeves, Katherine W; Degraffinreid, Cecilia R; Schwartz, Steven J; Clinton, Steven K; Paskett, Electra D

    2011-05-01

    To determine whether dietary modifications with tomato products and/or a soy supplement affected circulating levels of insulin-like growth factor (IGF)-1 and other markers of cell signaling in postmenopausal women at risk for developing breast cancer. Eligible and consented postmenopausal women at high risk for developing breast cancer were enrolled in a 26-week, two-arm (tomato and soy, 10 weeks each) longitudinal dietary intervention study in which each woman served as her own control. Changes in biochemical endpoints including IGF-I, IGF-binding protein (IGFBP)-3, estradiol, sex hormone-binding globulin (SHBG), C-peptide, and insulin were measured for each intervention arm. Carotenoid and isoflavone levels were measured to assess adherence. Significant increases in carotenoid and isoflavone levels during the tomato and soy study arms, respectively, suggested that women were adherent to both arms of the intervention. The tomato-rich diet had little effect on cell-signaling biomarkers previously associated with breast cancer risk. However, results of the soy intervention showed that concentrations of IGF-I and IGFBP-3 increased by 21.6 and 154.7 μmol/L, respectively (P = 0.001 for both) and SHBG decreased by 5.4 μmol/L (P protein intake may lead to small, but significant, increases in IGF-I and IGFBP-3. Soy consumption also led to a significant decrease in SHBG, which has been hypothesized to promote, rather than prevent, cancer growth. Previous epidemiologic studies, however, have confirmed protective effect of soy on breast cancer. Additional investigation about the effect of soy on breast cancer risk and its mechanism of action is warranted.

  13. Effects of an evaporative cooling system on plasma cortisol, IGF-I, and milk production in dairy cows in a tropical environment

    Science.gov (United States)

    Titto, Cristiane Gonçalves; Negrão, João Alberto; Titto, Evaldo Antonio Lencioni; Canaes, Taissa de Souza; Titto, Rafael Martins; Pereira, Alfredo Manuel Franco

    2013-03-01

    Access to an evaporative cooling system can increase production in dairy cows because of improved thermal comfort. This study aimed to evaluate the impact of ambient temperature on thermoregulation, plasma cortisol, insulin-like growth factor 1 (IGF-I), and productive status, and to determine the efficiency of an evaporative cooling system on physiological responses under different weather patterns. A total of 28 Holstein cows were divided into two groups, one with and the other without access to a cooling system with fans and mist in the free stall. The parameters were analyzed during morning (0700 hours) and afternoon milking (1430 hours) under five different weather patterns throughout the year (fall, winter, spring, dry summer, and rainy summer). Rectal temperature (RT), body surface temperature (BS), base of tail temperature (TT), and respiratory frequency (RF) were lower in the morning ( P < 0.01). The cooling system did not affect RT, and both the groups had values below 38.56 over the year ( P = 0.11). Cortisol and IGF-I may have been influenced by the seasons, in opposite ways. Cortisol concentrations were higher in winter ( P < 0.05) and IGF-I was higher during spring-summer ( P < 0.05). The air temperature and the temperature humidity index showed positive moderate correlations to RT, BS, TT, and RF ( P < 0.001). The ambient temperature was found to have a positive correlation with the physiological variables, independent of the cooling system, but cooled animals exhibited higher milk production during spring and summer ( P < 0.01).

  14. Relationships among magnetic resonance imaging, histological findings, and IGF-I in steroid-induced osteonecrosis of the femoral head in rabbits

    Institute of Scientific and Technical Information of China (English)

    Xing-can CHEN; Jian WENG; Xue-qun CHEN; Ji-zeng DU; Miao-ping ZHU; Yong-qing PAN; Miao LIU

    2008-01-01

    Objective: To study the relationships among magnetic resonance imaging (MRI), histological findings, and insulin-like growth factor-I (IGF-I) in steroid-induced osteonecrosis of the femoral head in rabbits. Methods: Thirty rabbits were randomly divided into experimental Group A (n=15) and control Group B (n=15). The 7.5 mg/kg (2 ml) ofdexamethasone (DEX)and physiological saline (2 ml) were injected into the fight gluteus medius muscle twice at one-week intervals in animals of Groups A and B, respectively. At 4, 8 and 16 weeks after obtaining an MRI, the rabbits were sacrificed and the femoral head from one side was removed for histological study of lacunae empty of osteocytes, subchondral vessels, and size of fat cells under microscopy, and the femoral head from the other side was removed for enzyme-linked immunoadsorbent assay (ELISA) for IGF-I.Results: At 4, 8 and 16 weeks after treatment, no necrotic lesions were detected in Group B, while they were detected in Group A.Light microscopy revealed that the fat cells of the marrow cavity were enlarged, subchondral vessels were evidently decreased,and empty bone lacunae were clearly increased. The IGF-I levels in Group A were significantly higher than those in Group B. At 8 weeks after the DEX injection, the MRI of all 20 femora showed an inhomogeneous, low signal intensity area in the femoral head,and at 16 weeks, the findings of all 10 femora showed a specific "line-like sign". The MRI findings of all femora in Group B were normal. Conclusion: MRI is a highly sensitive means of diagnosing early experimental osteonecrosis of the femoral head. However, the abnormal marrow tissues appeared later than 4 weeks when the expression of IGF-I increased. This reparative factor has an early and important role in response to steroid-induced osteonecrosis of the femoral head, and provides a theoretical foundation for understanding the pathology and designing new therapies.

  15. Granulocyte colony-stimulating factor induces neurogenesis and improves cognition in amyloid precursor protein transgenic mouse model of Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    朱正禹

    2012-01-01

    Objective To investigate the effect of granulocyte colony-stimulating factor (G-CSF) and its effect on the cognation in the PDGF-hAPPV717I transgenic mice of Alzheimer’s disease model. Methods Totally 36 PDGF-hAPPV717I transgenic mice were randomly divided into two groups:

  16. EVALUATION OF THE GROWTH FACTOR IGF-I IN THE IN VITRO MATURATION OF CANINE OOCYTES IN THE TCM 199 MEDIUM Evaluación del factor de crecimiento IGF-I en la maduración in vitro de ovocitos de perras en el medio TCM 199 AVALIAÇÃO DO FATOR DE CRESCIMENTO IGF-I NA MATURAÇÃO IN VITRO DE OÓCITOS CANINOS NO MEIO TCM 199

    Directory of Open Access Journals (Sweden)

    Maricy Apparício Ferreira

    2009-07-01

    Full Text Available The aim was to evaluate the supplementation of recombinant IGF-I growth factor at concentration of 100?g/mL in 500µL of TCM 199 medium in the in vitro maturation of canine oocytes. The oocytes were stained with isotiocianate of fluorescein (Lens cullinaris and Hoeschst 33342 for nuclear and cytoplasmatic assessment using an epifluorescence microscope (filter FITC: excitement 490nm and emission 520nm. There were no statistical differences between control and supplemented groups regarding cytoplasmatic and nuclear maturation when using Kruskal-Wallis test, p<0,05.

    Key words: Canine, IGF-I, maturation, oocyte.
    El estudio presente tuvo como objetivo principal evaluar la adición del factor de crecimiento IGF-I recombinante en la concentración de 100hg/mL en 500mL del medio TCM 199 en la maduración in vitro de ovocitos de perras. Se evaluó con eso el grado de maduración citoplasmático y nuclear por medio de tinción con isotiocianato de fluoresceína (Lens cullinaris y Hoeschst 33342 respectivamente bajo microscopía epifluorescente filtro FITC: 490nn y emisión 520nm. No hubo diferencias estadísticas entre los grupos control y tratamiento en la maduración in vitro, citoplasmática y nuclear de ovocitos de perras por el test de Kruskal – Wallis, p< 0,05. Palabras-clave: maduración, ovocito, perras, IGF-I pt Objetivou-se avaliar a adição do fator de crescimento recombinante IGF–I na concentração de 100?g/mL em 500µL de meio TCM 199 na maturação in vitro de oócitos caninos. Avaliou-se, com isso, o grau de maturação citoplasmática e nuclear por meio de coloração com isotiocianato de fluoresceína (Lens cullinaris e Hoeschst 33342, respectivamente, em microscópio epifluorescente filtro FITC: excitação 490nm e emissão 520nm. Como resultado, verificou-se que não houve diferenças estatísticas entre os grupos controle e tratamento na maturação in vitro, citoplasmática e nuclear, de oócitos caninos pelo

  17. Rac1 and Stathmin but Not EB1 Are Required for Invasion of Breast Cancer Cells in Response to IGF-I

    Directory of Open Access Journals (Sweden)

    Shigeru Morimura

    2011-01-01

    Full Text Available Cell migration is considered necessary for the invasion that accompanies the directional formation of the cellular protrusions termed lamellipodia. In invasive breast cancer MDA-MB-231 cells, lamellipodia formation is preceded by translocation of the actin cytoskeletal regulatory protein WAVE2 to the leading edge. WAVE2 translocation and lamellipodia formation require many signaling molecules, including PI3K, Rac1, Pak1, IRSp53, stathmin, and EB1, but whether these molecules are necessary for invasion remains unclear. In noninvasive breast cancer MCF7 cells, no lamellipodia were induced by IGF-I, whereas in MDA-MB-231 cells, Rac1, stathmin, and EB1 were overexpressed. Depletion of Rac1 or stathmin by small interfering RNA abrogated the IGF-I-induced invasion of MDA-MB-231 cells; however, depletion of EB1 did not, indicating the necessity of Rac1 and stathmin but not EB1 for invasion. The signaling pathway leading to cell invasion may not be identical but shares some common molecules, leading to cell migration through lamellipodia formation.

  18. rAAV-mediated overexpression of sox9, TGF-β and IGF-I in minipig bone marrow aspirates to enhance the chondrogenic processes for cartilage repair.

    Science.gov (United States)

    Frisch, J; Rey-Rico, A; Venkatesan, J K; Schmitt, G; Madry, H; Cucchiarini, M

    2016-03-01

    Administration of therapeutic gene sequences coding for chondrogenic and chondroreparative factors in bone marrow aspirates using the clinically adapted recombinant adeno-associated virus (rAAV) vector may provide convenient, single-step approaches to improve cartilage repair. Here, we tested the ability of distinct rAAV constructs coding for the potent SOX9, transforming growth factor beta (TGF-β) and insulin-like growth factor I (IGF-I) candidate factors to modify marrow aspirates from minipigs to offer a preclinical large animal model system adapted for a translational evaluation of cartilage repair upon transplantation in sites of injury. Our results demonstrate that high, prolonged rAAV gene transfer efficiencies were achieved in the aspirates (up to 100% for at least 21 days) allowing to produce elevated amounts of the transcription factor SOX9 that led to increased levels of matrix synthesis and chondrogenic differentiation and of the growth factors TGF-β and IGF-I that both increased cell proliferation, matrix synthesis and chondrogenic differentiation (although to a lower level than SOX9) compared with control (lacZ) condition. Remarkably, application of the candidate SOX9 vector also led to reduced levels of hypertrophic differentiation in the aspirates, possibly by modulating the β-catenin, Indian hedgehog and PTHrP pathways. The present findings show the benefits of modifying minipig marrow concentrates via rAAV gene transfer as a future means to develop practical strategies to promote cartilage repair in a large animal model.

  19. High-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model

    Science.gov (United States)

    2016-01-01

    Rheumatoid arthritis, a synthesized form of adjuvant arthritis exhibited throughout many animal species, inhibits liver function and circulation of IGF-I and contributes to the degradation of skeletal muscle mass. One of the primary goals of the present study is determining whether a high-Methionine (high-Met) diet is capable of reducing the adverse effects of arthritis, namely, loss of body mass. Following adjuvant injection, forty arthritic rats were randomly assigned to either a control group with a basal diet or a high-Met group with the same basal diet + 0.5% Methionine. After 14 days all rats were terminated. The high-Met group exhibited an increase in body weight and food intake in comparison with the control group (P < 0.05). High-Met diet debilitated arthritis-induced surges in the gastrocnemius in both atrogin-1 and the MuRF1 expressions; however, it was observed to have little to no effect on atrogin-1 and MuRF1 gene expression in soleus. At the same time, high-Met diet rats experienced a rise in IGF-I, with lowering of IGFBP-3 gene expression in the gastrocnemius and the soleus. These data suggest that arthritis severity can be partly attenuated by high-Met diet. PMID:27738392

  20. Growth hormone (GH) secretory dynamics in a case of acromegalic gigantism associated with hyperprolactinemia: nonpulsatile secretion of GH may induce elevated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels.

    Science.gov (United States)

    Yoshida, T; Shimatsu, A; Sakane, N; Hizuka, N; Horikawa, R; Tanaka, T

    1996-01-01

    We describe a case of pituitary gigantism with low levels of growth hormone (GH), elevated insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 (IGF-BP-3). The patient had characteristic clinical features of gigantism and acromegaly. The basal serum GH levels ranged from 1.2-1.9 micrograms/L, which were considered to be within normal limits. Serum GH response to either insulin-induced hypoglycemia or GH-releasing hormone was blunted. Frequent blood samplings during daytime and at night showed nonpulsatile GH secretion. Serum prolactin, IGF-I and IGF-binding protein-3 levels were elevated. After unsuccessful surgery, bromocryptine treatment normalized serum prolactin without affecting serum GH and IGF-I levels. Combined administration of octreotide and bromocryptine reduced serum GH and IGF-I levels. GH bioactivity as measured by Nb2 cell proliferation assay was within reference range. In the present case, nonpulsatile GH secretion and enhanced tissue sensitivity to GH may induce hypersecretion of IGF-I and IGF-BP-3 and cause clinical acromegalic gigantism.

  1. Low serum levels of free and total insulin-like growth factor I (IGF-I) in patients with anorexia nervosa are not associated with increased IGF-binding protein-3 proteolysis.

    Science.gov (United States)

    Støving, R K; Flyvbjerg, A; Frystyk, J; Fisker, S; Hangaard, J; Hansen-Nord, M; Hagen, C

    1999-04-01

    Patients with anorexia nervosa (AN) are GH resistant, with elevated GH levels and low serum levels of total insulin-like growth factor I (IGF-I). IGF-I action is modulated by IGF-binding proteins (IGFBPs), and a variety of catabolic states has been characterized by the presence of increased IGFBP-3 proteolysis. The present study was performed to examine the levels of free IGFs in AN and to clarify whether AN is associated with increased IGFBP-3 proteolytic activity. In 24 patients and 10 age-matched controls, the fasting serum concentrations of free IGF-I and -II were measured using ultrafiltration by centrifugation. In addition, GH, GH-binding protein, total IGFs, IGFBP-1 to -4, and IGFBP-3 proteolytic activity were measured. The IGFBPs were measured by both immunoassays and Western ligand blotting. Twelve of the patients were restudied 3 months after a minor increase in body mass index. In AN, the levels of GH-binding protein, free and total IGF-I, free IGF-II, and IGFBP-3 were significantly reduced; total IGF-II, IGFBP-2, and IGFBP-4 levels were unchanged; and IGFBP-1 was increased. No increased IGFBP-3 proteolytic activity could be detected in AN. In conclusion, the mechanisms responsible for the adaption of the GH-IGF-IGFBP axis in AN may be different from other catabolic conditions, because the low levels of free and total IGF-I in AN are not associated with increased IGFBP-3 proteolysis.

  2. Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke.

    Science.gov (United States)

    Font, M Angels; Arboix, Adriá; Krupinski, Jerzy

    2010-08-01

    Only very little is know about the neurovascular niche after cardioembolic stroke. Three processes implicated in neurorepair: angiogenesis, neurogenesis and synaptic plasticity, would be naturally produced in adult brains, but also could be stimulated through endogen neurorepair phenomena. Angiogenesis stimulation generates new vessels with the aim to increase collateral circulation. Neurogenesis is controlled by intrinsic genetic mechanisms and growth factors but also ambiental factors are important. The leading process of the migrating neural progenitor cells (NPCs) is closely associated with blood vessels, suggesting that this interaction provides directional guidance to the NPCs. These findings suggest that blood vessels play an important role as a scaffold for NPCs migration toward the damaged brain region. DNA microarray technology and blood genomic profiling in human stroke provided tools to investigate the expression of thousands of genes. Critical comparison of gene expression profiles after stroke in humans with those in animal models should lead to a better understanding of the pathophysiology of brain ischaemia. Probably the most important part of early recovery after stroke is limited capacity of penumbra/infarct neurones to recover. It became more clear in the last years, that penumbra is not just passively dying over time but it is also actively recovering. This initial plasticity in majority contributes towards later neurogenesis, angiogenesis and final recovery. Penumbra is a principal target in acute phase of stroke. Thus, the origin of newly formed vessels and the pathogenic role of neovascularization and neurogenesis are important unresolved issues in our understanding of the mechanisms after stroke. Biomaterials for promoting brain protection, repair and regeneration are new hot target. Recently developed biomaterials can enable and increase the target delivery of drugs or therapeutic proteins to the brain, allow cell or tissue transplants to

  3. 营养肾病和糖皮质激素对大鼠肝肾组织 IGF-I/IGFBPs mRNA表达的影响%Effects of Nutrition, Nephrosis and Glucocorticoid on IGF-I and IGFBPs mRNA Expressions in the Rat Liver and Kidney

    Institute of Scientific and Technical Information of China (English)

    刘建华; 易著文

    2001-01-01

    目的探讨营养不良、肾病本身和糖皮质激素作为各自独立因素对大鼠肝肾组织胰岛素样生长因子I/胰岛素样生长因子结合蛋白(IGF-I/IGFBPs) mRNA表达和血清浓度的影响。方法 24只周龄相同体重相近的雄性SD大鼠被随机分成正常对照、食物对照、阿霉素肾病和地塞米松治疗肾病4组。血清IGF-I/IGFBPs和肝肾组织IGF-I/IGFBPs mRNA表达分别采用RIA,Western ligand blot和RT-PCR法检测。结果①营养不良大鼠血清IGF-I减低,肝肾组织IGF-I mRNA表达增高;肾病本身对血清IGF-I,肝脏IGF-IA mRNA表达无影响,肾脏表达减低;激素治疗使血清IGF-I,肝肾组织IGF-IA mRNA表达均下降。②营养不良大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达减低,肾脏表达正常;肾病本身使大鼠血清IGFBP-2,肝脏IGFBP-2 mRNA表达增高,肾脏表达减低;激素治疗使肝肾组织IGFBP-2 mRNA表达均下降,但对血清浓度无影响。③营养不良大鼠血清IGFBP-3减低,肝脏IGFBP-3 mRNA表达正常;肾病本身使血清IGFBP-3,肝脏IGFBP-3 mRNA表达均下降;激素治疗使血清IGFBP-3增高,但肝脏IGFBP-3 mRNA表达下降。肾脏IGFBP-3 mRNA表达仅在激素治疗组大鼠能检测到。结论营养、肾病和糖皮质激素对大鼠肝肾组织IGF-I/IGFBPs mRNA表达的调节具有器官特异性;除血清IGF-I减低部分源于肾脏合成下降外,血清IGFBPs紊乱主要与肝脏合成有关;肾病时IGFBPs可能在不同的水平对IGF-I生物效应发挥调节作用。%Objective To investigate the effects of malnutrition, nephrosis itself and glucocorticoid therapy on IGF-I/IGFBPs mRNA expressions in the rat liver and kidney, and serum peptides. Methods Twenty-four male Sprague-Dawley (SD) rats were randomly grouped into control, pair-fed, doxorubincin-induced nephrotic and dexamethasone-treated nephrotic rats. IGF-I/IGFBPs mRNA in the rat liver and kidney, and serum peptides were

  4. Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3.

    Science.gov (United States)

    2005-01-01

    Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate

  5. Initial neurogenesis in Drosophila

    OpenAIRE

    Hartenstein, Volker; Wodarz, Andreas

    2013-01-01

    Early neurogenesis comprises the phase of nervous system development during which neural progenitor cells are born. In early development, the embryonic ectoderm is subdivided by a conserved signaling mechanism into two main domains, the epidermal ectoderm and the neurectoderm. Subsequently, cells of the neurectoderm are internalized and form a cell layer of proliferating neural progenitors. In vertebrates, the entire neurectoderm folds into the embryo to give rise to the neural tube. In Droso...

  6. NEUROGENESIS, INFLAMMATION AND BEHAVIOR

    OpenAIRE

    Kohman, Rachel A.; Rhodes, Justin S.

    2012-01-01

    Before the 1990s it was widely believed that the adult brain was incapable of regenerating neurons. However, it is now established that new neurons are continuously produced in the dentate gyrus of the hippocampus and olfactory bulb throughout life. The functional significance of adult neurogenesis is still unclear, but it is widely believed that the new neurons contribute to learning and memory and/or maintenance of brain regions by replacing dead or dying cells. Many different factors are k...

  7. Acromegalia: comparación de los niveles séricos de IGF-I por dos inmunoensayos y su correlación con la prueba de tolerancia oral a la glucosa Acromegaly: Comparison of serum IGF-1 levels measured by two immunoassays and their correlation with the Oral Glucose Tolerance Test

    Directory of Open Access Journals (Sweden)

    L. Boero

    2010-12-01

    Full Text Available Introducción: La determinación de IGF-I en suero o plasma es una herramienta esencial en el diagnóstico y seguimiento de la acromegalia. Sin embargo, se deben tener presentes algunos inconvenientes en su medición por diferentes inmunoensayos. Objetivos: Evaluar dos inmunoensayos para la determinación de IGF-I y su correlación con el nadir de GH en el TTOG en pacientes acromegalicos. Materiales y métodos: Se analizaron 37 pacientes acromegálicos, 20 mujeres y 17 hombres. IGF-I fue determinada por Immulite 1000, (IMM y por IRMA (DSL. Se realizó el TTOG y se determinó glucosa y GH en todos los tiempos (basal, 30, 60, 90 y 120min. Se consideró respuesta normal un nadir de GH 1ng/ml se encontró en el 70%, con nadir de GH normal en el 13,5%. IGF-I normal con nadir >1ng/ml en el 2,7% y con nadir de GH normal en el 13,5%. El área bajo las curvas ROC no mostró diferencias significativas. Conclusiones: Los niveles de IGF-I determinados por IMM y DSL fueron significativamente diferentes mostrando un bias negativo para IMM. La mayoría de los valores del nadir de GH fueron consistentes con los niveles de IGF-I observándose una discrepancia en el 30% de los pacientes, estuvieran o no bajo tratamiento.Introduction: IGF-I determination in serum or plasma is an essential tool in the diagnosis and follow-up of acromegaly. Hepatic production of IGF-I is regulated by GH and circulates bound to several IGF-I binding proteins which extends its half life. IGF-I is not released in a pulsatile pattern and has no significant variability in 24 h. Objective: To evaluate two different methodologies in IGF-I levels determination and their correlation with GH nadir in OGTT in acromegalic patients. Material and methods: We analyzed 37 acromegalic patients, 20 women and 17 men, mean age was 45±12 years. IGF-I levels were assayed by Immulite 1000, DPC (IMM and DSL-5600 ACTIVE® IGF-I Coated-Tube IRMA (DSL and OGTTs (at baseline and at 30, 60, 90 and 120 minutes

  8. Insulin-like growth factor I stimulates erythropoiesis in hypophysectomized rats

    Energy Technology Data Exchange (ETDEWEB)

    Kurtz, A.; Zapf, J.; Eckardt, K.U.; Clemons, G.; Froesch, E.R.; Bauer, C. (Universitaet Zurich (Switzerland))

    1988-10-01

    Stimulation of erythropoiesis during growth is necessary to ensure proportionality between erythrocyte mass and body mass. However, the way by which erythrocyte formation is adapted to body growth is still unknown. Growth arrest in hypophysectomized rats is accompanied by decreased erythropoiesis. The authors have, therefore, examined whether insulin-like growth factor I (IGF-I), the mediator of growth hormone effects on body growth, is able to restore erythropoiesis in these animals. Subcutaneous infusions of 120 {mu}g of recombinant human IGF-I per day in hypophysectomized rats led to increases in body weight, {sup 59}Fe incorporation into erythrocytes, and the number of reticulocytes that were similar to increases caused by infusions of 28 milliunits of human growth hormone per day. Body weight gain and {sup 59}Fe incorporation were linearly correlated. Like growth hormone, IGF-I also caused a significant rise in serum erythropoietin concentrations. However, the stimulatory effect on erythropoiesis occurred before serum erythropoietin levels had risen. These results demonstrate that IGF-I mediates the stimulatory effect of growth hormone on erythropoiesis in vivo and thus further support the somatomedin concept. They also show that IGF-I can stimulate erythropoiesis in an endocrine manner, and they suggest two possible routes of action: a direct one and an indirect one by means of enhanced erythropoietin production.

  9. “Associations of Serum Insulin-like Growth Factor (IGF-I) and IGFBP-3 Levels Biomarker-Calibrated Protein, Dairy, and Milk Intake in the Women's Health Initiative”1

    Science.gov (United States)

    Beasley, Jeannette M.; Gunter, Marc J.; LaCroix, Andrea Z.; Prentice, Ross L.; Neuhouser, Marian L.; Tinker, Lesley F.; Vitolins, Mara Z.; Strickler, Howard D.

    2014-01-01

    It is well-established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF-I) levels, and supplementation of 30 grams of whey protein daily increased serum IGF-1 levels by 8% after 2 years in a clinical trial(1). Cohort studies provide the opportunity to assess associations between dietary protein intake and the IGF-axis under more typical eating conditions. We studied the associations of circulating IGF-axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as dairy and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n=747). Analyses were conducted using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy, alcohol, smoking, physical activity, and hormone therapy use. There was a positive association between milk intake and free-IGF-1. A 3 serving increase in milk intake per day (~30 grams of protein) was associated with an estimated average 18.6% higher increase in free IGF-1 (95% CI 0.9% to 39.3%). Total IGF-I and IGFBP-3, however, were not associated with milk consumption, nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy, and free IGF-I, total IGF-I, or IGFBP-3. This study of postmenopausal women is consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels; albeit, in our dataset, this association was only statistically significant for free, but not total, IGF-I nor IGFBP-3. PMID:24094144

  10. High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age.

    OpenAIRE

    Dijk, M. van; Mulder, P.; Houdijk, M.; Mulder, J.; Noordam, K.; Odink, R.J.; Rongen-Westerlaken, C; P. Voorhoeve; Waelkens, J; Stokvis-Brantsma, J.; Hokken-Koelega, A C

    2006-01-01

    CONTEXT: Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. OBJECTIVE: The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. PATIENTS: Thirty-six prepubertal short SGA children were the subjects of this study. Intervention: Subjects received 1 (group A) ...

  11. Efeitos do treinamento físico no IGF-I hepático em ratos diabéticos experimentais

    OpenAIRE

    Leme, José Alexandre Curiacos de Almeida [UNESP

    2007-01-01

    Para investigar os efeitos do treinamento físico aeróbio nas concentrações de IGF-I em ratos diabéticos, ratos wistar foram distribuídos em quatro grupos: controle sedentário, controle treinado, diabético sedentário e diabético treinado. O diabetes foi induzido por aloxana (32 mg/kg) e o protocolo de treinamento consistiu de natação 1 hora/dia, 5 dias/semana, durante 8 semanas e suportando 5% do peso corporal. Durante o período experimental foram registrados semanalmente o peso, ingestão de á...

  12. Use of the ligand immunofunctional assay for human insulin-like growth factor ((IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and igf-i bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics.

    Science.gov (United States)

    Lassarre, C; Duron, F; Binoux, M

    2001-05-01

    The ligand immunofunctional assay for plasma insulin-like growth factor (IGF) binding protein (IGFBP)-3 developed in our laboratory provides for specific measurement of intact, as opposed to proteolyzed, IGFBP-3. IGFBP-bound IGFs are dissociated and separated by acid pH ultrafiltration; thereafter, intact and proteolyzed IGFBP-3 are captured by a monoclonal antibody in a solid-phase assay and incubated with (125)I-IGF-I, which detects the intact protein but not its proteolytic fragments. This assay was combined with assays for IGF-I (RIA of the ultrafiltrate) and total IGFBP-3 (immunoradiometric assay) to quantify the percentage of proteolyzed IGFBP-3 (percent proteolyzed IGFBP-3) and to calculate the IGF-I/intact IGFBP-3 ratio as an index of the fraction of exchangeable IGF-I bound to IGFBP-3. This fraction represents most of the IGF-I that is bioavailable. Because GH and insulin control the hepatic production and plasma concentrations of IGF-I and IGFBP-3, we set out to determine whether variations in the secretion of the two hormones are involved in the regulation of IGFBP-3 proteolysis. The study included adult populations of 36 healthy subjects, 23 hypopituitary patients untreated with GH, 43 acromegalics (13 untreated), 42 insulin-treated type 1 diabetics [insulin-dependent diabetes mellitus (IDDM)] patients, and 50 type 2 diabetics [non-IDDM (NIDDM)] patients, 22 of whom were insulin-treated and the remaining 28 treated with sulfonylurea and/or metformin). Unlike IGF-I and (to a lesser extent) total IGFBP-3 levels, which decline with age, percent proteolyzed IGFBP-3 seemed relatively stable. In healthy adults, the mean +/- SEM was 29.4 +/- 1.9 for subjects less than 45 yr old and was slightly (but not significantly) lower, 25.7 +/- 3, for those of more than 45 yr. There was no difference between male and female subjects. In GH-deficient patients, despite severely depressed IGF-I levels, percent proteolyzed IGFBP-3 and IGF-I/intact IGFBP-3 ratios were within

  13. Association between insulin-like growth factor I (IGF-I microsatellite polymorphisms and important economic traits in pigs Associação entre polimorfismos no marcador microssatélite do gene do fator de crescimento semelhante à insulina I (IGF-I com características de interesse econômico em suínos

    Directory of Open Access Journals (Sweden)

    Danielle Assis de Faria

    2009-02-01

    Full Text Available This study investigated the association between IGF-I microsatellite marker in an F2 population (N=459 generated by mating of native boars to Brazilian commercial sows with performance, carcass cut, and meat quality traits. Association analyses were carried out using a statistical model that included genotype, sex, and group as fixed effects and sire as random effect. The IGF-I genotypes were significantly associated with different quantitative traits and these results corroborate with previous QTL analyses obtained for this chromosome region in swine. Additive and dominance effects, as well as a genotype-sex interaction, were estimated and discussed in the text. According to the results obtained, this marker is suitable for QTL search in the genotyped population.Investigou-se neste trabalho a associação entre o marcador microssatélite IGF-I em uma população F2 (N=459 gerada pelo acasalamento entre suínos nativos brasileiros e fêmeas comerciais com características de desempenho, cortes de carcaça e qualidade da carne. A análise de associação foi feita por meio de um modelo que incluiu genótipo, sexo e grupo como efeitos fixos e pais como efeito aleatório. Os genótipos do IGF-I apresentaram associação significativa com nove características quantitativas, resultados que corroboram análises prévias de QTL obtidas para essa região cromossômica em suínos. Efeitos aditivos de dominância, assim como a interação genótipo × sexo, foram estimados e estão descritos neste trabalho. De acordo com os resultados obtidos, este marcador será útil nas análises de QTL na população analisada.

  14. Adult hippocampal neurogenesis and cognitive aging

    Directory of Open Access Journals (Sweden)

    Román Darío Moreno Fernández

    2013-12-01

    Full Text Available Aging is a normal developmental process associated with neurobiological changes leading to cognitive alterations with preserved, impaired, and enhanced functions. Evidence from animal and human studies is reviewed to explore the potential role of hippocampal plasticity on age-related cognitive changes with special attention to adult hippocampal neurogenesis. Results from lesion and stimulation strategies, as well as correlation data, support either a direct or modulatory role for adult newborn neurons in cognition at advanced ages. Further research on this topic may help to develop new treatments and to improve the quality of life of older people.

  15. Growth hormone (GH) provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF-I) and IGF-binding protein-3

    DEFF Research Database (Denmark)

    Juul, A; Kastrup, K W; Pedersen, S A

    1997-01-01

    .e. 45% of patients treated with GH during childhood because of isolated GHD had a normal GH response when retested in adulthood. Multiple regression analysis revealed that peak GH levels were dependent on the degree of hypopituitarism, body mass index, and duration of disease. IGF-I levels were below -2...

  16. 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

    DEFF Research Database (Denmark)

    Møller, S; Juul, A; Becker, U

    1995-01-01

    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...

  17. Low serum levels of free and total insulin-like growth factor I (IGF-I) in patients with anorexia nervosa are not associated with increased IGF-binding protein-3 proteolysis

    DEFF Research Database (Denmark)

    Støving, R K; Flyvbjerg, A; Frystyk, J

    1999-01-01

    of GH-binding protein, free and total IGF-I, free IGF-II, and IGFBP-3 were significantly reduced; total IGF-II, IGFBP-2, and IGFBP-4 levels were unchanged; and IGFBP-1 was increased. No increased IGFBP-3 proteolytic activity could be detected in AN. In conclusion, the mechanisms responsible...

  18. Growth hormone (GH) provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF-I) and IGF-binding protein-3

    DEFF Research Database (Denmark)

    Juul, A; Kastrup, K W; Pedersen, S A;

    1997-01-01

    Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect the endogenous GH secretion in healthy children and exhibit little diurnal variation, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although so...

  19. C-peptide, IGF-I, sex-steroid hormones and adiposity : a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

    NARCIS (Netherlands)

    Bezemer, ID; Rinaldi, S; Dossus, L; van Gils, CH; Peeters, PHM; Noord, PAH; Bueno-de-Mesquita, HB; Johnsen, SP; Overvad, K; Olsen, A; Tjonneland, A; Boeing, H; Lahmann, PH; Linseisen, J; Nagel, G; Allen, N; Roddam, A; Bingham, S; Khaw, KT; Kesse, E; Tehard, B; Clavel-Chapelon, F; Agudo, A; Ardanaz, E; Quiros, [No Value; Amiano, P; Martinez-Garcia, C; Tormo, MJ; Pala, [No Value; Panico, S; Vineis, P; Palli, D; Tumino, R; Trichopoulou, A; Baibas, N; Zilis, D; Hemon, B; Norat, T; Riboli, E; Kaaks, R

    2005-01-01

    Objectives: The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the Europe

  20. Neuropeptide y promotes neurogenesis in murine subventricular zone

    DEFF Research Database (Denmark)

    Agasse, Fabienne; Bernardino, Liliana; Christiansen, Søren H

    2008-01-01

    Stem cells of the subventricular zone (SVZ) represent a reliable source of neurons for cell replacement. Neuropeptide Y (NPY) promotes neurogenesis in the hippocampal subgranular layer and the olfactory epithelium and may be useful for the stimulation of SVZ dynamic in brain repair purposes. We...... describe that NPY promotes SVZ neurogenesis. NPY (1 microM) treatments increased proliferation at 48 hours and neuronal differentiation at 7 days in SVZ cell cultures. NPY proneurogenic properties are mediated via the Y1 receptor. Accordingly, Y1 receptor is a major active NPY receptor in the mouse SVZ......-Jun-NH(2)-terminal kinase signal in growing axons, consistent with axonogenesis. NPY, as a promoter of SVZ neurogenesis, is a crucial factor for future development of cell-based brain therapy. Disclosure of potential conflicts of interest is found at the end of this article....

  1. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Science.gov (United States)

    Khodanovich, M. Yu.

    2015-11-01

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  2. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Energy Technology Data Exchange (ETDEWEB)

    Khodanovich, M. Yu., E-mail: khodanovich@mail.tsu.ru [Tomsk State University, Research Institute of Biology and Biophysics, Laboratory of Neurobiology (Russian Federation)

    2015-11-17

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  3. Adult Neurogenesis in Fish.

    Science.gov (United States)

    Ganz, Julia; Brand, Michael

    2016-07-01

    Teleost fish have a remarkable neurogenic and regenerative capacity in the adult throughout the rostrocaudal axis of the brain. The distribution of proliferation zones shows a remarkable conservation, even in distantly related teleost species, suggesting a common teleost ground plan of proliferation zones. There are different progenitor populations in the neurogenic niches-progenitors positive for radial glial markers (dorsal telencephalon, hypothalamus) and progenitors with neuroepithelial-like characteristics (ventral telencephalon, optic tectum, cerebellum). Definition of these progenitors has allowed studying their role in normal growth of the adult brain, but also when challenged following a lesion. From these studies, important roles have emerged for intrinsic mechanisms and extrinsic signals controlling the activation of adult neurogenesis that enable regeneration of the adult brain to occur, opening up new perspectives on rekindling regeneration also in the context of the mammalian brain.

  4. Effects of Dietary Corn Gluten Meal on Growth Performance and Protein Metabolism in Relation to IGF-I and TOR Gene Expression of Juvenile Cobia (Rachycentron canadum)

    Institute of Scientific and Technical Information of China (English)

    LUO Yiwen; AI Qinghui; MAI Kangsen; ZHANG Wenbing; XU Wei; ZHANG Yanjiao; LIUFU Zhiguo

    2013-01-01

    A growth experiment was conducted on cobia (Rachycentron canadum,initial weight 108.2g±3.0g) to investigate the effects of dietary com gluten meal (CGM) levels on the fish growth,whole body composition and protein metabolism in relation to specific gene expression.Five isonitrogenous (crude protein 45%) and isoenergetic (gross energy 20kJg-1) practical diets were formulated by replacing 0% (the control),17.5%,35.0%,52.5%,and 70.0% of fish meal (FM) protein with CGM protein.No significant differences were observed in the survival,feed intake (FI),specific growth rate (SGR),feed efficiency (FE) and protein productive value (PPV) among fish fed diets with 0%,17.5%,35.0%,and 52.5% of CGM protein.However,these indices were significantly lower in fish fed the diet with 70.0% of CGM protein than those in fish fed the control diet (P<0.05).The whole-body crude protein and lipid contents were significantly lower while the whole-body moisture content was significantly higher in fish fed the diet with 70.0% of CGM protein compared with the control group (P< 0.05).When 70.0% of FM protein was replaced by CGM,plasma total protein and cholesterol contents were significantly lower than those in the control group (P<0.05).Fish fed the diet with 70.0% of CGM protein had significantly lower hepatic insulin-like growth factor I (IGF-I) expression levels than those in the control group (P < 0.05).However,no significant differences were observed in hepatic target of rapamycin (TOR),dorsal muscle IGF-I and TOR expression levels among dietary treatments.Results of the present study indicated that 52.5% of FM protein could be replaced by CGM in the diets without significant influences on the growth,feed utilization and protein metabolism of juvenile cobia.The present results might be useful for developing cost effective and sustainable cobia dietary formulations.

  5. Effects of dietary corn gluten meal on growth performance and protein metabolism in relation to IGF-I and TOR gene expression of juvenile cobia ( Rachycentron canadum)

    Science.gov (United States)

    Luo, Yiwen; Ai, Qinghui; Mai, Kangsen; Zhang, Wenbing; Xu, Wei; Zhang, Yanjiao; Liufu, Zhiguo

    2013-09-01

    A growth experiment was conducted on cobia ( Rachycentron canadum, initial weight 108.2 g ± 3.0 g) to investigate the effects of dietary corn gluten meal (CGM) levels on the fish growth, whole body composition and protein metabolism in relation to specific gene expression. Five isonitrogenous (crude protein 45%) and isoenergetic (gross energy 20 kJ g-1) practical diets were formulated by replacing 0% (the control), 17.5%, 35.0%, 52.5%, and 70.0% of fish meal (FM) protein with CGM protein. No significant differences were observed in the survival, feed intake (FI), specific growth rate (SGR), feed efficiency (FE) and protein productive value (PPV) among fish fed diets with 0%, 17.5%, 35.0%, and 52.5% of CGM protein. However, these indices were significantly lower in fish fed the diet with 70.0% of CGM protein than those in fish fed the control diet ( P < 0.05). The whole-body crude protein and lipid contents were significantly lower while the whole-body moisture content was significantly higher in fish fed the diet with 70.0% of CGM protein compared with the control group ( P < 0.05). When 70.0% of FM protein was replaced by CGM, plasma total protein and cholesterol contents were significantly lower than those in the control group ( P < 0.05). Fish fed the diet with 70.0% of CGM protein had significantly lower hepatic insulin-like growth factor I (IGF-I) expression levels than those in the control group ( P < 0.05). However, no significant differences were observed in hepatic target of rapamycin (TOR), dorsal muscle IGF-I and TOR expression levels among dietary treatments. Results of the present study indicated that 52.5% of FM protein could be replaced by CGM in the diets without significant influences on the growth, feed utilization and protein metabolism of juvenile cobia. The present results might be useful for developing cost effective and sustainable cobia dietary formulations.

  6. Insulin, IGF-I, and muscle MAPK pathway responses after sustained exercise and their contribution to growth and lipid metabolism regulation in gilthead sea bream.

    Science.gov (United States)

    Sánchez-Gurmaches, J; Cruz-Garcia, L; Ibarz, A; Fernández-Borrás, J; Blasco, J; Gutiérrez, J; Navarro, I

    2013-10-01

    Herein, we studied whether sustained exercise positively affects growth of gilthead sea bream by alterations in a) plasma concentrations of insulin and IGF-I, b) signaling pathways in muscle, or c) regulation of lipid metabolism. Specifically, we evaluated the effects of moderated swimming (1.5 body lengths per second; BL/s) on the circulating concentrations of insulin and IGF-I, morphometric parameters, and expression of genes related to lipid metabolism in gilthead sea bream (80-90 g BW). Exercise increased the specific growth rate (P growth and metabolic homeostasis during swimming. The observed decrease in plasma insulin concentrations (P = 0.016) could favor the mobilization of tissue reserves in exercised fish. In this sense, the increase in liver fatty acid content (P = 0.041) and the changes in expression of peroxisome proliferator-activated receptors PPARα (P = 0.017) and PPARγ (P = 0.033) indicated a hepatic lipid mobilization. Concentration of glycogen in both white and red muscles was decreased (P = 0.021 and P = 0.017, respectively) in exercised (n = 12) relative to control (n = 12) gilthead sea bream, whereas concentrations of glucose (P = 0.016) and lactate (P = 0.0007) were decreased only in red muscle, indicating the use of these substrates. No changes in the glucose transporter and in lipoprotein lipase mRNA expression were found in any of the tissues studied. Exercised sea bream had decreased content of PPARβ mRNA in white and red muscle relative to control sea bream expression (P = 0.001 and P = 0.049, respectively). Mitogen-activated protein kinase phosphorylation was significantly down-regulated in both white and red muscles of exercised sea bream (P = 0.0374 and P = 0.0371, respectively). Tumor necrosis factor-α expression of white muscle was down-regulated in exercised gilthead sea bream (P = 0.045). Collectively, these results contribute to the knowledge base about hormonal regulation of growth and lipid metabolism in exercised gilthead

  7. Neurogenesis in the aging brain

    National Research Council Canada - National Science Library

    Jin, Kunlin

    2008-01-01

    ...: Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain...

  8. Neurogenesis in the aging brain

    National Research Council Canada - National Science Library

    Galvan, Veronica; Jin, Kunlin

    2007-01-01

    Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain...

  9. Lack of stimulation of 24-hour growth hormone release by hypocaloric diet in obesity

    DEFF Research Database (Denmark)

    Rasmussen, M H; Juul, A; Kjems, L L

    1995-01-01

    . This suggests a reversible defect in GH release, rather than a persistent preexisting disorder. It is hypothesized that enhanced bioavailability of IGF-I, acting in concert with elevated proinsulin and insulin levels, may account for the lack of stimulation of 24-hr GH release by the hypocaloric diet in obese...... and perpetuate the obese state....

  10. Oestrogen requires the insulin-like growth factor-I receptor for stimulation of prolactin synthesis via mitogen-activated protein kinase.

    Science.gov (United States)

    Arroba, A I; Frago, L M; Argente, J; Chowen, J A

    2005-02-01

    Sex steroids and growth factors interact at the intracellular level in a variety of tissues to control numerous physiological functions. Oestrogen is known to stimulate prolactin synthesis and secretion, but the effect of insulin-like growth factor (IGF)-I is less clear. We used GH3 cells, a somatolactotroph cell line, to study the interaction of 17beta-oestradiol (E(2)) and IGF-I on prolactin protein levels and the intracellular mechanisms involved. Cell cultures were treated with E(2) (10 nM) and/or IGF-I (10 ng/ml) for 8 h. The real-time reverse transcriptase-polymerase chain reaction, Western blot and enzyme-immunoassay were used to determine changes in prolactin mRNA and protein levels. At this time-point, there were no significant changes in cell number, prolactin mRNA expression, or the amount of secreted prolactin. However, E(2) increased intracellular prolactin concentrations. IGF-I alone had no effect, but blocked the stimulatory effect of E(2). MAPK (ERK1/2) activation, as determined by Western blot analysis, increased with both E(2) and IGF-I, but not with the combination of these factors. The MAPK inhibitor PD98059 blocked the ability of E(2) to increase intracellular prolactin concentrations. Similarly, the IGF-I receptor antagonist, JB1, blocked the effect of E(2) on prolactin synthesis and MAPK activation, as did the oestrogen receptor antagonist ICI182 780. These results suggest that, to stimulate prolactin synthesis, E(2) activates the MAPK cascade and that this requires the presence of both oestrogen and IGF-I receptors.

  11. Salinity and temperature variations reflecting on cellular PCNA, IGF-I and II expressions, body growth and muscle cellularity of a freshwater fish larvae.

    Science.gov (United States)

    Martins, Y S; Melo, R M C; Campos-Junior, P H A; Santos, J C E; Luz, R K; Rizzo, E; Bazzoli, N

    2014-06-01

    The present study assessed the influence of salinity and temperature on body growth and on muscle cellularity of Lophiosilurus alexaxdri vitelinic larvae. Slightly salted environments negatively influenced body growth of freshwater fish larvae and we observed that those conditions notably act as an environmental influencer on muscle growth and on local expression of hypertrophia and hypeplasia markers (IGFs and PCNA). Furthermore, we could see that salinity tolerance for NaCl 4gl(-)(1) diminishes with increasing temperature, evidenced by variation in body and muscle growth, and by irregular morphology of the lateral skeletal muscle of larvae. We saw that an increase of both PCNA and autocrine IGF-II are correlated to an increase in fibre numbers and fibre diameter as the temperature increases and salinity diminishes. On the other hand, autocrine IGF-I follows the opposite way to the other biological parameters assessed, increasing as salinity increases and temperature diminishes, showing that this protein did not participate in muscle cellularity, but participating in molecular/cellular repair. Therefore, slightly salted environments may provide adverse conditions that cause some obstacles to somatic growth of this species, suggesting some osmotic expenditure with a salinity increment. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis

    DEFF Research Database (Denmark)

    Doessing, Simon; Heinemeier, Katja; Holm, Lars;

    2010-01-01

    young individuals. rhGH administration caused an increase in serum GH, serum IGF-I, and IGF-I mRNA expression in tendon and muscle. Tendon collagen I mRNA expression and tendon collagen protein synthesis increased by 3.9-fold and 1.3-fold, respectively (P ...RNA expression and muscle collagen protein synthesis increased by 2.3-fold and 5.8-fold, respectively (P protein synthesis was unaffected by elevation of GH and IGF-I. Moderate exercise did not enhance the effects of GH manipulation. Thus, increased GH availability stimulates...... matrix collagen synthesis in skeletal muscle and tendon, but without any effect upon myofibrillar protein synthesis. The results suggest that GH is more important in strengthening the matrix tissue than for muscle cell hypertrophy in adult human musculotendinous tissue....

  13. Neurogenesis in the aging brain

    Directory of Open Access Journals (Sweden)

    Veronica Galvan

    2008-01-01

    Full Text Available Veronica Galvan, Kunlin JinBuck Institute for Age Research, 8001 Redwood Blvd. Novato, CA, USAAbstract: Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain the functional stability of adult brain circuitry. However, recent studies have demonstrated that neurogenesis does indeed continue into and throughout adult life in discrete regions of the central nervous systems (CNS of all mammals, including humans. Although neurogenesis may contribute to the ability of the adult brain to function normally and be induced in response to cerebral diseases for self-repair, this nevertheless declines with advancing age. Understanding the basic biology of neural stem cells and the molecular and cellular regulation mechanisms of neurogenesis in young and aged brain will allow us to modulate cell replacement processes in the adult brain for the maintenance of healthy brain tissues and for repair of disease states in the elderly.Keywords: neurogenesis, aging, brain, neural stem cells, subgranular zone, subventricular zone

  14. Acromegalia: comparación de los niveles séricos de IGF-I por dos inmunoensayos y su correlación con la prueba de tolerancia oral a la glucosa Acromegaly: Comparison of serum IGF-1 levels measured by two immunoassays and their correlation with the Oral Glucose Tolerance Test

    OpenAIRE

    L. Boero; M S. Mallea Gil; M. Manavela; G. Stalldecker; K. Danilowicz; Guitelman, M.; Alfieri, A.; M.C. Ballarino; A. Chervin; N. García Basavilbaso; M. Glerean; M.G. Loto; J.A. Nahmías; A.S. Rogozinski; M. Servidio

    2010-01-01

    Introducción: La determinación de IGF-I en suero o plasma es una herramienta esencial en el diagnóstico y seguimiento de la acromegalia. Sin embargo, se deben tener presentes algunos inconvenientes en su medición por diferentes inmunoensayos. Objetivos: Evaluar dos inmunoensayos para la determinación de IGF-I y su correlación con el nadir de GH en el TTOG en pacientes acromegalicos. Materiales y métodos: Se analizaron 37 pacientes acromegálicos, 20 mujeres y 17 hombres. IGF-I fue determinada ...

  15. Impact of exogenous growth hormone on GH/IGF/IGFBP axis in colon cancer-bearing nude mice%生长激素荷人结肠癌裸鼠GH/IGF-I/IGFBP-3轴的影响

    Institute of Scientific and Technical Information of China (English)

    张毅; 梁道明; 李思齐; 袁勇; 赵辉; 陈嘉勇

    2013-01-01

    目的:探讨外源性生长激素(GH)对荷瘤裸鼠GH/胰岛素样生长因子(IGF)/胰岛素样生长因子结合蛋白3(IGFBP-3)轴的影响.方法:采用人结肠癌细胞株(HCT116)建立人结肠癌细胞裸鼠移植瘤模型.取48只荷瘤裸鼠随机均分为生理盐水处理组(NS组)、氟尿嘧啶处理组(FU组)、GH处理组(GH组),FU+GH处理组(FU+GH组).每组连续给药6d,在给药结束后24,72 h分别处死每组6只动物,取血及移植瘤标本,应用ELISA法检测血清GH,IGF-I,IGFBP-3含量和RT-PCR法检测移植瘤IGF-I,IGF-I受体(IGF-IR),IGFBP-3的mRNA表达.结果:ELISA结果显示,给药结束后24 h,GH组和FU+GH组血清GH,IGF-I,IGFBP-3含量较NS组与FU组明显升高(均P<0.05);给药结束后72 h,各组GH,IGF-I的水平无统计学差异(均P>0.05),但GH组和FU+GH组IGFBP-3水平仍高于NS组和FU组(均P<0.05).RT-PCR结果显示,给药结束后24 h,GH,FU,FU+GH组移植瘤组织IGF-I mRNA与IGF-IR mRNA的表达较NS组明显降低,而IGFBP-3 mRNA表达明显增加;给药结束后72 h,IGF-I mRNA与IGF-IR mRNA表达各组间无差别,但GH组,FU组和FU+GH组IGFBP-3 mRNA表达量仍明显高于NS组.结论:短期应用外源性GH所致GH/IGF/IGFBP-3轴的变化对人结肠癌移植瘤生长无促进作用.%Objective: To observe the impact of exogenous growth hormone (GH) on the axis of GH/insulin-like growth factor I (IGF-I)/insulin-like growth factor binding protein (GFBP) in colon cancer-bearing nude mice. Methods: Nude mice xenograft models of human colon cancer were established by using human colon cancer HCT116 cells. Subsequently, 48 tumor-bearing mice were equally randomized into normal saline treatment group (NS group), fluorouracil treatment group (FU group), GH treatment group (GH group) and FU plus GH treatment group (FU+GH group), and all treatment regimens were continued for 6 days. Mice were sacrificed to collect the blood and tumor xenograft samples at 24 and 72 h after the termination of regimens with 6

  16. Computational models of adult neurogenesis

    Science.gov (United States)

    Cecchi, Guillermo A.; Magnasco, Marcelo O.

    2005-10-01

    Experimental results in recent years have shown that adult neurogenesis is a significant phenomenon in the mammalian brain. Little is known, however, about the functional role played by the generation and destruction of neurons in the context of an adult brain. Here, we propose two models where new projection neurons are incorporated. We show that in both models, using incorporation and removal of neurons as a computational tool, it is possible to achieve a higher computational efficiency that in purely static, synapse-learning-driven networks. We also discuss the implication for understanding the role of adult neurogenesis in specific brain areas like the olfactory bulb and the dentate gyrus.

  17. Distribution and levels of [{sup 125}I]IGF-I, [{sup 125}I]IGF-II and [{sup 125}I]insulin receptor binding sites in the hippocampus of aged memory-unimpaired and -impaired rats

    Energy Technology Data Exchange (ETDEWEB)

    Quirion, R.; Rowe, W.; Kar, S.; Dore, S. [Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal (Canada)

    1997-08-11

    The insulin-like growth factors (IGF-I and IGF-II) and insulin are localized within distinct brain regions and their respective functions are mediated by specific membrane receptors. High densities of binding sites for these growth factors are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampal formation. IGFs and insulin, in addition to their growth promoting actions, are considered to play important roles in the development and maintenance of normal cell functions throughout life. We compared the anatomical distribution and levels of IGF and insulin receptors in young (five month) and aged (25 month) memory-impaired and memory-unimpaired male Long-Evans rats as determined in the Morris water maze task in order to determine if alterations in IGF and insulin activity may be related to the emergence of cognitive deficits in the aged memory-impaired rat. In the hippocampus, [{sup 125}I]IGF-I receptors are concentrated primarily in the dentate gyrus (DG) and the CA3 sub-field while high amounts of [{sup 125}I]IGF-II binding sites are localized to the pyramidal cell layer, and the granular cell layer of the DG. [{sup 125}I]insulin binding sites are mostly found in the molecular layer of the DG and the CA1 sub-field. No significant differences were found in [{sup 125}I]IGF-I, [{sup 125}I]IGF-II or [{sup 125}I]insulin binding levels in any regions or laminae of the hippocampus of young vs aged rats, and deficits in cognitive performance did not relate to altered levels of these receptors in aged memory-impaired vs aged memory-unimpaired rats. Other regions, including various cortical areas, were also examined and failed to reveal any significant differences between the three groups studied.It thus appears that IGF-I, IGF-II and insulin receptor sites are not markedly altered during the normal ageing process in the Long-Evans rat, in spite of significant learning deficits in a sub-group (memory-impaired) of

  18. EVALUACION DEL EFECTO MODULADOR DEL FACTOR DE CRECIMIENTO SIMILAR A LA INSULINA TIPO I (IGF-I EN LINFOCITOS T DE BAZO DE RATAS SOMETIDAS A ESTRÉS NUTRICIONAL

    Directory of Open Access Journals (Sweden)

    Francy Forero

    2009-04-01

    Full Text Available En este trabajo se estudió el papel del Factor de Crecimiento Similar a la Insulina Tipo I (IGF-I como factor modulador del estrés inducido por una restricción proteica en la dieta, en linfocitos T de bazo de rata. Se  encontró que la restricción proteica disminuye el peso corporal en un 15%,  el peso del bazo en un 32% y la población total de linfocitos T en un 42%. Igualmente, se observó en la población restringida un incremento en los porcentajes de  las subpoblaciones  T-CD4, T-CD8 y linfocitos B, y una relación T-CD4/T-CD8 disminuida, lo que sugiere una función inmune afectada por la malnutrición. Se encontró que los cultivos de linfocitos  provenientes de bazo de ratas en restricción proteica presentan menor proliferación que los provenientes de ratas bien alimentadas; dicha proliferación se incrementa al adicionar IGF-I de manera dependiente de la dosis. Esta respuesta depende, también, del contenido de proteína en la dieta, observándose una mayor y más pronta respuesta a IGF-I en el grupo bien nutrido. La concanavalina A incrementó, igualmente, la proliferación en ambos grupos de animales, y al combinarla con IGF-I se presentó un sinergismo  en la respuesta. En este trabajo  se encontró, también, que la restricción proteica incrementa la apoptosis de los linfocitos T, y que la adición de IGF-I logra proteger dichas células de la apoptosis soportando el papel inmunomodulador de esta hormona en estrés nutricional. 

  19. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.

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    Anna Fiorentini

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3β and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aβ deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

  20. Novel Control by the CA3 Region of the Hippocampus on Neurogenesis in the Dentate Gyrus of the Adult Rat

    OpenAIRE

    Jian Xin Liu; Pinnock, Scarlett B.; Joe Herbert

    2011-01-01

    The dentate gyrus is a site of continued neurogenesis in the adult brain. The CA3 region of the hippocampus is the major projection area from the dentate gyrus. CA3 sends reciprocal projections back to the dentate gyrus. Does this imply that CA3 exerts some control over neurogenesis? We studied the effects of lesions of CA3 on neurogenesis in the dentate gyrus, and on the ability of fluoxetine to stimulate mitotic activity in the progenitor cells. Unilateral ibotenic-acid generated lesions we...

  1. Taurine increases hippocampal neurogenesis in aging mice

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    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  2. Daily expression patterns for mRNAs of GH, PRL, SL, IGF-I and IGF-II in juvenile rabbitfish, Siganus guttatus, during 24-h light and dark cycles.

    Science.gov (United States)

    Ayson, Felix G; Takemura, Akihiro

    2006-12-01

    Most animals respond to changes in the external environment in a rhythmic fashion. In teleost fishes, daily rhythms are observed in plasma concentrations of some hormones but it is not clear whether these rhythms are exogenous or are entrained by predictable cues. We investigated whether the expression patterns for the mRNAs of growth hormone (GH), prolactin (PRL) and somatolactin (SL) in the pituitary gland, and insulin-like growth factor-I and II (IGF-I and IGF-II) in the liver, follow a daily rhythm when juvenile rabbitfish (Siganus guttatus) are reared under a normal 24-h light and dark cycle (LD), and when they are exposed to either continuous light (LL) or darkness (DD). Hormone mRNA levels were determined by real time PCR. Under LD conditions, GH mRNA expression in the pituitary was significantly lower during the light phase than during the dark phase suggesting a diurnal rhythm of expression. The rhythm disappeared when fish were exposed to LL or DD conditions. PRL mRNA expression pattern was irregular in all 3 conditions. Very low levels of SL mRNA were observed during the mid day under LD conditions. The expression pattern of SL mRNA became irregular under LL and DD conditions. No pattern could be observed in the expression profile of IGF-I and II mRNA in the liver during LD and LL conditions but a single peak in mRNA level was observed under DD conditions in both IGF-I and II. The results indicate that except for GH, the daily expression pattern for the mRNAs of the hormones examined do not seem to follow a rhythm according to light and dark cycles.

  3. A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians†

    Science.gov (United States)

    Schumacher, Fredrick R.; Cheng, Iona; Freedman, Matthew L.; Mucci, Lorelei; Allen, Naomi E.; Pollak, Michael N.; Hayes, Richard B.; Stram, Daniel O.; Canzian, Federico; Henderson, Brian E.; Hunter, David J.; Virtamo, Jarmo; Manjer, Jonas; Gaziano, J. Michael; Kolonel, Laurence N.; Tjønneland, Anne; Albanes, Demetrius; Calle, Eugenia E.; Giovannucci, Edward; Crawford, E. David; Haiman, Christopher A.; Kraft, Peter; Willett, Walter C.; Thun, Michael J.; Le Marchand, Loïc; Kaaks, Rudolf; Feigelson, Heather Spencer; Bueno-de-Mesquita, H. Bas; Palli, Domenico; Riboli, Elio; Lund, Eiliv; Amiano, Pilar; Andriole, Gerald; Dunning, Alison M.; Trichopoulos, Dimitrios; Stampfer, Meir J.; Key, Timothy J.; Ma, Jing

    2010-01-01

    The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj = 8.8 × 10−43) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90–1.14) and 1.20 (99% CI: 1.06–1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 × 10−3. IGF-I levels were significantly associated with PCa risk (Ptrend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians. PMID:20484221

  4. Efectos de un entrenamiento combinado de fuerza de intensidad moderada y aer??bico intenso, sobre la calidad de vida, IGF-I, fuerza y consumo de ox??geno, en mujeres sobrevivientes de c??ncer de mama

    OpenAIRE

    Fern??ndez Ortega, Jairo Alejandro

    2015-01-01

    247 p. El prop??sito del estudio fue determinar los efectos de un programa de ejercicio combinado de fuerza y aer??bico intenso, sobre la calidad de vida (QOL), fatiga, consumo pico de ox??geno, fuerza, e IGF-I, en ocho pacientes sobrevivientes de c??ncer de mama (PSCAM) sometidas a cirug??a, quimioterapia y/o radioterapia y en tratamiento con tamoxifeno. Las pacientes realizaron un programa de entrenamiento de fuerza de intensidad moderada y a??robico intenso, tres veces por semana, duran...

  5. Effect of the dry matter intake level on the sanguine profile of glucose, insulin, urea, estrogen and progesterone and concentration of IGF-I in the follicular liquid of crossbred heifers

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    Luiz Paulo Rigolon

    2009-02-01

    Full Text Available The aim of this work was to study effect of the dry matter intake level on the concentrations of glucose, insulin, urea, estrogen and progesterone in the blood and the level of IGF-I in the follicular liquid of heifers. Twenty seven crossbred heifers were used, in three treatments: 1.2, 1.6 and 2.6% of the live weight of dry matter intake (DMI daily. The sanguine concentrations of glucose and estrogen were higher in the animals with 1.6% of DMI and the insulin levels were higher in the animals with 2.6% of DMI. There was an increase in the sanguine levels of urea with the increase of the DMI. There was no effect of the DMI on the progesterone levels in the sanguine plasma collected from the jugular. The progesterone levels in caudal vena were higher in the animals with 2.6% of DMI. There was no effect of the DMI on the follicular levels of IGF-I.O objetivo deste trabalho foi estudar o efeito do nível de ingestão de matéria seca (IMS/% do PV sobre as concentrações sanguíneas de glicose, insulina, urea, estrógeno e progesterona e o nível de IGF-I no líquido folicular de novilhas. Vinte e sete novilhas cruzadas foram utilizadas, distribuídas em três tratamentos: 1,2%; 1,6% e 2,6% do peso vivo de ingestão de matéria seca por dia. As concentrações no plasma da veia jugular de glicose e estrógeno foram maiores nos animais com 1,6% de IMS e os níveis de insulina foram maiores nos animais com 2,6% de IMS. Houve um aumento dos níveis plasmáticos de uréia com aumento dos níveis de IMS. Não houve efeito da IMS sobre os níveis de progesterona no plasma sangüíneo coletado da jugular. No plasma sangüíneo coletado da veia cada caudal, os níveis de progesterona foram maiores (P<0,05 nos animais com 2,6% de IMS. Não houve efeito da IMS sobre os níveis foliculares de IGF-I.

  6. The effect of the synthetic oviductal fluid medium (SOF supplemented with insulin-like growth factor-I (IGF-I on in vitro maturation of canine oocytes (Canis familiaris/ Influência do fator de crescimento semelhante à insulina I (IGF-I adicionado ao meio fluido sintético de tuba uterina (SOF sobre a maturação in vitro de oócitos caninos (Canis familiaris

    Directory of Open Access Journals (Sweden)

    Kellen Oliveira

    2007-08-01

    Full Text Available The follicular growth and oocyte maturation knowledge are very important to the development and improvement ofnew biotechnologies such as in vitro fertilization and somatic cell nuclear transfer. In order to the necessity of clarifythe basic mechanisms related to canine oocyte maturation, this investigation focuses on the evaluation of the effectof insulin-like growth factor-i (IGF-I, added to synthetic oviductal fluid medium (SOF on the in vitro maturation ofdomestic dog oocytes. Thirty-seven bitches undergoing ovariohysterectomy for castration or due to pathologicalconditions of the uterus were selected as oocytes’ donors (n=875. The oocytes were allocated in the followinggroups: M0 (stained in the collection’s time, Control (72h in SOF and Experimental (72h in SOF plus 100 ng IGF-I.After 72 hours of maturation the oocytes’ nuclear status were assessed by Hoechst 33342 dye. The best results interms of oocyte harvest were observed in those juvenile donors, females in estrus, nuliparous and pure breeds. Nosignificant differences were observed between treatments control (SOF or experimental (IGF-I.O conhecimento da regulação do crescimento folicular e da maturação oocitária é de grande importância no desenvolvimento e aperfeiçoamento de novas biotecnologias como a fecundação in vitro e a transferência nuclear. Considerando-se a necessidade de elucidação dos mecanismos básicos envolvidos na maturação oocitária na espécie canina, a presente pesquisa foi desenvolvida com o objetivo de avaliar o efeito do fator de crescimento semelhante à insulina-I (IGF-I, adicionado ao meio fluido sintético de tuba uterina (SOF, sobre a maturação de oócitos caninos. Foram utilizadas 37 cadelas submetidas à ovariohisterectomia, eletivas e terapêuticas, como doadoras dos complexos cumulus oócitos grau 1 (n=875 que foram alocados em três grupos: M0 (coloração no momento da colheita, Controle (72 h no meio SOF e Experimental (72h no

  7. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice

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    Klaus Fabel

    2009-11-01

    Full Text Available Voluntary physical exercise (wheel running, RUN and environmental enrichment (ENR both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can “prime” the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.

  8. n-3 fatty acids: role in neurogenesis and neuroplasticity.

    Science.gov (United States)

    Crupi, R; Marino, A; Cuzzocrea, S

    2013-01-01

    Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n-3 fatty acids, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and antiapoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer's disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out.

  9. Effects of active shock avoidance learning on hippocampal neurogenesis and plasma levels of corticosterone

    NARCIS (Netherlands)

    van der Borght, Karin; Meerlo, Peter; Luiten, Paul G.M.; Eggen, Bart J.L.; van der Zee, Eddy A.

    2005-01-01

    Hippocampal granule neurons that are newly formed during adulthood might be involved in learning and memory processes. Experimental data suggest that only hippocampus-dependent learning tasks stimulate neurogenesis. To further address this issue, the effects of active shock avoidance (ASA) learning

  10. Schisandrin A and B affect subventricular zone neurogenesis in mouse.

    Science.gov (United States)

    Sun, Yi-Xue; Cong, Yan-Long; Liu, Yang; Jin, Bo; Si, Lu; Wang, Ai-Bing; Cai, Huan; Che, Guan-Yu; Tang, Bo; Wang, Chun-Feng; Li, Zi-Yi; Zhang, Xue-Ming

    2014-10-05

    Schisandrin A and B (Sch A and B) are the main effective components extracted from the oriental medicine Schisandra chinensis which is traditionally used to enhance mental and intellectual function. Although their neuroprotective effects have been demonstrated, their influences on neurogenesis are still unknown. In the brain, new neural cells born in the subventricular zone (SVZ) next to the lateral ventricles migrate along the rostral migratory stream (RMS) to the olfactory bulb (OB). To investigate the effects of Sch A and B on neurogenesis in the SVZ-RMS-OB system, Sch A and B were intragastrically administrated at dosages of 1, 10 and 20 mg/kg d respectively. The dose of 10 mg/kg d was selected for further analysis based on the preliminary analysis. In the SVZ, significant increases of phosphohistone H3 positive proliferating cells and the intensity of glial fibrillary acidic protein (GFAP+) cells were noticed in Sch B group. In the RMS, Sch A treatment augmented the intensity of doublecortin positive neuroblasts. In the OB, Sch A decreased tyrosine hydroxylase cells and Calbindin (CalB+) cells, while Sch B increased CalB+ cells and Calretinin (CalR+) cells. These results suggest that Sch B stimulates SVZ proliferation by enhancing GFAP+ cells and improves the survival of OB interneurons, while Sch A promotes neuroblast formation in the RMS but impairs the survival of OB interneurons. The present study provides the first evidence that Sch B exerts neuroprotective functions by enhancing neurogenesis, but Sch A mainly negatively regulates neurogenesis, in the adult SVZ-RMS-OB system.

  11. Adult neurogenesis and the vascular Nietzsche.

    Science.gov (United States)

    Palmer, Theo D

    2002-06-13

    Adult neurogenesis is mediated by immature neural precursors that divide within the residual germinal matrices of the brain. In the paper by in this issue of Neuron, the "cause and effect" of adult neurogenesis takes a major step forward with the description of a vascular signaling network that influences neuronal precursor migration and fate.

  12. 牛初乳中IGF-I提取物对肠黏膜修复作用的研究%Effect of bovine colostrum IGF-I extraction on the recovery of intestinal mucositis

    Institute of Scientific and Technical Information of China (English)

    吕剑光; 宋伟; 霍贵成

    2011-01-01

    目的:研究牛初乳中胰岛素生长因子-I(IGF—I)对大鼠受损肠黏膜的修复作用。方法:应用氨甲喋呤制备大鼠小肠炎模型,实验设正常对照组,MTX模型对照组(20ukg),牛初乳LIGF—I提取物修复组(75ug/kg),1GF—I修复组(75ug/kg)。后2组每天灌胃给药1次,给药时间从造模后第2d开始至实验结束,共5d。第6d检测大鼠血浆二氨氧化酶(DAO)活性、血浆D-乳酸水平,光镜下观察小肠组织病理形态学改变。结果:与对照组相比,模型组大鼠血浆DAO活性和血浆D-乳酸水平明显升高(P〈0.05),小肠损伤程度明显高于对照组(P〈0.05),牛初乳中IGF—I提取物组和IGF—I组可降低血浆DA0活性及D-乳酸水平(P〈0.05),减轻小肠损伤程度(P〈0.05)。结论:牛初乳中IGF—I提取物能够明显减轻大鼠肠黏膜的损伤,同时可减轻炎细胞的浸润,对实验性大鼠的小肠炎具有修复作用。%Objective: To study the effect of bovine colostrum insulin-like growth factor-I (IGF-I) extraction on injury of the intestine in rat. Methods: Rat model of enteritis was induced by Methotrexate (MTX). The experimental animals were randomly divided into four groups: normal greup,MTX model group (20pg/kg),bovine colostrum IGF-I extraction recovery group (75pg/kg) and IGF-I recovery group (75pg/kg). The last two groups were administered in corresponding groups by gastric irrigation daily for 5 days,and the administered time had been from 2nd day to 5th day. Plasma diamine oxidase (DAO) and D-lactate level were measured,histological changes in intestinal tissue were observed under the light microscope, Results: Compared with normal group,the activity of DAO and D-lactate level were significantly increased (P〈0.05),intestine injury was deeper than the normal group (P〈0.05). The bovine colostrum IGF-I extraction recovery group

  13. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Vadivel Parthsarathy

    Full Text Available Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2 into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01 in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001 of β-amyloid plaque count, a 44% reduction (p<0.0001 in the numbers of activated microglial cells, and a 25% reduction (p<0.0001 in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001, all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.

  14. Neurogenesis in the adult olfactory bulb

    Institute of Scientific and Technical Information of China (English)

    Angela Pignatelli; Cristina Gambardella; Ottorino Belluzzi

    2011-01-01

    Neurogenesis is the process by which cells divide, migrate, and subsequently differentiate into a neuronal phenotype. Significant rates of neurogenesis persist into adulthood in two brain regions, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricles. Cells of the subventricular zone divide and migrate via the rostral migratory stream to the olfactory bulb where they differentiate into granule and periglomerular cells. With the discovery of large-scale neurogenesis in the adult brain, there have been significant efforts to identify the mechanisms that control this process as well as the role of these cells in neuronal functioning. Although many questions remain unanswered, new insights appear daily about adult neurogenesis, regulatory mechanisms, and the fates of the progeny. In this review we highlight the main studies investigating factors that regulate neurogenesis in the subventricular zone, neuronal migration to the olfactory bulb, neuronal integration into the existing bulbar network and shortly discuss the functional meaning of this process.

  15. Neurogenesis and The Effect of Antidepressants

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

  16. 实验性吸烟对胎鼠及幼鼠血清IGF-I的影响%Effects of Environmental Tobacco Smoke Exposure in Utero and Postnatally on Serum IGF-I of Rats

    Institute of Scientific and Technical Information of China (English)

    孟药; 吴圣楣; 沈永年; 钱龙华

    2001-01-01

    目的用被动吸烟法建立宫内被动吸烟胎鼠及宫内至断乳前持续被动吸烟幼鼠动物模型,比较不同浓度香烟暴露对胎鼠及幼鼠血清IGF-I的影响。方法SD雌鼠于交配后第2d,入低、中、高三种香烟浓度的被动吸烟箱中,每日5h,孕21d剖宫取胎,收集胎鼠血清;或待孕鼠自然分娩,幼鼠置于与宫内相同香烟浓度的被动吸烟箱中,每日5h,至21d断乳,取幼鼠血清。结果不同浓度香烟暴露对胎鼠血清IGF-I的影响无显著差异,随香烟浓度增高幼鼠血清IGF-I呈下降趋势,高浓度组与对照组间差异显著。结论宫内至断乳前持续被动吸烟降低幼鼠血清IGF-I水平,随香烟浓度增高,差异显著。%Objective To evaluate whether environmental tobacco smoke exposure in utero or/ and postnatally affects serum IGF-I of rats. Methods Pregnant SD rats were exposed to air or to passive smoke for 5h/d, from day 2 to day 21 of pregnancy, then the fetal serum were collected. Or from day 2 of pregnancy until delivery, then their pups were exposed to the same environment till weaning. After completion of the exposures, the pups' serua were collected. Results Utero passive smoke had no effect on fetus's serum IGF-I Conclusion Utero till postnatum passive smoke reduced serum IGF-I of pups, in particular decreased significantly in the highest concentration group.

  17. Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice.

    Science.gov (United States)

    Liu, Hong; Xue, Xinhong; Shi, Huijian; Qi, Lifeng; Gong, Dianrong

    2015-01-01

    Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice.

  18. The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects.

    Science.gov (United States)

    Kondo, M; Nakamura, Y; Ishida, Y; Shimada, S

    2015-11-01

    Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects.

  19. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability

    Science.gov (United States)

    Mooney, Skyler J.; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

    2016-01-01

    Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID:27459643

  20. Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders

    Directory of Open Access Journals (Sweden)

    Heechul Jun

    2012-01-01

    Full Text Available Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

  1. Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure.

    Science.gov (United States)

    Cacao, Eliedonna; Cucinotta, Francis A

    2016-03-01

    Radiation impairment of neurogenesis in the hippocampal dentate gyrus is one of several factors associated with cognitive detriments after treatment of brain cancers in children and adults with radiation therapy. Mouse models have been used to study radiation-induced changes in neurogenesis, however the models are limited in the number of doses, dose fractions, age and time after exposure conditions that have been studied. The purpose of this study is to develop a novel predictive mathematical model of radiation-induced changes to neurogenesis using a system of nonlinear ordinary differential equations (ODEs) to represent the time, age and dose-dependent changes to several cell populations participating in neurogenesis as reported in mouse experiments exposed to low-LET radiation. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation treatment in altering neurogenesis: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN) and (4) glioblasts (GB). Because neurogenesis is decreasing with increasing mouse age, a description of the age-related dynamics of hippocampal neurogenesis is considered in the model, which is shown to be an important factor in comparisons to experimental data. A key feature of the model is the description of negative feedback regulation on early and late neuronal proliferation after radiation exposure. The model is augmented with parametric descriptions of the dose and time after irradiation dependences of activation of microglial cells and a possible shift of NSC proliferation from neurogenesis to gliogenesis reported at higher doses (∼10 Gy). Predictions for dose-fractionation regimes and for different mouse ages, and prospects for future work are then discussed.

  2. Neurogenesis dan Faktor-Faktor yang Berpengaruh

    Directory of Open Access Journals (Sweden)

    Ria Puspitawati

    2015-09-01

    Full Text Available Development of nerve tissue is known as neurogenesis. Vertebrate neve system has various functional capabilities from sensory perception, motor coordination, to the ability in producing motivation, spatial abilities, learning and memorizing due to various cell types that accurately connected and interact to each other. The connections between various nerve cells are continuously developed from the embryonic time until the early period of life. Recent studies have showed that neurogenesis in certain regions of nerve tissue can still be found in adults. This article reviews the cellular mechanism of neurogenesis and conditions that have role in the process.

  3. Hippocampal Neurogenesis and the Brain Repair Response to Brief Stereotaxic Insertion of a Microneedle

    Directory of Open Access Journals (Sweden)

    Shijie Song

    2013-01-01

    Full Text Available We tested the hypothesis that transient microinjury to the brain elicits cellular and humoral responses that stimulate hippocampal neurogenesis. Brief stereotaxic insertion and removal of a microneedle into the right hippocampus resulted in (a significantly increased expression of granulocyte-colony stimulating factor (G-CSF, the chemokine MIP-1a, and the proinflammatory cytokine IL12p40; (b pronounced activation of microglia and astrocytes; and (c increase in hippocampal neurogenesis. This study describes immediate and early humoral and cellular mechanisms of the brain’s response to microinjury that will be useful for the investigation of potential neuroprotective and deleterious effects of deep brain stimulation in various neuropsychiatric disorders.

  4. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 levels are increased in central precocious puberty

    DEFF Research Database (Denmark)

    Juul, A; Scheike, Thomas Harder; Nielsen, C T;

    1995-01-01

    Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn, s...

  5. Pertussis toxin nullifies the depolarisation of the membrane potential and the stimulation of the rapid phase of 45Ca2+ entry through L-type calcium channels that are produced by follicle stimulating hormone in 10- to 12-day-old-rat Sertoli cells.

    Directory of Open Access Journals (Sweden)

    Ana P Jacobus

    2010-10-01

    Full Text Available The aim of this study was to evaluate the effect of pertussis toxin (PTX on the depolarising component of the action of FSH on the membrane potential of Sertoli cells, which is linked to the rapid entry of Ca2+ into cells and to the Ca2+-dependent transport of neutral amino acids by the A system. This model allowed us to analyse the involvement of Gi proteins in the action of FSH in these phenomena. In parallel, using an inactive analogue of IGF-1, JB1, and an anti-IGF-I antibody we investigated the possible mediating role of IGF-I on these effects of FSH because IGF-I is produced and released by testicular cells in response to stimulation by FSH and shows depolarisation effects on membrane potential similar to those from FSH. Our results have the following implications: a the rapid membrane actions of FSH, which occur in a time-frame of seconds to min and include the depolarisation of the membrane potential, and stimulation of 45Ca2+ uptake and [14C]- methyl aminoisobutyric acid ([14C]-MeAIB transport, are nullified by the action of PTX and, therefore, are probably mediated by GiPCR activation; b the effects of FSH were also nullified by verapamil, an L-type voltage-dependent Ca2+ channel blocker; c wortmannin, an inhibitor of PI3K, prevented FSH stimulation of 45Ca2+ entry and [14C]-MeAIB transport; and d these FSH actions are independent of the IGF-I effects. In conclusion, these results strongly suggest that the rapid action of FSH on L-type Ca2+ channel activity in Sertoli cells from 10- to 12-day-old rats is mediated by the Gi/βγ/PI3Kγ pathway, independent of the effects of IGF-I.

  6. Adult neurogenesis transiently generates oxidative stress.

    Directory of Open Access Journals (Sweden)

    Noah M Walton

    Full Text Available An increasing body of evidence suggests that alterations in neurogenesis and oxidative stress are associated with a wide variety of CNS diseases, including Alzheimer's disease, schizophrenia and Parkinson's disease, as well as routine loss of function accompanying aging. Interestingly, the association between neurogenesis and the production of reactive oxidative species (ROS remains largely unexamined. The adult CNS harbors two regions of persistent lifelong neurogenesis: the subventricular zone and the dentate gyrus (DG. These regions contain populations of quiescent neural stem cells (NSCs that generate mature progeny via rapidly-dividing progenitor cells. We hypothesized that the energetic demands of highly proliferative progenitors generates localized oxidative stress that contributes to ROS-mediated damage within the neuropoietic microenvironment. In vivo examination of germinal niches in adult rodents revealed increases in oxidized DNA and lipid markers, particularly in the subgranular zone (SGZ of the dentate gyrus. To further pinpoint the cell types responsible for oxidative stress, we employed an in vitro cell culture model allowing for the synchronous terminal differentiation of primary hippocampal NSCs. Inducing differentiation in primary NSCs resulted in an immediate increase in total mitochondria number and overall ROS production, suggesting oxidative stress is generated during a transient window of elevated neurogenesis accompanying normal neurogenesis. To confirm these findings in vivo, we identified a set of oxidation-responsive genes, which respond to antioxidant administration and are significantly elevated in genetic- and exercise-induced model of hyperactive hippocampal neurogenesis. While no direct evidence exists coupling neurogenesis-associated stress to CNS disease, our data suggest that oxidative stress is produced as a result of routine adult neurogenesis.

  7. Effect of Opioid on Adult Hippocampal Neurogenesis

    OpenAIRE

    Yue Zhang; Loh, Horace H.; Ping-Yee Law

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opia...

  8. Neurogenesis in the adult peripheral nervous system

    Institute of Scientific and Technical Information of China (English)

    Krzysztof Czaja; Michele Fornaro; Stefano Geuna

    2012-01-01

    Most researchers believe that neurogenesis in mature mammals is restricted only to the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle in the central nervous system. In the peripheral nervous system, neurogenesis is thought to be active only during prenatal development, with the exception of the olfactory neuroepithelium. However, sensory ganglia in the adult peripheral nervous system have been reported to contain precursor cells that can proliferate in vitro and be induced to differentiate into neurons. The occurrence of insult-induced neurogenesis, which has been reported by several investigators in the brain, is limited to a few recent reports for the peripheral nervous system. These reports suggest that damage to the adult nervous system induces mechanisms similar to those that control the generation of new neurons during prenatal development. Understanding conditions under which neurogenesis can be induced in physiologically non-neurogenic regions in adults is one of the major challenges for developing therapeutic strategies to repair neurological damage. However, the induced neurogenesis in the peripheral nervous system is still largely unexplored. This review presents the history of research on adult neurogenesis in the peripheral nervous system, which dates back more than 100 years and reveals the evidence on the under estimated potential for generation of new neurons in the adult peripheral nervous system.

  9. Adult neurogenesis modifies excitability of the dentate gyrus.

    Science.gov (United States)

    Ikrar, Taruna; Guo, Nannan; He, Kaiwen; Besnard, Antoine; Levinson, Sally; Hill, Alexis; Lee, Hey-Kyoung; Hen, Rene; Xu, Xiangmin; Sahay, Amar

    2013-01-01

    Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG) such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL) is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD) imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern separation.

  10. Adult neurogenesis modifies excitability of the dentate gyrus

    Directory of Open Access Journals (Sweden)

    Taruna eIkrar

    2013-12-01

    Full Text Available Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern

  11. Sprouty2 in the dorsal hippocampus regulates neurogenesis and stress responsiveness in rats.

    Directory of Open Access Journals (Sweden)

    Antonia L Dow

    Full Text Available Both the development and relief of stress-related psychiatric conditions such as major depression (MD and post-traumatic stress disorder (PTSD have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis, which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP. Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2, an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2, which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.

  12. Linking adult olfactory neurogenesis to social behavior

    Directory of Open Access Journals (Sweden)

    Claudia E Feierstein

    2012-11-01

    Full Text Available In the adult brain, new neurons are added to two brain areas: the olfactory bulb and the hippocampus. Newly-generated neurons integrate into the preexisting circuits, bringing a set of unique properties, such as increased plasticity and responsiveness to stimuli. However, the functional implications of the constant addition of these neurons remain unclear, although they are believed to be important for learning and memory. The levels of neurogenesis are regulated by a variety of environmental factors, as well as during learning, suggesting that new neurons could be important for coping with changing environmental demands. Notably, neurogenesis has been shown to be physiologically regulated in relation to reproductive behavior: neurogenesis increases in female mice upon exposure to cues of the mating partners, during pregnancy and lactation, and in male mice upon exposure to their offspring. In this scenario, and because of the key contribution of olfaction to maternal behavior, we sought to investigate the contribution of adult-generated neurons in the olfactory system to maternal behavior and offspring recognition. To do so, we selectively disrupted neurogenesis in the olfactory pathway of female mice using focal irradiation. Disruption of adult neurogenesis in the olfactory bulb did not affect maternal behavior, or the ability of female mice to discriminate familiar from unfamiliar pups. However, reduction of olfactory neurogenesis resulted in abnormal social interaction of female mice, specifically with male conspecifics. Because the olfactory system is crucial for sex recognition, we suggest that the abnormal interaction with males could result from the inability to detect or discriminate male-specific odors and could therefore have implications for the recognition of potential mating partners. Here, I review the results of this and other studies, and discuss their implications for our understanding of the function of adult neurogenesis.

  13. Role for neuronal nitric-oxide synthase in cannabinoid-induced neurogenesis.

    Science.gov (United States)

    Kim, Sun Hee; Won, Seok Joon; Mao, Xiao Ou; Ledent, Catherine; Jin, Kunlin; Greenberg, David A

    2006-10-01

    Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabinoid agonist R(+)-Win 55212-2 [(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone] or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by approximately 25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by approximately 50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(+)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx- and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO.

  14. Relationships between dietary macronutrients and adult neurogenesis in the regulation of energy metabolism.

    Science.gov (United States)

    Yon, Marianne A; Mauger, Suzanna L; Pickavance, Lucy C

    2013-05-01

    Of the environmental factors which have an impact on body weight, nutrients are most influential. Within normal limits, hypothalamic and related neuronal populations correct perturbations in energy metabolism, to return the body to its nutritional set-point, either through direct response to nutrients or indirectly via peripheral appetite signals. Excessive intake of certain macronutrients, such as simple carbohydrates and SFA, can lead to obesity and attendant metabolic dysfunction, also reflected in alterations in structural plasticity, and, intriguingly,neurogenesis, in some of these brain regions. Neurogenesis, previously thought to occur only in the embryo, is now known to take place in the adult brain, dependent on numerous stimulating and inhibiting factors, including dietary components. Because of classic associations between neurogenesis and the hippocampus, in learning and cognition, this brain region has also been the focus of attention in the study of links between diet and neurogenesis. Recently, however, a more complete picture of this relationship has been building: not only has the hypothalamus been shown to satisfy the criteria for a neurogenic niche, but appetite-related mediators, including circulating hormones, such as leptin and ghrelin, pro-inflammatory cytokines and the endocannabinoid intracellular messengers, are also being examined for their potential role in mediating neurogenic responses to macronutrients. The present review draws together these observations and investigates whether n-3 PUFA may exert their attenuating effects on body weight through the stimulation of adult neurogenesis. Exploration of the effects of nutraceuticals on neurogenic brain regions may encourage the development of new rational therapies in the fight against obesity.

  15. Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb.

    Directory of Open Access Journals (Sweden)

    Tan Li

    Full Text Available Recent studies have led to the exciting idea that adult-born neurons in the olfactory bulb (OB may be critical for complex forms of olfactory behavior in mice. However, signaling mechanisms regulating adult OB neurogenesis are not well defined. We recently reported that extracellular signal-regulated kinase (ERK 5, a MAP kinase, is specifically expressed in neurogenic regions within the adult brain. This pattern of expression suggests a role for ERK5 in the regulation of adult OB neurogenesis. Indeed, we previously reported that conditional deletion of erk5 in adult neurogenic regions impairs several forms of olfactory behavior in mice. Thus, it is important to understand how ERK5 regulates adult neurogenesis in the OB. Here we present evidence that shRNA suppression of ERK5 in adult neural stem/progenitor cells isolated from the subventricular zone (SVZ reduces neurogenesis in culture. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, stimulates neurogenesis. Furthermore, inducible and conditional deletion of erk5 specifically in the neurogenic regions of the adult mouse brain interferes with cell cycle exit of neuroblasts, impairs chain migration along the rostral migratory stream and radial migration into the OB. It also inhibits neuronal differentiation and survival. These data suggest that ERK5 regulates multiple aspects of adult OB neurogenesis and provide new insights concerning signaling mechanisms governing adult neurogenesis in the SVZ-OB axis.

  16. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis

    DEFF Research Database (Denmark)

    Almeida, Ana S; Soares, Nuno L; Vieira, Melissa;

    2016-01-01

    Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activit...... cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies....

  17. BDNF control of adult SVZ neurogenesis.

    Science.gov (United States)

    Bath, Kevin G; Akins, Michael R; Lee, Francis S

    2012-09-01

    The sensory processing of odorants is a dynamic process that requires plasticity at multiple levels. In the olfactory bulb (OB), inhibitory interneurons undergo lifelong replacement through a process known as adult neurogenesis. These newly born cells are incorporated in a learning-dependent fashion, a process which has led some to suggest this as a primary mechanism through which the OB retains a high degree of plasticity throughout life. A continued focus of researchers in this field has been to understand the molecular mechanisms controlling adult subventricular zone (SVZ) neurogenesis and the innate functional role of these cells. Brain-derived neurotrophic factor (BDNF) has been identified as a strong candidate molecule regulating adult OB neurogenesis. We review what is known regarding the functional role of newly born cells, highlight the role of BDNF in this process, and describe preliminary findings from our lab implicating BDNF in the process of selecting of newly born cells for survival.

  18. Role of microglia in embryonic neurogenesis

    Science.gov (United States)

    Tong, Chih Kong

    2016-01-01

    Microglia begin colonizing the developing brain as early as embryonic day 9, prior to the emergence of neurons and other glia. Their ontogeny is also distinct from other central nervous system cells, as they derive from yolk sac hematopoietic progenitors and not neural progenitors. In this review, we feature these unique characteristics of microglia and assess the spatiotemporal similarities between microglia colonization of the central nervous system and embryonic neurogenesis. We also infer to existing evidence for microglia function from embryonic through to postnatal neurodevelopment to postulate roles for microglia in neurogenesis. PMID:27555616

  19. Differential effects of stress and glucocorticoids on adult neurogenesis.

    Science.gov (United States)

    Schoenfeld, Timothy J; Gould, Elizabeth

    2013-01-01

    Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms.

  20. Serum GH and IGF-I are significant determinants of bone turnover but not bone mineral density in active acromegaly: a prospective study of more than 70 consecutive patients.

    Science.gov (United States)

    Ueland, T; Fougner, S L; Godang, K; Schreiner, T; Bollerslev, J

    2006-11-01

    Acromegaly is characterized by a persistent hypersecretion of GH and provides information on long-term effects of GH on bone metabolism. The aim of this study was to examine the effect of gonadal status and disease activity on bone metabolism in active acromegaly. Seventy-three consecutive patients with active acromegaly: 40 women and 33 men (50 +/- 13 (mean +/- s.d.) and 49 +/- 10 years respectively) were evaluated and compared with age-, sex-, and body mass index (BMI)-matched controls by X-ray absorptiometry and biochemical analysis (markers of disease activity and bone turnover). We found that bone turnover, as evaluated by biochemical bone markers, is coupled and markedly increased in relation to disease activity in active acromegaly. Acromegalic women, but not men, were characterized by an increased bone area and slightly decreased bone mineral content resulting in significantly decreased bone mineral density (BMD) in the ultradistal radius, proximal radius, and total body. No differences in bone turnover or BMD were found between eu-and hypogonadal subjects. Multivariate analysis identified age, BMI, and gender as independent predictors of total BMD in acromegaly. Our study demonstrates a decreased total body BMD in women, not men, with active acromegaly, regardless of gonadal status or disease activity. Bone turnover is markedly increased in relation to disease activity, possibly counteracting the anabolic effects of excess GH/IGF-I in these subjects. We suggest more focus on biomechanical analyses when investigating endocrine disorders affecting bone size and distribution between compartments.

  1. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

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    Kuan Zhang

    Full Text Available Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG of the hippocampus and the sub-ventricular zone (SVZ of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCsin vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr and DG (approximately 10 Torr were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr. Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  2. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    Science.gov (United States)

    Zhang, Kuan; Zhou, Yanzhao; Zhao, Tong; Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

  3. Effect of Opioid on Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Yue Zhang

    2016-01-01

    Full Text Available During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

  4. Adult Neurogenesis, Chronic Stress and Depression

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.A.; Schouten, M.; Encinas, J.M.; Fitzsimons, C.P.; Canales, J.J.

    2016-01-01

    A major risk factor for depression in vulnerable individuals is exposure to stress during critical periods. Stress affects mood and cognition and is also one of the best known inhibitors of adult neurogenesis that has been associated with hippocampal changes and atrophy, common findings in major dep

  5. Adult Neurogenesis, Chronic Stress and Depression

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.A.; Schouten, M.; Encinas, J.M.; Fitzsimons, C.P.; Canales, J.J.

    2016-01-01

    A major risk factor for depression in vulnerable individuals is exposure to stress during critical periods. Stress affects mood and cognition and is also one of the best known inhibitors of adult neurogenesis that has been associated with hippocampal changes and atrophy, common findings in major

  6. Effect of Opioid on Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Zhang, Yue; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

  7. Traumatic Brain Injury Severity Affects Neurogenesis in Adult Mouse Hippocampus.

    Science.gov (United States)

    Wang, Xiaoting; Gao, Xiang; Michalski, Stephanie; Zhao, Shu; Chen, Jinhui

    2016-04-15

    Traumatic brain injury (TBI) has been proven to enhance neural stem cell (NSC) proliferation in the hippocampal dentate gyrus. However, various groups have reported contradictory results on whether TBI increases neurogenesis, partially due to a wide range in the severities of injuries seen with different TBI models. To address whether the severity of TBI affects neurogenesis in the injured brain, we assessed neurogenesis in mouse brains receiving different severities of controlled cortical impact (CCI) with the same injury device. The mice were subjected to mild, moderate, or severe TBI by a CCI device. The effects of TBI severity on neurogenesis were evaluated at three stages: NSC proliferation, immature neurons, and newly-generated mature neurons. The results showed that mild TBI did not affect neurogenesis at any of the three stages. Moderate TBI promoted NSC proliferation without increasing neurogenesis. Severe TBI increased neurogenesis at all three stages. Our data suggest that the severity of injury affects adult neurogenesis in the hippocampus, and thus it may partially explain the inconsistent results of different groups regarding neurogenesis following TBI. Further understanding the mechanism of TBI-induced neurogenesis may provide a potential approach for using endogenous NSCs to protect against neuronal loss after trauma.

  8. Natural variation and genetic covariance in adult hippocampal neurogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kempermann, Gerd [Center for Molecular Medicine, Berlin, Germany; Chesler, Elissa J [ORNL; Lu, Lu [University of Tennessee Health Science Center, Memphis; Williams, Robert [University of Tennessee Health Science Center, Memphis; Gage, Fred [Salk Institute for Biological Studies, The, San Diego, CA

    2006-01-01

    Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB?BXA, n ? 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1?CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis- cting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

  9. Increased cardiac alpha-myosin heavy chain in left atria and decreased myocardial insulin-like growth factor (Igf-I) expression accompany low heart rate in hibernating grizzly bears.

    Science.gov (United States)

    Barrows, N D; Nelson, O L; Robbins, C T; Rourke, B C

    2011-01-01

    Grizzly bears (Ursus arctos horribilis) tolerate extended periods of extremely low heart rate during hibernation without developing congestive heart failure or cardiac chamber dilation. Left ventricular atrophy and decreased left ventricular compliance have been reported in this species during hibernation. We evaluated the myocardial response to significantly reduced heart rate during hibernation by measuring relative myosin heavy-chain (MyHC) isoform expression and expression of a set of genes important to muscle plasticity and mass regulation in the left atria and left ventricles of active and hibernating bears. We supplemented these data with measurements of systolic and diastolic function via echocardiography in unanesthetized grizzly bears. Atrial strain imaging revealed decreased atrial contractility, decreased expansion/reservoir function (increased atrial stiffness), and decreased passive-filling function (increased ventricular stiffness) in hibernating bears. Relative MyHC-α protein expression increased significantly in the atrium during hibernation. The left ventricle expressed 100% MyHC-β protein in both groups. Insulin-like growth factor (IGF-I) mRNA expression was reduced by ∼50% in both chambers during hibernation, consistent with the ventricular atrophy observed in these bears. Interestingly, mRNA expression of the atrophy-related ubiquitin ligases Muscle Atrophy F-box (MAFBx) and Muscle Ring Finger 1 did not increase, nor did expression of myostatin or hypoxia-inducible factor 1α (HIF-1α). We report atrium-specific decreases of 40% and 50%, respectively, in MAFBx and creatine kinase mRNA expression during hibernation. Decreased creatine kinase expression is consistent with lowered energy requirements and could relate to reduced atrial emptying function during hibernation. Taken together with our hemodynamic assessment, these data suggest a potential downregulation of atrial chamber function during hibernation to prevent fatigue and dilation

  10. Immune modulation of learning, memory, neural plasticity and neurogenesis.

    Science.gov (United States)

    Yirmiya, Raz; Goshen, Inbal

    2011-02-01

    Over the past two decades it became evident that the immune system plays a central role in modulating learning, memory and neural plasticity. Under normal quiescent conditions, immune mechanisms are activated by environmental/psychological stimuli and positively regulate the remodeling of neural circuits, promoting memory consolidation, hippocampal long-term potentiation (LTP) and neurogenesis. These beneficial effects of the immune system are mediated by complex interactions among brain cells with immune functions (particularly microglia and astrocytes), peripheral immune cells (particularly T cells and macrophages), neurons, and neural precursor cells. These interactions involve the responsiveness of non-neuronal cells to classical neurotransmitters (e.g., glutamate and monoamines) and hormones (e.g., glucocorticoids), as well as the secretion and responsiveness of neurons and glia to low levels of inflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNFα, as well as other mediators, such as prostaglandins and neurotrophins. In conditions under which the immune system is strongly activated by infection or injury, as well as by severe or chronic stressful conditions, glia and other brain immune cells change their morphology and functioning and secrete high levels of pro-inflammatory cytokines and prostaglandins. The production of these inflammatory mediators disrupts the delicate balance needed for the neurophysiological actions of immune processes and produces direct detrimental effects on memory, neural plasticity and neurogenesis. These effects are mediated by inflammation-induced neuronal hyper-excitability and adrenocortical stimulation, followed by reduced production of neurotrophins and other plasticity-related molecules, facilitating many forms of neuropathology associated with normal aging as well as neurodegenerative and neuropsychiatric diseases. Copyright © 2010 Elsevier Inc. All rights reserved.

  11. Modeling physiological and pathological human neurogenesis in the dish

    Directory of Open Access Journals (Sweden)

    Vania eBroccoli

    2014-07-01

    Full Text Available New advances in directing the neuronal differentiation of human embryonic and induced pluripotent stem cells (hPSCs, abbreviation intended to convey both categories of pluripotent stem cells have promoted the development of culture systems capable of modeling early neurogenesis and neural specification at some of their critical milestones. The hPSC-derived neural rosette can be considered the in vitro counterpart of the developing neural tube, since both structures share a virtually equivalent architecture and related functional properties. Epigenetic stimulation methods can modulate the identity of the rosette neural progenitors in order to generate authentic neuronal subtypes, as well as a full spectrum of neural crest derivatives. The intrinsic capacity of induced pluripotent cell-derived neural tissue to self-organize has become fully apparent with the emergence of innovative in vitro systems that are able to shape the neuronal differentiation of hPSCs into organized tissues that develop in three dimensions. However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders or in building therapeutic strategies for cell replacement. In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons. Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process. Thus, full exploitation of this cellular system can provide a better understanding of the physiological events that shape human brain structures, as well as a solid platform to investigate the pathological mechanisms at the root of human diseases.

  12. Borna disease virus phosphoprotein impairs the developmental program controlling neurogenesis and reduces human GABAergic neurogenesis.

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    Chloé Scordel

    2015-04-01

    Full Text Available It is well established that persistent viral infection may impair cellular function of specialized cells without overt damage. This concept, when applied to neurotropic viruses, may help to understand certain neurologic and neuropsychiatric diseases. Borna disease virus (BDV is an excellent example of a persistent virus that targets the brain, impairs neural functions without cell lysis, and ultimately results in neurobehavioral disturbances. Recently, we have shown that BDV infects human neural progenitor cells (hNPCs and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function. Here, we sought to identify the viral proteins and molecular pathways that are involved. Using lentiviral vectors for expression of the bdv-p and bdv-x viral genes, we demonstrate that the phosphoprotein P, but not the X protein, diminishes human neurogenesis and, more particularly, GABAergic neurogenesis. We further reveal a decrease in pro-neuronal factors known to be involved in neuronal differentiation (ApoE, Noggin, TH and Scg10/Stathmin2, demonstrating that cellular dysfunction is associated with impairment of specific components of the molecular program that controls neurogenesis. Our findings thus provide the first evidence that a viral protein impairs GABAergic human neurogenesis, a process that is dysregulated in several neuropsychiatric disorders. They improve our understanding of the mechanisms by which a persistent virus may interfere with brain development and function in the adult.

  13. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

    Science.gov (United States)

    Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki; Brulet, Rebecca; Tafacory, Farrah; Zhang, Ling; Good, Levi; Ure, Kerstin; Kernie, Steven G; Birnbaum, Shari G; Scharfman, Helen E; Eisch, Amelia J; Hsieh, Jenny

    2015-03-26

    Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

  14. Adult hippocampal neurogenesis and its role in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Mu Yangling

    2011-12-01

    Full Text Available Abstract The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD. Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

  15. Detrimental role of prolonged sleep deprivation on adult neurogenesis

    Directory of Open Access Journals (Sweden)

    Carina eFernandes

    2015-04-01

    Full Text Available Adult mammalian brains continuously generate new neurons, a phenomenon called neurogenesis. Both environmental stimuli and endogenous factors are important regulators of neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and neurogenesis in brain function, such as learning, memory and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on neurogenesis.

  16. Chinese Traditional Medicine and Adult Neurogenesis in the Hippocampus

    Directory of Open Access Journals (Sweden)

    Endong Zhang

    2014-04-01

    Full Text Available Adult neurogenesis is an important therapeutic target in treating neurological disorders. Adult neurogenesis takes place in two regions of the brain: Subventricular zone and dentate gyrus in the hippocampus. The progressive understanding on hippocampal neurogenesis in aging and mood disorders increases the demand to explore powerful and subtle interventions on hippocampal neurogenesis. Traditional Chinese herbal medicine provides an abundant pharmaceutical platform for modulating hippocampal neurogenesis. Recent progress in exploring the effects of Chinese herbal medicine and the related mechanisms opens a new direction for regeneration therapy. The current review gives a thorough summary of the research progress made in traditional Chinese herbal formulas, and the effective compounds in Chinese herbs which are beneficial on hippocampal neurogenesis and the possible mechanisms involved.

  17. Alcohol and adult hippocampal neurogenesis: Promiscuous drug, wanton effects

    OpenAIRE

    Geil, Chelsea R.; Hayes, Dayna M.; McClain, Justin A.; Liput, Daniel J.; Marshall, S. Alex; Chen, Kevin Y.; Nixon, Kimberly

    2014-01-01

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may...

  18. Ecologically relevant spatial memory use modulates hippocampal neurogenesis

    OpenAIRE

    LaDage, Lara D.; Roth, Timothy C.; Fox, Rebecca A.; Pravosudov, Vladimir V.

    2009-01-01

    The adult hippocampus in birds and mammals undergoes neurogenesis and the resulting new neurons appear to integrate structurally and functionally into the existing neural architecture. However, the factors underlying the regulation of new neuron production is still under scrutiny. In recent years, the concept that spatial memory affects adult hippocampal neurogenesis has gained acceptance, although results attempting to causally link memory use to neurogenesis remain inconclusive, possibly ow...

  19. Spatial relational memory requires hippocampal adult neurogenesis.

    Directory of Open Access Journals (Sweden)

    David Dupret

    Full Text Available The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

  20. Adult neurogenesis: integrating theories and separating functions

    OpenAIRE

    2010-01-01

    The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons appear to function as pattern integrators of temporally adjacent events, thereby enhancing pattern s...

  1. Real time imaging of human progenitor neurogenesis.

    Directory of Open Access Journals (Sweden)

    Thomas M Keenan

    Full Text Available Human neural progenitors are increasingly being employed in drug screens and emerging cell therapies targeted towards neurological disorders where neurogenesis is thought to play a key role including developmental disorders, Alzheimer's disease, and depression. Key to the success of these applications is understanding the mechanisms by which neurons arise. Our understanding of development can provide some guidance but since little is known about the specifics of human neural development and the requirement that cultures be expanded in vitro prior to use, it is unclear whether neural progenitors obey the same developmental mechanisms that exist in vivo. In previous studies we have shown that progenitors derived from fetal cortex can be cultured for many weeks in vitro as undifferentiated neurospheres and then induced to undergo neurogenesis by removing mitogens and exposing them to supportive substrates. Here we use live time lapse imaging and immunocytochemical analysis to show that neural progenitors use developmental mechanisms to generate neurons. Cells with morphologies and marker profiles consistent with radial glia and recently described outer radial glia divide asymmetrically and symmetrically to generate multipolar intermediate progenitors, a portion of which express ASCL1. These multipolar intermediate progenitors subsequently divide symmetrically to produce CTIP2(+ neurons. This 3-cell neurogenic scheme echoes observations in rodents in vivo and in human fetal slice cultures in vitro, providing evidence that hNPCs represent a renewable and robust in vitro assay system to explore mechanisms of human neurogenesis without the continual need for fresh primary human fetal tissue. Knowledge provided by this and future explorations of human neural progenitor neurogenesis will help maximize the safety and efficacy of new stem cell therapies by providing an understanding of how to generate physiologically-relevant cell types that maintain their

  2. Forebrain neurogenesis: From embryo to adult

    Science.gov (United States)

    Dennis, Daniel; Picketts, David; Slack, Ruth S.; Schuurmans, Carol

    2017-01-01

    A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16–17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis: From embryo to adult. The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with ‘state of the art’ techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

  3. Inflammation is detrimental for neurogenesis in adult brain

    Science.gov (United States)

    Ekdahl, Christine T.; Claasen, Jan-Hendrik; Bonde, Sara; Kokaia, Zaal; Lindvall, Olle

    2003-11-01

    New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation.

  4. Neurogenesis in the Hippocampus of Patients with Temporal Lobe Epilepsy.

    Science.gov (United States)

    Zhong, Qin; Ren, Bo-Xu; Tang, Feng-Ru

    2016-02-01

    The mobilization of endogenous neural stem cells in order to substitute lost neurons in the adult brain may reduce the negative effects of patients with chronic neurodegenerative diseases. However, abnormal neurogenesis may be harmful and could lead to the worsening of patients' symptoms. In the brains of patients and animal models with temporal lobe epilepsy (TLE), increased newly generated neurons in the subgranular zone (SGZ) at early stages after brain insults have been speculated to be involved in epileptogenesis. However, this argument is unsupported by evidence showing that (1) hippocampal neurogenesis is reduced at chronic stages of intractable TLE, (2) decreased neurogenesis is involved in epileptogenesis, and (3) spontaneous recurrent seizures occur before newly generated neurons are integrated into hippocampal neural pathways. Therefore, the hypothesis of increased neurogenesis in epileptogenesis may need to be re-evaluated. In this paper, we systemically reviewed brain neurogenesis and relevant molecules in the regulation of neurogenesis in SGZ. We aimed to update researchers and epileptologists on current progresses on pathophysiological changes of neurogenesis at different stages of TLE in patients and animal models of TLE. The interactions among neurogenesis, epileptogenesis and cognitive impairment, and molecules' mechanism involved in neurogenesis would also be discussed. Future research directions are proposed at the end of this paper.

  5. Hippocampal adult neurogenesis: Does the immune system matter?

    Science.gov (United States)

    de Miranda, Aline Silva; Zhang, Cun-Jin; Katsumoto, Atsuko; Teixeira, Antônio Lúcio

    2017-01-15

    Adult hippocampal neurogenesis involves proliferation, survival, differentiation and integration of newborn neurons into pre-existing neuronal networks. Although its functional significance in the central nervous system (CNS) has not comprehensively elucidated, adult neurogenesis has been attributed a role in cognition, learning and memory. There is a growing body of evidence that CNS resident as well as peripheral immune cells participate in regulating hippocampal adult neurogenesis. Microglial cells are closely associated with neural stem/progenitor cell (NSPC) in the neurogenic niche engaged in a bidirectional communication with neurons, which may be important for adult neurogenesis. Microglial and neuronal crosstalk is mediated in part by CX3CL1/CX3CR1 signaling and a disruption in this pathway has been associated with impaired neurogenesis. It has been also reported that microglial neuroprotective or neurotoxic effects in adult neurogenesis occur in a context-dependent manner. Apart from microglia other brain resident and peripheral immune cells including pericytes, perivascular macrophages, mast cells and T-cells also modulate this phenomenon. It is worth mentioning that under some physiological circumstances such as normal aging there is a significant decrease in hippocampal neurogenesis. A role for innate and adaptive immune system in adult neurogenesis has been also reported during aging. Here, we review the current evidence regarding neuro-immune interactions in the regulation of neurogenesis under distinct conditions, including aging.

  6. Adult neurogenesis without germinal layers: the "atypical" cerebellum of rabbits.

    Science.gov (United States)

    Ponti, G; Crociara, P; Armentano, M; Bonfanti, L

    2010-06-01

    Unlike non mammalian vertebrates, adult neurogenesis in mammals is detectable in highly restricted brain sites. Persistent neurogenesis is thought to depend on stem cells residing in neural stem cell niches which are remnants of the embryonic germinal layers. Local progenitors which retain some proliferative capacity have been identified in the mature brain parenchyma, yet they do not support a constitutive, 'actual' neurogenesis, but rather a 'potential' neurogenesis which does not extrinsecate fully and spontaneously in vivo. In contrast with such a view, genesis of neuronal and glial cells from local progenitors does occur in the peripuberal and adult rabbit cerebellum. This process is independent from persisting germinal layers and involves different cell populations.

  7. Nitric oxide negatively regulates mammalian adult neurogenesis

    Science.gov (United States)

    Packer, Michael A.; Stasiv, Yuri; Benraiss, Abdellatif; Chmielnicki, Eva; Grinberg, Alexander; Westphal, Heiner; Goldman, Steven A.; Enikolopov, Grigori

    2003-08-01

    Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.

  8. RB: An essential player in adult neurogenesis.

    Science.gov (United States)

    Fong, Bensun C; Slack, Ruth S

    2017-01-01

    The fundamental mechanisms underlying adult neurogenesis remain to be fully clarified. Members of the cell cycle machinery have demonstrated key roles in regulating adult neural stem cell (NSC) quiescence and the size of the adult-born neuronal population. The retinoblastoma protein, Rb, is known to possess CNS-specific requirements that are independent from its classical role as a tumor suppressor. The recent study by Vandenbosch et al. has clarified distinct requirements for Rb during adult neurogenesis, in the restriction of proliferation, as well as long-term adult-born neuronal survival. However, Rb is no longer believed to be the main cell cycle regulator maintaining the quiescence of adult NSCs. Future studies must consider Rb as part of a larger network of regulatory effectors, including the other members of the Rb family, p107 and p130. This will help elucidate the contribution of Rb and other pocket proteins in the context of adult neurogenesis, and define its crucial role in regulating the size and fate of the neurogenic niche.

  9. Activated microglia enhance neurogenesis via trypsinogen secretion.

    Science.gov (United States)

    Nikolakopoulou, Angeliki M; Dutta, Ranjan; Chen, Zhihong; Miller, Robert H; Trapp, Bruce D

    2013-05-21

    White matter neurons in multiple sclerosis brains are destroyed during demyelination and then replaced in some chronic multiple sclerosis lesions that exhibit a morphologically distinct population of activated microglia [Chang A, et al. (2008) Brain 131(Pt 9):2366-2375]. Here we investigated whether activated microglia secrete factors that promote the generation of neurons from white matter cells. Adult rat brain microglia (resting or activated with lipopolysaccharide) were isolated by flow cytometry and cocultured with neonatal rat optic nerve cells in separate but media-connected chambers. Optic nerve cells cocultured with activated microglia showed a significant increase in the number of cells of neuronal phenotype, identified by neuron-specific class III beta-tubulin (TUJ-1) labeling, compared with cultures with resting microglia. To investigate the possible source of the TUJ-1-positive cells, A2B5-positive oligodendrocyte progenitor cells and A2B5-negative cells were isolated and cocultured with resting and activated microglia. Significantly more TUJ-1-positive cells were generated from A2B5-negative cells (∼70%) than from A2B5-positive cells (~30%). Mass spectrometry analysis of microglia culture media identified protease serine 2 (PRSS2) as a factor secreted by activated, but not resting, microglia. When added to optic nerve cultures, PRSS2 significantly increased neurogenesis, whereas the serine protease inhibitor, secretory leukocyte protease inhibitor, decreased activated microglia-induced neurogenesis. Collectively our data provide evidence that activated microglia increase neurogenesis through secretion of PRSS2.

  10. Brain size and limits to adult neurogenesis.

    Science.gov (United States)

    Paredes, Mercedes F; Sorrells, Shawn F; Garcia-Verdugo, Jose M; Alvarez-Buylla, Arturo

    2016-02-15

    The walls of the cerebral ventricles in the developing embryo harbor the primary neural stem cells from which most neurons and glia derive. In many vertebrates, neurogenesis continues postnatally and into adulthood in this region. Adult neurogenesis at the ventricle has been most extensively studied in organisms with small brains, such as reptiles, birds, and rodents. In reptiles and birds, these progenitor cells give rise to young neurons that migrate into many regions of the forebrain. Neurogenesis in adult rodents is also relatively widespread along the lateral ventricles, but migration is largely restricted to the rostral migratory stream into the olfactory bulb. Recent work indicates that the wall of the lateral ventricle is highly regionalized, with progenitor cells giving rise to different types of neurons depending on their location. In species with larger brains, young neurons born in these spatially specified domains become dramatically separated from potential final destinations. Here we hypothesize that the increase in size and topographical complexity (e.g., intervening white matter tracts) in larger brains may severely limit the long-term contribution of new neurons born close to, or in, the ventricular wall. We compare the process of adult neuronal birth, migration, and integration across species with different brain sizes, and discuss how early regional specification of progenitor cells may interact with brain size and affect where and when new neurons are added.

  11. Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis.

    Science.gov (United States)

    Mohan, Vishwa; Sinha, Rohit A; Pathak, Amrita; Rastogi, Leena; Kumar, Praveen; Pal, Amit; Godbole, Madan M

    2012-10-01

    Neuronal progenitor cell proliferation and their optimum number are indispensable for neurogenesis, which is determined by cell cycle length and cell cycle quitting rate of the dividing progenitors. These processes are tightly orchestrated by transcription factors like Tbr2, Pax6, and E2f-1. Radial glia and intermediate progenitor cells (IPC) through direct and indirect neurogenesis maintain surface area and neocortical thickness during development. Here we show that fetal neurogenesis is maternal thyroid hormone (MTH) dependent with differential effect on direct and indirect neurogenesis. MTH deficiency (MTHD) impairs direct neurogenesis through initial down-regulation of Pax6 and diminished progenitor pool with recovery even before the onset of fetal thyroid function (FTF). However, persistent decrease in Tbr2 positive IPCs, diminished NeuN positivity in layers I-III of neocortex, and reduced cortical thickness indicate a non-compensatory impairment in indirect neurogenesis. TH deficiency causes disrupted cell cycle kinetics and deranged neurogenesis. It specifically affects indirect neurogenesis governed by intermediate progenitor cells (IPCs). TH replacement in hypothyroid dams partially restored the rate of neurogenesis in the fetal neocortex. Taken together we describe a novel role of maternal TH in promoting IPCs derived neuronal differentiation in developing neo-cortex. We have also shown for the first time that ventricular zone progenitors are TH responsive as they express its receptor, TR alpha-1, transporters (MCT8) and deiodinases. This study highlights the importance of maternal thyroid hormone (TH) even before the start of the fetal thyroid function.

  12. Role of adult hippocampal neurogenesis in stress resilience

    Directory of Open Access Journals (Sweden)

    Brunno R. Levone

    2015-01-01

    Full Text Available There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders.

  13. Role of adult hippocampal neurogenesis in stress resilience

    Science.gov (United States)

    Levone, Brunno R.; Cryan, John F.; O'Leary, Olivia F.

    2014-01-01

    There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders. PMID:27589664

  14. Anti-Nogo-A Immunotherapy Does Not Alter Hippocampal Neurogenesis after Stroke in Adult Rats

    Science.gov (United States)

    Shepherd, Daniel J.; Tsai, Shih-Yen; O'Brien, Timothy E.; Farrer, Robert G.; Kartje, Gwendolyn L.

    2016-01-01

    Ischemic stroke is a leading cause of adult disability, including cognitive impairment. Our laboratory has previously shown that treatment with function-blocking antibodies against the neurite growth inhibitory protein Nogo-A promotes functional recovery after stroke in adult and aged rats, including enhancing spatial memory performance, for which the hippocampus is critically important. Since spatial memory has been linked to hippocampal neurogenesis, we investigated whether anti-Nogo-A treatment increases hippocampal neurogenesis after stroke. Adult rats were subject to permanent middle cerebral artery occlusion followed 1 week later by 2 weeks of antibody treatment. Cellular proliferation in the dentate gyrus was quantified at the end of treatment, and the number of newborn neurons was determined at 8 weeks post-stroke. Treatment with both anti-Nogo-A and control antibodies stimulated the accumulation of new microglia/macrophages in the dentate granule cell layer, but neither treatment increased cellular proliferation or the number of newborn neurons above stroke-only levels. These results suggest that anti-Nogo-A immunotherapy does not increase post-stroke hippocampal neurogenesis. PMID:27803646

  15. n-3 Fatty Acids Induce Neurogenesis of Predominantly POMC-Expressing Cells in the Hypothalamus.

    Science.gov (United States)

    Nascimento, Lucas F R; Souza, Gabriela F P; Morari, Joseane; Barbosa, Guilherme O; Solon, Carina; Moura, Rodrigo F; Victório, Sheila C; Ignácio-Souza, Letícia M; Razolli, Daniela S; Carvalho, Hernandes F; Velloso, Lício A

    2016-03-01

    Apoptosis of hypothalamic neurons is believed to play an important role in the development and perpetuation of obesity. Similar to the hippocampus, the hypothalamus presents constitutive and stimulated neurogenesis, suggesting that obesity-associated hypothalamic dysfunction can be repaired. Here, we explored the hypothesis that n-3 polyunsaturated fatty acids (PUFAs) induce hypothalamic neurogenesis. Both in the diet and injected directly into the hypothalamus, PUFAs were capable of increasing hypothalamic neurogenesis to levels similar or superior to the effect of brain-derived neurotrophic factor (BDNF). Most of the neurogenic activity induced by PUFAs resulted in increased numbers of proopiomelanocortin but not NPY neurons and was accompanied by increased expression of BDNF and G-protein-coupled receptor 40 (GPR40). The inhibition of GPR40 was capable of reducing the neurogenic effect of a PUFA, while the inhibition of BDNF resulted in the reduction of global hypothalamic cell. Thus, PUFAs emerge as a potential dietary approach to correct obesity-associated hypothalamic neuronal loss. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  16. Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

    Science.gov (United States)

    Wagenführ, Lisa; Meyer, Anne Karen; Marrone, Lara

    2016-01-01

    Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen-dependent transcription factor hypoxia-inducible factor 1α (HIF-1α) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1α conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1α signaling. These data—in agreement with in vitro data—indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment. PMID:26577812

  17. Differential roles of phospholipases A2 in neuronal death and neurogenesis: implications for Alzheimer disease.

    Science.gov (United States)

    Schaeffer, Evelin L; da Silva, Emanuelle R; Novaes, Barbara de A; Skaf, Heni D; Gattaz, Wagner F

    2010-12-01

    The involvement of phospholipase A(2) (PLA(2)) in Alzheimer disease (AD) was first investigated nearly 15 years ago. Over the years, several PLA(2) isoforms have been detected in brain tissue: calcium-dependent secreted PLA(2) or sPLA(2) (IIA, IIC, IIE, V, X, and XII), calcium-dependent cytosolic PLA(2) or cPLA(2) (IVA, IVB, and IVC), and calcium-independent PLA(2) or iPLA(2) (VIA and VIB). Additionally, numerous in vivo and in vitro studies have suggested the role of different brain PLA(2) in both physiological and pathological events. This review aimed to summarize the findings in the literature relating the different brain PLA(2) isoforms with alterations found in AD, such as neuronal cell death and impaired neurogenesis process. The review showed that sPLA(2)-IIA, sPLA(2)-V and cPLA(2)-IVA are involved in neuronal death, whereas sPLA(2)-III and sPLA(2)-X are related to the process of neurogenesis, and that the cPLA(2) and iPLA(2) groups can be involved in both neuronal death and neurogenesis. In AD, there are reports of reduced activity of the cPLA(2) and iPLA(2) groups and increased expression of sPLA(2)-IIA and cPLA(2)-IVA. The findings suggest that the inhibition of cPLA(2) and iPLA(2) isoforms (yet to be determined) might contribute to impaired neurogenesis, whereas stimulation of sPLA(2)-IIA and cPLA(2)-IVA might contribute to neurodegeneration in AD.

  18. Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

    Science.gov (United States)

    Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

    2013-11-01

    The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress.

  19. Cranial Radiation Therapy and Damage to Hippocampal Neurogenesis

    Science.gov (United States)

    Monje, Michelle

    2008-01-01

    Cranial radiation therapy is associated with a progressive decline in cognitive function, prominently memory function. Impairment of hippocampal neurogenesis is thought to be an important mechanism underlying this cognitive decline. Recent work has elucidated the mechanisms of radiation-induced failure of neurogenesis. Potential therapeutic…

  20. Revealing the Hidden Powers that Fuel Adult Neurogenesis.

    Science.gov (United States)

    Feng, Weijun; Liu, Hai-Kun

    2017-02-02

    A defining characteristic of diverse stem cell populations is their distinct metabolic state, although how these states change during adult hippocampal neurogenesis is unclear. Recently in Neuron, Beckervordersandforth et al. (2017) report that adult neurogenesis requires mitochondrial electron transport and oxidative phosphorylation and that disrupting these pathways induces premature aging phenotypes.

  1. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

    Science.gov (United States)

    Geil, Chelsea R; Hayes, Dayna M; McClain, Justin A; Liput, Daniel J; Marshall, S Alex; Chen, Kevin Y; Nixon, Kimberly

    2014-10-03

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology. Alcohol is a pharmacologically promiscuous drug capable of interfering with adult neurogenesis through multiple mechanisms. This review will discuss the primary mechanisms underlying alcohol-induced changes in adult hippocampal neurogenesis including alcohol's effects on neurotransmitters, CREB and its downstream effectors, and the neurogenic niche.

  2. Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia.

    Science.gov (United States)

    Tan, S; Zhi, P K; Luo, Z K; Shi, J

    2015-09-10

    Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (Phyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling.

  3. Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia.

    Science.gov (United States)

    Mattei, Daniele; Djodari-Irani, Anaïs; Hadar, Ravit; Pelz, Andreas; de Cossío, Lourdes Fernandez; Goetz, Thomas; Matyash, Marina; Kettenmann, Helmut; Winter, Christine; Wolf, Susanne A

    2014-05-01

    Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1β and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.

  4. A study on the change and correlation of bone mineral density,vitamin D,IGF-I,IGF-II in T2DM male patients%T2DM 男性患者骨密度、IGF-I、IGF-II、维生素 D 的变化及相关性研究

    Institute of Scientific and Technical Information of China (English)

    张燕; 曾荣峰; 李延兵

    2015-01-01

    Objective To investigate the type 2 diabetes mellitus(T2DM)and bone mineral density(BMD) in male patients with insulin-like growth factor I(IGF-I),insulin-like growth factor II(IGF-II),the change and correlation of vitamin D.Methods One hundred cases of T2DM patients were chosen as T2DM group,50 cases of healthy controls undergoing physical examinations during the same period were chosen as control group and lumbar vertebral body(L2-4 )and femoral neck BMD,IGF-I,IGF-II and serum 25-hydroxy vitamin D3 were detected and correlation analysis was performed.Results In T2DM group,L2-4 and femoral neck BMD,IGF-I,IGF-II, 25-hydroxy vitamin D3 were lower than that of the control group( P <0.01).L2-4 bone mineral density and bone mineral density of fem-oral neck,IGF-I,IGF-II,25-hydroxy vitamin D3 between the two groups showed a positive correlation( P <0.01).Conclusion T2DM male patients may suffer from reduced bone mineral density,lower levels of IGF-I,IGF-II,vitamin D,and reduced IGF-I,IGF-II and vi-tamin D levels may be the relative factors causing decrease of BMD in T2DM male patients.%目的:探讨2型糖尿病(T2DM)男性患者骨密度、胰岛素样生长因子 I(IGF-I)、胰岛素样生长因子 II(IGF-II)及维生素 D 的变化及相关性。方法选取 T2DM 男性患者100例(T2DM 组),同期选取健康体检男性50例(对照组),分别检测两组腰椎体(L2~4)与股骨颈骨密度、IGF-I、IGF-II 及血清25-羟维生素 D3水平变化,分析其相关性。结果T2DM 组患者 L2~4与股骨颈骨密度、IGF-I、IGF-II、25-羟维生素 D3均低于对照组( P <0.01);L2~4骨密度、股骨颈骨密度、IGF-I、IGF-II、25-羟维生素 D3间两两比较均呈正相关性(均 P <0.01)。结论T2DM 男性患者存在骨密度、IGF-I、IGF-II 及维生素 D 水平降低, IGF-I、IGF-II、维生素 D 水平降低可能是引发 T2DM 男性患者骨密度降低的相关原因。

  5. Electroconvulsive stimulation results in long-term survival of newly generated hippocampal neurons in rats

    DEFF Research Database (Denmark)

    Olesen, Mikkel Vestergaard; Wörtwein, Gitta; Folke, Jonas

    2017-01-01

    Electroconvulsive stimulation (ECS) is one of the strongest stimulators of hippocampal neurogenesis in rodents that represents a plausible mechanism for the efficacy of electroconvulsive therapy (ECT) in major depressive disorder. Using design-based stereological cell counting, we recently...... documented an initial 2.6-fold increase in neurogenesis following a clinical relevant schedule of ECS, a treatment also rescuing depression-like behavior in rats. However, these results gave no demonstration of the longevity of newly generated neurons. The present study is a direct continuation...... in neurogenesis facilitates the behavioral outcome of the forced swim test (FST), an animal model of depression. The results showed that ECS in conjunction with CRS stimulates hippocampal neurogenesis, and that a significant quantity of the newly formed hippocampal neurons survives up to 12 months. The new Brd...

  6. Relación entre los niveles circulantes del factor de crecimiento similar a la insulina tipo I (IGF-I) y la expresión diferencial de genes relacionados con migración en células linfoides / Relatioship between circulating levels of insulin-like growth factor-I and differential expression of genes related to lymphoid cell migration

    OpenAIRE

    Cuervo Escobar, Sergio Andrei

    2011-01-01

    A partir de investigaciones realizadas en los últimos años, se ha hecho evidente la comunicación bidireccional entre los sistemas inmune y endocrino. Existe un gran cuerpo de evidencia que sugiere que el eje conformado por la hormona de crecimiento (GH) y el factor de crecimiento similar a la insulina tipo I (IGF-I) tiene un papel importante en la funcionalidad del sistema inmune. Los efectos de estas hormonas sobre los diferentes tipos celulares y tejidos pueden darse por meca...

  7. Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function

    Science.gov (United States)

    Lee, Eun-Hye

    2016-01-01

    Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports. PMID:28043116

  8. Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function.

    Science.gov (United States)

    Han, Myung-Hoon; Lee, Eun-Hye; Koh, Seong-Ho

    2016-12-01

    Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports.

  9. The Contradictory Effects of Neuronal Hyperexcitationon Adult Hippocampal Neurogenesis.

    Directory of Open Access Journals (Sweden)

    Juan Manuel Encinas

    2016-03-01

    Full Text Available Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An excitation-neurogenesis rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis.

  10. Reducing central serotonin in adulthood promotes hippocampal neurogenesis.

    Science.gov (United States)

    Song, Ning-Ning; Jia, Yun-Fang; Zhang, Lei; Zhang, Qiong; Huang, Ying; Liu, Xiao-Zhen; Hu, Ling; Lan, Wei; Chen, Ling; Lesch, Klaus-Peter; Chen, Xiaoyan; Xu, Lin; Ding, Yu-Qiang

    2016-02-03

    Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER(T2) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.

  11. Adult hippocampal neurogenesis in natural populations of mammals.

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    Amrein, Irmgard

    2015-05-01

    This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection.

  12. Granulocyte colony-stimulating factor induces neurogenesis and improves cognition in amyloid precursor protein transgenic mouse model of Alzheimer's disease%粒细胞集落刺激因子诱导淀粉样前体蛋白转基因小鼠神经再生及对认知功能的改善

    Institute of Scientific and Technical Information of China (English)

    朱正禹; 王萍; 郭雨霁; 谢兆宏; 来超; 毕建忠

    2012-01-01

    目的 探讨粒细胞集落刺激因子(G-CSF)对淀粉样前体蛋白(APP)转基因小鼠认知功能的改善及对神经再生的影响. 方法 选用36只APP转基因小鼠作为AD动物模型,随机分为G-CSF治疗组和对照组各18只.治疗组皮下注射G-CSF,对照组给予等体积磷酸盐缓冲液(PBS)皮下注射.给药后第7d、14d、28d进行Morris水迷宫测试,计算其逃避潜伏期.水迷宫测试后取外周血,利用流式细胞术观察G-CSF对骨髓造血干细胞的诱导作用.免疫组化及免疫荧光双标观察脑内神经元再生. 结果 与对照组比较,治疗组小鼠在第7d、14 d、28 d的逃避潜伏期分别为(27.19±4.07)s、(26.48±5.29)s、(24.97±3.61)s,较对照组明显缩短(P值分别为0.000、0.010、0.002);治疗组小鼠外周血CD 34+/CD 45双阳性细胞百分率在第7d、14 d、28 d分别为0.358±0.161、0.223±0.038、0.168±0.049,较对照组明显增加(P值分别为0.007、0.000、0.003),脑内检测到CD34′阳性细胞,海马齿状回、皮质均可见BrdU+阳性细胞,同时可检测到BrdU+/Nestin+和BrdU-/MAP-2+双阳性细胞. 结论 G-CSF皮下注射可明显改善APP转基因小鼠的认知功能,可能与动员外周骨髓造血干细胞增殖、分化,并向脑内定向迁移有关.%Objective To investigate the effect of granulocyte colony-stimulating factor(G-CSF)and its effect on the cognation in the PDGF hAPPV717I transgenic mice of Alzheimer's disease model.Methods Totally 36 PDGF hAPPV717I transgenic mice were randomly divided into two groups:G-CSF group and control group.The G CSF group was subcutaneously injected with 50 μg · kg-1 · d-1 of G-CSF for 7 days.The control group was injected subcutaneously with an equal volume of PBS in parallel.The animals were tested in Morris water maze on the 7th,14th,and 28th days after the last day of the injection,and the escape latency was recorded.Once the test was completed,the peripheral blood was taken to evaluate the effect of G

  13. Peso vivo final, ganho de peso, características de carcaça e concentrações plasmáticas de IGF-I e hormônios tireoideanos de bezerros mestiços Angus-Nelore recebendo somatotropina bovina recombinante (rbST até a desmama Effects of recombinant bovine somatotropin (rbST on production, carcass traits, and plasmatic concentrations of IGF-I and thyroid hormones on pre-weaning crossbred Angus-Nellore calves

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    Rafael da Costa Cervieri

    2005-12-01

    Full Text Available Objetivando estudar o efeito da somatotropina bovina recombinante (rbST sobre o desempenho, as características de carcaça e as concentrações plasmáticas de IGF-I e hormônios tireoideanos, 36 bezerros mestiços ½ Angus-Nelore com idade de 63 ± 17 dias e pesando 76,8 ± 14,7 kg, criados em pastagens de Brachiaria decumbens e suplementados em creep feeding, foram submetidos a dois tratamentos até a desmama (217 dias: I 18 bezerros receberam 1,4 mg/kg de rbST (Boostin® a cada 14 dias; II 18 bezerros controle receberam solução salina. As pesagens e colheitas de sangue foram realizadas a cada 28 dias e, à desmama, foram abatidos cinco animais de cada tratamento, para avaliação das características de carcaça. Os animais tratados apresentaram maior ganho de peso médio diário e peso vivo final, maiores concentrações plasmáticas de IGF-I e T4 que os bezerros controle. Os parâmetros peso de carcaça quente, rendimento de carcaça, pesos de traseiro e dianteiro, gordura peri-renal, peso de fígado, área de olho de lombo, espessura de gordura subcutânea, pesos dos músculos do quarto do traseiro e concentração plasmática de T3 não diferiram entre os tratamentos. A utilização de rbST proporcionou aumento de 7,9% no ganho de peso vivo e alterou o perfil hormonal de bezerros suplementados em creep feeding durante a fase de cria, não refletindo, entretanto, em maior peso ou rendimento de carcaça.The objective of this study was to evaluate the effects of recombinant bovine somatotropin (rbST on production, carcass traits, and plasmatic concentrations of IGF-I and thyroid hormones on crossbred Angus-Nellore male calves. Thirty-six calves averaging 63 ± 17 days old and 76.8 ± 14.7 kg of body weight (BW grazing Brachiaria decumbens and creep fed were randomly assigned (18 calves per treatment to one of two treatments until weaning (217 days as follows: I 1.4 mg of rbST (Boostin®/kg of BW every 14 days or II similar dosage of

  14. Zinc chelation reduces hippocampal neurogenesis after pilocarpine-induced seizure.

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    Jin Hee Kim

    Full Text Available Several studies have shown that epileptic seizures increase hippocampal neurogenesis in the adult. However, the mechanism underlying increased neurogenesis after seizures remains largely unknown. Neurogenesis occurs in the subgranular zone (SGZ of the hippocampus in the adult brain, although an understanding of why it actively occurs in this region has remained elusive. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ. Previously, we demonstrated that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia. Using a lithium-pilocarpine model, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after seizure. Then, we injected the zinc chelator, clioquinol (CQ, 30 mg/kg, into the intraperitoneal space to reduce brain zinc availability. Neuronal death was detected with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after seizure. The total number of degenerating and live neurons was similar in vehicle and in CQ treated rats at 1 week after seizure. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX immunostaining 1 week after seizure. The number of BrdU, Ki67 and DCX positive cell was increased after seizure. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. Intracellular zinc chelator, N,N,N0,N-Tetrakis (2-pyridylmethyl ethylenediamine (TPEN, also reduced seizure-induced neurogenesis in the hippocampus. The present study shows that zinc chelation does not prevent neurodegeneration but does reduce seizure-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal neurogenesis after seizure.

  15. Vascular regulation of adult neurogenesis under physiological and pathological conditions

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    Masato eSawada

    2014-03-01

    Full Text Available Neural stem cells in the mammalian adult brain continuously produce new neurons throughout life. Accumulating evidence in rodents suggests that various aspects of adult neurogenesis, including the genesis, migration, and maturation of new neurons, are regulated by factors derived from blood vessels and their microenvironment. Brain injury enhances both neurogenesis and angiogenesis, thereby promoting the cooperative regeneration of neurons and blood vessels. In this paper, we briefly review the mechanisms for the vascular regulation of adult neurogenesis in the ventricular-subventricular zone under physiological and pathological conditions, and discuss their clinical potential for brain regeneration strategies.

  16. Early Postnatal but Not Late Adult Neurogenesis Is Impaired in the Pitx3-Mutant Animal Model of Parkinson's Disease

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    Moritz D. Brandt

    2017-08-01

    Full Text Available The generation of new neurons in the adult dentate gyrus has functional implications for hippocampal formation. Reduced hippocampal neurogenesis has been described in various animal models of hippocampal dysfunction such as dementia and depression, which are both common non-motor-symptoms of Parkinson's disease (PD. As dopamine plays an important role in regulating precursor cell proliferation, the loss of dopaminergic neurons in the substantia nigra (SN in PD may be related to the reduced neurogenesis observed in the neurogenic regions of the adult brain: subventricular zone (SVZ and dentate gyrus (DG. Here we examined adult hippocampal neurogenesis in the Pitx3-mutant mouse model of PD (aphakia mice, which phenotypically shows a selective embryonic degeneration of dopamine neurons within the SN and to a smaller extent in the ventral tegmental area (VTA. Proliferating cells were labeled with BrdU in aphakia mice and healthy controls from 3 to 42 weeks of age. Three weeks old mutant mice showed an 18% reduction of proliferating cells in the DG and of 26% in the SVZ. Not only proliferation but also the number of new neurons was impaired in young aphakia mice resulting in 33% less newborn cells 4 weeks after BrdU-labeling. Remarkably, however, the decline in the number of proliferating cells in the neurogenic regions vanished in older animals (8–42 weeks indicating that aging masks the effect of dopamine depletion on adult neurogenesis. Region specific reduction in precursor cells proliferation correlated with the extent of dopaminergic degeneration in mesencephalic subregions (VTA and SN, which supports the theory of age- and region-dependent regulatory effects of dopaminergic projections. Physiological stimulation of adult neurogenesis by physical activity (wheel running almost doubled the number of proliferating cells in the dentate gyrus of 8 weeks old aphakia mice to a number comparable to that of wild-type mice, abolishing the slight

  17. 消痰通腑方对结肠癌荷瘤小鼠肝组织中IGF-I及其受体(IR)蛋白和基因表达的影响%Effects of Xiaotan Tongfu Recipe on IGF-I/IGF-IR Protein and Gene Expression in Liver Tissue of Mice with Tumor-burdened Colon Cancer

    Institute of Scientific and Technical Information of China (English)

    赵颖; 李勇进

    2012-01-01

    目的:观察消痰通腑方对小鼠结肠癌CT26盲肠原位移植瘤肝转移的影响及肝组织中胰岛素生长因子IGF-I/IR表达的影响,探讨消痰通腑方干预结肠癌肝转移的作用机制.方法:将造模成功的小鼠随机分为模型组、中药组,另设正常组,每组10只,中药组给予消痰通腑方灌胃,每日2次.待模型组小鼠成恶病质状态时,处死小鼠,取瘤组织及肝组织,观察各组荷瘤鼠肿瘤生长情况及抑瘤率;并运用免疫组化及实时荧光定量聚合酶链式反应(real time PCR)观察各组荷瘤鼠结肠癌组织IGF-I/IGF-IR蛋白及mRNA表达.结果:中药组小鼠瘤重、肝重、肝脏指数均低于模型组(P<0.05),与空白组比较,差异无统计学意义(P>0.05),中药组小鼠肝组织中IGF-I/IGF-IR蛋白及mRNA的表达均低于模型组(P<0.05),与空白组比较,差异无统计学意义(P>0.05).结论:消痰通腑方可明显抑制小鼠结肠癌CT26原位移植瘤的生长,且能抑制肝脏转移,下调结肠癌肝转移组织中IGF-I/IGF-IR蛋白及mRNA的表达,可能是其抗结肠癌肝转移的机制之一.%Objective:To observe the effects of Xiaotan Tongfu Recipe on IGF - I/IGF - IR protein and gene expression in liver tissue of mice with tumor - burdened colon cancer and discuss Xiaotan Tongfu Recipes mechanism of action on colon liver metastasis. Methods · The successful model of the mice were randomly divided into model group and Xiaotan Tongfu recipe group,normal group was set. Xiaotan Tongfu recipe was given to mice for 4 weeks in Xiaotan Tongfu recipe group. At the end of the experiment, the mice were killed and the mice's tumor weights, tumor suppression rates, liver weights,liver indexes,IGF - I/IGF - IR of the liver were detected by immunohistochemistry and real - time fluorescence quota PCR. Results:The tumor weight, liver weight and liver index of Xiaotan Tongfu recipe group were significantly lower than that of the model group,compared with the

  18. Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats.

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    Yolanda Cruz

    Full Text Available Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate protective autoimmunity (PA. The most renowned of these peptides is copolymer-1 (Cop-1 also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood-brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke. The aim of this work was to evaluate the effect of Cop-1 on neurogenesis and neurological recovery during the acute phase (7 days and the chronic phase of stroke (60 days in a rat model of transient middle cerebral artery occlusion (tMCAo. BDNF and NT-3 were quantified and infarct volumes were measured. We demonstrated that Cop-1 improves neurological deficit, enhances neurogenesis (at 7 and 60 days in the SVZ, SGZ, and cerebral cortex through an increase in NT-3 production. It also decreased infarct volume even at the chronic phase of tMCAo. The present manuscript fortifies the support for the use of Cop-1 in acute ischemic stroke.

  19. Adult neurogenesis: integrating theories and separating functions.

    Science.gov (United States)

    Aimone, James B; Deng, Wei; Gage, Fred H

    2010-07-01

    The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

  20. Functional neurogenesis in the adult hippocampus

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    van Praag, Henriette; Schinder, Alejandro F.; Christie, Brian R.; Toni, Nicolas; Palmer, Theo D.; Gage, Fred H.

    2002-02-01

    There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning and memory. However, it is not known whether these new neurons become functional, as the methods used to study adult neurogenesis are limited to fixed tissue. We use here a retroviral vector expressing green fluorescent protein that only labels dividing cells, and that can be visualized in live hippocampal slices. We report that newly generated cells in the adult mouse hippocampus have neuronal morphology and can display passive membrane properties, action potentials and functional synaptic inputs similar to those found in mature dentate granule cells. Our findings demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain.

  1. Role of adult hippocampal neurogenesis in persistent pain.

    Science.gov (United States)

    Apkarian, A Vania; Mutso, Amelia A; Centeno, Maria V; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T; Miller, Richard J; Radulovic, Jelena; Hen, René; Kessler, John A

    2016-02-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.

  2. THE SOCIAL ENVIRONMENT AND NEUROGENESIS IN THE ADULT MAMMALIAN BRAIN

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    Claudia eLieberwirth

    2012-05-01

    Full Text Available Adult neurogenesis—the formation of new neurons in adulthood—has been shown to be modulated by a variety of endogenous (e.g., trophic factors, neurotransmitters, and hormones as well as exogenous (e.g., physical activity and environmental complexity factors. Research on exogenous regulators of adult neurogenesis has focused primarily on the non-social environment. Most recently, however, evidence has emerged suggesting that the social environment can also affect adult neurogenesis. The present review details the effects of adult-adult (e.g., mating, conspecific, and chemosensory signal exposure and adult-offspring (e.g., gestation, parenthood, and exposure to offspring interactions on adult neurogenesis. In addition, the effects of a stressful social environment (e.g., lack of social support and dominant-subordinate interactions on adult neurogenesis are reviewed. The underlying hormonal mechanisms and potential functional significance of adult-generated neurons in mediating social behaviors are also discussed.

  3. Linking adult hippocampal neurogenesis with human physiology and disease.

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    Bowers, Megan; Jessberger, Sebastian

    2016-07-01

    We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc.

  4. Persistent Gliosis Interferes with Neurogenesis in Organotypic Hippocampal Slice Cultures.

    Science.gov (United States)

    Gerlach, Johannes; Donkels, Catharina; Münzner, Gert; Haas, Carola A

    2016-01-01

    Neurogenesis in the adult hippocampus has become an intensively investigated research topic, as it is essential for proper hippocampal function and considered to bear therapeutic potential for the replacement of pathologically lost neurons. On the other hand, neurogenesis itself is frequently affected by CNS insults. To identify processes leading to the disturbance of neurogenesis, we made use of organotypic hippocampal slice cultures (OHSC), which, for unknown reasons, lose their neurogenic potential during cultivation. In the present study, we show by BrdU/Prox1 double-immunostaining that the generation of new granule cells drops by 90% during the first week of cultivation. Monitoring neurogenesis dynamically in OHSC from POMC-eGFP mice, in which immature granule cells are endogenously labeled, revealed a gradual decay of the eGFP signal, reaching 10% of initial values within 7 days of cultivation. Accordingly, reverse transcription quantitative polymerase chain reaction analysis showed the downregulation of the neurogenesis-related genes doublecortin and Hes5, a crucial target of the stem cell-maintaining Notch signaling pathway. In parallel, we demonstrate a strong and long-lasting activation of astrocytes and microglial cells, both, morphologically and on the level of gene expression. Enhancement of astroglial activation by treating OHSC with ciliary neurotrophic factor accelerated the loss of neurogenesis, whereas treatment with indomethacin or an antagonist of the purinergic P2Y12 receptor exhibited potent protective effects on the neurogenic outcome. Therefore, we conclude that OHSC rapidly lose their neurogenic capacity due to persistent inflammatory processes taking place after the slice preparation. As inflammation is also considered to affect neurogenesis in many CNS pathologies, OHSC appear as a useful tool to study this interplay and its molecular basis. Furthermore, we propose that modification of glial activation might bear the therapeutic potential

  5. Neurogenesis in Cancun: where science meets the sea.

    Science.gov (United States)

    Hsieh, Jenny; Zhang, Chun-Li

    2016-05-15

    In March 2016, meeting organizers Sebastian Jessberger and Hongjun Song brought together over 100 scientists from around the world to Cancun, Mexico to present the latest research on neurogenesis. The meeting covered diverse aspects of embryonic and adult neurogenesis with a focus on novel technologies, including chemogenetics and optogenetics, live cell two-photon imaging, cell fate reprogramming and human pluripotent stem cell models. This Meeting Review describes the exciting work that was presented and some of the emerging themes from the meeting.

  6. Persistent gliosis interferes with neurogenesis in organotypic hippocampal slice cultures

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    Johannes eGerlach

    2016-05-01

    Full Text Available Neurogenesis in the adult hippocampus has become an intensively investigated research topic, as it is essential for proper hippocampal function and considered to bear therapeutic potential for the replacement of pathologically lost neurons. On the other hand, neurogenesis itself is frequently affected by CNS insults. To identify processes leading to the disturbance of neurogenesis, we made use of organotypic hippocampal slice cultures (OHSC, which, for unknown reasons, lose their neurogenic potential during cultivation. In the present study, we show by BrdU/Prox1 double-immunostaining that the generation of new granule cells drops by 90% during the first week of cultivation. Monitoring neurogenesis dynamically in OHSC from POMC-eGFP mice, in which immature granule cells are endogenously labeled, revealed a gradual decay of the eGFP signal, reaching 10% of initial values within seven days of cultivation. Accordingly, RT-qPCR analysis showed the downregulation of the neurogenesis-related genes doublecortin and Hes5, a crucial target of the stem cell-maintaining Notch signaling pathway. In parallel, we demonstrate a strong and long-lasting activation of astrocytes and microglial cells, both, morphologically and on the level of gene expression. Enhancement of astroglial activation by treating OHSC with ciliary neurotrophic factor (CNTF accelerated the loss of neurogenesis, whereas treatment with indomethacin or an antagonist of the purinergic P2Y12 receptor exhibited potent protective effects on the neurogenic outcome. Therefore, we conclude that OHSC rapidly lose their neurogenic capacity due to persistent inflammatory processes taking place after the slice preparation. As inflammation is also considered to affect neurogenesis in many CNS pathologies, OHSC appear as a useful tool to study this interplay and its molecular basis. Furthermore, we propose that modification of glial activation might bear the therapeutic potential of enabling

  7. Enhanced post-ischemic neurogenesis in aging rats

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    Yao-Fang Tan

    2010-08-01

    Full Text Available Hippocampal neurogenesis persists in adult mammals, but its rate declines dramatically with age. Evidence indicates that experimentally-reduced levels of neurogenesis (e.g. by irradiation in young rats has profound influence on cognition as determined by learning and memory tests. In the present study we asked whether in middle-aged, 10-13 months old rats, cell production can be restored towards the level present in young rats. To manipulate neurogenesis we induced bilateral carotid occlusion with hypotension. This procedure is known to increase neurogenesis in young rats, presumably in a compensatory manner, but until now, has never been tested in aging rats. Cell production was measured at 10, 35 and 90 days after ischemia. The results indicate that neuronal proliferation and differentiation can be transiently restored in middle-aged rats. Furthermore, the effects are more pronounced in the dorsal as opposed to ventral hippocampus thus restoring the dorso-ventral gradient seen in younger rats. Our results support previous findings showing that some of the essential features of the age-dependent decline in neurogenesis are reversible. Thus, it may be possible to manipulate neurogenesis and improve learning and memory in old age.

  8. Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration

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    Rusznák, Zoltán; Henskens, Willem; Schofield, Emma; Kim, Woojin S.

    2016-01-01

    The subgranular zone (SGZ) and subventricular zone (SVZ) are developmental remnants of the germinal regions of the brain, hence they retain the ability to generate neuronal progenitor cells in adult life. Neurogenesis in adult brain has an adaptive function because newly produced neurons can integrate into and modify existing neuronal circuits. In contrast to the SGZ and SVZ, other brain regions have a lower capacity to produce new neurons, and this usually occurs via parenchymal and periventricular cell genesis. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration, especially in diseases associated with altered neurogenesis and/or gliogenesis, cell loss, or disturbed homeostasis of cellular constitution. The present review discusses important neuroanatomical features of adult neurogenesis and gliogenesis, aiming to explore how these processes could be modulated toward functional repair of the adult brain. PMID:27358578

  9. Decoding the ubiquitous role of microRNAs in neurogenesis.

    Science.gov (United States)

    Nampoothiri, Sreekala S; Rajanikant, G K

    2017-04-01

    Neurogenesis generates fledgling neurons that mature to form an intricate neuronal circuitry. The delusion on adult neurogenesis was far resolved in the past decade and became one of the largely explored domains to identify multifaceted mechanisms bridging neurodevelopment and neuropathology. Neurogenesis encompasses multiple processes including neural stem cell proliferation, neuronal differentiation, and cell fate determination. Each neurogenic process is specifically governed by manifold signaling pathways, several growth factors, coding, and non-coding RNAs. A class of small non-coding RNAs, microRNAs (miRNAs), is ubiquitously expressed in the brain and has emerged to be potent regulators of neurogenesis. It functions by fine-tuning the expression of specific neurogenic gene targets at the post-transcriptional level and modulates the development of mature neurons from neural progenitor cells. Besides the commonly discussed intrinsic factors, the neuronal morphogenesis is also under the control of several extrinsic temporal cues, which in turn are regulated by miRNAs. This review enlightens on dicer controlled switch from neurogenesis to gliogenesis, miRNA regulation of neuronal maturation and the differential expression of miRNAs in response to various extrinsic cues affecting neurogenesis.

  10. Adult Human Neurogenesis: from Microscopy to Magnetic Resonance Imaging

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    Amanda eSierra

    2011-04-01

    Full Text Available Neural stem cells reside in well-defined areas of the adult human brain and are capable of gene-rating new neurons throughout the life span. In rodents, it is well established that the new born neurons are involved in olfaction as well as in certain forms of memory and learning. In humans, the functional relevance of adult human neurogenesis is being investigated, in particular its implication in the etiopathology of a variety of brain disorders. Adult neurogenesis in the human brain was discovered by utilizing methodologies directly imported from the rodent research, such as immunohistologica